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The Distribution Volume of 18F-Albumin as a Potential Biomarker of Antiangiogenic Treatment Efficacy.

ABSTRACT: Objective: 18F-albumin, a vascular imaging agent, may have potential to assess tumor responses to anti-angiogenic therapies. In these studies tumor distribution volume of 18F-albumin were first determined in various human tumor xenografts from biodistribtuion measurments and then one of the tumor type was used to evaluate changes in 18F-albumin uptake in anti-angiognic tumor model. Method: 18F-albumin was synthesized via conjugation of 6-[18F]fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester, [18F]F-Py-TFP, with rat albumin. From the biodistribution of 18F-albumin in various human tumor xenografts tumor distribution volumes (DVs; tumor%ID/g:blood%ID/g) were first determined at various time points. Then, the ability of 18F-albumin to detect tumor angiogenic inhibition in one of these tumor types (U87MG) following treatment with sunitinib was evaluated by position emission tomography (PET) imaging at 0, 7, 14, and 21 days post treatment. Caliper measurements of tumor dimensions were also made at these same times. At Day 21, following imaging, biodistributions, autoradiography of tumor tissues and tumor blood vessel counts (CD31 IHC) were performed. Results: 18F-albumin retention in various tumors steadily increased over time with U87MG tumor exhibiting the highest uptake (DV) at all times. Significant decreases in 18F-albumin DVs were observed one week post-treatement (-39%) vs. controls whereas tumor caliper volumes were not significantly decreased until days 14 and 21. At day 21 the significant decrease in DVs in the treatment group (-44%) paralleled biodistribution DV measurements and was consistent with autoradiography and CD31 IHC findings. Conclusion: These data suggest that 18F-albumin DVs obtained by imaging may serve as an early biomarker of the effectiveness of anti-angiogenic therapy and thus aid in patient management and treatment planning.

SUBMITTER: Roy J

PROVIDER: S-EPMC6533790 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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The Distribution Volume of 18F-Albumin as a Potential Biomarker of Antiangiogenic Treatment Efficacy.

Roy Jyoti J Kuo Frank F Basuli Falguni F Williams Mark R MR Wong Karen K Green Michael V MV Seidel Jurgen J Adler Stephen S SS Xu Biying B Choyke Peter L PL Jagoda Elaine M EM

Cancer biotherapy & radiopharmaceuticals 20190215 4

Objective: 18F-albumin, a vascular imaging agent, may have potential to assess tumor responses to anti-angiogenic therapies. In these studies tumor distribution volume of 18F-albumin were first determined in various human tumor xenografts from biodistribtuion measurments and then one of the tumor type was used to evaluate changes in 18F-albumin uptake in anti-angiognic tumor model. Method: 18F-albumin was synthesized via con ...[more]

PMID: 30767667

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Project description:BackgroundThe aim of this study was to evaluate 18F-AlF-NOTA-PRGD2 positron emission tomography/computed tomography (18F-RGD PET/CT) and serum inflammation biomarkers for predicting outcomes of patients receiving combined antiangiogenic treatment for advanced non-small cell lung cancer (NSCLC).MethodsPatients with advanced NSCLC underwent 18F-RGD PET/CT examination and provided blood samples before treatments commenced. PET/CT parameters included maximum standard uptake value (SUVmax) and mean standard uptake value (SUVmean), peak standard uptake value (SUVpeak) and metabolic tumor volume (MTV) for all contoured lesions. Biomarkers for inflammation included pretreatment neutrophil-to-lymphocyte ratio (PreNLR), pretreatment platelet-to-lymphocyte ratio (PrePLR), and pretreatment lymphocyte-to-monocyte ratio (PreLMR). Receiver operating characteristic (ROC) curve analysis was used to describe response prediction accuracy. Logistic regression and Cox's regression analysis was implemented to identify independent factors for short-term responses and progression-free survival (PFS).ResultsThis study included 23 patients. According to ROC curve analysis, there were significant correlations between the SUVmax, SUVmean, and 18F-RGD PET/CT MTV and short-term responses (p<0.05). SUVmax was identified using logistic regression analysis as a significant predictor of treatment sensitivity (p=0.008). Cox's multivariate regression analysis suggested that high SUVpeak (p=0.021) and high PreLMR (p=0.03) were independent PFS predictors. Combining SUVpeak and PreLMR may also increase the prognostic value for PFS, enabling us to identify a subgroup of patients with intermediate PFS.Conclusion18F-RGD uptake on PET/CT and serum inflammation biomarker pretreatment may predict outcomes for combined antiangiogenic treatments for advanced NSCLC patients. Higher 18F-RGD uptake and higher PreLMR also appear to predict improved short-term responses and PFS. Combining biomarkers may therefore provide a basis for risk stratification, although further research is required.

Project description:ObjectiveBoron neutron capture therapy (BNCT) is a noninvasive radiation therapy method for cancer treatment. In BNCT, 4-borono-2-[18F]-fluoro-L-phenylalanine (18F-FBPA) PET has been employed to estimate 10B accumulation in target tumors and normal tissues if 10B borono-L-phenylalanine (10B-BPA) is used as a boron carrier. The purpose of the current study was to evaluate the total distribution volume (Vt) of 18F-FBPA in normal organs of healthy volunteers by kinetic analysis and to estimate boron concentration in normal organs for the therapeutic dose of 10B-BPA using obtained Vt values.MethodsSix healthy volunteers were injected with 18F-FBPA (3-5 MBq/kg), and 7 PET-CT scans were performed subsequently. 18F-FBPA radioactivity in whole blood and plasma was measured before, and eight times after the injection. PET images were analyzed by PMOD software. Twelve volumetric regions of interest including the brain, heart, right lung, spleen, liver, parotid salivary glands, esophagus, stomach, pancreas, intestines, and bone marrow were drawn manually for each subject and analyzed with the Logan plot and two Ichise multilinear analyses (MA1 and MA2). The better model was defined by several goodness-of-fit parameters and residual distribution. After Vt values had been derived, boron concentration was estimated in ppm for the 10B-BPA-fructose (10B-BPA-fr) dose 30 g 1 and 2 h post-injection using Vt and interpolated plasma activity data.ResultsThe Ichise MA2 model showed the best fit among all models. Akaike Information Criterion (AIC) was the lowest for the Ichise's MA2 in all regions (mean AIC value - 14.0) comparing to the other models (Logan plot mean AIC 31.4; Ichise MA1 model mean AIC - 4.2). Mean Vt values of the Ichise MA2 model ranged from 0.94?±?0.14 ml/ml in the pancreas to 0.16?±?0.02 ml/ml in the right lung. Estimated boron concentration for 10B-BPA-fr had the highest value in the pancreas (14.0?±?1.9 ppm 1 h after, and 5.7?±?1.7 ppm 2 h after the 18F-FBPA administration) and the lowest value in the right lung (2.4?±?0.3 ppm 1 h, and 1.0?±?0.3 ppm 2 h post-injection).ConclusionThe 10B concentration in normal tissues was best estimated using Vt values of 18F-FBPA with the Ichise multilinear analysis 2 (MA2).Trail registryThe UMIN clinical trial number: UMIN000022850.

Project description:Purpose/objectivesMultiparametric advanced MR and [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging may be important biomarkers for prognosis as well for distinguishing recurrent glioblastoma multiforme (GBM) from treatment-related changes.Methods/materialsWe retrospectively evaluated 30 patients treated with chemoradiation for GBM and underwent advanced MR and FDG-PET for confirmation of tumor progression. Multiparametric MRI and FDG-PET imaging metrics were evaluated for their association with 6-month overall (OS) and progression-free survival (PFS) based on pathological, radiographic, and clinical criteria.Results17 males and 13 females were treated between 2001 and 2014, and later underwent FDG-PET at suspected recurrence. Baseline FDG-PET and MRI imaging was obtained at a median of 7.5?months [interquartile range (IQR) 3.7-12.4] following completion of chemoradiation. Median follow-up after FDG-PET imaging was 10?months (IQR 7.2-13.0). Receiver-operator characteristic curve analysis identified that lesions characterized by a ratio of the SUVmax to the normal contralateral brain (SUVmax/NB index) >1.5 and mean apparent diffusion coefficient (ADC) value of ?1,400?×?10-6?mm2/s correlated with worse 6-month OS and PFS. We defined three patient groups that predicted the probability of tumor progression: SUVmax/NB index >1.5 and ADC ?1,400?×?10-6 mm2/s defined high-risk patients (n?=?7), SUVmax/NB index ?1.5 and ADC >1,400?×?10-6 mm2/s defined low-risk patients (n?=?11), and intermediate-risk (n?=?12) defined the remainder of the patients. Median OS following the time of the FDG-PET scan for the low, intermediate, and high-risk groups were 23.5, 10.5, and 3.8?months (p?<?0.01). Median PFS were 10.0, 4.4, and 1.9?months (p?=?0.03). Rates of progression at 6-months in the low, intermediate, and high-risk groups were 36, 67, and 86% (p?=?0.04).ConclusionRecurrent GBM in the molecular era is associated with highly variable outcomes. Multiparametric MR and FDG-PET biomarkers may provide a clinically relevant, non-invasive and cost-effective method of predicting prognosis and improving clinical decision making in the treatment of patients with suspected tumor recurrence.

Project description:Multiparametric imaging of tumor perfusion and hypoxia with dynamic 18F-fluoromisonidazole (18F-FMISO) PET may allow for an improved response assessment to antiangiogenic therapies. Cediranib (AZD2171) is a potent inhibitor of tyrosine kinase activity associated with vascular endothelial growth factor receptors 1, 2, and 3, currently in phase II/III clinical trials. Serial dynamic 18F-FMISO PET was performed to investigate changes in tumor biomarkers of perfusion and hypoxia after cediranib treatment. Methods: Twenty-one rats bearing HT29 colorectal xenograft tumors were randomized into a vehicle-treated control group (0.5% methylcellulose daily for 2 d [5 rats] or 7 d [4 rats]) and a cediranib-treated test group (3 mg/kg daily for 2 or 7 d; 6 rats in both groups). All rats were imaged before and after treatment, using a 90-min dynamic PET acquisition after administration of 42.1 ± 3.9 MBq of 18F-FMISO by tail vein injection. Tumor volumes were delineated manually, and the input function was image-derived (abdominal aorta). Kinetic modeling was performed using an irreversible 1-plasma 2-tissue compartmental model to estimate the kinetic rate constants K1, K1/k2, and k3-surrogates for perfusion, 18F-FMISO distribution volume, and hypoxia-mediated entrapment, respectively. Tumor-to-blood ratios (TBRs) were calculated on the last dynamic frame (80-90 min). Tumors were assessed ex vivo by digital autoradiography and immunofluorescence for microscopic visualization of perfusion (pimonidazole) and hypoxia (Hoechst 33342). Results: Cediranib treatment resulted in significant reduction of mean voxelwise 18F-FMISO TBR, K1, and K1/k2 in both the 2-d and the 7-d groups (P < 0.05). The k3 parameter was increased in both groups but reached significance only in the 2-d group. In the vehicle-treated groups, no significant change in TBR, K1, K1/k2, or k3 was observed (P > 0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower 18F-FMISO uptake. Conclusion:18F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced mean K1 reflects a reduction in tumor vascular perfusion, whereas the increased k3 reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in 18F-FMISO uptake after treatment with cediranib may be mistakenly interpreted as a global decrease, rather than an increase, in tumor hypoxia. These findings support the use of 18F-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion.

Project description:BackgroundPSMA-based alpha therapy using 225Ac-PSMA-I&T provides treatment for metastatic castration-resistant prostate cancer (mCRPC), even after the failure of 177Lu-PSMA radioligand therapy (RLT). In clinical routine, the total tumor volume (TTV) on PSMA PET impacts therapy outcomes and plays an increasing role in mCRPC patients. Hence, we aimed to assess TTV and its changes during 225Ac-PSMA-I&T RLT.MethodsmCRPC patients undergoing RLT with 225Ac-PSMA-I&T with available 18F-PSMA-1007 PET/CT prior to therapy initiation were included. TTV was assessed in all patients using established cut-off values. Image derived, clinical and biochemistry parameters (PSA, LDH, AP, pain score) were analyzed prior to and after two cycles of 225Ac-PSMA. Changes in TTV and further parameters were directly compared and then correlated with established response criteria, such as RECIST 1.1 or mPERCIST.Results13 mCRPC patients were included. The median overall survival (OS) was 10 months. Prior to 225Ac-PSMA RLT, there was no significant correlation between TTV with other clinical parameters (p > 0.05 each). Between short-term survivors (STS, <10 months OS) and long-term survivors (LTS, ≥10 months OS), TTV and PSA were comparable (p = 0.592 & p = 0.286, respectively), whereas AP was significantly lower in the LTS (p = 0.029). A total of 7/13 patients completed two cycles and underwent a follow-up 18F-PSMA-1007 PET/CT. Among these patients, there was a significant decrease in TTV (median 835 vs. 201 mL, p = 0.028) and PSA (median 687 ng/dL vs. 178 ng/dL, p = 0.018) after two cycles of 225Ac-PSMA RLT. Here, percentage changes of TTV after two cycles showed no direct correlation to all other clinical parameters (p > 0.05 each). In two patients, new PET-avid lesions were detected on 18F-PSMA-1007 PET/CT. However, TTV and PSA were decreasing or stable.ConclusionPET-derived assessment of TTV is an easily applicable imaging biomarker independent of other established parameters prior to 225Ac-PSMA RLT in these preliminary follow-up data. Even after the failure of 177Lu-PSMA, patients with extensive TTV seem to profit from RLT. All but one patient who was eligible for ≥2 cycles of 225Ac-PSMA-RLT demonstrated drastic TTV decreases without direct correlation to other biomarkers, such as serum PSA changes. Changes in TTV might hence improve the response assessment compared to standard classifiers by reflecting the current tumor load independent of the occurrence of new lesions.

Dataset Information

The Distribution Volume of 18F-Albumin as a Potential Biomarker of Antiangiogenic Treatment Efficacy.

Publications

The Distribution Volume of <sup>18</sup>F-Albumin as a Potential Biomarker of Antiangiogenic Treatment Efficacy.

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