A phase I study of combined docetaxel and repeated high activity <Superscript>186</Superscript>Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial)

Purpose  

Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and ¹⁸⁶Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity.     

Micronucleus evaluation for determining the chromosomal breakages after radionuclide synovectomy in patients with hemophilia

Objective  

To investigate the genotoxic effects of ⁹⁰Y and ¹⁸⁶Re in patients with hemophilia who were undergoing radionuclide synovectomy (RS) procedure in the last 3 years.     

Preparation and evaluation of 186/188Re-labeled antibody (A7) for radioimmunotherapy with rhenium(I) tricarbonyl core as a chelate site

Objective  

Rhenium is one of the most valuable elements for internal radiotherapy because ¹⁸⁶Re and ¹⁸⁸Re have favorable physical characteristics. However, there are problems when proteins such as antibodies are used as carriers of ^186/188Re. Labeling methods that use bifunctional chelating agents such as MAG3 require the conjugation of the ^186/188Re complex to protein after radiolabeling with the bifunctional chelating agent. These processes are complicated. Therefore, we planned the preparation by a simple method and evaluation of a stable ^186/188Re-labeled antibody. For this purpose, we selected ^186/188Re(I) tricarbonyl complex as a chelating site. In this study, A7 (an IgG1 murine monoclonal antibody) was used as a model protein. ^186/188Re-labeled A7 was prepared by directly reacting a ^186/188Re(I) tricarbonyl precursor, [^186/188Re(CO)₃(H₂O)₃]⁺, with A7. We then compared the biodistribution of ^186/188Re-labeled A7 in tumor-bearing mice with ¹²⁵I-labeled A7.     

In Vitro Comparison of the Antiproliferative Effects of Rhenium-186 and Rhenium-188 on Human Aortic Endothelial Cells

Purpose  

Rhenium-186 (¹⁸⁶Re) and rhenium-188 (¹⁸⁸Re) are promising radionuclides for the inhibition of restenosis after percutaneous transluminal angioplasty or other vascular interventions. Until now the maximal dose tolerance of endothelial cells has not been clearly known.     

Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of <Superscript>186</Superscript>Re-MAG3-conjugated bisphosphonate (<Superscript>186</Superscript>Re-MAG3-HBP), an agent for treatment of painful bone metastases

Purpose  We have developed a ¹⁸⁶Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate (¹⁸⁶Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of ¹⁸⁶Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of ^99mTc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution. Methods  The displacement effects of several protein-binding inhibitors on the protein binding of ¹⁸⁶Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering ¹⁸⁶Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline. Results  The protein binding of ¹⁸⁶Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of ¹⁸⁶Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone. Conclusions  The findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein.     

A meta-analysis of <Superscript>18</Superscript>FDG-PET,MRI and bone scintigraphy for diagnosis of bone metastases in patients with breast cancer

Objective  

To perform a meta-analysis comparing the diagnostic value of ¹⁸FDG-PET, MRI, and bone scintigraphy (BS) in detecting bone metastases in patients with breast cancer.     

[11C]Choline PET/CT detection of bone metastases in patients with PSA progression after primary treatment for prostate cancer: comparison with bone scintigraphy

Purpose  

The aim of this study was to evaluate the clinical usefulness of [¹¹C]choline positron emission tomography (PET)/CT in comparison with bone scintigraphy (BS) in detecting bone metastases (BM) of patients with biochemical progression after radical treatment for prostate cancer (PCa).     

Effective treatment of pancreatic neuroendocrine tumours transfected with the sodium iodide symporter gene by <Superscript>186</Superscript>Re-perrhenate in mice

Purpose  

ReO₄⁻ has similar kinetics regarding the sodium iodide symporter (NIS) to I⁻ and TcO₄⁻ in NIS-expressing tissue. We investigated the therapeutic potential of ¹⁸⁶ReO₄⁻ in NIS-transfected neuroendocrine tumour tissue.     

<Superscript>18</Superscript>F-Fluoromethylcholine (FCH) PET imaging in patients with castration-resistant prostate cancer: prospective comparison with standard imaging

Purpose  

The aim of the study was to assess the utility of ¹⁸F-fluorocholine (FCH), compared to standard imaging of bone scan (BS) and contrast-enhanced abdominopelvic computed tomography (CT), in patients with castration-resistant prostate carcinoma.     

Detection of bone metastases in patients with lung cancer: <Superscript>99m</Superscript>Tc-MDP planar bone scintigraphy, <Superscript>18</Superscript>F-fluoride PET or <Superscript>18</Superscript>F-FDG PET/CT

Purpose  

The aim of the study was to compare the diagnostic accuracy of ¹⁸F-fluorodeoxyglucose (FDG) PET/CT versus standard planar bone scintigraphy (BS) and ¹⁸F-labelled NaF (¹⁸F) PET for the detection of bone metastases (BM) in non-small cell lung cancer (NSCLC).     

Bone metabolic activity in hyperostosis cranialis interna measured with 18F-fluoride PET

Purpose  

¹⁸F-Fluoride PET/CT is a relatively undervalued diagnostic test to measure bone metabolism in bone diseases. Hyperostosis cranialis interna (HCI) is a (hereditary) bone disease characterised by endosteal hyperostosis and osteosclerosis of the skull and the skull base. Bone overgrowth causes entrapment and dysfunction of several cranial nerves. The aim of this study is to compare standardised uptake values (SUVs) at different sites in order to quantify bone metabolism in the affected anatomical regions in HCI patients.     

Diagnosis of bone metastases: a meta-analysis comparing 18FDG PET, CT, MRI and bone scintigraphy

Objective  

To perform a meta-analysis to compare ¹⁸FDG PET, CT, MRI and bone scintigraphy (BS) for the diagnosis of bone metastases.     

Changes observed in radionuclide bone scans during and after teriparatide treatment for osteoporosis

Purpose  

Visual changes on radionuclide bone scans have been reported with teriparatide treatment. To assess this, serial studies were evaluated and quantified in ten postmenopausal women with osteoporosis treated with teriparatide (20 μg/day subcutaneous) who had ^99mTc-methylene diphosphonate (MDP) bone scans (baseline, 3 and 18 months, then after 6 months off therapy).     

186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours

Purpose

Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z_HER2:342 has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for ^99mTc-labelling, we have found that synthetic Z_HER2:342 conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy.

Methods

maGGG-Z_HER2:342 and maGSG-Z_HER2:342 were labelled with ¹⁸⁶Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by ¹⁸⁶Re-maGSG-Z_HER2:342 were studied.

Results

Gluconate-mediated labelling of maGGG-Z_HER2:342 and maGSG-Z_HER2:342 with ¹⁸⁶Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both ¹⁸⁶Re-maGGG-Z_HER2:342 and ¹⁸⁶Re-maGSG-Z_HER2:342 demonstrated lower renal uptake than their ^99mTc-labelled counterparts. ¹⁸⁶Re-maGSG-Z_HER2:342 provided the lowest uptake in healthy tissues. Biodistribution of ¹⁸⁶Re-maGSG-Z_HER2:342 in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84±0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold.

Conclusion

Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.     

Prospective evaluation of 68Ga-DOTANOC PET-CT in differentiated thyroid cancer patients with raised thyroglobulin and negative 131I-whole body scan: comparison with 18F-FDG PET-CT

Purpose

The purpose of the study was to evaluate the role of ⁶⁸Ga-DOTANOC PET-CT in differentiated thyroid cancer (DTC) patients with negative ¹³¹I-whole body scan (WBS) along with serially increasing serum thyroglobulin (Tg), and compare the same with ¹⁸F-FDG PET-CT.

Methods

Sixty two DTC patients with serially rising Tg levels and negative ¹³¹I-WBS were prospectively enrolled. All patients underwent ⁶⁸Ga-DOTANOC PET-CT and ¹⁸F-FDG PET-CT within an interval of two weeks. PET-CT analysis was done on a per-patient basis, location wise and lesion wise. All PET-CT lesions were divided into four categories-local, nodal, pulmonary and skeletal. Histopathology and/or serial serum Tg level, clinical and imaging follow up (minimum-1 year) were used as a reference standard.

Results

Ga-DOTANOC PET-CT demonstrated disease in 40/62 (65 %) patients and ¹⁸F-FDG PET-CT in 45/62 (72 %) patients, with no significant difference on McNemar analysis (p?=?0.226). Per-patient sensitivity and specificity of ⁶⁸Ga-DOTANOC PET-CT was 78.4 %, 100 %, and for ¹⁸F-FDG PET-CT was 86.3 %, 90.9 %, respectively. Out of 186 lesions detected by both PET-CTs, 121/186 (65 %) lesions were seen on ⁶⁸Ga-DOTANOC PET-CT and 168/186 (90.3 %) lesions on ¹⁸F-FDG PET-CT (p?<?0.0001). There were 103/186 (55 %) lesions concordant on both. Excellent agreement was noted between ⁶⁸Ga-DOTANOC PET-CT and ¹⁸F-FDG PET-CT for detection of local disease (??=?0.92), while moderate agreement was noted for nodal and pulmonary disease (??=?0.67). ⁶⁸Ga-DOTANOC PET-CT changed management in 21/62 (34 %) patients and ¹⁸F-FDG PET-CT in 17/62 (27 %) patients.

Conclusion

Ga-DOTANOC PET-CT is inferior to ¹⁸F-FDG PET-CT on lesion based but not on patient based analysis for detection of recurrent/residual disease in DTC patients with negative WBS scan and elevated serum Tg levels. It can also help in selection of potential candidates for peptide receptor radionuclide therapy.     

Biopsy versus FDG PET/CT in the initial evaluation of bone marrow involvement in pediatric lymphoma patients

Purpose  

The objective is to assess the role of ¹⁸F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/CT versus bone marrow biopsy (BMB) in the initial evaluation of bone marrow (BM) involvement in pediatric lymphoma patients.     

Biodistribution and radiation dosimetry of a positron emission tomographic ligand, 18F-SP203, to image metabotropic glutamate subtype 5 receptors in humans

Purpose  

A new PET ligand, 3-fluoro-5-(2-(2-¹⁸F-(fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile (¹⁸F-SP203), is a positron emission tomographic radioligand selective for metabotropic glutamate subtype 5 receptors. The purposes of this study were to estimate the radiation-absorbed doses of ¹⁸F-SP203 in humans and to determine from the distribution of radioactivity in bone structures with various proportions of bone and red marrow whether ¹⁸F-SP203 undergoes defluorination.     

Comparison of MRI and (18) F-NaF PET/CT in patients with patellofemoral pain

Purpose:

To determine whether bone metabolic activity corresponds to bone and cartilage damage in patients with patellofemoral pain.

Materials and Methods:

We acquired magnetic resonance imaging (MRI) and ¹⁸F‐NaF positron emission tomography (PET) / computed tomography (CT) scans of the knees of 22 subjects. We compared locations of increased tracer uptake on the ¹⁸F‐NaF PET images to bone marrow edema and cartilage damage visualized on MRI.

Results:

We found that increased bone activity on ¹⁸F‐NaF PET does not always correspond to structural damage in the bone or cartilage as seen on MRI.

Conclusion:

Our results suggest that ¹⁸F‐NaF PET/CT may provide additional information in patellofemoral pain patients compared to MRI. J. Magn. Reson. Imaging 2012;36:928–932. © 2012 Wiley Periodicals, Inc.     

Phase I/II trials of <Superscript>186</Superscript>Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

Purpose

To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit.

Methods

Clinical data from 57 patients who received 2.5–5.1 GBq of ¹⁸⁶Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan–Meier curves, log-rank tests, Cox’s proportional hazards model and Pearson’s correlation coefficients were used for overall survival (OS) and correlation analyses.

Results

A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10–0.58, P?=?0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r?=?0.65, P?=?0.001) and the whole-body absorbed dose (r?=?0.63, P?=?0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of ¹⁸⁶Re-HEDP (P?=?0.03) and patient mean absorbed dose (P?=?0.01), whilst only the disease volume remained significant in a multivariable analysis (P?=?0.004).

Conclusion

This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose–response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.