123I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting ,method by an international panel.

PURPOSE: A robust method is required to standardise objective reporting of diagnostic 123I-mIBG images in neuroblastoma. Prerequisites for an appropriate system are low inter- and intra-observer error and reproducibility across a broad disease spectrum. We present a new reporting method, developed and tested for SIOPEN by an international expert panel. METHOD: Patterns of abnormal skeletal 123I-mIBG uptake were defined and assigned numerical scores [0-6] based on disease extent within 12 body segments. Uptake intensity was excluded from the analysis. Data sets from 82 patients were scored independently by six experienced specialists as unblinded pairs (pre- and post-induction chemotherapy) and in random order as a blinded study. Response was defined as ≥50 % reduction in post induction score compared with baseline. RESULTS: In total, 1968 image sets were reviewed individually. Response rates of 88 % and 82 % were recorded for patients with baseline skeletal scores ≤23 and 24-48 respectively, compared with 44 % response in patients with skeletal scores >48 (p = 0.02). Reducing the number of segments or extension scale had a small but statistically negative impact upon the number of responses detected. Intraclass correlation coefficients [ICCs] calculated for the unblinded and blinded study were 0.95 at diagnosis and 0.98 and 0.99 post-induction chemotherapy, respectively. CONCLUSIONS: The SIOPEN mIBG score method is reproducible across the full spectrum of disease in high risk neuroblastoma. Numerical assessment of skeletal disease extent avoids subjective evaluation of uptake intensity. This robust approach provides a reliable means with which to examine the role of 123I mIBG scintigraphy as a prognostic indicator in neuroblastoma.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

A conjugate of gemcitabine with bisphosphonate (Gem/BP) shows potential as a targeted bone-specific therapeutic agent in an animal model of human breast cancer bone metastases.

Bone metastases in advanced breast cancer patients remains a significant treatment challenge. Bisphosphonates are now a routine first line treatment for prevention and treatment of skeletal damage caused by malignancies and, moreover, have shown an ability to transport therapeutic drugs to the bone. Here, we describe the effect of a conjugate between the potent anticancer drug gemcitabine and a bisphosphonate molecule (Gem/BP) in an animal model of breast cancer metastases. We have previously demonstrated the targeting of this compound to bone in normal mice using an analog labeled with the radionuclide 99mTc. Using a bone metastasis model in nude mice produced by intracardiac injection of the human breast cancer cell line MDA-MB-231BO, we examined the effect of Gem/BP and gemcitabine in reducing the frequency and severity of osteolytic bone lesions. High-resolution radiographs and microPET images showed that Gem/ BP reduced the number and size of bone metastases relative to the gemcitabine-treated and the untreated control groups. Histological examination of the humeri and femurs of the control and gemcitabine groups revealed large metastatic cancer lesions in the outer and inner cortices and the medullary cavities. In contrast, Gem/BP-treated mice showed occasional small wedge-shaped metastases under the periosteum of the outer cortex and very occasionally in the medulla. These findings suggest that Gem/BP should be further evaluated for use in the treatment of bone metastases in breast cancer.

Synthesis and hypoxia selective radiosensitization potential of beta-2-FAZA and beta-3-FAZL: fluorinated azomycin beta-nucleosides.

(18)F-Labelled fluoroazomycin arabinoside ([(18)F]FAZA) is a 2-nitroimidazole (azomycin) based PET tracer used extensively in cancer clinics to diagnose tumour hypoxia. The hypoxia-specific uptake and rapid blood clearance kinetics of FAZA contribute to good tumor-to-background ratios (T/B ratios) and high image contrast. However, FAZA, an alpha-configuration nucleoside, is not transported by cellular nucleoside transporters. It enters cells only via diffusion, therefore not achieving the high uptake and T/B ratios characteristic of actively transported radiopharmaceuticals. The present work describes the synthesis, physicochemical properties and preliminary assessment of the radiosensitization properties of two novel azomycin nucleosides, 1-beta-D-(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole (beta-2-FAZA) and 1-beta-D-(3-deoxy-3-fluorolyxofuranosyl)-2-nitroimidazole (beta-3-FAZL) (fluorination yields 60% and 55%, respectively). The tosylated precursors required to synthesize the corresponding F-18 labeled radiopharmaceuticals are also reported. The partition coefficients (P) for beta-2-FAZA (1.0) and beta-3-FAZL (0.95) were marginally lower than reported for FAZA (1.1). The radiosensitization properties of both these compounds are similar to that of FAZA, with sensitizer enhancement ratios (SER) of approximately 1.8 for HCT-116 cells.

Robust high-yield ~1 TBq production of cyclotron based sodium [99mTc]pertechnetate.

This paper presents the irradiation and processing of high-current 100Mo targets at the University of Alberta (UofA) in a GMP compliant setting. For purpose of comparison with a second production facility, additional studies at Centre Hospitalier Universitaire de Sherbrooke (CHUS) are also described. INTRODUCTION: More than 70% of today's diagnostic radiopharmaceuticals are based on 99mTc, however the conventional supply chain for obtaining 99mTc is fragile. The aim of this work was to demonstrate reliable high yield production and processing of 99mTc with medium-energy, high-current, cyclotrons. METHODS: We used two cyclotrons (TR-24, Advanced Cyclotron Systems, Inc) for irradiations with 22 MeV or 24 MeV incident energy and 400 µA current up to a maximum of 6 h. The irradiated 100Mo was dissolved using peroxide, basified using ammonium carbonate, and purified using a PEG-based solid phase extraction technique. RESULTS: High-yield productions with 22 MeV (400 µA, 6 h) yielded an average isolated [99mTc]TcO4- yield of 878 GBq ±â€¯99 GBq (23.7 Ci ±â€¯2.7 Ci) decay corrected to EOB, n = 8 (isolated saturation yield: 4.36 ±â€¯0.49 GBq/µA). Irradiations with 24 MeV (400 µA, 6 h) resulted in an average isolated [99mTc]TcO4- yield of 993 GBq ±â€¯100 GBq (26.8 Ci ±â€¯2.7 Ci) decay corrected to EOB, n = 7 (isolated saturation yield: 4.97 ±â€¯0.50 GBq/µA). These yields corresponds to 600-700 GBq (16-19 Ci) of [99mTc]TcO4- at release (i.e. 3 hour post-EOB). For all tested batches, the QC results were within the recently published specifications in the European Pharmacopoeia. CONCLUSION: Reliable near-TBq production yields for 99mTc can be obtained using medium-energy cyclotrons. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This work presents evidence that medium-energy high-current cyclotrons can provide high yields of [99mTc]TcO4- with radionuclidic impurities levels within the specifications of the existing European Pharmacopoeia monograph, indicating that this technology can have a share in the future 99mTc supply market.

Low-Activity Radioactive Iodine Therapy for Thyroid Carcinomas Exhibiting Nodal Metastases and Extrathyroidal Extension May Lead to Early Disease Recurrence.

BACKGROUND: The application of radioactive iodine in differentiated thyroid carcinomas has become more selective in an attempt to decrease morbidity. While ablative success has been documented, it is less clear how changes in radioactive iodine treatment strategies will influence long-term recurrence rates for patients with larger tumors and adverse pathological features, including extrathyroidal extension and nodal metastases. METHODS: Patients diagnosed between 1995 and 2008 with differentiated thyroid carcinoma treated with thyroidectomy followed by radioactive iodine treatment were eligible. All patients were followed for a minimum of five years using a standardized follow-up protocol requiring both biochemical and imaging assessments for recurrent disease (n = 219). Patients were stratified by initial radioactive iodine activity, and disease-free survival was calculated using the Kaplan-Meier method, with significant differences defined by the log-rank test. RESULTS: In this cohort, 46% of patients had clinical metastases and 74% had primary tumors >1.5 cm. Patients who had recurrences were more likely to present with extrathyroidal extension (p = 0.002) and lymph node metastases at diagnosis (p < 0.001). Patients presenting with both extrathyroidal extension and lymph node metastases had a significantly worse time to progression if treated with <1850 MBq radioactive iodine compared to those patients treated with >1850 MBq (25 months vs. 121 months; p = 0.004). The use of lower-activity radioactive iodine ablative therapy was associated with more early recurrences (p = 0.003). Being aged younger or older than 45 years did not impact the time to recurrence nor did the use of level 6 dissection. On multivariate analysis, lymph node metastases at diagnosis and multiple applications of radioactive iodine were linked to increased risk of recurrence. Patients with neither, or only one, adverse pathologic feature had excellent outcomes, regardless of initial ablative activity, with <10% of patients recurring over a 10-year time span. CONCLUSIONS: Recurrent disease in differentiated thyroid carcinoma is more common in patients treated with low-activity radioactive iodine in patients with lymph node metastases and extrathyroidal extension. These recurrences typically occur within four years of initial treatment. Patients lacking both of these risk factors treated with low radioactive iodine activity (<1850 MBq) have excellent outcomes, even after 10 years.

Treating the right patient at the right time: access to cardiovascular nuclear imaging.

Cardiovascular nuclear medicine uses agents labelled with radioisotopes that can be imaged with cameras (single-photon emission tomography [SPECT] or positron emission tomography [PET]) capable of detecting gamma photons to show physiological parameters such as myocardial perfusion, myocardial viability or ventricular function. There is a growing body of literature providing guidelines for the appropriate use of these techniques, but there are little data regarding the appropriate timeframe during which the procedures should be accessed. An expert working group composed of cardiologists and nuclear medicine specialists conducted an Internet search to identify current wait times and recommendations for wait times for a number of cardiac diagnostic tools and procedures, including cardiac catheterization and angioplasty, bypass grafting and vascular surgery. These data were used to estimate appropriate wait times for cardiovascular nuclear medicine procedures. The estimated times were compared with current wait times in each province. Wait time benchmarks were developed for the following: myocardial perfusion with either exercise or pharmacological stress and SPECT or PET imaging; myocardial viability assessment with either fluorodeoxyglucose SPECT or PET imaging, or thallium-201 SPECT imaging; and radionuclide angiography. Emergent, urgent and nonurgent indications were defined for each clinical examination. In each case, appropriate wait time benchmarks were defined as within 24 h for emergent indications, within three days for urgent indications and within 14 days for nonurgent indications. Substantial variability was noted from province to province with respect to access for these procedures. For myocardial perfusion imaging, mean emergent/urgent wait times varied from four to 24 days, and mean nonurgent wait times varied from 15 to 158 days. Only Ontario provided limited access to viability assessment, with fluorodeoxyglucose available in one centre. Mean emergent/urgent wait times for access to viability assessment with thallium-201 SPECT imaging varied from three to eight days, with the exception of Newfoundland, where an emergent/urgent assessment was not available; mean nonurgent wait times varied from seven to 85 days. Finally, for radionuclide angiography, mean emergent/urgent wait times varied from two to 20 days, and nonurgent wait times varied from eight to 36 days. Again, Newfoundland centres were unable to provide emergent/urgent access. The publication of these data and proposed wait times as national targets is a step toward the validation of these recommendations through consultation with clinicians caring for cardiac patients across Canada.

Separation of [(99m)Tc]pertechnetate and molybdate using polyethylene glycol coated C18 and C30 resins.

Hydrophobic adsorbents such as C18 and C30 were coated with PEG and subsequently used for the separation of Mo/Tc. The most effective resin for adsorbing PEG was the C18-U resin, which demonstrated a coating capacity of 97.6±2.8mg PEG per g of resin. The ability to adsorb pertechnetate was proportional to the amount of PEG coated on the hydrophobic resin. The [(99m)Tc]pertechnetate recovery during the separation of cyclotron produced (99m)Tc from (100)Mo was 91.8±0.3% (n=2). The resultant product met relevant USP monograph specifications.

Use of radionuclides for the palliation of bone metastases.

Pain palliation with bone-seeking radiopharmaceuticals is an effective and cost-effective management tool in patients with advanced cancer metastatic to bone. Strontium-89 ((89)Sr) (Metastron) and samarium-153 ((153)Sm) EDTMP (Lexidronam) are licensed for use in patients in the United States. Patients with a positive bone scan using technetium 99m methylene diphosphonate ((99m)Tc MDP) are eligible for treatment, and indications and contraindications for use are now well defined. The evidence in the literature now suggests that the radiopharmaceuticals can significantly reduce pain and analgesic requirements, can improve quality of life, can reduce lifetime radiotherapy requirements and management costs, and may slow the progression of painful metastatic lesions. Retreatment is safe and effective. Rhenium-186 ((186)Re) HEDP and Tin-117m diethylenetriaminepenta-acetic acid (DTPA) are in phase II/III trials to evaluate efficacy and compare efficacy with the licensed agents. Phosphorus-32 ((32)P) has been reassessed in two trials evaluating efficacy in comparison with (89)Sr and safety. Toxicity is reversible myelosuppression, which may be significant, and the treatments should not be given to patients with suspected disseminated intravascular coagulation.

A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone.

The palliative efficacy of strontium-89 chloride has been evaluated in a prospective double-blind crossover study comparing it with stable strontium as placebo in 32 patients with prostate cancer metastatic to bone. Response was assessed 5 weeks after each treatment. 26 patients were evaluable. Complete pain relief was only reported following strontium-89 injection. Statistical comparison between placebo and strontium-89 showed clear evidence of a therapeutic response to strontium-89 compared with only a limited placebo effect (P less than 0.01).

Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer: results of a randomized controlled trial.

In a multicenter, randomized controlled trial involving 126 patients with endocrine-resistant advanced prostate cancer, all of whom received external beam radiotherapy, additional treatment with a single injected dose of 400 MBq strontium-89 (Metastron) significantly improved overall pain control. Adjuvant therapy with strontium-89 also significantly reduced analgesia requirements compared with placebo and delayed disease progression, as indicated by the requirement for further external beam radiotherapy. On certain measures, patients receiving strontium-89 also showed enhanced quality of life. Accompanying these changes, levels of prostate tumor markers were significantly reduced by strontium-89 treatment. The benefits resulting from adjuvant strontium therapy were associated with tolerable hematologic toxicity. The addition of strontium-89 to external beam radiation had no effect on survival. However, it has clear implications for improved palliation in advanced prostate cancer and may also impact positively on treatment costs.

Targeted radiotherapy of multicell neuroblastoma spheroids with high specific activity [125I]meta-iodobenzylguanidine.

PURPOSE: Iodine-125 induces cell death by a mechanism similar to that of high linear energy transfer (high-LET) radiation. This study investigates the cytotoxicity of high-specific-activity [125I]meta-iodobenzylguanidine (125I-mIBG) in human SK-N-MC neuroblastoma cells grown as three-dimensional multicellular spheroids. MATERIALS AND METHODS: Spheroids were incubated with high-specific-activity 125I-mIBG (6 mCi/microg, 1000 times that of the conventional specific activity used for autoradiography). Cytotoxicity was assessed by fluorescence viability markers and confocal microscopy for intact spheroids, fluorescence-activated cell sorting and clonogenic assay, and clonogenic assays for dispersed whole spheroids. Distribution of radioactive mIBG was determined by quantitative light-microscope autoradiography of spheroid cryostat sections. Dose estimation was based on temporal knowledge of the retained radioactivity inside spheroids, and of the radiolabel's emission characteristics. Findings were compared with those of spheroids treated under the same conditions with 131I-mIBG, cold mIBG, and free iodine-125. RESULTS: 125I-mIBG exerted significant cell killing. Complete spheroids were eradicated when they were treated with 500 microCi of 125I-mIBG, while those treated with 500 microCi or 1000 microCi of 131I-mIBG were not. The observed difference in cytotoxicity between treatments with 125I- and 131I-mIBG could not be accounted for by the absorbed dose of spheroid alone. The peripheral, proliferating cell layer of the spheroids remained viable at the moderate radioactivity of 100 microCi for both isotopes. Cytotoxicity induced by 125I-mIBG was quantitatively comparable by the peripheral rim thickness to that of 131I-mIBG at the dose of 100 microCi. The peripheral rim thickness decreased most significantly in the first 17 hours after initial treatment. There was no statistical decrease in the rim thickness identified afterwards for the second, third, and fourth days of incubation. CONCLUSION: The cytotoxic effect of high-specific-activity 125I-mIBG appears to be comparable to, if not more efficient than that of conventionally used 131I-mIBG at the same level of total radioactivity. 125I-mIBG may improve the therapeutic index over that of 131I-mIBG in the clinical management of metastatic neuroblastoma due to the short range of Auger electrons.

Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer.

PURPOSE: A large proportion of the practice of radiotherapy in the management of metastatic adenocarcinoma of the prostate is associated with palliation of pain from osseous metastases and improving quality of life. Radiation therapy is well known to be effective in treating painful sites and may also be effective in reducing the propensity for adjuvantly treated disease to become symptomatic. Strontium-89 is a systemic radionuclide that has clinical efficacy in the palliation of pain from bony metastases. METHODS AND MATERIALS: The study was a Phase-III randomized placebo control trial performed in eight Canadian Cancer Centers to evaluate the effectiveness of strontium-89 as an adjunct to local field radiotherapy. Patients with endocrine refractory metastatic prostate cancer received local field radiotherapy and either strontium-89 as a single injection of 10.8 mCi or placebo. RESULTS: One hundred twenty-six patients were recruited. No significant differences in survival or in relief of pain at the index site where noted. Intake of analgesics over time demonstrated a significant reduction in the arm treated with strontium-89. Progression of pain as measured by sites of new pain or the requirement for radiotherapy showed statistically significant differences between the arms in favor of strontium-89. Tumor makers including prostate specific antigen, acid phosphatase, and alkaline phosphatase were also reduced in patients receiving strontium-89. A Quality-of-Life analysis was performed as a multivariate data set and demonstrated an overall superiority of strontium-89 with alleviation of pain and improvement in physical activity being statistically significant. Toxicity was evaluated and demonstrated increased hematological toxicity in the group receiving strontium-89. CONCLUSIONS: It is concluded that the addition of strontium-89 is an effective adjuvant therapy to local field radiotherapy reducing progression of disease as evidenced by new sites of pain and the requirement of further radiotherapy and improving quality-of-life and need for analgesic support in this group of patients.

Interactive three-dimensional region of interest analysis of HMPAO SPECT brain studies.

An interactive computer program has been developed to align a three-dimensional region of interest (ROI) model to technetium-99m-hexamethylpropylenamine oxime (99mTc-HMPAO) single-photon emission computed tomography (SPECT) studies of the brain. The ROI model subdivides the human brain into fourteen discrete regions. A study was performed to determine normal ranges for HMPAO uptake in the ROIs defined by the model, and to assess the relative interobserver variability using the fitting program. HMPAO SPECT studies of twelve normal volunteers were independently analyzed by four observers. Small but significant differences between operators occurred primarily because of difficulty in defining the angle of the orbitomeatal plane on sagittal SPECT images. Despite this difficulty, the program and model have proven useful in defining ranges for normal cerebral perfusion in a healthy adult population. A study of a small group of patients with Alzheimer's dementia suggests that this procedure may be of use in the diagnosis of this disease.

Safety and clinical utility of combined intravenous dipyridamole/symptom-limited exercise stress test with thallium-201 imaging in patients with known or suspected coronary artery disease.

Dipyridamole-induced coronary hyperemia with 201Tl myocardial perfusion scintigraphy can detect ischemic regions in individuals unable to perform adequate exercise, but it has several limitations. Symptom-limited exercise supplementation to intravenous dipyridamole can potentially overcome them, but the safety and diagnostic accuracy for this combination has not been established. Between 1987 and 1991, 441 consecutive patients were assessed for combined symptom-limited exercise test preceded by i.v. dipyridamole. Clinical records could not be obtained for 37 patients, and 40 patients were not exercised because they were unable; therefore 384 patients (mean age 58 +/- 9.8 yr, 278 men) underwent symptom-limited exercise preceded by 0.56 mg/kg of dipyridamole and followed by planar 201Tl perfusion scintigraphy. Following dipyridamole infusion, systolic blood pressure fell by 10 +/- 14 mmHg and heart rate increased by 8 +/- 11 bpm. Adverse effects were experienced by 77 people (dizziness in 44; headache in 11; nausea in 9; syncope in 2 and chest pain in 11). Exercise heart rate was 69% +/- 16% of predicted maximum and ST shift was -0.9 +/- 0.9 mm. Following exercise, seven patients required aminophylline (four after dizziness, two after headache, one after chest pain), which was uniformly successful. There were no episodes of prolonged chest pain, MI, death or serious arrhythmia. Safety was maintained for people with severe triple coronary artery disease, the elderly (> 70 yr) and those with significant pulmonary disease. Sensitivity was 95% for at least one with > 70% luminal stenosis and 94% for at least one with > 40% luminal stenosis. Specificity was 28% and 53% respectively. The addition of a symptom-limited exercise test to i.v. dipyridamole is safe for all groups of patients referred for 201Tl study.

Strontium-89 therapy: measurement of absorbed dose to skeletal metastases.

We report measurements of absorbed dose to vertebral metastases in ten patients referred for 89Sr therapy for disseminated prostatic carcinoma. Patients received a tracer dose of 85Sr at the time of 89Sr treatment and metastatic strontium retention was monitored scintigraphically for 6 mo. Metastatic 85Sr activity corrected for tissue attenuation was measured using the conjugate view principle, with special care taken to eliminate errors due to the selection of the metastatic region of interest. Metastatic volume was determined from high resolution CT images, and density inferred from Hounsfield number using the QCT bone mineral calibration of Genant and Cann. The mean absorbed dose was 850 rad/mCi (23 cGy/MBq) with a range from 220-2260 rad/mCi (6 to 61 cGy/MBq). The wide range found was consistent with the variation expected to arise due to differences in strontium renal plasma clearance (range 0.1-11.81/day) and extent of skeletal metastatic disease (varying from two small metastases to a superscan on [99mTc]MDP images) among the patients studied.

Dosimetry estimations for 123I-IAZA in healthy volunteers.

UNLABELLED: 123I-Labeled iodoazomycin arabinoside (IAZA) is a marker of hypoxia in vivo. It has been used clinically to image hypoxic tissue in solid tumors, peripheral vascular disease of diabetic origin, blunt brain trauma, and rheumatoid joints and in an animal model of cerebrovascular disease. The radiation dose biodistribution for 123I-IAZA was studied to assess and characterize its suitability as a clinical radiopharmaceutical. METHODS: Six healthy volunteers each received a nominal 185-MBq (5 mCi) dose of 123I-IAZA administered as a slow (1-3 min) intravenous injection in the arm. Anterior and posterior whole-body planar images were acquired for each volunteer beginning immediately after injection and at 1-2, 3-4, 6-8, and 20-24 h after injection. Venous blood samples (0 h predose through 28 h after dosing) and 28-h cumulative urine samples were taken from each volunteer for pharmacokinetic analysis. Radiation dose estimates were performed for all volunteers, with "reference adult" (for men) and "adult female" (for women) phantoms, and both the International Commission on Radiological Protection 30 gastrointestinal tract model and the dynamic bladder model, using the MIRDOSE3 program. Two sets of estimates, 1 using a pharmacokinetic analysis of total serum radioactivity and 1 based on scintigraphic image data, were obtained for each volunteer after 123I-IAZA administration. RESULTS: Two compartments were discernible by pharmacokinetic analysis, and 4 compartments were discernible by image analysis. The urinary bladder wall received the greatest radiation dose (6.3E-02 +/- 8.7E-03 mGy/MBq), followed by the upper large intestinal wall (5.6E-02 +/- 1.2E-02 mGy/MBq), the lower large intestinal wall (5.0E-02 +/- 1.2E-02 mGy/MBq), and the thyroid (4.4E-02 +/- 1.4E-02 mGy/MBq). Approximately 90% of physiologically eliminated radioactivity was excreted through the kidneys. Radioactivity entering the intestinal tract from the gallbladder constituted <10% of biologically eliminated activity. CONCLUSION: The dosimetric analysis of 123I-IAZA in 6 healthy volunteers indicated that both disposition kinetics and radiation dosimetry support its clinical use for imaging tissue hypoxia.

Measurement of PDT-induced hypoxia in Dunning prostate tumors by iodine-123-iodoazomycin arabinoside.

Photodynamic therapy (PDT) is known to produce vascular damage in solid tumors resulting in secondary ischemia and tumor cell death from hypoxia. The oxygenation status of both non-treated and PDT-treated Dunning R3327-AT prostate tumors growing in Fischer X Copenhagen rats was investigated with the novel hypoxic marker, 123I-iodoazomycin arabinoside (IAZA). Both qualitative and quantitative data from planar scintigraphy of anesthetized tumor-bearing rats showed increased retention of 123I-IAZA in tumors treated with PDT. Tumor perfusion in the same tumors was measured with 99mTc-hexamethylpropyleneamine oxime (HM-PAO). Region of interest analyses revealed an inverse correlation between tumor hypoxia measured by 123I-IAZA and tumor perfusion as measured by 99mTc-HMPAO (coefficient of correlation, r = -0.72). Planar images of 2-mm frozen sections from a large tumor showed 123I-IAZA selectively retained in the region that had been treated with PDT. This and other iodinated azomycin nucleosides, labeled with 123I, show promise for monitoring tumor oxygenation status non-invasively and, in particular, for monitoring the effectiveness of interstitial PDT treatments where perfusion shutdown is a major mechanism of tumor response.

Iodine-131 MIBG scintigraphy of neuroendocrine tumors other than pheochromocytoma and neuroblastoma.

Metaiodobenzylguanidine (MIBG) locates most pheochromocytomas and neuroblastomas. The tracer is concentrated in intracellular storage vesicles by an active process. Many other neuroendocrine tumors of the amine precursor uptake and decarboxylation (APUD) series have hormonal storage vesicles and, thus, the potential to take up [131I]MIBG. A variety of neuroendocrine tumors in 57 patients were studied 1, 2, and 3 days after 0.5 mCi [131I]MIBG. Views from skull to pelvis were obtained. Results of MIBG scans were compared with all available imaging modalities (including plain radiography, liver scan, ultrasound, computed tomography, and angiography) and surgical exploration. The neuroendocrine nature of the tumor was determined by histology, immunohistochemistry, electron microscopy, and the assay of appropriate biogenic amines and peptide hormones. Results were (positive/total cases): carcinoids (four of ten), nonsecreting paragangliomas (three of three), sporadic medullary carcinomas of the thyroid (MCT) (one of five), familial MCT (one of 26), chemodectomas (two of five), oat cell carcinomas (zero of four), choriocarcinoma (one of one), atypical schwannoma (with storage granules) (one of one), Merkel cell skin cancer (one of one), islet cell carcinoma (zero of one). We conclude that a wide range of neuroendocrine tumors show [131I]MIBG uptake; tumors other than pheochromocytomas and neuroblastomas are less often seen scintigraphically, but in certain cases (e.g., carcinoid and nonsecreting paragangliomas) scintigraphy may be useful in depicting the extent and location of disease and may indicate therapeutic potential. Iodine-131 MIBG shows promise in the diagnosis and staging of tumors of varied types.

Imaging tumor hypoxia and tumor perfusion.

Tumor perfusion and oxygenation status have been suggested as factors which may influence treatment outcome in cancer patients. Nuclear medicine assays of tumor perfusion [99mTc-hexamethylpropylenamine oxime (HMPAO)] and tumor hypoxia [123I-iodoazomycin arabinoside (IAZA)] have recently been developed and described. We report on measurements of perfusion and oxygenation status of 27 tumors in 22 patients using these probes. An inverse correlation between tumor uptake of HMPAO and IAZA was measured (p < 0.05), with severe perfusion deficit usually associated with an increased uptake of the hypoxic marker. This trend was observed for limited stage small-cell lung carcinoma, squamous-cell carcinoma of the head and neck, soft-tissue sarcoma, brain metastases from small-cell lung carcinoma and adenocarcinoma of the prostate as a group, but not for glioblastoma multiforme. Whereas each imaging agent can yield information about the physiological status of tumor and normal tissue, the information resulting from their combined use could be important in cancer therapy.