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Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling. - EJNMMI research
We applied a non-linear immunokinetic model to quantitatively compare absolute antibody uptake and turnover in subcutaneous LNCaP human prostate cancer (PCa) xenografts of two radiolabeled forms of the humanized anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((124)I-J591 and (89)Zr-J591). Using the model, we examined the impact of dose on the tumor and plasma positron emission tomography (PET)-derived time-activity curves. We also sought to predict the optimal targeting index (ratio of integrated-tumor-to-integrated-plasma activity concentrations) for radioimmunotherapy.The equilibrium rates of antibody internalization and turnover in the tumors were derived from PET images up to 96Â h post-injection using compartmental modeling with a non-linear transfer rate. In addition, we serially imaged groups of LNCaP tumor-bearing mice injected with (89)Zr-J591 antibody doses ranging from antigen subsaturating to saturating to examine the suitability of using a non-linear approach and derived the time-integrated concentration (in Î¼Mâˆ™hours) of administered tracer in tumor as a function of the administered dose of antibody.The comparison of (124)I-J591 and (89)Zr-J591 yielded similar model-derived values of the total antigen concentration and internalization rate. The association equilibrium constant (k a) was twofold higher for (124)I, but there was a ~tenfold greater tumoral efflux rate of (124)I from tumor compared to that of (89)Zr. Plots of surface-bound and internalized radiotracers indicate similar behavior up to 24Â h p.i. for both (124)I-J591 and (89)Zr-J591, with the effect of differential clearance rates becoming apparent after about 35Â h p.i. Estimates of J591/PSMA complex turnover were 3.9-90.5â€‰Ã—â€‰10(12) (for doses from 60 to 240Â Î¼g) molecules per hour per gram of tumor (20Â % of receptors internalized per hour).Using quantitative compartmental model methods, surface binding and internalization rates were shown to be similar for both (124)I-J591 and (89)Zr-J591 forms, as expected. The large difference in clearance rates of the radioactivity from the tumor is likely due to differential trapping of residualizing zirconium versus non-residualizing iodine. Our non-linear model was found to be superior to a conventional linear model. This finding and the calculated activity persistence time in tumor have important implications for radioimmunotherapy and other antibody-based therapies in patients.
A Phase I/II Study for Analytic Validation of 89Zr-J591 ImmunoPET as a Molecular Imaging Agent for Metastatic Prostate Cancer. - Clinical cancer research : an official journal of the American Association for Cancer Research
Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of (89)Zr-DFO-huJ591 ((89)Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared with conventional imaging modalities (CIM) and pathology.Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of (89)Zr-J591. Whole-body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis and with biopsies of metastatic sites.Median standardized uptake value for (89)Zr-J591-positive bone lesions (n = 491) was 8.9 and for soft-tissue lesions (n = 90), it was 4.8 (P < 0.00003). (89)Zr-J591 detected 491 osseous sites compared with 339 by MDP and 90 soft-tissue lesions compared with 124 by computed tomography (CT). Compared with all CIMs combined, (89)Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone and 25 soft tissue) were biopsied in 34 patients; 18 of 19 (89)Zr-J591-positive osseous sites and 14 of 16 (89)Zr-J591-positive soft tissue sites were positive for prostate cancer. The overall accuracy of (89)Zr-J591 was 95.2% (20 of 21) for osseous lesions and 60% (15 of 25) for soft-tissue lesions.(89)Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft-tissue lesions was less optimal, although (89)Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed prostate-specific membrane antigen (PSMA) targeting agents for prostate cancer. Clin Cancer Res; 21(23); 5277-85. Â©2015 AACR.Â©2015 American Association for Cancer Research.
â¸â¹Zr-huJ591 immuno-PET imaging in patients with advanced metastatic prostate cancer. - European journal of nuclear medicine and molecular imaging
Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. (89)Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection.Ten patients with metastatic prostate cancer received 5 mCi of (89)Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by (89)Zr-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of (89)Zr-huJ591 was done. Optimal time for imaging post-injection was determined.The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of (89)Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 Â± 4.5 h (range 1.1-14 h) and 62 Â± 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 Â± 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 Â± 1.5 cGy/mCi, renal cortex 3.5 Â± 0.4 cGy/mCi, and bone marrow 1.2 Â± 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 Â± 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on (89)Zr-huJ591, while the remaining 11 lesions were (89)Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on (89)Zr-huJ591 study, while the conventional imaging modality was negative.(89)Zr-huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 Â± 1 days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer.
Visualization of orbital involvement of Erdheim-Chester disease on PET/CT. - Clinical nuclear medicine
We report a 58-year-old man who presented with swelling and redness in his left eye, headache, and blurred vision. A contrast-enhanced CT of the orbits revealed bilateral orbital masses. Whole-body PET/CT showed bilateral retrobulbar hypermetabolic soft tissue lesions, multiple areas of soft tissue involvement, and osseous lesions in bilateral lower extremities. An open surgical biopsy of the left orbital mass revealed xanthomatous non-Langerhans histiocytic infiltrate with Touton giant cells, positive for CD68 but negative for CD1a, establishing a diagnosis of Erdheim-Chester disease.
Molecular imaging and therapy of merkel cell carcinoma. - Cancers
Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review the current modalities and their impact on MCC in this brief review article.
FDG PET/CT findings in a rare case of giant fibrovascular polyp of the esophagus harboring atypical lipomatous tumor/well-differentiated liposarcoma. - Clinical nuclear medicine
A 70-year-old man with a history of chronic lymphocytic leukemia (CLL) underwent FDG PET/CT scan, which revealed a large polypoid soft tissue lesion in the esophagus with peripheral FDG avidity. An endoscopic biopsy revealed inflammatory changes with scattered CLL cells. The final histopathology demonstrated an 18-cm long and 4-cm wide giant fibrovascular polyp that was removed in 2 pieces. The polyp was composed of atypical adipose tissue with scattered giant cells and spindle-shaped cells as well as foci of CLL. Mouse double minute 2 homolog amplification was noted by fluorescence in situ hybridization diffusely in the giant polyp consistent with well-differentiated liposarcoma in a giant fibrovascular polyp.
FDG PET/CT detection of intussusception caused by lymphoma in a pediatric patient. - Clinical nuclear medicine
A previously healthy 9-year-old boy presented to an outside hospital with a history of abdominal pain and vomiting. An abdominal x-ray was unremarkable. A CT of the abdomen and pelvis performed to evaluate possible obstruction after weight loss and vomiting over a 3-week period demonstrated a large retroperitoneal mass. Laparoscopic biopsy showed diffuse large B-cell lymphoma. FDG PET/CT was performed for staging. An ileocolic intussusception was identified on the PET/CT. The intussusception was successfully managed with medical treatment. We present FDG PET/CT findings in intussusception with non-Hodgkin lymphoma as the lead point in a pediatric patient.
Pilot study of 68Ga-DOTA-F(ab')2-trastuzumab in patients with breast cancer. - Nuclear medicine communications
68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-F(ab')2-trastuzumab [68Ga-DOTA-F(ab')2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here our initial clinical experience in the assessment of the toxicity, pharmacokinetics, biodistribution, and dosimetry profile of 68Ga-DOTA-F(ab')2-trastuzumab with PET/computed tomography using a mean of 236 MBq/5 mg administered intravenously.A group of 16 women with breast cancer were enrolled in this study. The one patient who did not receive 68Ga-DOTA-F(ab')2-trastuzumab was excluded from analysis. Both HER2-negative (n=7) and HER2-positive (n=8) cases were studied. Among the latter, seven had undergone trastuzumab treatment previously and one had not.It was determined that 68Ga-DOTA-F(ab')2-trastuzumab was well tolerated, with a TÂ½ of â‰ˆ 3.6 Â± 0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease.The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.
Evaluation of kidney damage in patients with acute lymphoblastic leukemia in long-term follow-up: value of renal scan. - American journal of hematology
In order to evaluate potential long-term kidney damage of childhood leukemia and risk factors affecting renal damage, we studied 116 children treated for acute lymphoblastic leukemia (ALL) using the St. Jude Total XI and XIII protocols in 1991-1998. The median follow-up period after the completion of treatment was 35 months. The following parameters were examined: urinalysis, urinary creatinine (Cr), calcium (Ca), phosphorus, beta2-microglobulin, glomerular filtration rate (GFR), tubular phosphorus reabsorption (TPR), and renal function tests. Radiological evaluation included renal ultrasonography (US), and renal scans with DMSA or MAG-3 were performed. Blood chemistry and renal US patients were normal in all patients except two. GFR, TPR, urinary Ca/Cr, beta2-microglobulin, and renal scan were abnormal in 19.0%, 16.4%, 13.8%, 6.0%, and 40.5% of patients, respectively. The abnormality rate in GFR was significantly higher in patients <2 years of age. TPR abnormality was found to be significantly higher in patients who did not have G-CSF. An abnormal renal scan was associated with Hb < 10 g/dL, kidney infiltration, or hypertension at presentation and also occurred patients who underwent methotrexate treatment with frequent intervals during the follow-up period. Patients should be followed-up after cessation of therapy with the conventional tests mentioned above. In case of any abnormality, further detailed tests should be performed; renal scan seems to be more predictive for renal damage.Copyright 2004 Wiley-Liss, Inc.
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