Johannes Czernin

CSU Mentor, Long Beach, California, United States

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Publications (272)1413.72 Total impact

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    ABSTRACT: Prostate specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. (68)Ga-PSMA Imaging & Therapy (PSMA I&T) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated. Five patients with a history of prostate cancer were injected intravenously with 91-148 MBq (68)Ga-PSMA I&T (mean: 128±23 MBq). Following an initial series of rapid whole-body scans, 3 static whole-body scans were acquired 1h, 2hrs, and 4hrs after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ absorbed doses and effective doses were calculated using OLINDA/EXM. Injection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy) followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each) and liver (7 mGy). (68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable (kidneys) or lower than those delivered by (18)F-FDG. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 04/2015; 56(6). DOI:10.2967/jnumed.115.156133 · 5.56 Impact Factor
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    ABSTRACT: Somatostatin receptor imaging with (68)Ga-DOTATATE-PET/CT (DOTATATE) is increasingly used for managing patients with neuroendocrine tumors. The objective of this study was to determine referring physicians' perspectives on the impact of DOTATATE on the management of neuroendocrine tumors. A set of 2 questionnaires (pre-PET and post PET) was sent to the referring physicians of 100 consecutive patients with known or suspected neuroendocrine tumors, who were evaluated with DOTATATE. Questionnaires on 88 patients were returned (response rate: 88%). Referring physicians categorized the DOTATATE findings on the basis of the written PET reports as negative, positive or equivocal for disease. The likelihood for metastatic disease was scored as low, moderate or high. Intended management prior to and changes as a consequence of the PET study were indicated. The indications for PET/CT were initial and subsequent treatment strategy assessments in 14% and 86% of patients, respectively. Referring physicians reported that DOTATATE led to a change in suspicion for metastatic disease in 21 patients (24%; increased and decreased suspicion in 9 (10%) and 12 (14%) patients, respectively). Intended management changes were reported in 53/88 (60%) patients. Twenty patients (23%) scheduled to undergo chemotherapy were switched to treatments without chemotherapy and six (7%) were switched from watch and wait to other treatment strategies. Conversely, five patients (6%) were switched from their initial treatment strategy to watch and wait. This survey of referring physicians demonstrates a substantial impact of (68)Ga-DOTATATE PET/CT on the intended management of patients with neuroendocrine tumors. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 12/2014; DOI:10.2967/jnumed.114.148247 · 5.56 Impact Factor
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    ABSTRACT: Purpose Diffusion magnetic resonance imaging (MRI) and 6-[18F]fluoro-l-dopa ([18F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [18F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas. Procedures We retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [18F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [18F]FDOPA PET, ADC, and mitotic index were performed. Results Areas of high [18F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [18F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [18F]FDOPA and ADC for all patients. Median [18F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [18F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue. Conclusions A significant association may exist between [18F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas.
    Molecular Imaging & Biology 12/2014; 17(3). DOI:10.1007/s11307-014-0807-3 · 2.87 Impact Factor
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    ABSTRACT: Because only pathologic examination can confirm the presence or absence of malignant disease in cancer patients, a certain rate of misinterpretation in any kind of imaging study is inevitable. For the accuracy of interpretation to be improved, determination of the nature, causes, and magnitude of this problem is needed. This study was designed to collect pertinent information from physicians referring patients for oncologic (18)F-FDG PET/CT. A total of 662 referring physicians completed an 11-question survey focused on their experience with the interpretation of oncologic (18)F-FDG PET/CT studies. The participants were oncologists (36.1%; n = 239), hematologists (14.5%; n = 96), radiation oncologists (7.4%; n = 49), surgeons (33.8%; n = 224), and other physicians (8.2%; n = 54). Questions were aimed at determining the frequency, nature, and causes of scan misinterpretations as well as potential solutions to reduce the frequency of misinterpretations. Perceived misinterpretation rates ranged from 5% to 20%, according to most (59.3%) of the participants; 20.8% of respondents reported rates of less than 5%. Overinterpretation rather than underinterpretation was more frequently encountered (68.9% vs. 8.7%, respectively). Limited availability of a patient's history and limited experience of interpreters were the major contributors to this phenomenon, according to 46.8% and 26.7% of the participants, respectively. The actions most commonly suggested to reduce misinterpretation rates (multiple suggestions were possible) were the institution of multidisciplinary meetings (59.8%), the provision of adequate history when ordering an examination (37.4%), and a discussion with imaging specialists when receiving the results of the examination (38.4%). Overinterpretation rather than underinterpretation of oncologic (18)F-FDG PET/CT studies prevails in clinical practice, according to referring physicians. Closer collaboration of imaging specialists with referring physicians through more multidisciplinary meetings, improved communication, and targeted training of interpreting physicians are actions suggested to reduce the rates of misinterpretation of oncologic (18)F-FDG PET/CT studies. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 12/2014; 55(12):1925-9. DOI:10.2967/jnumed.114.145607 · 5.56 Impact Factor
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    ABSTRACT: Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.
    Journal of Medicinal Chemistry 10/2014; 57(22). DOI:10.1021/jm501124j · 5.48 Impact Factor
  • Caius G. Radu, David A. Nathanson, Johannes Czernin
    Cancer Research 10/2014; 74(19 Supplement):5097-5097. DOI:10.1158/1538-7445.AM2014-5097 · 9.28 Impact Factor
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    ABSTRACT: High-grade gliomas (HGGs) are the most common malignant primary tumors of the central nervous system. PET probes of amino acid transport such as O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET), 3,4-dihydroxy-6-(18)F-fluoro-l-phenylalanine ((18)F-DOPA), and (11)C-methionine ((11)C-MET) detect primary and recurrent tumors with a high accuracy. (18)F-FET is predominantly used in Europe, whereas amino acid transport imaging is infrequently done in the United States. The aim of this study was to determine whether (18)F-FET and (18)F-DOPA PET/CT provide comparable information in HGG.
    Journal of Nuclear Medicine 08/2014; 55(10). DOI:10.2967/jnumed.114.140608 · 5.56 Impact Factor
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    ABSTRACT: Absolute quantitation of myocardial blood flow (MBF) by PET is an established method of analyzing coronary artery disease (CAD) but subject to the various shortcomings of available radiotracers. Flurpiridaz F 18 is a novel PET radiotracer that exhibits properties of an ideal tracer. Methods: A new absolute perfusion quantitation method with flurpiridaz was developed, taking advantage of the early kinetics and high first-pass extraction by the myocardium of this radiotracer, and the first-in-human measurements of MBF performed in 7 healthy subjects and 8 patients with documented CAD. PET images with time-activity curves were acquired at rest and during adenosine stress. Results: In healthy subjects, regional MBF between coronary artery territories did not differ significantly, leading to a mean global MBF of 0.73 mL/min/g at rest and 2.53 mL/min/g during stress, with a mean global myocardial flow reserve (MFR) of 3.70. CAD vascular territories with <50% stenosis demonstrated a mean MBF of 0.73 at rest and 2.02 during stress, leading to a mean MFR of 2.97. CAD vascular territories with stenosis exhibited a mean MBF of 0.86 at rest and 1.43 during stress, leading to a mean MFR of 1.86. Differences in stress MBF and MFR between normal and CAD territories, as well as between <50% and >= 50% stenosis vascular territories, were significant (P < 0.01). Conclusion: Absolute quantitation of MBF in humans with the novel PET radiotracer flurpiridaz is feasible over a wide range of cardiac flow in the presence or absence of stress-inducible myocardial ischemia. The significant decrease in stress MBF and ensuing MFR in CAD territories allows a clear distinction between vascular territories exhibiting stress-inducible myocardial ischemia and those with normal perfusion.
    Journal of Nuclear Medicine 07/2014; 55(9). DOI:10.2967/jnumed.114.141093 · 5.56 Impact Factor
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    ABSTRACT: Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer. Different radionuclides that emit β-rays such as (153)Samarium and (89)Strontium and achieve palliation are commercially available. In contrast to β-emitters, (223)Radium as a α-emitter has a short path-length. The advantage of the α-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms. Due to the limited range of the α-particles the bone surface to red bone marrow dose ratio is also lower for (223)Radium which is expressed in a lower myelotoxicity. The α emitter (223)Radium dichloride is the first radiopharmaceutical that significantly prolongs life in castrate resistant prostate cancer patients with wide-spread bone metastatic disease. In a phase III, randomized, double-blind, placebo-controlled study 921 patients with castration-resistant prostate cancer and bone metastases were randomly assigned. The analysis confirmed the (223)Radium survival benefit compared to the placebo (median, 14.9 mo vs 11.3 mo; P < 0.001). In addition, the treatment results in pain palliation and thus, improved quality of life and a delay of skeletal related events. At the same time the toxicity profile of (223)Radium was favourable. Since May 2013, (223)Radium dichloride (Xofigo(®)) is approved by the US Food and Drug Administration.
  • Johannes Czernin, Lisa Ta, Ken Herrmann
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    ABSTRACT: Various integrated PET/MR imaging systems have recently been developed to provide improved clinical assessments of cancers in tissues that may be anatomically better characterized with MR imaging than with CT, to explore whether the combined anatomic and functional capabilities of MR imaging together with the molecular PET information provide new insights into disease phenotypes and biology, and to reduce radiation exposure to vulnerable populations such as children and women of child-bearing age. The following review summarizes the published studies and informs about the potential diagnostic advantages of this new technology.
    Journal of Nuclear Medicine 05/2014; 55(Supplement_2). DOI:10.2967/jnumed.114.141838 · 5.56 Impact Factor
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    ABSTRACT: The contrast recovery coefficients (CRC) were evaluated for five different small animal PET scanners: GE Explore Vista, Genisys4, MiniPET-2, nanoScan PC and Siemens Inveon. The NEMA NU-4 2008 performance test with the suggested image quality phantom (NU4IQ) does not allow the determination of the CRC values for the hot regions in the phantom. This drawback of NU4IQ phantom motivated us to develop a new method for this purpose. The method includes special acquisition and reconstruction protocols using the original phantom, and results in an artificially merged image enabling the evaluation of CRC values. An advantageous feature of this method is that it stops the cold wall effect from distorting the CRC calculation. Our suggested protocol results in a set of CRC values contributing to the characterization of small animal PET scanners. GATE simulations were also performed to validate the new method and verify the evaluated CRC values. We also demonstrated that the numerical values of this parameter depend on the actual object contrast of the hot region(s) and this mainly comes from the spillover effect. This effect was also studied while analysing the background activity level around the hot rods. We revealed that the calculated background mean values depended on the target contrast in a scanner specific manner. Performing the artificially merged imaging procedure and additional simulations using the micro hollow sphere (MHS) phantom geometry, we also proved that the inactive wall around the hot spheres can have a remarkable impact on the calculated CRC. In conclusion, we have shown that the proposed artificial merging procedure and the commonly used NU4IQ phantom prescribed by the NEMA NU-4 can easily deliver reliable CRC data otherwise unavailable for the NU4IQ phantom in the conventional protocol or the MHS phantom.
    Physics in Medicine and Biology 05/2014; 59(11):2727. DOI:10.1088/0031-9155/59/11/2727 · 2.92 Impact Factor
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    ABSTRACT: We have developed an efficient, streamlined, cost-effective approach to obtain Investigational New Drug (IND) approvals from the Food and Drug Administration (FDA) for positron emission tomography (PET) imaging probes (while the FDA uses the terminology PET drugs, we are using “PET imaging probes,” “PET probes,” or “probes” as the descriptive terms). The required application and supporting data for the INDs were collected in a collaborative effort involving appropriate scientific disciplines. This path to INDs was successfully used to translate three [18 F]fluoro-arabinofuranosylcytosine (FAC) analog PET probes to phase 1 clinical trials. In doing this, a mechanism has been established to fulfill the FDA regulatory requirements for translating promising PET imaging probes from preclinical research into human clinical trials in an efficient and cost-effective manner. Electronic supplementary material The online version of this article (doi:10.1007/s11307-014-0735-2) contains supplementary material, which is available to authorized users.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 04/2014; 16(4). DOI:10.1007/s11307-014-0735-2 · 2.87 Impact Factor
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    ABSTRACT: This study compares the value of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) PET and MRI in assessing outcome during antiangiogenic treatment in patients with recurrent high-grade gliomas. Thirty patients were prospectively studied with 18F-FDOPA PET scans immediately before, and two and six weeks after start of bevacizumab therapy. 18F-FDOPA metabolic tumor volumes (MTV) as well as max and mean SUVs within this MTV were obtained. MRI treatment response was assessed at 6 weeks. The predictive ability of 18F-FDOPA PET and MRI response assessment were evaluated with regard to progression-free survival (PFS) and overall survival (OS). 30, 28, and 24 18F-FDOPA PET scans at baseline, 2 weeks, and 6 weeks, were available for analysis, respectively. 18F-FDOPA PET SUVs as well as their changes through therapy were not predictive of outcome. However, metabolic tumor volume (MTV) parameters such as MTV changes were highly prognostic. Interestingly, absolute MTV at the first follow up scan provides the most significant prediction for increased OS (P < 0.0001) as well as PFS (P = 0.001). This surprising result was scrutinized with cross-validation and simulation analysis. Responders based on 18F-FDOPA PET data survived 3.5 times longer (12.1 vs. 3.5 months median OS, P < 0.001) than non-responders (17 vs. 11 patients, respectively). In comparison, responders based on MRI data lived 1.5 times longer (11.4 vs 7.7 mo, P = 0.03) than non-responders (22 vs. 7 patients, respectively). 18F-FDOPA PET identifies treatment responders to antiangiogenic therapy as early as two weeks after treatment initiation.
    Clinical Cancer Research 03/2014; 20(13). DOI:10.1158/1078-0432.CCR-13-1440 · 8.19 Impact Factor
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    ABSTRACT: This workshop was held a year after the initial positron emission tomography/magnetic resonance (PET/MR) workshop in Tübingen, which was recently reported in this journal. The discussions at the 2013 workshop, however, differed substantially from those of the initial workshop, attesting to the progress of combined PET/MR as an innovative imaging modality. Discussions were focused on the search for truly novel, unique clinical and research applications as well as technical issues such as reliable and accurate approaches for attenuation and scatter correction of PET emission data. The workshop provided hands-on experience with PET and MR imaging. In addition, structured and moderated open discussion sessions, including six dialogue boards and two roundtable discussions, provided input from current and future PET/MR imaging users. This summary provides a snapshot of the current achievements and challenges for PET/MR.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 03/2014; 16(3). DOI:10.1007/s11307-014-0725-4 · 2.87 Impact Factor
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    ABSTRACT: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.
    Clinical Cancer Research 03/2014; 20(9). DOI:10.1158/1078-0432.CCR-13-3017 · 8.19 Impact Factor
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    ABSTRACT: Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies.
    Journal of Experimental Medicine 02/2014; 211(3). DOI:10.1084/jem.20131738 · 13.91 Impact Factor
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    ABSTRACT: Whole Body PET scans are typically performed as a series of image sets acquired at discrete axial positions to cover most or all of the body. The acquisition time at each axial position is typically kept fixed for all positions although the total imaging time is typically adjusted according to the patient’s weight. Because of the varying amount of attenuation for different sections of the body, it is expected that the image Signal-to-Noise (S/N) will vary accordingly. The aim of this work is to investigate the possibility of varying the acquisition time at different sections of the body such that the image S/N is kept relatively constant for all slices. To estimate the acquisition times for the different sections of the body we propose to use the attenuation correction (AC) sinogram generated from the CT scan that is acquired prior to the PET scan. Both simulations and phantom measurements of different diameter cylinders with activity distributions were performed. The image noise was estimated in every pixel from multiple replicate image sets. The image noise was compared to the average AC factors through the center of each body slice. A simple polynomial function was found for both the simulations and the phantom measurement images to accurately describe the image noise as a function of AC factors. These results indicate that the noise properties of whole body images can be made more uniform axially by adjusting the acquisition time according to the amount of attenuation. Instead of using a fixed scan time per bed position, the acquisition time can be reduced in areas of lower attenuation and increased in more absorbing sections of the body. Since there is a strong correlation of the image noise and the AC factors, the relative acquisition times can be quickly calculated using a simple functional relationship.
    IEEE Transactions on Nuclear Science 02/2014; 61(1):115-120. DOI:10.1109/TNS.2013.2290195 · 1.46 Impact Factor
  • Aron K Krizsan, Johannes Czernin, Magnus Dahlbom
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    ABSTRACT: Whole Body PET scans are typically performed as a series of image sets acquired at discrete axial positions to cover most or all of the body. The acquisition time at each axial position is typically kept fixed for all positions although the imaging time is typically adjusted according to the patient's weight. Because of the varying amount of attenuation for different sections of the body, it is expected that the image S/N will vary accordingly. The aim of this work is to investigate the possibility of varying the acquisition time at different sections of the body such that the image S/N is kept relatively constant for all slices. To estimate the acquisition times for the different sections of the body we propose to use the attenuation correction (AC) generated from the CT scan that is acquired prior to the PET scan.
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    ABSTRACT: Aim: To elucidate techniques most commonly used for interpreting oncologic PET/CT studies. This survey forms a basis to work on standardization of reporting and highlight the most important issues to be addressed.Methods: A web-based survey of 329 PET/CT imaging specialists was designed with the intent to determine image interpretation patterns. The questionnaire consisted of 19 questions. Of the 329 participants, 230 were nuclear medicine specialists, 46 were radiologists, and 53 had dual-board certification. Results:Report ofstandardized uptake values (SUV) is not consistent;only50.2% of respondents always report SUVs, while 45.2% report only if needed or requested. 80.9% of respondents indicated that reporting of SUV is only appropriate when its limitations are understood whereby a large majority prefer to report SUVmax. Maximum intensity projection (MIP) images are almost always reviewed by 91.1% of the respondents. An accurate and detailed clinical history is considered an essential element for reading PET/CT studies by 84.0%, but only 20.7% report that this is always available. The most common self-reported average time for reviewing and reporting of whole body PET/CT (with no prior comparison scan) was 15-20 min (27.5%). Conclusion:PET readers have considerable reservations regarding the use and reporting of SUVs. SUVmax is more frequently used than SUVmean. Evaluation of MIP images is considered an important element of PET/CT interpretation. Although availability of sufficient patient's history is considered essential, this is rarely available.
    Nuklearmedizin 01/2014; 53(2). DOI:10.3413/Nukmed-0613-13-07 · 1.67 Impact Factor
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    ABSTRACT: Access to diverse PET tracers for preclinical and clinical research remains a major obstacle to research in cancer and other disease research. The prohibitive cost and limited availability of tracers could be alleviated by microfluidic radiosynthesis technologies combined with a high-yield microscale radiosynthetic method. In this report, we demonstrate the multistep synthesis of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) with high yield on an electrowetting-on-dielectric (EWOD) microfluidic radiosynthesizer, previously developed in our group. We have identified and established several parameters that are most critical in the microscale radiosynthesis, such as the reaction time, reagent concentration, and molar ratios, to successfully synthesize (18)F-FLT in this compact platform. (18)F-FLT was synthesized from the 3-N-Boc-1-[5-O-(4,4'-dimethoxytrityl)-3-O-nosyl-2-deoxy-β-D-lyxofuranosyl] thymine precursor on the EWOD chip starting from the first solvent exchange and (18)F-fluoride ion activation step to the final deprotection step. The fluorination reaction was performed in a mixture of thexyl alcohol and dimethyl sulfoxide. The crude product after deprotection was collected from the chip and purified on a custom-made solid-phase extraction cartridge and subjected to quality control testing. The purified (18)F-FLT was suitable for small-animal PET studies in multiple nude mice xenografted with the A431 carcinoma cell line. (18)F-FLT was successfully synthesized on the EWOD microdevice coupled with an off-chip solid-phase extraction purification with a decayed-corrected radiochemical yield of 63% ± 5% (n = 5) and passed all of the quality control tests required by the U.S. Pharmacopeia for radiotracers to be injected into humans. We have successfully demonstrated the synthesis of several batches of (18)F-FLT on EWOD, starting with approximately 333 MBq of radioactivity and obtained up to 52 MBq (non-decay-corrected) of (18)F-FLT on cartridge purification. The specific activity of 2 representative preparations of (18)F-FLT synthesized on the EWOD chip were measured to be 1,800 and 2,400 GBq/μmol. The EWOD microchip and optimized synthesis method in combination represent an effective platform for synthesizing (18)F-FLT with high yield and of good quality for imaging. This compact platform, with configurable synthesis steps, could potentially form the basis of a stand-alone system that decouples PET probe production from the cyclotron and specialized radiochemistry facilities and increases diversity and flexibility in probe production.
    Journal of Nuclear Medicine 12/2013; 55(2). DOI:10.2967/jnumed.113.121053 · 5.56 Impact Factor

Publication Stats

10k Citations
1,413.72 Total Impact Points

Institutions

  • 1996–2014
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 1993–2014
    • University of California, Los Angeles
      • • Department of Molecular and Medical Pharmacology
      • • Department of Medicine
      • • Department of Surgery
      Los Ángeles, California, United States
  • 2013
    • University of Wuerzburg
      • Institute for Pathology
      Würzburg, Bavaria, Germany
  • 2010
    • University of Freiburg
      • Department of Pathology
      Freiburg, Baden-Württemberg, Germany
  • 1997–2007
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2001
    • Università di Pisa
      Pisa, Tuscany, Italy
    • California State University
      • Department of Medicine
      Long Beach, California, United States
  • 1999–2000
    • Aarhus University Hospital
      • Department of Cardiology
      Århus, Central Jutland, Denmark