Use Of PET Imaging Research Articles

Changes in Imaging Surveillance of Diffuse Large B-Cell Lymphoma Survivors after Publication of the American Society of Hematology Choosing Wisely® Recommendations

Introduction:The role of surveillance imaging in diffuse large B-cell lymphoma (DLBCL) after treatment with curative intent is debated. In 2013, the American Society of Hematology (ASH) Choosing Wisely® campaign (Hicks LK, et al. Blood 2013) released a recommendation to “limit surveillance CT scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma.” This was based on previous studies demonstrating a lack of survival benefit as well as a significant impact on the patient in terms of cost, anxiety, incidental findings and radiation exposure. Similar findings have been described regarding the use of PET imaging, especially in low risk patients. We aimed to study the changes in practice patterns of surveillance imaging for DLBCL survivors treated with curative intent before and after the publication of the ASH Choosing Wisely® campaign.Methods:Administrative claims data from a large U.S commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify adult patients with an incident diagnosis of DLBCL between 2008 and 2016 and at least one year of follow-up. We excluded those who did not receive treatment with curative intent: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) x 6 cycles or RCHOP x 3-5 cycles plus radiation. Patients were also excluded if they had a co-existing or second cancer, or if they received any chemotherapy/radiation during their surveillance period, as to exclude anyone with a recurrence of their lymphoma. The surveillance period started 90 days after the last chemotherapy or radiation and continued for the duration of follow-up. Surveillance imaging was defined as any PET, PET-CT, CT chest, CT abdomen, and/or CT pelvis. To examine trends over time, three time periods were defined: 2008-2010, 2011-2013 and 2014-2016. The Cochran Armitage test was used to test the trend hypothesis.Results:A total of 1,472 patients were included. Cohort characteristics by time period are described in Table 1. Surveillance imaging frequency decreased from 84% in Year 1 of surveillance to 43% in Year 5 (Figure 1). Overall, surveillance imaging during the first 3 surveillance years significantly decreased over the three time periods (Figure 2) (P<0.01 for Years 1 and 2, P=0.04 for Year 3). Imaging surveillance for the first two years of surveillance did not significantly decrease from 2008-2010 to 2011-2013 (P>0.05), but significantly decreased from 2011-2013 to 2014-2016 (P<0.01). Of the groups that received imaging surveillance during year 1, the median number of scans during the first year was 2 (inter-quartile range, 1-2) and did not significantly change over time. In addition, PET/PET-CT surveillance decreased from 49% in Year 1 to <10% in Year 5. PET/PET-CT also decreased over the three time periods, from 62% (2008-2010) to 48% (2011-2013) to 43% (2014-2016) during the first year of surveillance and 40% to 31% to 25% during the second year. Younger age (<65 years versus ≥65 years) was associated with higher imaging utilization (86% versus 81%, respectively), and specifically PET/PET-CT utilization (55% versus 43%, respectively), during the first year of surveillance. However, race (white versus non-white) did not significantly affect imaging (85% versus 83%) or PET utilization (50% versus 47%) during the first year of surveillance.Conclusions:Our study demonstrates that the rate of surveillance CT and PET imaging in DLBCL patients treated with curative intent decreased significantly in the years after the publication of the ASH Choosing Wisely® campaign. However, over half of the DLBCL patients diagnosed in 2014-2016 continued to undergo surveillance imaging, indicating either incomplete guideline dissemination or ongoing debate regarding optimal surveillance practice. Future studies are necessary to determine whether such a decline in surveillance imaging is sustained and to examine factors (patient, provider, and payer) associated with surveillance imaging in DLBCL. DisclosuresNo relevant conflicts of interest to declare.

P2.17-28 Real-World Data: Survival Outcomes of Chemotherapy Regimens Given Concurrently with Radiotherapy for Locally Advanced NSCLC

Initial management for inoperable Stage III non-small cell lung cancer (NSCLC) treated for curative intent is platinum-based chemotherapy with concurrent thoracic radiotherapy (TRT). However, a lack of consensus on the optimal chemotherapy regimen administered with TRT remains. In Alberta, Canada, cisplatin/etoposide (EP), given Days 1-5 + 8 of a 28-day cycle, and cisplatin/vinorelbine (VP), given Days 1 +8 of a 21-day cycle, have been the two regimens used preferentially. Weekly carboplatin/paclitaxel (CP) has historically been used as an alternative in patients (pts) with borderline performance status or contraindication to cisplatin. Here, we retrospectively compare survival outcomes of these chemotherapy regimens. The Alberta Cancer Registry identified pts diagnosed with locally advanced NSCLC between 2010 and 2015 and treated with EP, VP or CP chemotherapy with concurrent TRT. Patient and tumour characteristics were collected along with treatment parameters. Progression-free survival (PFS) and overal survival (OS) was determined for each chemotherapy regimen. Survival outcomes were compared using Kaplan-Meier analysis and Cox proportional hazard regression models adjusting for age, gender, tumour histological subtype (squamous vs. non-squamous NSCLC) and 7th edition TNM Stage (IIIA vs. IIIB). Of 148 pts reviewed, 44, 79, and 25 pts were treated with EP, VP, and CP, respectively, with median ages of 63, 62, and 68 years. Gender, tumour histological subtype, distribution of Stage IIIA vs. IIIB, and use of PET imaging for staging were balanced between regimens. Median PFS (EP 9.5 mo; VP 12.9 mo; CP 11.2 mo; p=0.875) and OS (EP 17.8 mo; VP 25.3 mo; CP 33.2 mo; p=0.509) were not significantly affected. Non-squamous median OS (EP 33.4 mo; VP 31.0 mo; CP 33.2 mo; p=0.997) and squamous median OS (EP 13.4 mo; VP 22.3 mo; CP not reached (N=11); p=0.406) also did not differ by regimen. Multivariate Cox regression analysis demonstrated Stage (IIIA vs. IIIB) as the only parameter that significantly altered PFS and OS. This retrospective analysis of real-word data from 2010 to 2015, in the absence of consolidation durvalumab, shows that PFS and OS in locally advanced NSCLC pts treated with concurrent chemoradiotherapy are similar for the EP, VP or CP regimens. Dose scheduling and respective toxicities will likely determine choice of chemotherapy regimen given with TRT. Further review of the CP regimen, given the small sample size in this study, and the use of next generation chemotherapy regimens such as platinum/pemetrexed for non-squamous NSCLC is warranted.

Specific 18F-FDHT Accumulation in Human Prostate Cancer Xenograft Murine Models Is Facilitated by Prebinding to Sex Hormone-Binding Globulin.

Tremendous efforts are currently dedicated to the development of novel therapies targeting the androgen receptor (AR), the major driver of prostate cancer disease and its progression to castration resistance. The ability to noninvasively interrogate AR expression over time in murine models of prostate cancer would permit longitudinal preclinical analysis of novel compounds that could not otherwise be accomplished ex vivo. Although PET imaging with 16β-18F-fluoro-5α-dihydrotestosterone (18F-FDHT) has successfully quantified AR levels clinically, no rodent model of 18F-FDHT imaging has been reported so far. One difference between humans and rodents is the absence in the latter of the sex hormone-binding globulin (SHBG), a glycoprotein that binds to testosterone in the bloodstream, Here, we explore the role of SHBG in developing a working model of rodent AR imaging. Methods: Three human prostate cancer cell lines and xenografts (LNCaP, 22Rv1, and PC3) were used to examine the uptake of free 18F-FDHT and SHBG-bound 18F-FDHT. Both ligands were examined for stability and competitive binding to AR over time in vitro before in vivo studies. PET/CT imaging was used to dynamically measure the uptake of both tracers over 4 h, whereas specificity was determined by competitive binding with the AR antagonist enzalutamide. Results: AR levels correlated with the uptake of both 18F-FDHT and SHBG-18F-FDHT in prostate cancer cell lines. Interestingly, whereas both free and SHBG-bound 18F-FDHT had a similar cellular accumulation at 1 and 2.5 h, SHBG-18F-FDHT accumulated at significantly higher levels after 4 h-evidence that receptor-mediated uptake of SHBG accounted for later time-point differences. This observation was also seen in 22Rv1 tumor-bearing mice, in which SHBG-18F-FDHT exhibited a significantly increased uptake (average tumor-to-background ratio [TBR], 1.62 ± 0.62) in comparison to unbound 18F-FDHT (TBR, 0.81 ± 0.08) at 4 h. Furthermore, the specificity of the SHBG-18F-FDHT accumulation at 4 h was demonstrated by a reduced tumor uptake after AR blockade with enzalutamide (TBR, 1.07 ± 0.13). Conclusion: Prebinding of 18F-FDHT to SHBG allows accurate and quantitative PET imaging of AR levels in murine models of prostate cancer. This procedure may permit the use of PET imaging to study the longitudinal effects of AR-targeting therapies, accelerating novel-drug development.

From mono- to bivalent: improving theranostic properties of target modules for redirection of UniCAR T cells against EGFR-expressing tumor cells in vitro and in vivo.

CAR-modified T cells show impressive results in clinical trials. However, cytokine release syndrome and “on-target, off-tumor” reactions represent most concerning side effects. To improve the safety of CAR-T cell therapy, we established a switchable CAR platform termed UniCAR system consisting of two components: UniCAR-modified T cells and tumor-specific target modules (TM). For treatment of EGFR+ epithelial tumors, we recently described a monovalent nanobody-based α-EGFR TM, either expressed in bacteria or eukaryotic cells. In spite of the identical primary sequence the eukaryotic TM showed a reduced killing capability and affinity. Here we describe a novel bivalent α-EGFR-EGFR TM. As expected, the avidity of the bivalent TM is higher than that of its monovalent counterpart. Binding of neither the monovalent α-EGFR TM nor the bivalent α-EGFR-EGFR TM to EGFR effected the EGF-mediated signaling. While the monovalent α-EGFR TM could only mediate the killing of tumor cells expressing high levels of EGFR, the bivalent α-EGFR-EGFR TM could redirect UniCAR T cells to tumor cells expressing low levels of EGFR. According to PET experiments in vivo, the increased avidity of the bivalent α-EGFR-EGFR TM improves the enrichment at the tumor site and its use for PET imaging.

Flow and Microwave Induced Pellizzari Reactions: Synthesis of Heterocyclic Analogues of the Benzoxazepine Antipsychotic Agents Loxapine and JL-13

An expeditious route to fused triazolo-pyrido benzoxazepines has been developed using flow and microwave-mediated cyclization chemistry. A range of substituted aryl hydrazides are coupled with a core chloroimine in good to excellent yield via a Pellizzari type process, producing 1,2,4-triazolo-pyrido [2,3-b] [1,5] benzoxazepines with structural similarity to known antipsychotic agents. Modifications allow for strategically functionalized derivatives, and installation of a fluoro group for use in PET imaging is also demonstrated. Given the affinity of the tricyclic core for 5-HT and dopamine receptors, the derivatives are expected to find utility in CNS research.

Rapid and simplified synthesis of [18F]Fluoromisonidazole and its use in PET imaging in an experimental model of subarachnoid hemorrhage

Cerebral damage secondary to the vasospasm due to subarachnoid hemorrhage (SAH) is an important cause of morbid-mortality. We propose the use of the PET tracer [18F]Fluoromisonidazole to visualize the hypoxia due to the vasospasm. On the other hand [18F]Fluoromisonidazole synthesis process was optimized, avoiding HPLC purification using SPE cartridges instead, and reducing some synthesis steps. [18F]Fluoromisonidazole in vitro stability was tested for ten hours, and in vivo PET/CT images showed higher cerebral uptake in hemorrhagic animals than in control rats.

Delivering FLT to the Central Nervous System by Means of a Promising Targeting System: Synthesis, [11C]Radiosynthesis, and in Vivo Evaluation.

The development of delivery systems to transport some specific radiotracers across the blood-brain barrier (BBB) needs to be investigated for brain imaging. [18F]FLT (3'-deoxy-3'-18F-fluoro-l-thymidine), an analogue substrate of the nucleoside thymidine, has been developed as a proliferation tracer for oncological PET studies. Unfortunately, low-grade brain tumors are poorly visualized due to the low uptake of [18F]FLT in brain tissue, preventing its use in PET imaging to detect brain tumors at an early stage. Based on our previous work, a redox chemical delivery system (CDS) related to Bodor's strategy was developed to enable the penetration of FLT into the brain. To this end, FLT was covalently linked to a series of lipophilic carriers based on a 1,4-dihydroquinoline structure. To determine the best carrier, various sets of [11C]CDS-FLT were prepared and injected into rats. Pleasingly, in vivo results let us suggest that this CDS is a promising approach to overcome the BBB to target low-grade brain tumors for PET imaging.

PET imaging in patients with meningioma-report of the RANO/PET Group.

Meningiomas are the most frequent nonglial primary brain tumors and represent about 30% of brain tumors. Usually, diagnosis and treatment planning are based on neuroimaging using mainly MRI or, rarely, CT. Most common treatment options are neurosurgical resection and radiotherapy (eg, radiosurgery, external fractionated radiotherapy). For follow-up after treatment, a structural imaging technique such as MRI or CT is used. However, these structural imaging modalities have limitations, particularly in terms of tumor delineation as well as diagnosis of posttherapeutic reactive changes. Molecular imaging techniques such as PET can characterize specific metabolic and cellular features which may provide clinically relevant information beyond that obtained from structural MR or CT imaging alone. Currently, the use of PET in meningioma patients is steadily increasing. In the present article, we provide recommendations for the use of PET imaging in the clinical management of meningiomas based on evidence generated from studies being validated by histology or clinical course.

Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas.

This guideline provides recommendations for the use of PET imaging in gliomas. The review examines established clinical benefit in glioma patients of PET using glucose ((18)F-FDG) and amino acid tracers ((11)C-MET, (18)F-FET, and (18)F-FDOPA). An increasing number of studies have been published on PET imaging in the setting of diagnosis, biopsy, and resection as well radiotherapy planning, treatment monitoring, and response assessment. Recommendations are based on evidence generated from studies which validated PET findings by histology or clinical course. This guideline emphasizes the clinical value of PET imaging with superiority of amino acid PET over glucose PET and provides a framework for the use of PET to assist in the management of patients with gliomas.

Pretargeted Immuno-PET: Overcoming Limitations of Space and Time

Although the development of radiolabeled antibodies for preclinical and clinical use in PET imaging continues to mature into a widespread technique ([1][1]–[4][2]), limitations still remain: namely space, in which the antigens to which our antibody is targeting are located (intracellularly or cell

Trends in Use of PET Imaging in Surveillance of Lung Cancer: Implications of the Choosing Wisely Initiative

Trends in Use of PET Imaging in Surveillance of Lung Cancer: Implications of the Choosing Wisely Initiative

Synthesis and preliminary evaluation of an 18F-labeled oleic acid analog for PET imaging of fatty acid uptake and metabolism

IntroductionImaging fatty acid uptake and utilization has broad impact in investigating myocardial diseases, hepatic functions, tumor progression, and the metabolic state of adipose tissue. The SPECT tracer 123I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) is a clinically used nuclear medicine tracer to image myocardial uptake of fatty acid. Although FTHA (18F-5) has been in clinical use for PET imaging of adipose tissue as well as the myocardium, here we developed a click oleate analog to compare to FTO, with the goal of improved stability to defluorination and suitability for imaging myocardial uptake and oxidation of fatty acids. MethodsA rapid and convenient synthetic approach for a precursor to a 18F-labeled oleate analog using click chemistry was developed and evaluated for PET imaging in fasted mice. ResultsThe overall yield for the preparation of the labeling precursor of the clicked oleate analog was 12%. This precursor was efficiently radiolabeled with F-18 in 17% non-decay-corrected radiochemical yield. PET/CT imaging and biodistribution results show that this fatty acid analog had reasonable heart uptake (0.94±0.28 %ID/g at 0.5h p.i.) and heart-to-muscle ratio (2.05±0.39 at 0.5h p.i.) and is a potential lead for developing new PET tracers to image fatty acid uptake and utilization using click chemistry methodologies. The synthetic route to FTO was optimized to three steps from known starting materials. ConclusionWhile the uptake of the clicked oleic acid analog was sufficient for visualizing the myocardium in mice, the preliminary metabolism data suggest that only a fraction of the uptake was due to fatty acid beta-oxidation. Studies are under way to explore the uptake/oxidation mechanism and kinetics.

A high-affinity [18 F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

IntroductionIn this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. Methodsp-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [18F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(−) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. ResultsThe crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [18F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(−) cells (0.08%) at 4h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4h. ConclusionsWe have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [18F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. Advances in KnowledgeThe only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [18F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials.Implications for Patient CareOur preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.

SU‐E‐J‐138: On the Ion Beam Range and Dose Verification in Hadron Therapy Using Sound Waves

Purpose:Accurate range verification is of great importance to fully exploit the potential benefits of ion beam therapies. Current research efforts on this topic include the use of PET imaging of induced activity, detection of emerging prompt gamma rays or secondary particles. It has also been suggested recently to detect the ultrasound waves emitted through the ion energy absorption process. The energy absorbed in a medium is dissipated as heat, followed by thermal expansion that leads to generation of acoustic waves. By using an array of ultrasound transducers the precise spatial location of the Bragg peak can be obtained. The shape and intensity of the emitted ultrasound pulse depend on several variables including the absorbed energy and the pulse length. The main objective of this work is to understand how the ultrasound wave amplitude and shape depend on the initial ion energy and intensity. This would help guide future experiments in ionoacoustic imaging.Methods:The absorbed energy density for protons and carbon ions of different energy and field sizes were obtained using Fluka Monte Carlo code. Subsequently, the system of coupled equations for temperature and pressure is solved for different ion pulse intensities and lengths to obtain the pressure wave shape, amplitude and spectral distribution.Results:The proposed calculations show that the excited pressure wave amplitude is proportional to the absorbed energy density and for longer ion pulses inversely proportional to the ion pulse duration. It is also shown that the resulting ionoacoustic pressure distribution depends on both ion pulse duration and time between the pulses.Conclusion:The Bragg peak localization using ionoacoustic signal may eventually lead to the development of an alternative imaging method with sub‐millimeter resolution. It may also open a way for in‐vivo dose verification from the measured acoustic signal.

Trends in use of PET imaging in surveillance of lung and colorectal cancer.

6563 Background: Surveillance PET imaging following curative intent treatment of non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) is not supported by available evidence. ASCO and ABIM'...

The role of PET/CT in the management of patients affected by head and neck tumors: a review of the literature.

The management of head and neck tumor (HNSCC) has been changing over the years, especially due to the aid of imaging techniques that help physicians to attain a correct diagnosis. These techniques represent a valuable tool to help tailor treatment and during follow-up of patients affected by malignancies. The aim of this review is to summarize the results of the most recent and relevant studies about the use of PET imaging in HNSCCs. This review is divided into six chapters: (1) The role of PET/CT in the pre-treatment phase; (2) PET/CT and radiotherapy planning; (3) PET/CT in the post-treatment setting; (4) PET/CT and SUVmax for prediction of prognosis; (5) miscellanea on the utility of PET in specific HNSCCs; (6) non-FDG PET tracers used in HNSCC. Promising results have been obtained so far. Despite the encouraging outcomes, more investigations are needed to warrant the value of this technique, especially in the pre-treatment setting.

Abstract 103: 64-Cu-NOTA-panitumumab F(ab')2 fragments for PET/CT imaging of pancreatic cancer

Abstract Background: Pancreatic cancer is a leading cause of cancer related death. Radiolabeled panitumumab (Pmab) has potential as an imaging agent for pancreatic cancer because it targets over-expression of human epidermal growth factor receptor (EGFR) commonly found in the disease. Our aim was to develop a Pmab-based radioimmunoconjugate (RIC) for use for PET imaging of pancreatic cancer. Methods: Pmab Fab fragments (PmabFab), F(ab')2 fragments (PmabF(ab')2), intact IgG (PmabIgG) and irrelevant anti-CD20 rituximab F(ab')2 (RmabF(ab')2) were derivatized with NOTA then 64Cu-labeled to ≥95 % radiochemical purity. RIC immunoreactivity was assessed by binding assays with MDA-MB-468 breast cancer cells (1 × 10E6 EGFR/cell), PANC-1 pancreatic cancer cells (4 × 10E5 EGFR/cell), and a primary pancreatic tumour cell line, OCIP-23 (4 × 10E5 EGFR/cell). RICs (4 MBq, 10 µg) were injected i.v. (tail vein) into non-tumour bearing Balb/c mice and biodistribution was assessed at 18 h post injection (p.i). Tumours were established in NOD-Scid or CD1 nude mice by s.c. inoculation with 1 × 10E7 PANC-1 cells or 1 × 10E7 MDA-MB-468 cells. RICs were injected i.v. (tail vein) into tumour-bearing mice (30 MBq, 10 µg) then PET/CT imaging and biodistribution studies were performed at 24 and 48 h p.i. Results: MDA-MB-468 cell binding assays showed 89.0 ± 0.7 % of applied 50 nM 64Cu-PmabFab and 88.8 ± 4.5 % of 64Cu-PmabF(ab')2 was displaced by 100-fold molar excess PmabIgG, demonstrating specificity for EGFR. Assessment of 64Cu-PmabF(ab')2 binding to pancreatic cell lines showed that 90.1 ± 2.0 % in PANC-1 cells and 80.2 ± 1.0 % in OCIP-23 cells of applied RIC was displaced by PmabIgG. In Balb/c mice, kidney uptake of 64Cu-PmabFab was significantly higher at 90.8 ± 9.0 % ID/g than that of 64Cu-PmabF(ab')2 and PmabIgG with 6.9 ± 0.7 % ID/g and 11.2 ± 1.0 % ID/g, respectively; (p≤0.05). Liver uptake of 64Cu-PmabF(ab')2 was lower at 5.4 ± 0.6 % ID/g than 64Cu-PmabIgG at 8.7 ± 0.9 % ID/g (p≤0.05). 64Cu-PmabF(ab')2 was selected for PET/CT imaging and biodistribution studies. The tumour:blood ratio in MDA-MB-468 xenografted mice was 1:1 at 24 h, but increased at 48 h to 5:1, with tumour uptake of 8.0 ± 0.8 % ID/g. 64Cu-RmabF(ab')2 tumour uptake in MDA-MB-468 xenografted mice at 48 h was 0.5 ± 0.1 % ID/g, significantly lower than that of 64Cu-PmabF(ab')2 (p≤0.005). The tumour:blood ratio in PANC-1 xenografted mice was 1:1 at 24 h, and improved to 2.4:1 at 48 h, with 6.2 ± 1.1 % ID/g tumour uptake. MDA-MB-468 and PANC-1 tumours were imaged by PET/CT. Studies with primary pancreatic tumour OCIP-23 xenografts are in progress. Conclusions: F(ab')2 is the optimal form of Pmab for PET/CT imaging due to lower kidney uptake than Fab fragments, and lower liver uptake than intact IgG. EGFR-positive PANC-1 and MDA-MB-468 xenografts were well visualized with 64Cu-PmabF(ab')2 at 48 h p.i. Supported by a grant from the Canadian Cancer Society Research Institute with funds from the Canadian Cancer Society. Citation Format: Amanda J. Boyle, David W. Hedley, Sachdev S. Sidhu, Mitchell A. Winnik, Raymond M. Reilly. 64-Cu-NOTA-panitumumab F(ab')2 fragments for PET/CT imaging of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 103. doi:10.1158/1538-7445.AM2014-103

Use of PET imaging to screen subjects for trials in prodromal and Mild Alzheimer's disease and the relationship between PET and CSF findings

Use of PET imaging to screen subjects for trials in prodromal and Mild Alzheimer's disease and the relationship between PET and CSF findings

Abstract P4-12-29: Assessment of safety and activity in an expanded phase 1 study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced HER2-positive (HER2+) breast cancer

Abstract Background: MM-302 is a novel antibody drug conjugate (ADC) combining PEGylated liposomal doxorubicin with anti-HER2 scFvs. MM-302 was designed to overcome the limitations associated with using anthracyclines in the treatment of HER2-positive breast cancer. Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clear-cut efficacy advantages. MM-302 specifically targets tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. This Phase 1 study evaluates the safety of MM-302 in patients with HER2+ advanced breast cancer. Methods: Patients aged ≥ 18 years with histologically confirmed HER2+ advanced breast cancer that have progressed or recurred on standard therapy or for which no standard therapy exists having measurable disease, adequate performance status, bone marrow reserve and organ function, were eligible for the study. A post-treatment biopsy was required. A 3 + 3 dose escalation design (8, 16, 30, 40 and 50 mg/m2 administered i.v. q4w) is used to identify a Phase 2 dose followed by expansion arms at 40 and 50 mg/m2 for a preliminary indication of activity. Secondary endpoints included determination of dose-limiting toxicity, adverse event(s), and PK of MM-302, as well as overall response and clinical benefit rates of MM-302. Results: We report data from MM-302 dose levels (30, 40 and 50 mg/m2 as monotherapy) that are expected to be therapeutically relevant. Eight patients dosed at presumed sub-therapeutic dose levels of 8 and 16 mg/m2 were excluded from the efficacy analysis. Patients had received a median of 9.5 prior agents (range 3-19) in all settings. All patients had been treated with trastuzumab, 96% with prior taxanes, 67% lapatinib, 54% anthracyclines and 33% T-DM1. At the time of this analysis (n = 27), overall response rate was 17% (4 out of 24 evaluable patients) and the estimated median Progression Free Survival (PFS) was 5.7 months, with six patients still receiving treatment. Eight patients (30%) had a PFS of greater than 6.0 months. Neutropenia was the most common treatment-related grade 3/4 toxicity and occurred in 15% of patients. The most common adverse events include fatigue, nausea, vomiting, and decreased appetite. Constipation, stomatitis, headache and rash were also observed in greater than 20% of patients. No patients discontinued treatment for toxicity. There was no protocol defined cardiotoxicity observed across all dose cohorts and five patients have had cumulative anthracycline exposure exceeding 550 mg/m2 without a reduction in left ventricular ejection fraction. Conclusion: Overall MM-302 appears to be well tolerated with promising activity in this ongoing trial. Further development is continuing combining MM-302 with trastuzumab and/or cyclophosphamide. In addition, we are evaluating the use of PET imaging to correlate liposomal tumor deposition as an additional potential patient preselection strategy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-29.

Dual isotope labeling: Conjugation of 32P-oligonucleotides with 18F-aryltrifluoroborate via copper(I) catalyzed cycloaddition

A one-pot-two-step labeling of an oligonucleotide with an 18F-ArBF3−(aryltrifluoroborate) radioprosthetic is reported herein. In order to characterize labeling in terms of radiochemistry, phosphorus-32 was also introduced to the 5′-terminus of the oligonucleotide via enzymatic phosphorylation. A pendant azide group was subsequently conjugated to the 5′-phosphate of the oligonucleotide. Copper(I) catalyzed [2+3] cycloaddition was undertaken to conjugate an alkyne-bearing18F-ArBF3− to the oligonucleotide. Following polyacrylamide gel electrophoresis, this doubly-labeled bioconjugate exhibited decay properties of both the phosphorus-32 and fluorine-18, that were confirmed by autoradiography at selected lengths of time, which in turn provided concrete evidence of successful conjugation. These results are corroborated by HPLC analysis of the labeled material. Taken together this work demonstrates viable use of 18F-ArBF3− prosthetics for labeling oligonucleotides for use in PET imaging.