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Simple Summary: In order to grow, tumors need nutrients and oxygen, which are supplied by new blood vessels that are often abnormal and leaky. The development of these blood vessels is driven by proteins called growth factors, which bind to receptor proteins on other cells. We show for the first time that an antibody against a vascular growth factor called VEGF-B, when used to treat mice with tumors, reduces the amount of abnormal tumor blood vessels, and inhibits tumor growth, as well as improving the response to chemotherapy. These results suggest that targeting VEGF-B could be a potential approach for anti-cancer therapy, particularly in combination with chemotherapy. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key regulators of blood vessel formation, including in tumors, where their deregulated function can promote the production of aberrant, leaky blood vessels, supporting tumor development. Here we investigated the VEGFR1 ligand VEGF-B, which we demonstrate to be expressed in tumor cells and in tumor stroma and vasculature across a range of tumor types. We examined the anti-VEGF-B-specific monoclonal antibody 2H10 in preclinical xenograft models of breast and colorectal cancer, in comparison with the anti-VEGF-A antibody bevacizumab. Similar to bevacizumab, 2H10 therapy was associated with changes in tumor blood vessels and intra-tumoral diffusion consistent with normalization of the tumor vasculature. Accordingly, treatment resulted in partial inhibition of tumor growth, and significantly improved the response to chemotherapy. Our studies indicate the importance of VEGF-B in tumor growth, and the potential of specific anti-VEGF-B treatment to inhibit tumor development, alone or in combination with established chemotherapies. [ABSTRACT FROM AUTHOR]

Background. This study investigates the use of 18F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC). Material and methods. The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP). Results. The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138). Conclusion. Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To evaluate the accuracy of 11C-choline PET scans in defining dominant intraprostatic lesions (DILs) for radiotherapy target volume definition. Material and methods: Eight men with prostate cancer who had 11C-choline PET scans prior to radical prostatectomy were studied. Several methods were used to contour the DIL on the PET scans: visual, PET Edge, Region Grow, absolute standardised uptake value (SUV) thresholds and percentage of maximum SUV thresholds. Prostatectomy specimens were sliced in the transverse plane and DILs were delineated on these by a pathologist. These were then compared with the PET scans. The accuracy of correlation was assessed by the Dice similarity coefficient (DSC) and the Youden index. Results: The contouring method resulting in both the highest DSC and the highest Youden index was 60% of the maximum SUV (SUV60%), with values of 0.64 and 0.51, respectively. However SUV60% was not statistically significantly better than all of the other methods by either measure. Conclusions: Although not statistically significant, SUV60% resulted in the best correlation between 11C-choline PET and pathology amongst all the methods studied. The degree of correlation shown here is consistent with previous studies that have justified using imaging for DIL radiotherapy target volume definition. [Copyright &y& Elsevier]

Purpose: To demonstrate the technical feasibility of intensity modulated radiation therapy (IMRT) dose painting using 11C-choline positron emission tomography PET scans in patients with localized prostate cancer. Methods and Materials: This was an RT planning study of 8 patients with prostate cancer who had 11C-choline PET scans prior to radical prostatectomy. Two contours were semiautomatically generated on the basis of the PET scans for each patient: 60% and 70% of the maximum standardized uptake values (SUV60% and SUV70%). Three IMRT plans were generated for each patient: PLAN78, which consisted of whole-prostate radiation therapy to 78 Gy; PLAN78-90, which consisted of whole-prostate RT to 78 Gy, a boost to the SUV60% to 84 Gy, and a further boost to the SUV70% to 90 Gy; and PLAN72-90, which consisted of whole-prostate RT to 72 Gy, a boost to the SUV60% to 84 Gy, and a further boost to the SUV70% to 90 Gy. The feasibility of these plans was judged by their ability to reach prescription doses while adhering to published dose constraints. Tumor control probabilities based on PET scan-defined volumes (TCPPET) and on prostatectomy-defined volumes (TCPpath), and rectal normal tissue complication probabilities (NTCP) were compared between the plans. Results: All plans for all patients reached prescription doses while adhering to dose constraints. TCPPET values for PLAN78, PLAN78-90, and PLAN72-90 were 65%, 97%, and 96%, respectively. TCPpath values were 71%, 97%, and 89%, respectively. Both PLAN78-90 and PLAN72-90 had significantly higher TCPPET (P=.002 and .001) and TCPpath (P<.001 and .014) values than PLAN78. PLAN78-90 and PLAN72-90 were not significantly different in terms of TCPPET or TCPpath. There were no significant differences in rectal NTCPs between the 3 plans. Conclusions: IMRT dose painting for localized prostate cancer using 11C-choline PET scans is technically feasible. Dose painting results in higher TCPs without higher NTCPs. [Copyright &y& Elsevier]

Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Methods: Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 ( 124 I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/m 2 124 I-PEG-AVP0458 in patients with TAG-72 positive relapsed/ metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of 124 I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. Results: PEG-AVP0458 was radiolabeled with 124 I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to 124 I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of 124 I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. Conclusions: These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients., Competing Interests: Competing Interests: M. Oh was a consultant to Avipep Pty Ltd. Michael J. Wheatcroft was an employee of Avipep Pty Ltd as Research Manager. P.J. Hudson was a consultant to Avipep Pty Ltd as Chief Scientist., (© The author(s).)

Background: DS-8273a, an anti-human death receptor 5 (DR5) agonistic antibody, has cytotoxic activity against human cancer cells and induces apoptosis after specific binding to DR5. DS-8273a is currently being used in clinical Phase I trials. This study evaluated the molecular imaging of DR5 expression in vivo in mouse tumor models using SPECT/CT and PET/MRI, as a tool for drug development and trial design. Methods: DS-8273a was radiolabeled with indium-111 and zirconium-89. Radiochemical purity, immunoreactivity, antigen binding affinity and serum stability were assessed in vitro . In vivo biodistribution and pharmacokinetic studies were performed, including SPECT/CT and PET/MR imaging. A dose-escalation study using a PET/MR imaging quantitative analysis was also performed to determine DR5 receptor saturability in a mouse model. Results: 111 In-CHX-A″-DTPA-DS-8273a and 89 Zr-Df-Bz-NCS-DS-8273a showed high immunoreactivity (100%), high serum stability, and bound to DR5 expressing cells with high affinity (K a , 1.02-1.22 × 10 10 M -1 ). The number of antibodies bound per cell was 32,000. In vivo biodistribution studies showed high and specific uptake of 111 In-CHX-A″-DTPA-DS-8273a and 89 Zr-Df-Bz-NCS-DS-8273a in DR5 expressing COLO205 xenografts, with no specific uptake in normal tissues or in DR5-negative CT26 xenografts. DR5 receptor saturation was observed in vivo by biodistribution studies and quantitative PET/MRI analysis. Conclusion: 89 Zr-Df-Bz-NCS-DS-8273a is a potential novel PET imaging reagent for human bioimaging trials, and can be used for effective dose assessment and patient response evaluation in clinical trials., Competing Interests: Masakatsu Kotsuma, Toshiaki Ohtsuka and Giorgio Senaldi are employees of Daiichi Sankyo Co. Ltd. This work was supported by funding from Daiichi Sankyo Co. Ltd.

Background: This study investigates the use of (18)F-fluoromisonidazole (FMISO) PET-guided radiotherapy dose painting for potentially overcoming the radioresistant effects of hypoxia in head and neck squamous cell carcinoma (HNSCC)., Material and Methods: The study cohort consisted of eight patients with HNSCC who were planned for definitive radiotherapy. Hypoxic subvolumes were automatically generated on pre-radiotherapy FMISO PET scans. Three radiotherapy plans were generated for each patient: a standard (STD) radiotherapy plan to a dose of 70 Gy, a uniform dose escalation (UDE) plan to the standard target volumes to a dose of 84 Gy, and a hypoxia dose-painted (HDP) plan with dose escalation only to the hypoxic subvolume to 84 Gy. Plans were compared based on tumor control probability (TCP), normal tissue complication probability (NTCP), and uncomplicated tumor control probability (UTCP)., Results: The mean TCP increased from 73% with STD plans to 95% with the use of UDE plans (p < 0.001) and to 93% with HDP plans (p < 0.001). The mean parotid NTCP increased from 26% to 44% with the use of UDE plans (p = 0.003), and the mean mandible NTCP increased from 2% to 27% with the use of UDE plans (p = 0.001). There were no statistically significant differences between any of the NTCPs between the STD plans and HDP plans. The mean UTCP increased from 48% with STD plans to 66% with HDP plans (p = 0.016) and dropped to 37% with UDE plans (p = 0.138)., Conclusion: Hypoxia-targeted radiotherapy dose painting for head and neck cancer using FMISO PET is technically feasible, increases the TCP without increasing the NTCP, and increases the UTCP. This approach is superior to uniform dose escalation.

Unlabelled: Amyloid-beta (Abeta) imaging with N-methyl-(11)C-2-(4'-methylamino-phenyl)-6-hydroxy-benzothiazole ((11)C-6-OH-BTA-1; also known as (11)C-PIB) shows a robust increase in cortical binding in Alzheimer's disease (AD). The aim of this study was to explore the clinical potential of Abeta imaging for the diagnosis of AD by comparison of the accuracy of visual reading of (11)C-PIB images with quantitative analysis and (18)F-FDG., Methods: Fifteen AD patients (age, 71.1 +/- 11.3 y [mean +/- SD]; mini-mental state examination [MMSE], 18.9 +/- 9.3 [mean +/- SD]) and 25 healthy control (HC) subjects (age, 71.9 +/- 6.82 y; MMSE >or= 28) underwent 90-min dynamic (11)C-PIB PET and 20-min static (18)F-FDG PET. (11)C-PIB images, generated from data acquired between 40 and 70 min after injection, and (18)F-FDG images were rated separately by 2 readers as normal, possible AD, or probable AD. Quantitative analyses used the distribution volume ratio (DVR) of frontal cortex, parietotemporal cortex, posterior cingulate, and caudate nucleus for (11)C-PIB and standardized uptake value ratio (SUVR) of parietotemporal cortex and posterior cingulate for (18)F-FDG, using cerebellar cortex as the reference region. Receiver-operating-characteristic (ROC) analysis was performed to compare the accuracy of quantitative measures. To determine the effect of age on diagnostic accuracy, the median age of the AD subjects (74 y) was chosen to separate the cohort into younger (64.4 +/- 5.8 y) and older (78.6 +/- 4.1 y) groups., Results: Visual agreement between readers was excellent for (11)C-PIB (kappa = 0.90) and good for (18)F-FDG (kappa = 0.56). (11)C-PIB was more accurate than (18)F-FDG both on visual reading (accuracy, 90% vs. 70%, P = 0.05) and ROC analysis (95% vs. 83%, P = 0.02). Accuracy declined more with (18)F-FDG than with (11)C-PIB in the older group., Conclusion: Visual analysis of (11)C-PIB images appears more accurate than visual reading of (18)F-FDG for identification of AD and has accuracy similar to quantitative analysis of a 90-min dynamic scan. The accuracy of (11)C-PIB PET is limited by cortical binding in some healthy elderly subjects, consistent with postmortem studies of cerebral Abeta. Longitudinal follow-up is required to determine if this represents detection of preclinical AD.

Respiratory motion artifacts can be a significant factor that limits the PET image quality. To improve image quality, surveillance systems have been developed to track the movements of the subject during scanning. Gating techniques utilizing the tracking information, are able to compensate for subject motion, thereby improving lesion detection. In this paper, we present a gating method that utilizes the geometric sensitivity gating (GSG) of a 3D-PET scanner system operating in list event acquisition mode. GSG method has several advantages over the existing methods, it only uses LOR events and is non-invasive, no additional hardware device is required and there is no additional patient preparation required. Using GATE (GEANT4 Application Tomographic Emission) and NCAT (NURBs(Non Uniform Rational B-Splines) Cardiac Torso) software packages with an Allegro PET configuration, realistic simulations of respiratory motion demonstrate that GSG can be used for respiratory gating.