17 results on '"James B. Stubbs"'
Search Results
2. Phase-1 Clinical Trial Results of High-Specific-Activity Carrier-Free 123I-Iobenguane
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James F. Kronauge, Jorge Oldan, Neil A. Petry, Frank J. Femia, James B. Stubbs, Kevin P. Maresca, John W. Babich, Michael G. Stabin, Thomas Armor, Shawn Hillier, Jianqing Chen, Bennett B. Chin, and Olga James
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Adult ,Male ,Carrier free ,Time Factors ,Contrast Media ,Phases of clinical research ,Radiation Dosage ,Iodine Radioisotopes ,Electrocardiography ,chemistry.chemical_compound ,Spect imaging ,Iobenguane ,Humans ,Medicine ,Dosimetry ,Tissue Distribution ,Whole Body Imaging ,Radiology, Nuclear Medicine and imaging ,Clinical imaging ,Radiometry ,Tomography, Emission-Computed, Single-Photon ,Phantoms, Imaging ,business.industry ,Mediastinum ,Heart ,Middle Aged ,Healthy Volunteers ,Imaging agent ,3-Iodobenzylguanidine ,chemistry ,High specific activity ,Radiographic Image Interpretation, Computer-Assisted ,Female ,Radiopharmaceuticals ,business ,Nuclear medicine - Abstract
A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of 123I-iobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent. Methods: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy. Results: A reference clinical imaging database acquired over time for healthy men and women injected with high-specific-activity 123I-iobenguane showed organ distribution and whole-body retention similar to those of conventional 123I-iobenguane. The heart-to-mediastinum ratios for the high-specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions. Conclusion: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity 123I-iobenguane.
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- 2014
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3. Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy
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Boris Hadaschik, Jürgen Debus, Ali Afshar-Oromieh, James B. Stubbs, John W. Babich, John Joyal, Tom Armor, Klaus Kopka, Christian M. Zechmann, Walter Mier, and Uwe Haberkorn
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Glutamate Carboxypeptidase II ,Male ,Organs at Risk ,Biodistribution ,urologic and male genital diseases ,Iodine Radioisotopes ,Prostate cancer ,Antigen ,Glutamates ,Dosimetry ,Radioiodinated PSMA ligand ,Glutamate carboxypeptidase II ,Medicine ,Humans ,Urea ,Radiology, Nuclear Medicine and imaging ,Molecular Targeted Therapy ,Neoplasm Metastasis ,PSMA targeting ,Radiometry ,Membrane antigen ,Aged ,Absorbed dose estimates ,medicine.diagnostic_test ,business.industry ,Prostatic Neoplasms ,Radiotherapy Dosage ,General Medicine ,Middle Aged ,medicine.disease ,Small molecule ,Treatment Outcome ,Radiology Nuclear Medicine and imaging ,Positron emission tomography ,Positron-Emission Tomography ,Antigens, Surface ,Cancer research ,Original Article ,Radiopharmaceuticals ,Safety ,business ,Nuclear medicine ,Tomography, X-Ray Computed - Abstract
Introduction Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[124I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of 131I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of 131I-MIP-1095. Methods Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of 124I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of 131I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA. Results I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed. Conclusion Based on the biodistribution and dose calculations of the PSMA-targeted small molecule 124I-MIP-1095 therapy with the authentic analog 131I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy. Electronic supplementary material The online version of this article (doi:10.1007/s00259-014-2713-y) contains supplementary material, which is available to authorized users.
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- 2014
4. Biodistribution and Radiation Dosimetry of the Integrin Marker 18F-RGD-K5 Determined from Whole-Body PET/CT in Monkeys and Humans
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R. Katherine Alpaugh, James J. Zhang, Vani P. Mocharla, Hartmuth C. Kolb, Joseph C. Walsh, Margaret von Mehren, Mohan Doss, Michael G. Stabin, Michael S. Haka, Jian Q. Yu, James B. Stubbs, Marie-Jose Belanger, and Eric D. Hostetler
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Adult ,Male ,Biodistribution ,Whole body imaging ,Urine ,Multimodal Imaging ,Peptides, Cyclic ,Effective dose (radiation) ,Article ,medicine ,Animals ,Humans ,Dosimetry ,Whole Body Imaging ,Radiology, Nuclear Medicine and imaging ,Radiometry ,Aged ,medicine.diagnostic_test ,business.industry ,Gallbladder ,Middle Aged ,Integrin alphaVbeta3 ,Macaca mulatta ,medicine.anatomical_structure ,Positron emission tomography ,Positron-Emission Tomography ,Absorbed dose ,Female ,Tomography, X-Ray Computed ,business ,Nuclear medicine ,Oligopeptides ,Biomarkers - Abstract
2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-18F-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid (18F-RGD-K5) has been developed as an αvβ3 integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from 18F-RGD-K5 using whole-body PET/CT scans in monkeys and humans. Methods: Successive whole-body PET/CT scans were obtained after intravenous injection of 18F-RGD-K5 in 3 rhesus monkeys (167 ± 19 MBq) and 4 healthy humans (583 ± 78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of 18F-RGD-K5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions. Results:18F-RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased 18F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31 ± 1 μSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376 ± 19 μGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15 ± 1 μSv/MBq for the effective dose and 103 ± 4 μGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2 ± 0.6 mSv for the 4.8-h model, reducing to 8.3 ± 0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2 ± 2.4 mSv for the 4.8-h model and 12.8 ± 0.2 mSv for the 1-h model. Conclusion: The biodistribution profile of 18F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of 18F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. 18F-RGD-K5 can be used safely for imaging αvβ3 integrin expression in humans.
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- 2012
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5. Biodistribution and dosimetry of 18F-EF5 in cancer patients with preliminary comparison of 18F-EF5 uptake versus EF5 binding in human glioblastoma
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Alexander V. Kachur, Jason Driesbaugh, Stephen M. Hahn, Chaitanya R. Divgi, Kevin Judy, Cameron J. Koch, James B. Stubbs, D. Smith, Joel S. Karp, Joshua Scheuermann, Sydney M. Evans, Richard Freifelder, Janet S. Reddin, and Susan Prendergast
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Male ,Fluorine Radioisotopes ,Biodistribution ,Pathology ,medicine.medical_specialty ,Hydrocarbons, Fluorinated ,medicine.drug_class ,Monoclonal antibody ,Article ,Glioma ,medicine ,Humans ,Dosimetry ,Tissue Distribution ,Whole Body Imaging ,Radiology, Nuclear Medicine and imaging ,Etanidazole ,Radiometry ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,Cancer ,Biological Transport ,General Medicine ,Middle Aged ,Hypoxia (medical) ,medicine.disease ,Immunohistochemistry ,Cell Hypoxia ,Positron emission tomography ,Positron-Emission Tomography ,Cancer research ,Female ,medicine.symptom ,Glioblastoma ,business - Abstract
The primary purpose of this study was to assess the biodistribution and radiation dose resulting from administration of (18)F-EF5, a lipophilic 2-nitroimidazole hypoxia marker in ten cancer patients. For three of these patients (with glioblastoma) unlabeled EF5 was additionally administered to allow the comparative assessment of (18)F-EF5 tumor uptake with EF5 binding, the latter measured in tumor biopsies by fluorescent anti-EF5 monoclonal antibodies.(18)F-EF5 was synthesized by electrophilic addition of (18)F(2) gas, made by deuteron bombardment of a neon/fluorine mixture in a high-pressure gas target, to an allyl precursor in trifluoroacetic acid at 0° then purified and administered by intravenous bolus. Three whole-body images were collected for each of ten patients using an Allegro (Philips) scanner. Gamma counts were determined in blood, drawn during each image, and urine, pooled as a single sample. PET images were analyzed to determine radiotracer uptake in several tissues and the resulting radiation dose calculated using OLINDA software and standard phantom. For three patients, 21 mg/kg unlabeled EF5 was administered after the PET scans, and tissue samples obtained the next day at surgery to determine EF5 binding using immunohistochemistry techniques (IHC).EF5 distributes evenly throughout soft tissue within minutes of injection. Its concentration in blood over the typical time frame of the study (∼3.5 h) was nearly constant, consistent with a previously determined EF5 plasma half-life of ∼13 h. Elimination was primarily via urine and bile. Radiation exposure from labeled EF5 is similar to other (18)F-labeled imaging agents (e.g., FDG and FMISO). In a de novo glioblastoma multiforme patient, focal uptake of (18)F-EF5 was confirmed by IHC.These results confirm predictions of biodistribution and safety based on EF5's characteristics (high biological stability, high lipophilicity). EF5 is a novel hypoxia marker with unique pharmacological characteristics allowing both noninvasive and invasive measurements.
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- 2010
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6. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen: pharmacokinetics and biodistribution studies in healthy subjects and patients with metastatic prostate cancer
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Irina Lipai, Joseph R. Osborne, John W. Babich, Robert Crummet, Scott T. Tagawa, James B. Stubbs, John Joyal, Anastasia Nikolopoulou, Kevin P. Maresca, Stanley J. Goldsmith, Shankar Vallabhajosula, Lilja Solnes, and Thomas Armor
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Glutamate Carboxypeptidase II ,Male ,Pathology ,medicine.medical_specialty ,Biodistribution ,Time Factors ,Antineoplastic Agents ,Lesion ,Prostate cancer ,Pharmacokinetics ,Glutamate carboxypeptidase II ,medicine ,Image Processing, Computer-Assisted ,Humans ,Radiology, Nuclear Medicine and imaging ,Whole Body Imaging ,Neoplasm Metastasis ,Radiometry ,Radionuclide Imaging ,Lymph node ,Aged ,Tomography, Emission-Computed, Single-Photon ,Cross-Over Studies ,business.industry ,Prostatic Neoplasms ,Technetium ,Organotechnetium Compounds ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Treatment Outcome ,Antigens, Surface ,Histopathology ,Lymph ,Patient Safety ,medicine.symptom ,Radiopharmaceuticals ,business - Abstract
Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel 99m Tc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects. Methods: Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of 99m Tc-MIP-1404 and 99m Tc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Wholebody images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection. Results: Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1–2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with 99mTc-MIP-1404 and 99mTc-MIP-1405. The high-contrast images exhibited tumor-tobackground ratios from 3:1 to 9:1 at 4 and 20 h. Conclusion: Compared with the standard-of-care bone scanning, 99mTc-MIP1404 and 99mTc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because 99mTc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.
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- 2014
7. Dosimetric properties of a novel brachytherapy balloon applicator for the treatment of malignant brain-tumor resection-cavity margins
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Timothy J. Patrick, James B. Stubbs, J. Williams, James F. Dempsey, and Jeffrey F. Williamson
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Cancer Research ,Neoplasm, Residual ,Radiation ,Brain Neoplasms ,business.industry ,medicine.medical_treatment ,Brachytherapy ,Lumpectomy ,Malignant brain tumor ,Brain tumor ,Radiotherapy Dosage ,Balloon ,medicine.disease ,Catheterization ,Iodine Radioisotopes ,Radiation therapy ,Inflatable ,Oncology ,medicine ,Humans ,Dosimetry ,Radiology, Nuclear Medicine and imaging ,Nuclear medicine ,business - Abstract
Purpose: This paper characterizes the dosimetric properties of a novel balloon brachytherapy applicator for the treatment of the tissue surrounding the resection cavity of a malignant brain tumor. Methods and Materials: The applicator consists of an inflatable silicone balloon reservoir attached to a positionable catheter that is intraoperatively implanted into the resection cavity and postoperatively filled with a liquid radionuclide solution. A simple dosimetric model, valid in homogeneous media and based on results from Monte Carlo photon-transport simulations, was used to determine the dosimetric characteristics of spherical geometry balloons filled with photon-emitting radionuclide solutions. Fractional depth-dose (FDD) profiles, along with activity densities, and total activities needed to achieve specified dose rates were studied as a function of photon energy and source-containment geometry. Dose–volume histograms (DVHs) were calculated to compare idealized balloon-applicator treatments to conventional 125 I seed volume implants. Results: For achievable activity densities and total activities, classical low dose rate (LDR) treatments of residual disease at distances of up to 1 cm from the resection cavity wall are possible with balloon applicators having radii between 0.5 cm and 2.5 cm. The dose penetration of these applicators increases approximately linearly with balloon radius. The FDD profile can be made significantly more or less penetrating by combining selection of radionuclide with source-geometry manipulation. Comparisons with 125 I seed-implant DVHs show that the applicator can provide a more conformal therapy with no target tissue underdosing, less target tissue overdosing, and no healthy tissue "hot spots;" however, more healthy tissue volume receives a dose of the prescribed dosage or less. Conclusions: This device, when filled with 125 I solution, is suitable for classical LDR treatments and may be preferable to 125 I interstitial-seed implants in several respects. Manipulation of the dosimetric properties of the device can improve its characteristics for brain tumor treatment and may make it suitable for boosting the lumpectomy margins in conservative breast cancer treatment.
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- 1998
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8. First-in-man evaluation of 2 high-affinity PSMA-avid small molecules for imaging prostate cancer
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William C. Eckelman, John A. Barrett, R. Edward Coleman, John W. Babich, Neil A. Petry, Thomas Armor, Steve Y. Cho, James B. Stubbs, Stanley J. Goldsmith, Michael G. Stabin, Kevin P. Maresca, John Joyal, and Shankar Vallabhajosula
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Male ,medicine.medical_specialty ,Urine ,Radiation Dosage ,Multimodal Imaging ,Iodine Radioisotopes ,Prostate cancer ,Pharmacokinetics ,Glutamates ,medicine ,Humans ,Urea ,Radiology, Nuclear Medicine and imaging ,Tissue Distribution ,Aged ,Aged, 80 and over ,Cross-Over Studies ,medicine.diagnostic_test ,business.industry ,Soft tissue ,Prostatic Neoplasms ,Middle Aged ,medicine.disease ,Crossover study ,Positron emission tomography ,Pharmacodynamics ,Positron-Emission Tomography ,Histopathology ,Radiopharmaceuticals ,business ,Nuclear medicine ,Tomography, X-Ray Computed - Abstract
This phase 1 study was performed to determine the pharmacokinetics and ability to visualize prostate cancer in bone, soft-tissue, and the prostate gland using 123 I-MIP-1072 and 123 I-MIP-1095, novel radiolabeled small molecules targeting prostate-specific membrane antigen. Methods: Seven patients with a documented history of prostate cancer by histopathology or radiologic evidence of metastatic disease were intravenously administered 370 MBq (10 mCi) of 123 I-MIP-1072 and 123 I-MIP-1095 2 wk apart in a crossover trial design. 123I-MIP-1072 was also studied in 6 healthy volunteers. Whole-body planar and SPECT/CT imaging was performed and pharmacokinetics studied over 2– 3d . Target-to-background ratios were calculated. Absorbed radiation doses were estimated using OLINDA/EXM. Results: 123I-MIP1072 and 123 I-MIP-1095 visualized lesions in soft tissue, bone, and the prostate gland within 0.5–1 h after injection, with retention beyond 48 h. Target-to-background ratios from planar images averaged 2:1 at 1 h, 3:1 at 4–24 h, and greater than 10:1 at 4 and 24 h for SPECT/CT. Both agents cleared the blood in a biphasic manner; clearance of 123 I-MIP-1072 was approximately 5 times faster. 123 I-MIP-1072 was excreted in the urine, with 54% and 74% present by 24 and 72 h, respectively. In contrast, only 7% and 20% of 123 I-MIP-1095 had been renally excreted by 24 and 72 h, respectively. Estimated absorbed radiation doses were 0.054 versus 0.110 mGy/MBq for the kidneys and 0.024 versus 0.058 mGy/MBq for the liver, for 123 I-MIP-1072 and 123 I-MIP1095, respectively. Conclusion: 123I-MIP-1072 and 123I-MIP1095 detect lesions in soft tissue, bone, and the prostate gland at as early as 1–4 h. These novel radiolabeled small molecules have excellent pharmacokinetic and pharmacodynamic profiles and warrant further development as diagnostic and potentially when labeled with 131 I therapeutic radiopharmaceuticals.
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- 2013
9. Human biodistribution and dosimetry of the SPECT D2 dopamine receptor radioligand [123I]IBF
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Paul B. Hoffer, Dennis S. Charney, Christopher H. van Dyck, James B. Stubbs, Yolanda Zea-Ponce, Gary Wisniewski, Robert B. Innis, Sami S. Zoghbi, Ronald M. Baldwin, and John Seibyl
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Adult ,Male ,Cancer Research ,Biodistribution ,Pyrrolidines ,Urine ,Single-photon emission computed tomography ,Ligands ,Radiation Dosage ,Iodine Radioisotopes ,Excretion ,Radioligand ,medicine ,Humans ,Dosimetry ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Benzofurans ,Tomography, Emission-Computed, Single-Photon ,Kidney ,medicine.diagnostic_test ,Receptors, Dopamine D2 ,business.industry ,Chemistry ,medicine.anatomical_structure ,Absorbed dose ,Molecular Medicine ,Female ,Nuclear medicine ,business - Abstract
The research discussed in this article aimed to characterize better the biodistribution, excretion and radiation dosimetry of the single photon emission computed tomography (SPECT) D 2 Dopamine receptor radioligand [ 123 I]IBF. Following administration of 111 ± 12 MBq [ 123 I]IBF, seven healthy human subjects were scanned serially with a whole body imager over a 48-h period. Transmission images were obtained with a scanning line source for attenuation correction of the emission images. Urine was collected for 48 h to measure the fraction of activity voided by the renal system. Radiation absorbed dose estimates were performed using biokinetic modeling and the Medical Internal Radiation Dose (MIRD) schema. Highest absorbed doses were to the kidney (0.13 ± 0.02 mGy/MBq) and urinary bladder wall (0.11 ± 0.01 mGy/ MBq). The effective dose equivalent was 0.041 ± 0.005 mSv/MBq. Peak brain uptake represented 8% of the injected activity. Rapid urinary excretion minimized the absorbed dose to most tissues. The mean cumulative urinary excretion fraction was 69%. Thus [ 123 I]IBF is a promising SPECT agent for imaging the D 2 dopamine receptor in humans with high brain uptake and favorable dosimetry.
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- 1996
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10. Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-11C]iomazenil
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Samuel M. Mazza, J. Douglas Bremner, Chin K. Ng, Andrew G. Horti, Ronald M. Baldwin, Yolanda Zea-Ponce, Richard B. Sparks, Robert F. Dannals, Robert Soufer, Robert B. Innis, James B. Stubbs, Morgan D. Stratton, Hayden T. Ravert, Dennis S. Charney, and Holley M. Dey
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Adult ,Flumazenil ,Male ,Cancer Research ,Biodistribution ,Ligands ,Whole-Body Counting ,High-performance liquid chromatography ,Iodine Radioisotopes ,chemistry.chemical_compound ,In vivo ,medicine ,Animals ,Humans ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Carbon Radioisotopes ,Iomazenil ,Desmethyl ,Receptors, GABA-A ,chemistry ,Isotope Labeling ,Molecular Medicine ,Dimethylformamide ,Female ,Spectrophotometry, Ultraviolet ,Papio ,Tomography, Emission-Computed ,medicine.drug ,Nuclear chemistry ,Methyl iodide - Abstract
The central benzodiazepine receptor tracer [ N -methyl- 11 C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [ 11 C]methyl iodide. The [ 11 C]CH 3 I (prepared by reduction of [ 11 C]CO 2 with LiAlH 4 followed by reaction with HI) was reacted with noriomazenil in N,N -dimethylformamide and Bu 4 N + OH − for 1 min at 80 °C and purified by HPLC (C 18 , 34% CH 3 CN/H 2 O, 7 mL/min). The product was obtained with synthesis time 35 ± 5 min (mean ± SD, n = 7), radiochemical yield (EOB) 36 ± 16%, radiochemical purity 99 ± 1%, and specific activity 5100 ± 2800 mCi/μmol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [ 11 C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [ 11 C]flumazenil PET and [ 123 I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14mCi injection. These results suggest that [ 11 C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.
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- 1995
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11. Dose escalation study of no-carrier-added 131I-metaiodobenzylguanidine for relapsed or refractory neuroblastoma: new approaches to neuroblastoma therapy consortium trial
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Hollie A. Jackson, John M. Maris, Heike E. Daldrup-Link, Alexander J. Towbin, Ashok Panigrahy, Hiroyuki Shimada, John W. Babich, Brian Weiss, James B. Stubbs, Steven G. DuBois, Fariba Goodarzian, Norman LaFrance, Judith G. Villablanca, John Barrett, Denice D. Tsao-Wei, Katherine K. Matthay, Randall A. Hawkins, Susan Groshen, and Gregory A. Yanik
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Adult ,Male ,Adolescent ,Maximum Tolerated Dose ,medicine.medical_treatment ,Chemistry, Pharmaceutical ,Hematopoietic stem cell transplantation ,Radiation Dosage ,Neuroblastoma ,Young Adult ,Refractory ,medicine ,Dosimetry ,Humans ,Radiology, Nuclear Medicine and imaging ,Tissue Distribution ,Child ,Radiometry ,business.industry ,Brain Neoplasms ,Hematopoietic Stem Cell Transplantation ,Infant ,Common Terminology Criteria for Adverse Events ,Dose-Response Relationship, Radiation ,medicine.disease ,Magnetic Resonance Imaging ,Dose–response relationship ,3-Iodobenzylguanidine ,Drug Resistance, Neoplasm ,Child, Preschool ,Toxicity ,Quality of Life ,Female ,Neoplasm Recurrence, Local ,Radiopharmaceuticals ,Nuclear medicine ,business ,Tomography, X-Ray Computed ,Progressive disease ,Software - Abstract
131I-metaiodobenzylguanidine (MIBG) is specifically taken up in neuroblastoma, with a response rate of 20%–37% in relapsed disease. Nonradioactive carrier MIBG molecules inhibit uptake of 131I-MIBG, theoretically resulting in less tumor radiation and increased risk of cardiovascular toxicity. Our aim was to establish the maximum tolerated dose of no-carrier-added (NCA) 131I-MIBG, with secondary aims of assessing tumor and organ dosimetry and overall response. Methods: Eligible patients were 1–30 y old with resistant neuroblastoma, 131I-MIBG uptake, and cryopreserved hematopoietic stem cells. A diagnostic dose of NCA 131I-MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. The treatment dose of NCA 131I-MIBG (specific activity, 165 MBq/μg) was adjusted as necessary on the basis of critical organ tolerance limits. Autologous hematopoietic stem cells were infused 14 d after therapy to abrogate prolonged myelosuppression. Response and toxicity were evaluated on day 60. The NCA 131I-MIBG was escalated from 444 to 777 MBq/kg (12–21 mCi/kg) using a 3 + 3 design. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/μL within 28 d or platelets to greater than 20,000/μL within 56 d, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: Three patients each were evaluable at 444, 555, and 666 MBq/kg without DLT. The dose of 777 MBq/kg dose was not feasible because of organ dosimetry limits; however, 3 assigned patients were evaluable for a received dose of 666 MBq/kg, providing a total of 6 patients evaluable for toxicity at 666 MBq/kg without DLT. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight patients had 13 soft-tissue lesions with tumor-absorbed doses of 26–378 Gy. Four of 15 patients had a complete (n = 1) or partial (n = 3) response, 1 had a mixed response, 4 had stable disease, and 6 had progressive disease. Conclusion: NCA 131I-MIBG with autologous peripheral blood stem cell transplantation is feasible at 666 MBq/kg without significant nonhematologic toxicity and with promising activity.
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- 2012
12. Biodistribution and Radiation Dosimetry of the Hypoxia Marker 18F–HX4 in Monkeys and Humans Determined from Whole-body PET/CT
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Eric D. Hostetler, Marie-Jose Belanger, Hartmuth C. Kolb, James B. Stubbs, R. Katherine Alpaugh, James J. Zhang, Mohan Doss, and Jian Q. Yu
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Male ,Biodistribution ,medicine.medical_specialty ,Whole body imaging ,Radiation ,Article ,Species Specificity ,Medicine ,Dosimetry ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Whole Body Imaging ,Hypoxia ,Radiometry ,medicine.diagnostic_test ,business.industry ,Radiation dose ,General Medicine ,Haplorhini ,Middle Aged ,Triazoles ,Tomography x ray computed ,Positron emission tomography ,Nitroimidazoles ,Positron-Emission Tomography ,Whole body pet ,Female ,Radiology ,Radiopharmaceuticals ,business ,Nuclear medicine ,Tomography, X-Ray Computed ,Biomarkers - Abstract
F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans.Successive whole-body PET/CT scans were done after the injection of F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software.The bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 μGy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 μSv/MBq from monkey data and 27±2 μSv/MBq from human data.Bladder, kidneys, and liver have the highest uptake of injected F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of F-HX4 is comparable with that of other F-based imaging agents.
- Published
- 2010
13. Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma
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James F. Kronauge, Robert J. Mairs, John A. Barrett, Matthias Friebe, Shawn Hillier, Michael G. Stabin, Kevin P. Maresca, Martin G. Pomper, John C. Marquis, Jianqing Chen, Ludger Dinkelborg, Sridhar Nimmagadda, John W. Babich, Kenneth L. Gage, James B. Stubbs, John Joyal, and Marie Boyd
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Male ,Cancer Research ,Drug Evaluation, Preclinical ,Melanoma, Experimental ,Mice, Nude ,Single-photon emission computed tomography ,Pharmacology ,Article ,Melanin ,Iodine Radioisotopes ,chemistry.chemical_compound ,Mice ,Medicine ,Dosimetry ,Animals ,Humans ,Neoplasm Metastasis ,Benzamide ,Survival rate ,Melanins ,Tomography, Emission-Computed, Single-Photon ,medicine.diagnostic_test ,business.industry ,Melanoma ,Washout ,Radiotherapy Dosage ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Survival Rate ,Macaca fascicularis ,Oncology ,chemistry ,Benzamides ,Female ,Radiopharmaceuticals ,business - Abstract
Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [131I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [131I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [131I]MIP-1145 at 25 MBq or 2.5 GBq/m2 in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [131I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma. Cancer Res; 70(10); 4045–53. ©2010 AACR.
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- 2010
14. Biodistribution and imaging with (123)I-ADAM: a serotonin transporter imaging agent
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Andrew B, Newberg, Karl, Plössl, P David, Mozley, James B, Stubbs, Nancy, Wintering, Michelle, Udeshi, Abass, Alavi, Tomi, Kauppinen, and Hank F, Kung
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Adult ,Male ,Serotonin Plasma Membrane Transport Proteins ,Tomography, Emission-Computed, Single-Photon ,Serotonin ,Membrane Glycoproteins ,Cinanserin ,Brain ,Membrane Transport Proteins ,Nerve Tissue Proteins ,Middle Aged ,Radiation Dosage ,Iodine Radioisotopes ,Humans ,Female ,Tissue Distribution ,Radiopharmaceuticals ,Carrier Proteins - Abstract
2-((2-((Dimethylamino)methyl)phenyl)thio)-5-(123)I-iodophenylamine ((123)I-ADAM) is a new radiopharmaceutical that selectively binds the central nervous system serotonin transporters. The purpose of this study was to measure its whole-body biokinetics and estimate its radiation dosimetry in healthy human volunteers. The study was conducted within a regulatory framework that required its pharmacologic safety to be assessed simultaneously.The sample included 7 subjects ranging in age from 22 to 54 y old. An average of 12.7 whole-body scans were acquired sequentially on a dual-head camera for up to 50 h after the intravenous administration of 185 MBq (5 mCi) (123)I-ADAM. The fraction of the administered dose in 13 regions of interest (ROIs) was quantified from the attenuation-corrected geometric mean counts in conjugate views. Multiexponential functions were iteratively fit to each time-activity curve using a nonlinear, least-squares regression algorithm. These curves were numerically integrated to yield source organ residence times. Gender-specific radiation doses were then estimated with the MIRD technique. SPECT brain scans obtained 3 h after injection were evaluated using an ROI analysis to determine the range of values for the region to cerebellum.There were no pharmacologic effects of the radiotracer on any of the subjects, including no change in heart rate, blood pressure, or laboratory results. Early planar images showed differentially increased activity in the lungs. SPECT images demonstrated that the radiopharmaceutical localized in the midbrain in a distribution that is consistent with selective transporter binding. The dose-limiting organ in both men and women was the distal colon, which received an average of 0.12 mGy/MBq (0.43 rad/mCi) (range, 0.098-0.15 mGy/MBq). The effective dose equivalent and effective dose for (123)I-ADAM were 0.037 +/- 0.003 mSv/MBq and 0.036 +/- 0.003 mSv/MBq, respectively. The mean adult male value of effective dose for (123)I-ADAM is similar in magnitude to that of (111)In-diethylenetriaminepentaacetic acid (0.035 mGy/MBq), half that of (111)In-pentetreotide (0.81 mGy/MBq), and approximately twice that of (123)I-inosine 5'-monophosphate (0.018 mGy/MBq). The differences in results between this study and a previous publication are most likely due to several factors, the most prominent being this dataset used attenuation correction of the scintigraphic data. Region-to-cerebellum ratios for the brain SPECT scans were 1.95 +/- 0.13 for the midbrain, 1.27 +/- 0.10 for the medial temporal regions, and 1.11 +/- 0.07 for the striatum.(123)I-ADAM may be a safe and effective radiotracer for imaging serotonin transporters in the brain and the body.
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- 2004
15. Radiation dose estimates for radiopharmaceuticals
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R. E. Toohey, Michael G. Stabin, and James B. Stubbs
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Radionuclide ,Adult male ,business.industry ,Internal dose ,Radiation dose ,Medicine ,Radiation ,Information center ,Nuclear medicine ,business ,Imaging phantom ,Calculation methods - Abstract
Tables of radiation dose estimates based on the Cristy-Eckerman adult male phantom are provided for a number of radiopharmaceuticals commonly used in nuclear medicine. Radiation dose estimates are listed for all major source organs, and several other organs of interest. The dose estimates were calculated using the MIRD Technique as implemented in the MIRDOSE3 computer code, developed by the Oak Ridge Institute for Science and Education, Radiation Internal Dose Information Center. In this code, residence times for source organs are used with decay data from the MIRD Radionuclide Data and Decay Schemes to produce estimates of radiation dose to organs of standardized phantoms representing individuals of different ages. The adult male phantom of the Cristy-Eckerman phantom series is different from the MIRD 5, or Reference Man phantom in several aspects, the most important of which is the difference in the masses and absorbed fractions for the active (red) marrow. The absorbed fractions for flow energy photons striking the marrow are also different. Other minor differences exist, but are not likely to significantly affect dose estimates calculated with the two phantoms. Assumptions which support each of the dose estimates appears at the bottom of the table of estimates for a given radiopharmaceutical. In most cases, the model kinetics or organ residence times are explicitly given. The results presented here can easily be extended to include other radiopharmaceuticals or phantoms.
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- 1996
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16. Characterization of the dopamine transporter in nonhuman primate brain: homogenate binding, whole body imaging, and ex vivo autoradiography using [125I] and [123I]IPCIT
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B.Ellen Scanley, Yolanda Zea-Ponce, Mohammed S. Al-Tikriti, Dennis S. Charney, Suzanne S. Giddings, Sami S. Zoghbi, James B. Stubbs, Paul B. Hoffer, John Seibyl, Robert B. Innis, Richard B. Sparks, Shaoyin Wang, Ronald M. Baldwin, Marc Laruelle, and John L. Neumeyer
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Cancer Research ,medicine.medical_specialty ,Ovariectomy ,Nerve Tissue Proteins ,Striatum ,Biology ,Models, Biological ,Whole-Body Counting ,Iodine Radioisotopes ,chemistry.chemical_compound ,Cocaine ,In vivo ,Dopamine ,Internal medicine ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Tissue Distribution ,Dopamine transporter ,Brain Chemistry ,Tomography, Emission-Computed, Single-Photon ,Dopamine Plasma Membrane Transport Proteins ,Membrane Glycoproteins ,Membrane Transport Proteins ,Tropane ,Transporter ,Endocrinology ,Biochemistry ,chemistry ,biology.protein ,Molecular Medicine ,Autoradiography ,Female ,Serotonin ,Carrier Proteins ,Ex vivo ,medicine.drug ,Papio ,Protein Binding - Abstract
IPCIT [2 beta-carboisopropoxy-3 beta-(4-iodophenyl)tropane; also designated RTI-121] is the isopropyl ester of beta-CIT [2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane]. Although beta-CIT binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters, IPCIT has been reported to be selective for the DA transporter. IPCIT was labeled with 125I and its receptor binding to membranes prepared from baboon striatum was compared with that of [125I] beta-CIT. These studies confirmed the relative selectivity of IPCIT for the DA transporter in comparison to 5-HT and NE transporters. The nonspecific binding of [125I]IPCIT was almost four times greater than that of [125I] beta-CIT. The biodistribution of IPCIT was examined in two baboons with whole body imaging for 24-30 h after administration of 3 mCi of 123I-labeled tracer. The brain uptake peaked within the first hour at 9.2% of the injected dose and the majority of activity in the body cleared through the hepatobiliary system. The distribution of activity within the brain was examined with ex vivo autoradiography in one monkey injected with [123I]IPCIT. Activity was concentrated in the caudate and putamen and had values of 5 and 7 microCi/cm3 per microCi/g, respectively. The distribution in brain regions receiving moderately dense serotonergic innervation (e.g. superior colliculus and thalamus) had levels of activity equivalent to that in cerebellum. This study confirmed the in vitro and in vivo selectivity of IPCIT for the DA transporter but also showed that [125I]IPCIT had higher in vitro nonspecific binding than [125I] beta-CIT.
- Published
- 1995
17. Safety and reproducibility of the 14C-urea breath test
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James B. Stubbs, Barry J. Marshall, D.A. | Buck, and M.J. Combs
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Reproducibility ,Chromatography ,Hepatology ,medicine.diagnostic_test ,business.industry ,Urea breath test ,Gastroenterology ,medicine ,business - Published
- 1995
- Full Text
- View/download PDF
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