Six Year Extension Study of Patients From a Randomised Clinical Trial Comparing Venefit, Radiofrequency Induced Thermal Therapy, and Endovenous Radiofrequency Ablation for Treatment of Incompetent Great Saphenous Veins.

OBJECTIVE: To compare long term outcomes after great saphenous vein (GSV) treatment with three radiofrequency (RF) thermal devices: Venefit (Closurefast), Radiofrequency Induced Thermal Therapy (RFITT), and Endovenous Radiofrequency (EVRF). DESIGN: A 72 month follow up of patients who were treated in the randomised 3RF study. METHODS: A total of 172 participants from the 3RF study were invited to take part in a single visit, long term, follow up study. Failure of GSV closure was assessed with duplex ultrasound (DUS) and constituted the primary outcome. Patients completed questionnaires for secondary outcomes: Aberdeen Varicose Vein Questionnaire (AVVQ), Euroqol 5D (EQ-5D), and patient reported varicose veins measured by counting vein occupying boxes in AVVQ question 1. RESULTS: Twenty-two patients (12%) had already been re-treated. Of the remainder, 13 (7%) could not be contacted, 20 (11%) declined invitation, and one did not consent. Therefore, 116 (64%) and 95 (53%) participants completed questionnaires and DUS, respectively. Failure of GSV closure on 72 month DUS was 16%, 21%, and 37% for Venefit, RFITT, and EVRF, respectively (p = .14), whilst outcomes for all failures were 14%, 17%, and 44% (p < .001) (Venefit vs. EVRF: p < .001; RFITT vs. EVRF: p < .001; and Venefit vs. RFITT: p = .63). There were no between group differences in AVVQ or EQ-5D scores. Rates of patient reported presence of any varicose veins were high for all groups (97%, 92%, and 97% after Venefit, RFITT, and EVRF, respectively; p = .48). The EVRF treated participants reported more extensive recurrence than the Venefit and RFITT participants (p = .008). CONCLUSION: Long term technical outcomes after RF ablation for GSV varicose veins were significantly better after Venefit and RFITT compared with EVRF treatment. However, quality of life scores showed no differences after 72 months. Rates of patient reporting any varicose veins were high for all treatments. CLINICALTRIALS: gov Identifier: NCT04720027.

Baseline Radiomic Signature to Estimate Overall Survival in Patients With NSCLC.

INTRODUCTION: We aimed to define a baseline radiomic signature associated with overall survival (OS) using baseline computed tomography (CT) images obtained from patients with NSCLC treated with nivolumab or chemotherapy. METHODS: The radiomic signature was developed in patients with NSCLC treated with nivolumab in CheckMate-017, -026, and -063. Nivolumab-treated patients were pooled and randomized to training, calibration, or validation sets using a 2:1:1 ratio. From baseline CT images, volume of tumor lesions was semiautomatically segmented, and 38 radiomic variables depicting tumor phenotype were extracted. Association between the radiomic signature and OS was assessed in the nivolumab-treated (validation set) and chemotherapy-treated (test set) patients in these studies. RESULTS: A baseline radiomic signature was identified using CT images obtained from 758 patients. The radiomic signature used a combination of imaging variables (spatial correlation, tumor volume in the liver, and tumor volume in the mediastinal lymph nodes) to output a continuous value, ranging from 0 to 1 (from most to least favorable estimated OS). Given a threshold of 0.55, the sensitivity and specificity of the radiomic signature for predicting 3-month OS were 86% and 77.8%, respectively. The signature was identified in the training set of patients treated with nivolumab and was significantly associated (p < 0.0001) with OS in patients treated with nivolumab or chemotherapy. CONCLUSIONS: The radiomic signature provides an early readout of the anticipated OS in patients with NSCLC treated with nivolumab or chemotherapy. This could provide important prognostic information and may support risk stratification in clinical trials.

Evaluation of a PEGylated Fibroblast Growth Factor 21 Variant Using Novel Preclinical Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Mouse Model of Nonalcoholic Steatohepatitis.

BACKGROUND: Treatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI-HFF) and magnetic resonance elastography (MRE-SS), respectively, are biomarkers for hepatic steatosis and fibrosis. PURPOSE: This study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]-FGF21v) on MRI-HFF and MRE-SS in a NASH mouse model. STUDY TYPE: Preclinical. ANIMAL MODEL: This study included a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) model and 6-week-old, male C57BL/6J mice (N = 78). FIELD STRENGTH/SEQUENCE: This study was performed using: 3T: gradient-echo two-point Dixon and spin-echo (SE) echo-planar imaging elastography (200 Hz) and 7T: SE two-point Dixon and SE elastography (200 Hz). ASSESSMENT: MRI and MRE were performed before control diet (CD) or CDAHFD (BD), before PEG-FGF21v dosing (baseline), and after PEG-FGF21v treatment (WK4/8). Regions of interest for MRI-HFF and MRE-SS were delineated by J.L. and H.T. (>5 years of experience each). Fibrosis and steatosis were measured histologically after picrosirius red and H&E staining. Alkaline phosphatase, alanine transaminase, bile acids, and triglycerides (TGs) were measured. STATISTICAL TESTS: Two-tailed Dunnett's tests were used for statistical analysis; untreated CDAHFD or baseline was used for comparisons. Imaging and histology/biochemistry data were determined using Spearman correlations. Bayesian posterior distributions for MRE-SS at WK8, posterior means, and 95% credible intervals were presented. RESULTS: CDAHFD significantly increased baseline MRI-HFF (3T: 21.97% ± 0.29%; 7T: 40.12% ± 0.35%) and MRE-SS (3T: 1.25 ± 0.02; 7T: 1.78 ± 0.06 kPa) vs. CD (3T: 3.45% ± 0.7%; 7T: 12.06% ± 1.4% and 3T: 1.01 ± 0.02; 7T: 0.89 ± 0.06 kPa). At 7T, PEG-FGF21v significantly decreased MRI-HFF (WK4: 28.97% ± 1.22%; WK8: 20.93% ± 1.15%) and MRE-SS (WK4: 1.57 ± 0.04; WK8: 1.36 ± 0.05 kPa) vs. untreated (WK4: 36.36% ± 0.62%; WK8: 30.58% ± 0.81% and WK4: 2.03 ± 0.06; WK8: 2.01 ± 0.04 kPa); 3T trends were similar. WK8 SS posterior mean percent attenuation ratios (RDI ) were -68% (-90%, -44%; 3T) and -64% (-78%, -52%; 7T). MRI-HFF was significantly correlated with H&E (3T, r = 0.93; 7T, r = 0.94) and TGs (both, r = 0.92). DATA CONCLUSIONS: MRI-HFF and MRE-SS showed PEG-FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic.

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors target the important molecular interplay between PD-1 and PD-L1, a key pathway contributing to immune evasion in the tumor microenvironment (TME). Long-term clinical benefit has been observed in patients receiving PD-(L)1 inhibitors, alone and in combination with other treatments, across multiple tumor types. PD-L1 expression has been associated with response to immune checkpoint inhibitors, and treatment strategies are often guided by immunohistochemistry-based diagnostic tests assessing expression of PD-L1. However, challenges related to the implementation, interpretation, and clinical utility of PD-L1 diagnostic tests have led to an increasing number of preclinical and clinical studies exploring interrogation of the TME by real-time imaging of PD-(L)1 expression by positron emission tomography (PET). PET imaging utilizes radiolabeled molecules to non-invasively assess PD-(L)1 expression spatially and temporally. Several PD-(L)1 PET tracers have been tested in preclinical and clinical studies, with clinical trials in progress to assess their use in a number of cancer types. This review will showcase the development of PD-(L)1 PET tracers from preclinical studies through to clinical use, and will explore the opportunities in drug development and possible future clinical implementation.

The value of imaging and clinical outcomes in a phase II clinical trial of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by worsening dyspnea and lung function and has a median survival of 2-3 years. Forced vital capacity (FVC) is the primary endpoint used most commonly in IPF clinical trials as it is the best surrogate for mortality. This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 - an LPA1 receptor antagonist - in patients with IPF. METHODS: HRCT scans from 96% (137/142) of randomized subjects were utilized. Quantitative lung fibrosis (QLF) scores were calculated from the HRCT images. QLF improvement was defined as ⩾2% reduction in QLF score from baseline to week 26. RESULTS: In the placebo arm, 5% of patients demonstrated an improvement in QLF score at week 26 compared with 15% and 27% of patients in the BMS-986020 600 mg once daily (QD) and twice daily (BID) arms, respectively [versus placebo: p = 0.08 (600 mg QD); p = 0.0098 (600 mg BID)]. Significant correlations were found between changes in QLF and changes in percent predicted FVC, diffusing capacity for carbon monoxide (DLCO), and shortness of breath at week 26 (ρ = -0.41, ρ = -0.22, and ρ = 0.27, respectively; all p < 0.01). CONCLUSIONS: This study demonstrated the utility of quantitative HRCT as an efficacy endpoint for IPF in a double-blind, placebo-controlled clinical trial setting.The reviews of this paper are available via the supplemental material section.

Synthesis and Preclinical Evaluation of a 68Ga-Labeled Adnectin, 68Ga-BMS-986192, as a PET Agent for Imaging PD-L1 Expression.

Blocking the interaction of the immune checkpoint molecule programmed cell death protein-1 and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression PET imaging may potentially allow for a better prediction of response to programmed cell death protein-1-targeted therapies. Imaging of PD-L1 expression is feasible by PET with the adnectin protein 18F-BMS-986192. However, radiofluorination of proteins such as BMS-986192 remains complex and labeling yields are low. The goal of this study was therefore the development and preclinical evaluation of a 68Ga-labeled adnectin protein (68Ga-BMS-986192) to facilitate clinical trials. Methods:68Ga labeling of DOTA-conjugated adnectin (BXA-206362) was performed in NaOAc-buffer at pH 5.5 (50°C, 15 min). In vitro stability in human serum at 37°C was analyzed using radio-thin layer chromatography and radio-high-performance liquid chromatography. PD-L1 binding assays were performed using the transduced PD-L1-expressing lymphoma cell line U-698-M and wild-type U-698-M cells as a negative control. Immunohistochemical staining studies, biodistribution studies, and small-animal PET studies of 68Ga-BMS-986192 were performed using PD-L1-positive and PD-L1-negative U-698-M-bearing NSG mice. Results:68Ga-BMS-986192 was obtained with quantitative radiochemical yields of more than 97% and with high radiochemical purity. In vitro stability in human serum was at least 95% after 4 h of incubation. High and specific binding of 68Ga-BMS-986192 to human PD-L1-expressing cancer cells was confirmed, which closely correlates with the respective PD-L1 expression level determined by flow cytometry and immunohistochemistry staining. In vivo, 68Ga-BMS-986192 uptake was high at 1 h after injection in PD-L1-positive tumors (9.0 ± 2.1 percentage injected dose [%ID]/g) and kidneys (56.9 ± 9.2 %ID/g), with negligible uptake in other tissues. PD-L1-negative tumors demonstrated only background uptake of radioactivity (0.6 ± 0.1 %ID/g). Coinjection of an excess of unlabeled adnectin reduced tumor uptake of PD-L1 by more than 80%. Conclusion:68Ga-BMS-986192 enables easy radiosynthesis and shows excellent in vitro and in vivo PD-L1-targeting characteristics. The high tumor uptake combined with low background accumulation at early imaging time points demonstrates the feasibility of 68Ga-BMS-986192 for imaging of PD-L1 expression in tumors and is encouraging for further clinical applications of PD-L1 ligands.

Identification of Non-Small Cell Lung Cancer Sensitive to Systemic Cancer Therapies Using Radiomics.

PURPOSE: Using standard-of-care CT images obtained from patients with a diagnosis of non-small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity of tumors to nivolumab, docetaxel, and gefitinib. EXPERIMENTAL DESIGN: Data were collected prospectively and analyzed retrospectively across multicenter clinical trials [nivolumab, n = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, n = 50, CheckMate017; gefitinib, n = 46, (NCT00588445)]. Patients were randomized to training or validation cohorts using either a 4:1 ratio (nivolumab: 72T:20V) or a 2:1 ratio (docetaxel: 32T:18V; gefitinib: 31T:15V) to ensure an adequate sample size in the validation set. Radiomics signatures were derived from quantitative analysis of early tumor changes from baseline to first on-treatment assessment. For each patient, 1,160 radiomics features were extracted from the largest measurable lung lesion. Tumors were classified as treatment sensitive or insensitive; reference standard was median progression-free survival (NCT01642004, NCT01721759) or surgery (NCT00588445). Machine learning was implemented to select up to four features to develop a radiomics signature in the training datasets and applied to each patient in the validation datasets to classify treatment sensitivity. RESULTS: The radiomics signatures predicted treatment sensitivity in the validation dataset of each study group with AUC (95 confidence interval): nivolumab, 0.77 (0.55-1.00); docetaxel, 0.67 (0.37-0.96); and gefitinib, 0.82 (0.53-0.97). Using serial radiographic measurements, the magnitude of exponential increase in signature features deciphering tumor volume, invasion of tumor boundaries, or tumor spatial heterogeneity was associated with shorter overall survival. CONCLUSIONS: Radiomics signatures predicted tumor sensitivity to treatment in patients with NSCLC, offering an approach that could enhance clinical decision-making to continue systemic therapies and forecast overall survival.

Quantification of PD-L1 Expression with 18F-BMS-986192 PET/CT in Patients with Advanced-Stage Non-Small Cell Lung Cancer.

The aim of this work was to quantify the uptake of 18F-BMS-986192, a programmed cell death ligand 1 (PD-L1) adnectin PET tracer, in patients with non-small cell lung cancer. To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as SUV was investigated. Methods: Data from a study with 18F-BMS-986192 in patients with advanced-stage non-small cell lung cancer eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of 18F-BMS-986192, a 60-min dynamic PET/CT scan was started, followed by a 30-min whole-body PET/CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time-activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor-to-blood ratio as well as several SUV measures. Results: Twenty-two tumors in 9 patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 of 18 tumor time-activity curves. The distribution volume (VT ) ranged from 0.4 to 4.8 mL⋅cm-3 Similar values were obtained with an image-derived input function. From the simplified measures, SUV normalized for body weight at 50 and 67 min after injection correlated best with VT , with an R2 of more than 0.9. Conclusion: A single-tissue reversible model can be used to quantify tumor uptake of the PD-L1 PET tracer 18F-BMS-986192. SUV at 60 min after injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. To assess its predictive value for response evaluation during programmed cell death protein 1 or PD-L1 immune checkpoint inhibition, further validation of SUV against VT based on an image-derived input function is recommended.

A Randomised Controlled Trial Comparing Three Different Radiofrequency Technologies: Short-Term Results of the 3-RF Trial.

OBJECTIVE: To date there has been no comparison of outcomes of endovenous radiofrequency (RF) devices. The 3-RF trial is the first randomised controlled trial of three commercially available RF ablation technologies. METHODS: Patients were recruited [182/302 patients with great saphenous vein (GSV) incompetence] into a prospective double blind randomised trial of Venefit, radiofrequency induced thermal therapy (RFITT), and endovenous radiofrequency (EVRF). The primary outcome measure was GSV closure (total/partial/failed) at six months. Secondary outcome measures included ablation times, complications, pain scores, analgesia requirements, and quality of life (QoL) scores to 12 months. RESULTS: Patients treated [180: Venefit (57), RFITT (64), EVRF (59)] were matched for age, sex, and vein characteristics. At six months, complete GSV closure was significantly better after Venefit and RFITT treatment (100% and 98%, respectively) compared with EVRF treatment (79%, p < .001). Mean treatment time was significantly faster for RFITT than for Venefit and EVRF (p < .0001). Euroqol 5D (EQ5D) visual analogue score (VAS) did not differ between groups at any time point. The only difference between groups in EQ5D domain scores was for the pain/discomfort domain at two weeks when significantly fewer EVRF patients reported no problems compared with Venefit and RFITT. This difference had disappeared at six and 12 months. The Aberdeen Varicose Vein Questionnaire (AVVQ) improved for all groups at six and 12 months compared with pre-treatment levels; however, there was no significant difference between groups. CONCLUSION: Compared with Venefit and RFITT, EVRF was associated with significant failure of truncal ablation at six months; however, clinical outcomes did not differ significantly at 12 months. clinicaltrials.gov identifier: NCT02441881, NHS Health Research Authority (Hampstead Research Ethics Committee) number: 14/LO/1232.

Mapping the central effects of (±)-ketamine and traxoprodil using pharmacological magnetic resonance imaging in awake rats.

Major depressive disorder is a leading cause of disability globally. Improvements in the efficacy of antidepressant therapy are needed as a high proportion (>40%) of individuals with major depressive disorder fail to respond adequately to current treatments. The non-selective N-methyl-D-aspartate receptor channel blocker, (±)-ketamine, has been reported to produce a rapid and long-lasting antidepressant response in treatment-resistant major depressive disorder patients, which provides a unique opportunity for investigation of mechanisms that mediate its therapeutic effect. Efforts have also focused on the development of selective N-methyl-D-aspartate receptor subtype 2B antagonists which may retain antidepressant activity but have lower potential for dissociative/psychotomimetic effects. In the present study, we examined the central nervous system effects of acute, intravenous administration of (±)-ketamine or the N-methyl-D-aspartate receptor subtype 2B antagonist, traxoprodil, in awake rats using pharmacological magnetic resonance imaging. The study contained five treatment groups: vehicle, 3 mg/kg (±)-ketamine, and three doses of traxoprodil (0.3 mg/kg, 5 mg/kg, and 15 mg/kg). Non-linear model fitting was performed on the temporal hemodynamic pharmacological magnetic resonance imaging data to generate brain activation maps as well as regional responses based on blood oxygen level dependent signal changes for group analysis. Traxoprodil at 5 mg/kg and 15 mg/kg produced a dose-dependent pharmacological magnetic resonance imaging signal in rat forebrain regions with both doses achieving >80% N-methyl-D-aspartate receptor subtype 2B occupancy determined by ex vivo [3H]Ro 25-6981 binding. The middle dose of traxoprodil (5 mg/kg) generated region-specific activations in medial prefrontal cortex, ventral orbital cortex, and anterior cingulate cortex whereas the high dose (15 mg/kg) produced a widespread pharmacological magnetic resonance imaging response in both cortical and subcortical brain regions which was similar to that produced by (±)-ketamine (3 mg/kg, intravenous).

Evaluation of the Lysophosphatidic Acid Receptor Type 1 Radioligand 11C-BMT-136088 for Lung Imaging in Rhesus Monkeys.

The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage. Thus, a LPA1 PET radiotracer may be useful for studying lung fibrosis or for developing LPA1-targeting drugs. We developed and evaluated the radiotracer 11C-BMT-136088 (1-(4'-(3-methyl-4-(((1(R)-(3-11C-methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. Methods: The study consisted of 3 parts: test-retest scans; self-saturation to estimate the tracer's in vivo dissociation constant, nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution (VT) was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). Results:11C-BMT-136088 baseline VT was 1.83 ± 0.16 (MA1, n = 5) or 2.1 ± 0.55 (EA, n = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test-retest variability of -6% (MA1, n = 1) or -1% ± 14% (EA, n = 2). For the self-saturation study, 11C-BMT-136088 VND and BPND were estimated to be 0.9 ± 0.08 mL of plasma per gram of tissue and 1.1 ± 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of 11C-BMT-136088 specific binding were 73 ± 30 nmol/kg and 28 ± 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer's in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 ± 4.9 and 68.9 ± 9.4 µSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 ± 0.6 and 8.7 ± 0.6 µSv/MBq, respectively. Conclusion: Specific binding of 11C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo.

Synthesis and Biologic Evaluation of a Novel 18F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression.

The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 adnectin after 18F-fluorine labeling. Methods: An anti-PD-L1 adnectin was labeled with 18F in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generate 18F-BMS-986192. 18F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1-negative (PD-L1(-)) and PD-L1-positive (PD-L1(+)) subcutaneous tumors. 18F-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. Results:18F-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled with 18F to yield a PET radioligand for assessing PD-L1 expression in vivo. 18F-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(+), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 percentage injected dose per gram, P < 0.0001) was observed in L2987 than in control HT-29 (PD-L1(-)) tumors. Coadministration of 3 mg/kg ADX_5322_A02 anti-PD-L1 adnectin reduced tumor uptake at 2 h after injection by approximately 70%, whereas HT-29 uptake remained unchanged, demonstrating PD-L1-specific binding. Biodistribution in a nonhuman primate showed binding in the PD-L1-rich spleen, with rapid blood clearance through the kidneys and bladder. Binding in the PD-L1(+) spleen was reduced by coadministration of BMS-986192. Dosimetry estimates indicate that the kidney is the dose-limiting organ, with an estimated human absorbed dose of 2.20E-01 mSv/MBq. Conclusion:18F-BMS-986192 demonstrated the feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies. Clinical studies with 18F-BMS-986192 are under way to measure PD-L1 expression in human tumors.

Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

BACKGROUND: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD). METHODS: Primary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169. RESULTS: Dasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313). CONCLUSIONS: In patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT00764309.

Radiosynthesis and preclinical PET evaluation of 89Zr-nivolumab (BMS-936558) in healthy non-human primates.

Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types. This study reports the preparation and in vivo evaluation of 89Zr labeled nivolumab in healthy non-human primates (NHP) as a preliminary study of biodistribution and clearance. The radiochemical and in vivo stabilities of the 89Zr complex were shown to be acceptable for imaging. Three naïve NHPs were intravenously injected with tracer only or tracer co-injected with nivolumab followed by co-registered by positron emission tomography (PET) and magnetic resonance imaging (MRI), acquired for eight days following injection. Image-derived standardized uptake values (SUV) were quantified by region of interest (ROI) analysis. Radioactivity in the spleen was significantly reduced by addition of excess nivolumab compared to the tracer only study at all imaging time points. Liver uptake of the radiotracer was consistent as a clearance organ with minimal signal from other tissues: lung, muscle, brain, heart, and kidney. The results indicate specific biodistribution to the spleen, which can be blocked by co-administration of excess nivolumab. Distribution to other organs is consistent with elimination pathways of antibodies, with primary clearance through the liver.

Does motivation predict outcome of pelvic floor muscle retraining?

AIMS: Although pelvic floor muscle training (PFMT) is effective for stress urinary incontinence (SUI), patients need to be motivated to obtain cure. An instrument to assess motivation in such patients was published in 2009: the Incontinence Treatment Motivation Questionnaire (ITMQ). The ITMQ consists of five domains: (i) positive attitudes toward PFMT; (ii) reasons for not doing PFMT; (iii) difficulties living with incontinence; (iv) desire for treatment; and (v) incontinence severity influencing motivation. The aim of the present study was to examine the relationship between ITMQ scores and treatment success. METHODS: After referral for PFMT, women with SUI completed the ITMQ. Pre- and post-treatment outcomes were the International Consultation on Incontinence Questionnaire (ICIQ) score and a 24-hr pad test. Correlations between ITMQ scores and baseline, as well as post-treatment change in ICIQ scores and pad test results were examined. Additionally, the demographics of non-participants, participants, and patients lost to follow-up were compared. RESULTS: Of 85 recruits, 18 did not complete the ITMQ, 14 were lost to follow-up, thus 53 completed the PFMT programme and undertook either one or both outcomes. Pre-treatment, severity on ICIQ correlated with total ITMQ (ρ = 0.33, P = 0.01). Post-treatment change in pad test was inversely correlated with Domain 2 (ρ = -0.33, P = 0.03). CONCLUSIONS: The pre-treatment severity of incontinence was significantly associated with motivation for treatment. Unfortunately, post-treatment change correlated with only one domain of the questionnaire. Further modification of the ITMQ is envisaged. Neurourol. Urodynam. 36:316-321, 2017. © 2015 Wiley Periodicals, Inc.

RECIST 1.1-Update and clarification: From the RECIST committee.

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.

RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group.

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation.

The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial.

OBJECTIVES: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques. METHODS: Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR ≥ 1.6) at the baseline). RESULTS: Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; ΔTBR AS: -0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = -0.24 [95% CI: -0.46, -0.01], p = 0.04). CONCLUSIONS: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation.

Safety, pharmacokinetic, and positron emission tomography evaluation of serotonin and dopamine transporter occupancy following multiple-dose administration of the triple monoamine reuptake inhibitor BMS-820836.

RATIONALE: BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine. OBJECTIVE: This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [(11)C]MADAM or [(11)C]PE2I, respectively. METHODS: Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1-4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4-8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions. RESULTS: Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0-5.5 h post-dose; estimated elimination half-life was 44-74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose. CONCLUSIONS: Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.

Repeatability of metabolically active tumor volume measurements with FDG PET/CT in advanced gastrointestinal malignancies: a multicenter study.

PURPOSE: To evaluate the feasibility and repeatability of various metabolically active tumor volume ( MATV metabolically active tumor volume ) quantification methods in fluorine 18 fluorodeoxyglucose ( FDG fluorine 18 fluorodeoxyglucose ) positron emission tomography (PET)/computed tomography (CT) in a multicenter setting and propose the optimal MATV metabolically active tumor volume method together with the minimal threshold for future response evaluation studies. MATERIALS AND METHODS: The study was approved by the institutional review board of all four participating centers, and patients provided written informed consent. Thirty-four patients with advanced gastrointestinal malignancies underwent two FDG fluorine 18 fluorodeoxyglucose PET/CT examinations within 1 week. MATV metabolically active tumor volume s were defined semiautomatically with 27 variations of tumor delineation methods with different reference values. Feasibility was determined as the percentage of successful tumor segmentations per MATV metabolically active tumor volume method. Repeatability was determined with intraclass correlation coefficients, Bland-Altman plots, and limits of agreement ( LOA limit of agreement s) of the percentage difference between the test and repeat test measurements. In addition, LOA limit of agreement variability per center was investigated. RESULTS: In total, 136 lesions were identified. Feasibility of tumor segmentation ranged from 54% to 100% (74-136 of 136 lesions); repeatability was evaluated for 19 MATV metabolically active tumor volume methods with feasibility of greater than 95%. The median MATV metabolically active tumor volume derived with 50% threshold of mean standardized uptake value ( SUV standardized uptake value ) of a sphere of 12-mm diameter with highest local intensity ( SUVhp mean SUV of a sphere of 12-mm diameter with highest local intensity ), which may not include the voxel with highest SUV standardized uptake value corrected for local background, was 5.7 and 6.1 mL for test and retest scans, respectively, with a relative LOA limit of agreement of 36.1%. Comparable repeatability was found between centers. A difference in uptake time between scan 1 and 2 of 15 minutes or longer had a minor negative influence on repeatability. CONCLUSION: MATV metabolically active tumor volume measured with 50% of SUVhp mean SUV of a sphere of 12-mm diameter with highest local intensity corrected for local background is recommended in multicenter FDG fluorine 18 fluorodeoxyglucose PET/CT studies on the basis of a high feasibility (96%) and repeatability ( LOA limit of agreement of 36.1%).