Biomedical subjects

Donald A Podoloff

Publications and source records attributed to Donald A Podoloff.

29 records · Page 2Linked to original sources

PubMed2004

Imaging taxane-induced tumor apoptosis using PEGylated, 111In-labeled annexin V.

UNLABELLED: 99mTc-Labeled annexin V has been used for the imaging of tumor apoptosis induced by chemotherapy. However, owing to the short half-life of annexin V, multiple injections of the radiotracer are necessary to capture the peak apoptotic activity. In this study, we evaluated the imaging properties of an (111)In-labeled, long-circulating annexin V. METHODS: Both polyethylene glycol (PEG) and the metal chelator diethylenetriaminepentaacetic acid (DTPA) were simultaneously introduced to annexin V or ovalbumin through the use of a heterofunctional PEG precursor. Imaging studies were performed in mice bearing subcutaneously inoculated human mammary MDA-MB-468 tumors. The mice were treated with poly(L-glutamic acid)-paclitaxel, monoclonal antibody C225, or a combination of poly(L-glutamic acid)-paclitaxel and C225, followed by intravenous injection of (111)In-DTPA-PEG-annexin V. Images were acquired 48 h after the injection of the radiotracer. Autoradiography and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling) staining were performed on adjacent tumor slices for the localization of apoptotic cells. The imaging properties of unPEGylated annexin V and PEGylated ovalbumin were also determined to permit assessment of the specificity of (111)In-DTPA-PEG-annexin V. RESULTS: Tumor apoptotic index increased from 1.67% +/- 0.31% at baseline to 7.60% +/- 0.72% and 11.07% +/- 1.81%, respectively, 4 d after treatment with poly(L-glutamic acid)-paclitaxel or combined poly(L-glutamic acid)-paclitaxel and C225. Tumor uptake (percentage of injected dose per gram of tumor [%ID/g]) of PEGylated (111)In-DTPA-PEG-annexin 4 d after treatment was significantly higher in tumors treated with poly(L-glutamic acid)-paclitaxel (10.76 +/- 1.38 %ID/g; P = 0.001) and with combined poly(L-glutamic acid)-paclitaxel and C225 (9.84 +/- 2.51 %ID/g; P = 0.029) than in nontreated tumors (6.14 +/- 0.67 %ID/g), resulting in enhanced visualization of treated tumors. (111)In-DTPA-PEG-annexin V distributed into the central zone of tumors, whereas (111)In-DTPA-annexin V was largely confined to the tumor periphery. Furthermore, uptake of (111)In-DTPA-PEG-annexin V by tumors correlated with apoptotic index (r = 0.87, P = 0.02). Increase in tumor uptake of the nonspecific PEGylated protein (111)In-DTPA-PEG-ovalbumin was also observed after poly(L-glutamic acid)-paclitaxel treatment (55.6%), although this increase was less than that observed for (111)In-DTPA-PEG-annexin V (96.7%). CONCLUSION: Increased uptake of and improved visualization with (111)In-DTPA-PEG-annexin V in solid tumors after chemotherapy are mediated through both specific binding to apoptotic cells and nonspecific retention of macromolecular contrast agents in the tumors. (111)In-Labeled, PEGylated annexin V may be used to assess tumor response to chemotherapy.

Animals↗

PubMed2004

Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck.

UNLABELLED: This study assessed the radiation dosimetry of 99mTc-labeled ethylene dicysteine (EC) C225 (EC-C225), a promising radioligand for functional tumor imaging. METHODS: Whole-body scanning was performed on 6 patients with head and neck squamous cell carcinoma up to 24 h after administration of 99mTc-EC-C225. Alternate patients who had been randomized to receive C225 in a phase III trial received 99mTc-EC-C225 before their 20-mg test dose or after their 400 mg/m2 loading dose of unlabeled C225 (patients 1/3/5 and 2/4/6, respectively). Radiation dosimetry was assessed using the MIRD method. RESULTS: The critical organ was the kidney, with an average radiation-absorbed dose for all 6 patients of 0.0274 mGy/MBq. The average total-body absorbed dose was 0.0022 mGy/MBq (0.243 cGy/1,110 MBq). CONCLUSION: The new radiopharmaceutical 99mTc-EC-C225 appears to have reasonable dosimetric properties for a diagnostic nuclear medicine agent. Correlation of the imaging results with clinical findings is the next step.

Antibodies, Monoclonal↗

PubMed2004

Performance characteristics of a newly developed PET/CT scanner using NEMA standards in 2D and 3D modes.

UNLABELLED: This study evaluates the 2-dimensional (2D) and 3-dimensional (3D) performance characteristics of a newly developed PET/CT scanner using the National Electrical Manufacturers Association (NEMA) NU 2-1994 (NU94) and NEMA NU 2-2001 (NU01) standards. The PET detector array consists of 10,080 individual bismuth germanate crystals arranged in 24 rings of 420 crystals each. The size of each crystal is 6.3 x 6.3 x 30 mm in the axial, transaxial, and radial dimensions, respectively. The PET detector ring diameter is 88.6 cm with axial and transaxial fields of view (FOVs) of 15.7 and 70 cm, respectively. The scanner has a uniform patient port of 70 cm throughout the PET and CT FOV, and the PET scanner is equipped with retractable septa to allow 2D and 3D imaging. METHODS: Spatial resolution, scatter fraction, sensitivity, counting rate, image quality, and accuracy as defined by the NEMA protocols of NU94 and NU01 for 2D and 3D modes are evaluated. The 2D mode data were acquired with a maximum ring difference of 5, whereas the 3D mode acquisition used ring differences of 23. Both 2D and 3D mode data were acquired with an energy window of 375-650 keV. Random estimation from singles counting rate was applied to all relevant analysis. In addition, images from 2 clinical whole-body oncology studies acquired in 2D and 3D modes are shown to demonstrate the image quality obtained from this scanner. RESULTS: The 2D NU94 transaxial resolution is 6.1-mm full width at half maximum (FWHM) 1 cm off center and increases to 6.9 mm tangential and 8.1 mm radial at a radius (R) of 20 cm. NU01 2D average transaxial (axial) FWHM resolution measured 6.1 (5.2) mm at R = 1 cm and 6.7 (6.1) mm at R = 10 cm. The NU94 scatter fraction for 2D (3D) was 13% (29%), whereas the NU01 scatter fraction gave 19% (45%). NU01 peak 2D (3D) noise equivalent counting rate (T(2)/[T + R + S]) was 90.2 (67.8) kilocount per second (kcps) at 52.5 (12) kBq/mL. Total 2D (3D) system sensitivity for true events is 8 (32.9) kcps/kBq/mL for NU94 and 1.95 (9.2) kcps/Bq for NU01. CONCLUSION: The results show excellent system sensitivity with relatively uniform resolution throughout the FOV, making this scanner highly suitable for whole-body studies.

Adult↗

PubMed2003

Radiation dosimetry results from a Phase II trial of ibritumomab tiuxetan (Zevalin) radioimmunotherapy for patients with non-Hodgkin's lymphoma and mild thrombocytopenia.

This was a 30-patient Phase II trial of reduced-dose (90)Y ibritumomab tiuxetan (Zevalin) RIT for patients with low-grade, follicular, or transformed B-cell NHL and mild thrombocytopenia. Patients were given an imaging dose of (111)In-labeled ibritumomab tiuxetan for dosimetry measurements. One week later, patients were administered a therapeutic dose of 0.3 mCi/kg (11 MBq/kg) (90)Y ibritumomab tiuxetan. Both (111)In- and (90)Y-labeled ibritumomab tiuxetan doses were preceded by an infusion of 250 mg/m(2) rituximab (Rituxan, MabThera) an unlabeled chimeric anti-CD20 antibody, to clear peripheral blood B cells and improve biodistribution of the radiolabeled antibody. For all 30 patients, normal organ and red marrow radiation absorbed doses were well below protocol-defined limits of 2000 cGy and 300 cGy, respectively. Median radiation absorbed doses were 48 cGy to red marrow (range: 6.5-95 cGy), 393 cGy to liver (range: 92-1581 cGy), 522 cGy to spleen (range: 165-1711 cGy), 162 cGy to lungs (41-295 cGy), and 14 cGy to kidneys (0.03-65 cGy). Though most correlative analyses were negative, certain analyses demonstrated a statistically significant correlation between the severity or duration of thrombocytopenia and pharmacokinetic or dosimetric parameters. These correlations were not consistent across the total patient population, and therefore, could not be exploited to predict hematologic toxicity.

Adolescent↗

PubMed2003

Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody.

Epidermal growth factor receptor (EGFR) plays an important role in cell division and cancer progression, as well as angiogenesis and metastasis. Since many tumor cells exhibit the EGFR on their surface, functional imaging of EGFR provides not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-EGFR therapy could be assessed effectively. C225 is a chimeric monoclonal antibody that targets the human extracellular EGFR and inhibits the growth of EGFR-expressing tumor cells. Also, it has been demonstrated that C225, in combination with chemotherapeutic drugs or radiotherapy, is effective in eradicating well-established tumors in nude mice. We have developed 99mTc-labeled C225 using ethylenedicysteine (EC) as a chelator. This study aimed at measuring uptake of 99mTc-EC-C225 in EGFR+ tumor-bearing animal models and preliminary feasibility of imaging patients with head and neck carcinomas. In vitro Western blot analysis and cytotoxicity assays were used to examine the integrity of EC-C225. Tissue distribution studies of 99mTc-EC-C225 were evaluated in tumor-bearing rodents at 0.5-4 h. In vivo biodistribution of 99mTc-EC-C225 in tumor-bearing rodents showed increased tumor-to-tissue ratios as a function of time. In vitro and biodistribution studies demonstrated the possibility of using 99mTc-EC-C225 to assess EGFR expression. SPECT images confirmed that the tumors could be visualized with 99mTc-EC-C225 from 0.5 to 4 h in tumor bearing rodents. We conclude that 99mTc-EC-C225 may be useful to assess tumor EGFR expression. This may be useful in the future for selecting patients for treatment with C225.

Animals↗

PubMed2003

Imaging with 99mTc ECDG targeted at the multifunctional glucose transport system: feasibility study with rodents.

PURPOSE: To evaluate the feasibility of technetium 99m ((99m)Tc) ethylenedicysteine-deoxyglucose (ECDG) imaging in tumor-bearing rodents. MATERIALS AND METHODS: ECDG was synthesized by means of reacting ethylenedicysteine with glucosamine, with carbodiimide as the coupling agent. Hexokinase assays were performed at an ultraviolet wavelength of 340 nm. To determine whether blood glucose level could be altered, ECDG or glucosamine was injected into six rats. In a separate study, ECDG followed by insulin was administered to three rats. To determine biodistribution, lung tumor cells were intramuscularly injected into the hind legs of 18 nude mice. The animals were then injected with (99m)Tc ECDG or fluorine 18 ((18)F) fluorodeoxyglucose (FDG) (0.037-0.074 MBq per mouse). Radioactivity was measured in tissue excised from the animals. Scintigraphy was performed in three groups: in group 1 to demonstrate that different-sized tumors could be imaged after (99m)Tc ECDG administration, in group 2 to ascertain whether tumor uptake of (99m)Tc ECDG was perfusion related, and in group 3 to demonstrate that tumor uptake of (99m)Tc ECDG occurred by means of a glucose-mediated process. RESULTS: ECDG was positive for phosphorylation at hexokinase assay. Blood glucose level increased with ECDG injection and decreased with insulin administration. Tumor-to-brain tissue and tumor-to-muscle tissue ratios of (99m)Tc ECDG uptake were higher than those of (18)F FDG uptake. Scintigraphic results demonstrated the feasibility of (99m)Tc ECDG imaging. CONCLUSION: There are similarities between (99m)Tc ECDG uptake and (18)F FDG uptake in tumors, and study findings supported the potential use of (99m)Tc ECDG as a functional imaging agent.

Animals↗

PubMed2003

Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined data from 4 clinical trials.

UNLABELLED: Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT). Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were combined and assessed for correlations with toxicity data. METHODS: Data from 179 patients were available for analysis. Common eligibility criteria included <25% bone marrow involvement by NHL, no prior myeloablative therapy, and no prior RIT. The baseline platelet count was required to be > or = 100,000 cells/mm(3) for the reduced (90)Y-ibritumomab tiuxetan administered dose (7.4-11 MBq/kg [0.2-0.3 mCi/kg]) or > or = 150,000 cells/mm(3) for the standard (90)Y-ibritumomab tiuxetan administered dose (15 MBq/kg [0.4 mCi/kg]). Patients were given a tracer administered dose of 185 MBq (5 mCi) (111)In-ibritumomab tiuxetan on day 0, evaluated with dosimetry, and then a therapeutic administered dose of 7.4-15 MBq/kg (0.2-0.4 mCi/kg) (90)Y-ibritumomab tiuxetan on day 7. Both ibritumomab tiuxetan administered doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve ibritumomab tiuxetan biodistribution. Residence times for (90)Y in blood and major organs were estimated from (111)In biodistribution, and the MIRDOSE3 computer software program was used, with modifications to account for patient-specific organ masses, to calculate radiation absorbed doses to organs and red marrow. RESULTS: Median radiation absorbed doses for (90)Y were 7.42 Gy to spleen, 4.50 Gy to liver, 2.11 Gy to lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image-derived method) to red marrow, and 0.57 Gy to total body. The median effective blood half-life was 27 h, and the area under the curve (AUC) was 25 h. No patient failed to meet protocol-defined dosimetry safety criteria and all patients were eligible for treatment. Observed toxicity was primarily hematologic, transient, and reversible. Hematologic toxicity did not correlate with estimates of red marrow radiation absorbed dose, total-body radiation absorbed dose, blood effective half-life, or blood AUC. CONCLUSION: Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.

Adult↗

PubMed2003

Evaluation of 111In-DTPA-folate as a receptor-targeted diagnostic agent for ovarian cancer: initial clinical results.

UNLABELLED: The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We report here the initial clinical study of such an agent, (111)In-diethylenetriaminepentaacetic acid (DTPA)-folate, evaluated for diagnosis of ovarian malignancy. METHODS: Thirty-five women were enrolled in a phase I/II clinical study, with 33 completing the surgical follow-up required by the study protocol for definition of disease status. Patients either had a pathologically proven malignancy or were scheduled for surgery for suspected new ovarian cancer (n = 26), recurrent ovarian cancer (n = 5), or endometrial cancer (n = 2). (111)In-DTPA-folate was administered as an intravenous bolus, and whole-body images were obtained at 30 min, 4 h, and (for the first 19 patients) 24 h after injection; SPECT also was done at the delayed imaging times. For 19 of the patients, unlabeled free folic acid was injected before administration of (111)In-DTPA-folate to also assess the impact of folate loading on tracer biodistribution. Masked and unmasked readings of the images by 2 nuclear medicine physicians were compared with the pathologic findings after surgery. RESULTS: Among 33 patients who had surgical intervention, 14 had new or recurrent malignant tumors. All of 7 newly diagnosed ovarian carcinomas were identified by both masked readers (sensitivity, 100%). The sensitivity for detection of 7 recurrent malignancies was 38% for masked readings and 85% for unmasked readings, indicating that correlation with anatomic imaging studies (CT) was highly important in diagnosis of these lesions. Eighteen of the studied patients were found to have benign masses; for this limited population, the specificity of (111)In-DTPA-folate scintigraphy was 76% and 82% for the masked and unmasked analyses, respectively. CONCLUSION: (111)In-DTPA-folate is safe, and possibly effective, for scintigraphy differentiating between malignant and benign ovarian masses.

Adult↗

PubMed2002

Assessment of antiangiogenic effect using 99mTc-EC-endostatin.

PURPOSE: Tumor vascular density may provide a prognostic indicator of metastatic potential or survival. The purpose of this study was to develop 99mTc-ethylenedicysteine-endostatin (99mTc-EC-endostatin) for the evaluation of anti-angiogenesis therapy. METHOD: 99mTc-EC-endostatin was prepared by conjugating ethylenedicysteine (EC) to endostatin, followed by adding pertechnetate and tin chloride. Radiochemical purity was > 95%. In vitro cell viability, affinity and TUNEL assays were performed. Tissue distribution and planar imaging of radiolabeled endostatin were determined in tumor-bearing rats. To assess anti-angiogenic treatment response, rats were treated with endostatin, paclitaxel and saline, followed by imaging with 99mTc-EC-endostatin. Tumor response to endostatin therapy in tumor-bearing animal models was assessed by correlating tumor uptake dose with microvessel density, VEGF, bFGF and IL-8 expression during endostatin therapy. RESULTS: In vitro cell viability and TUNEL assays indicated no marked difference between EC-endostatin and endostatin. Cellular uptake assay suggests that endostatin binds to endostatin receptor. Biodistribution of 99mTc-EC-endostatin in tumor-bearing rats showed increased tumor-to-tissue count density ratios as a function of time. Tumor uptake (%ID/g) of 99mTc-EC-endostatin was 0.2-0.5. Planar images confirmed that the tumors could be visualized clearly with 99mTc-EC-endostatin. The optimal time for imaging using radiolabeled endostatin was 2 hrs. 99mTc-EC-endostatin could assess treatment response. There was a correlation between tumor uptake and cellular targets expression. CONCLUSION: The results indicate that it is feasible to use 99mTc-EC-endostatin to assess efficiency of anti-angiogenesis therapy.

Angiogenesis Inhibitors↗

PubMed2002

Diagnostic and therapeutic applications of radiolabeled somatostatin analogs: current status in an oncology center.

From the prospective of a major oncology center in the United States, somatostatin analog radiopeptides currently have limited diagnostic and therapeutic utility. Diagnostic modalities utilitizing Somatostatin Receptor Imaging are now commercially available and the role of this type of method is currently being evaluated. Unlike the unique properties of thyroid tissue facilitating I-131 uptake, targeting of other tissues has required a carrier for the nuclide. Somastostatin peptide analogs have proved attractive based on the ubiquity of distribution and up-regulation in diseased tissue but prospective data is currently scarce. Interest in therapeutic applications of somatostatin analogs as carriers of yttrium, indium and more recently rhenium have resulted in trials with these agents both for endocrine and non-endocrine tumors. At this time, insufficient data exists to justify the indication of "first-line" therapy. The principles of Somatostatin Receptor Imaging and radiotherapy are discussed in this article along with the current status of these modalities in clinical practice as viewed by the author.

Humans↗

PubMed2002

Whole-body lymphoscintigraphy using transmission scans.

OBJECTIVE: Our objective was to show the advantages of performing whole-body lymphoscintigraphy using transmission sources. This technique should decrease scanning time, help locate the sentinel lymph node, and decrease radiation exposure to the technologist. METHODS: Twenty patients with proven melanoma received 18.5 MBq (0.5 mCi) filtered (0.22 microm) (99m)Tc-sulfur colloid in a 0.2-mL volume, administered as multiple intradermal or subcutaneous injections around the known melanoma lesion or scar. All 20 patients underwent serial static imaging immediately after the injection, along with whole-body scanning after the static imaging. The static emission images were acquired for 5 min and the transmission images for 1 min using a 256 x 256 matrix. The whole-body transmission scans were acquired after the whole-body emission scans. The transmission scans were obtained with the same parameters as the emission scans, with the addition of placement of a (57)Co sheet source on one of the detectors of the large-field-of-view dual-head camera. The planar static axial images (transmission, emission) were compared with the whole-body images (transmission, emission) to determine whether the same number of lymph nodes was visualized with each technique. Posterior outlines were obtained through computer manipulation of anterior transmission images. RESULTS: In all 20 patients, the number of lymph nodes seen on the static images was the same as that seen on the whole-body emission and transmission images. The whole-body emission and transmission scanning time was an average of 30 min less than the time required to acquire the serial static images. CONCLUSION: The anatomic location of the sentinel lymph node is seen more easily on whole-body images, both anterior transmission and posterior transmission, than on planar static images. Whole-body emission and transmission imaging decreased scanning time and thus improved patient comfort and throughput. Technologists received less radiation exposure when handling the (57)Co source only twice during whole-body imaging, as opposed to several times during static imaging.

Humans↗