Molecular radiotherapy: the NUKFIT software for calculating the time-integrated activity coefficient.

PURPOSE: Calculation of the time-integrated activity coefficient (residence time) is a crucial step in dosimetry for molecular radiotherapy. However, available software is deficient in that it is either not tailored for the use in molecular radiotherapy and/or does not include all required estimation methods. The aim of this work was therefore the development and programming of an algorithm which allows for an objective and reproducible determination of the time-integrated activity coefficient and its standard error. METHODS: The algorithm includes the selection of a set of fitting functions from predefined sums of exponentials and the choice of an error model for the used data. To estimate the values of the adjustable parameters an objective function, depending on the data, the parameters of the error model, the fitting function and (if required and available) Bayesian information, is minimized. To increase reproducibility and user-friendliness the starting values are automatically determined using a combination of curve stripping and random search. Visual inspection, the coefficient of determination, the standard error of the fitted parameters, and the correlation matrix are provided to evaluate the quality of the fit. The functions which are most supported by the data are determined using the corrected Akaike information criterion. The time-integrated activity coefficient is estimated by analytically integrating the fitted functions. Its standard error is determined assuming Gaussian error propagation. The software was implemented using MATLAB. RESULTS: To validate the proper implementation of the objective function and the fit functions, the results of NUKFIT and SAAM numerical, a commercially available software tool, were compared. The automatic search for starting values was successfully tested for reproducibility. The quality criteria applied in conjunction with the Akaike information criterion allowed the selection of suitable functions. Function fit parameters and their standard error estimated by using SAAM numerical and NUKFIT showed differences of <1%. The differences for the time-integrated activity coefficients were also <1% (standard error between 0.4% and 3%). In general, the application of the software is user-friendly and the results are mathematically correct and reproducible. An application of NUKFIT is presented for three different clinical examples. CONCLUSIONS: The software tool with its underlying methodology can be employed to objectively and reproducibly estimate the time integrated activity coefficient and its standard error for most time activity data in molecular radiotherapy.

Biodistribution, cellular uptake and DNA-incorporation of the 2'-fluoro stabilized 5-iodo-2'-deoxyuridine analog 5-iodo-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (FIAU).

AIM: 5-Iodo-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FIAU) has been used for non-invasive monitoring of gene therapy and as an antiviral agent experimentally and in patients. However, FIAU metabolism in tumor cells is largely unknown. Here, the biological characteristics of FIAU in human leukemia and lymphoma cells in vitro and in a xenotransplant severe combined immunodeficient (SCID)-mouse model were investigated. METHODS: The susceptibility of FIAU to glycosidic bond cleavage by thymidine phosphorylase (TP) and its phosphorylation by human thymidine kinase 1 (hTK1) were examined. Cellular uptake and DNA-incorporation were determined in the leukemia cell line HL60 and the lymphoma cell line DoHH2. Biodistribution, in vivo stability of FIAU and expression of proliferation marker(67)Ki and thymidylate synthase were assessed in SCID-mice bearing HL60 xenotransplants. Cellular distribution of FIAU was imaged by microautoradiography. RESULTS: FIAU proved to be stable against degradation by TP and was phosphorylated by hTK1. Significant cellular uptake in DoHH2 and in HL60 cells was observed. The majority of intracellular [(131)I]FIAU was DNA incorporated. In vivo, moderate dehalogenation of [(131)I]FIAU was observed. Biodistribution studies showed a tumor uptake of 1.8+/-0.4% ID/g after 30 min. The half-life of [(131)I]FIAU in blood was 43+/-2 min. Microautoradiography showed a modest accumulation of [(125)I]FIAU in proliferating cells of small intestine, spleen and tumor. CONCLUSION: Despite phosphorylation by the hTK, efficient incorporation into the DNA and high in vivo stability, FIAU accumulates only moderately and transiently in proliferating cells, suggesting that FIAU is probably not appropriate for imaging of proliferation.

Activation of intrinsic apoptotic pathway by Re-188 irradiation and paclitaxel in coronary artery smooth muscle cells.

AIM: Intravascular brachytherapy efficiently reduces vascular smooth muscle cell (SMC) proliferation, interstitial matrix production, vascular remodeling and restenosis rate after revascularization injury of coronary arteries. In this study we examined the molecular mechanisms of the cytotoxic effect of Re-188-mediated beta-irradiation on a SMC culture model compared to that of paclitaxel. METHODS: SMC were irradiated with 1, 3, 10 and 30 Gy with Re-188 or treated with 1, 5, 10 microg/mL paclitaxel. After 24, 48 and 72 h, cell death, apoptosis pathways and cell cycle were examined. RESULTS: Irradiation and paclitaxel induced cell cycle arrest in G1. Dose-dependent cell death ranged from 40% at 1 Gy to 80% at 30 Gy irradiation, and induced in 45% of SMC treated with paclitaxel. Irradiation induced increasing rates of necrotic cell death up to 40% at 30 Gy. Activation of caspase-3 was detected, and poly(ADP-ribose)polymerase (PARP), the prototype substrate of caspases, was cleaved upon beta-irradiation. In addition, beta-irradiation-mediated apoptosis activated caspase-9, indicating that mitochondria were involved. Further-more, Bax was upregulated. However, upregulation of death-inducing ligands (DIL) or receptors (DIL-R) was not involved in beta-irradiation-induced apoptosis in SMC. Similar to beta-irradiation, the intrinsic mitochondrial apoptosis pathway was activated by paclitaxel. CONCLUSION: These findings demonstrate that beta-irradiation and paclitaxel induced apoptosis and activated apoptosis signaling pathways in SMC at several levels by triggering intrinsic mitochondrial but not external death receptor mediated pathways.

Radiosynthesis and evaluation of [11C]BTA-1 and [11C]3'-Me-BTA-1 as potential radiotracers for in vivo imaging of beta-amyloid plaques.

AIM: To evaluate the in vitro and in vivo characteristics of [N-methyl-(11)C]2-(4'-(methylaminophenyl)-benzothiazole ([(11)C]BTA-1) as well as [N-methyl-(11)C]2-(3'-methyl-4'-(methylamino)phenyl)-benzothiazole ([(11)C]3'-Me-BTA-1) as diagnostic markers of amyloid-beta (Abeta) in Alzheimer's disease (AD). MATERIAL, METHODS: Brain uptake and clearance was determined in wild-type mice. Binding affinities (K(i)) of [(11)C]BTA-1 and [(11)C]3'-Me-BTA-1 for aggregated Abeta(1-40) fibrils were assessed. Autoradiography was performed on brain sections of AD patients. To demonstrate binding specificity in vivo BTA-1 was injected i.p. in transgenic mice (Tg2576). Brain sections were analysed consecutively. Additionally, a [(11)C]BTA-1 PET study of an AD patient and a healthy control was performed. RESULTS: In mice brain uptake and clearance of [(11)C]BTA-1 is compatible with the half life of (11)C (2 min: 12.7 % ID/g; 30 min: 4.6% ID/g). In contrast clearance rate of [(11)C]3'-Me-BTA-1 is too slow (2 min 4% ID/g; 30 min 12% ID/g) to achieve sufficient clearance of free and non specifically bound radioactivity. K(i) of [(11)C]BTA-1 is 11 nmol/l and that of [(11)C]3'-Me-BTA-1 27 nmol/l. Both radioligands label Abeta selectively and specifically in AD patients and transgenic mice in vitro. The in vivo stained brain sections show a labelling of Abeta plaques. The AD patient has a higher prefrontal, parietal and striatal [(11)C]BTA-1 accumulation than the healthy control. Metabolite analysis revealed approximately 75% intact [(11)C]BTA-1 after 30min in plasma.[(11)C]BTA-1 is favourable for in vivo imaging of Abeta due to its rapid brain entry, sufficient clearance and good binding affinity for Abeta. CONCLUSION: The ability to label Abeta plaques in vivo in human subjects supports the suitability of [(11)C]BTA-1 as a plaque imaging agent.

Radiation dosimetry and biodistribution of the beta-amyloid plaque imaging tracer 11C-BTA-1 in humans.

AIM: [N-methyl-(11)C]2-(4'-(methylaminophenyl)-benzothiazole ((11)C-BTA-1) is a thioflavin-T derivative that has been one of the promising PET tracers for imaging of amyloid plaque distribution in the Alzheimer patients brain in vivo. The biodistribution and dosimetry of this tracer in humans is presented and compared to the results of a previous dosimetry and biodistribution study of another thioflavin-T derivative [N-methyl-(11)C]2-hydroxy-(4'-(methylaminophenyl)-benzothiazole ((11)C-OH-BTA-1) in baboons. METHODS: Five subjects underwent 2D dynamic PET imaging. Source organs were segmented using a semiautomatic algorithm based on clustering. Residence times for each source organ were determined by analytical integration of an exponential fit of the time activity curves. Finally organ doses were estimated using the software OLINDA/EXM. RESULTS: The administration of 286 +/- 93 MBq (11)C-BTA-1 was well tolerated by all subjects. Effective radiation dose was 4.3 microSv/MBq, range 3.6-5.0 microSv/MBq. In four of the five subjects the liver, in one of the subjects the gallbladder was the critical organ. CONCLUSION: The radiation burden of a single dose of 300 MBq (11)C-BTA-1 is within the accepted limits for research purpose. In contrast to the previous non-human primate study revealing the gallbladder as the critical organ for (11)C-6-OH-BTA-1, we found the liver as the critical organ in humans using (11)C-BTA-1. Possible explanations may be (1) a reduced bile concentration of (11)C-BTA-1 due to the absent OH-group or (2) a different hepatic metabolism of thioflavin derivatives in human and baboon.

Improved non-invasive T-Staging in non-small cell lung cancer by integrated 18F-FDG PET/CT.

AIM: In this prospective study, reliability of integrated (18)F-FDG PET/CT for staging of NSCLC was evaluated and compared to MDCT or PET alone. PATIENTS, METHODS: 240 patients (pts) with suspected NSCLC were examined using PET/CT. Of those patients 112 underwent surgery comprising 80 patients with NSCLC (T1 n = 26, T2 n = 37, T3 n = 11, T4 n = 6). Imaging modalities were evaluated independently. RESULTS: MDCT, PET and PET/CT diagnosed the correct T-stage in 40/80 pts (50%; CI: 0.39-0.61), 40/80 pts (50%; CI: 0.39-0.61) and 51/80 pts (64%; CI: 0.52-0.74), respectively, whereas equivocal T-stage was found in 15/80 pts (19%; CI: 0.11-0.19), 12/80 pts (15%; CI: 0.08-0.25) and 4/80 pts (5%; CI: 0.01-0.12), respectively. With PET/CT, T-stage was more frequently correct compared to MDCT (p = 0.003) or PET (p = 0.019). Pooling stages T1/T2, T-stage was correctly diagnosed with MDCT, PET and PET/CT in 54/80 pts (68%; CI: 0.56-0.78), 56/80 pts (70%; CI: 0.59-0.80) and 65/80 pts (81%; CI: 0.71-0.89). T3 stage was most difficult to diagnose. T3 tumors were correctly diagnosed with MDCT in 2/11 pts (18%; CI: 0.02-0.52) versus 0/11 pts (0%; CI: 0.00-0.28) with PET and 5/11 pts (45%; CI: 0.17-0.77) with PET/CT. In all imaging modalities, there were no equivocal findings for T4 tumors. Of these, MDCT found the correct tumor stage in 4/6 pts (67%; CI: 0.22-0.95), PET in 3/6 pts (50%; CI: 0.12-0.88) and PET/CT in 5/6 pts (83%; CI: 0.36-0.99). CONCLUSION: Integrated PET/CT was significantly more accurate for T-staging of NSCLC compared to MDCT or PET alone. The advantages of PET/CT are especially pronounced combining T1- and T2-stage as well as in advanced tumors.

Internal radionuclide therapy: software for treatment planning using tomographic data.

AIM: Accurate dosimetry must be performed for each patient before therapy with unsealed radionuclides. Recently, the software tool ULMDOS was developed to facilitate planar dosimetric calculations and to support traceability and documentation as a prerequisite for good clinical practice. Here, the extended version of ULMDOS for processing of tomographic data is presented. METHODS: ULMDOS is developed in IDL 6.1 (Interactive Data Language) under Windows XP/2000. Serial tomographic data can be loaded in an ECAT7 or DICOM format, and presented as maximum intensity projection. The definition of volumes of interest is supported by various tools (e.g., freehand, isocontour, polygon), region growing, and cluster analysis. Residence times are calculated from fits of the time activity data to exponential functions. RESULTS, DISCUSSION: Quantitative 3-dimensional data allow performing a more individualized dosimetry, as problems due to organ overlay, insufficient attenuation and scatter correction in the planar approach can be avoided. For traceability, documentation, retrospective examination and later processing all data can be saved in binary or ASCII format. Dosimetric calculations can be conducted within a single environment, thus it spares the time-consuming transfer of data between different software tools.

[PET and PET/CT in relapsing prostate carcinoma]. / PET und PET/CT in der Rezidivdiagnostik des Prostatakarzinoms.

Of patients with carcinoma of the prostate undergoing therapeutic regimes with curative intent, 15-23% will ultimately relapse and 16-35% will need some sort of salvage therapy within 5 years. Of relapsing patients, 50% will have local recurrence and 50% systemic disease with or without local recurrence. Therefore, localization of recurrent prostate cancer is critical for selecting a local or systemic therapeutic strategy. Modern fusion imaging with PET/CT and 11C/18F-choline or 11C-acetate has augmented the diagnostic imaging spectrum for assessment of relapsing prostate cancer. In 60-70% of patients with biochemical relapse, recurrent tumor can be detected and anatomically precisely localized. Detection sensitivity is probably negatively correlated with serum PSA concentration. Below a PSA level of 1 ng/ml, mean detection sensitivity is probably 50-66%. Fusion imaging with 11C-choline PET/CT and MRI possesses a high potential for early localization of recurrent prostate carcinoma.

[Advancement of PET and PET/CT in prostate carcinoma]. / Weiterentwicklung der PET und des PET/CT beim Prostatakarzinom.

Functional imaging of prostate carcinoma was examined with the metabolic substrates 2-(18)F-fluorodeoxyglucose, (11)C-methionine, (18)F-fluorodihydrotestosterone, (11)C-acetate and (11)C/(18)F-choline. Based on upregulated enzymes of phospholipid metabolism in prostate carcinoma, (11)C/(18)F-choline is preferentially incorporated into phosphatidylcholine of membrane lipids of prostate cancer cells. PET allows sensitive detection of the (11)C/(18)F-choline signal and PET/CT fusion imaging enables intraprostatic signal localisation. Most published studies report a high detection rate of prostate carcinoma with (11)C/(18)F-choline PET/CT. Differentiation of prostate carcinoma from benign hyperplasia and from focal chronic prostatitis may be difficult; acute prostatitis accumulates (11)C/(18)F-choline with an intensity comparable to prostate carcinoma.

Dosimetry with (188)Re-labelled monoclonal anti-CD66 antibodies. A simplified approach based on a single measurement 3 h p.i.

AIM: For the therapeutic application of radiopharmaceuticals the activity is determined on an individual basis. Here we investigated the accuracy for a simplified assessment of the residence times for a (188)Re-labelled anti-CD66 monoclonal antibody. PATIENTS, METHODS: For 49 patients with high risk leukaemia (24 men, 25 women, age: 44 +/- 12 years) the residence times were determined for the injected (188)Re-labelled anti-CD66 antibodies (1.3 +/- 0.4 GBq, 5-7 GBq/mg protein, >95% (188)Re bound to the antibody) based on 5 measurements (1.5, 3, 20, 26, and 44 h p.i.) using planar conjugate view gamma camera images (complete method). In a simplified method the residence times were calculated based on a single measurement 3 h p.i. RESULTS: The residence times for kidneys, liver, red bone marrow, spleen and remainder of body for the complete method were 0.4 +/- 0.2 h, 1.9 +/- 0.8 h, 7.8 +/- 2.1 h, 0.6 +/- 0.3 h and 8.6 +/- 2.1 h, respectively. For all organs a linear correlation exists between the residence times of the complete method and the simplified method with the slopes (correlation coefficients R > 0.89) of 0.89, 0.99, 1.23, 1.13 and 1.09 for kidneys, liver, red bone marrow, spleen and remainder of body, respectively. CONCLUSION: The proposed approach allows reliable prediction of biokinetics of (188)Re-labelled anti-CD66 monoclonal antibody biodistribution with a single study. Efficient pretherapeutic estimation of organ absorbed dose may be possible, provided that a more stable anti-CD66 antibody preparation is available.

[Significance of PET for ENT-tumors]. / Stellenwert der PET bei Kopf-Hals-Tumoren.

Significance for ENT-tumors. Molecular imaging with PET is based on the use of specific radioactive molecules as source of image contrast. In ENT-tumors mostly glucose and occasionally amino acid/protein metabolism were assessed with PET for tumor diagnosis. Thymidine salvage pathway and proliferation as well as tissue hypoxia are tested already in clinical studies and bear considerable potential for modulation of radiation ports and therapeutic response of cytoreductive regimens. This short review summarises actual clinical indications and potential of PET in ENT-tumors. For both nodal staging as well as detection of recurrent disease, sensitivity and specifity of FDG-PET were 80 - 100 %. FDG-PET proved to be superior to conventional imaging in most published studies. In CUP-syndrome the primary could be detected in 25 - 50 % of patients. Acquisition of PET and CT images in a combined scanner allow versatile PET based metabolic imaging in combination with high resolution and anatomical precise CT-based morphological imaging and thus combines advantages of both imaging modalities. Clinical as well as scientific potential of this functional metabolic and high resolution morphological imaging approach is high.

Lymph node staging in lung cancer using [18F]FDG-PET.

BACKGROUND: Mediastinal lymph node staging is essential to determine treatment options in patients with NSCLC. Positron emission tomography (PET) detects increased glucose uptake in malignant tissue using the glucose analogue 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG). PATIENTS AND METHODS: In the present study were evaluated 155 patients with focal pulmonary tumors who underwent both preoperative computed tomography (CT) and FDG-PET scanning (116 malignant and 39 benign lesions). RESULTS: Findings in 155 patients included 116 malignant and 39 benign lesions. For N-staging, FDG-PET showed a sensitivity of 88%, a specificity of 91%, and an accuracy of 89%. Corresponding figures for CT were 77%, 76%, and 77%, respectively. CONCLUSIONS: FDG-PET is an effective, noninvasive method for staging thoracic lymph nodes in patients with lung cancer and is superior to CT scanning in the assessment of hilar and mediastinal nodal metastases. With regard to operability, FDG-PET could differentiate reliable between patients with N1/N2 disease and those with unresectable N3 disease.

[18F] 3-deoxy-3'-fluorothymidine positron emission tomography: alternative or diagnostic adjunct to 2-[18f]-fluoro-2-deoxy-D-glucose positron emission tomography in the workup of suspicious central focal lesions?

BACKGROUND: 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography has been established as a standard diagnostic imaging method in the preoperative workup of suspicious pulmonary focal lesions, showing a sensitivity of more than 90% and a specificity of about 80%. Determination of malignant pulmonary lesions with FDG positron emission tomography depends on the assessment of glucose metabolism. However, false-positive findings can occur in inflammatory processes, such as sarcoidosis or pneumonia. The thymidine analogue 3-deoxy-3[(18)F]-fluorothymidine (FLT) is a new positron emission tomography tracer that more specifically targets proliferative activity of malignant lesions. The objective of this study was to determine whether FLT positron emission tomography, in comparison with FDG positron emission tomography, provides additional information in the preoperative workup of central pulmonary focal lesions. METHODS: In this prospective study FLT and FDG positron emission tomography examinations were performed as a part of the preoperative workup in 20 patients with histologically confirmed bronchial carcinoma, 7 patients with benign lesions, and 1 patient with an atypical carcinoid. Results were compared with final pathologic findings. RESULTS: For staging of the primary tumor, FLT positron emission tomography revealed a sensitivity of 86% and a specificity of 100% compared with a sensitivity of 95% and a specificity of 73% for FDG positron emission tomography. For N staging, the sensitivity of FLT positron emission tomography was 57% and the specificity was 100%, and for FDG positron emission tomography, the sensitivity was 86% and the specificity was 100%, respectively. CONCLUSIONS: Our preliminary findings indicate specific FLT uptake in malignant lesions. The number of false-positive findings in FDG positron emission tomography might be reduced with FLT positron emission tomography. Therefore positron emission tomography imaging with FLT represents a useful supplement to FDG in assessing the malignancy of central pulmonary focal lesions.

Intraindividual comparison of [11C]acetate and [11C]choline PET for detection of metastases of prostate cancer.

UNLABELLED: In a pilot trial we investigated whether significant differences in prostate cancer (PCA) imaging would be observed using [(11)C]acetate and [(11)C]choline positron emission tomography (PET). METHODS: Twelve patients were studied with both radiotracers. Whole body PET without attenuation correction was performed after injection of 0.95 +/- 0.15 GBq [(11)C]acetate and 0.84 +/- 0.13 GBq [(11)C]choline, respectively, from 5 to 60 min p. i. Focally increased uptake in bone, below the urinary bladder or in a lymph node region was considered as tumour. Primary tumour, lymph node involvement, bone metastases, local recurrence; and no evidence of disease were known in 2, 4, 2, 2; and 2 patients, respectively. RESULTS: [(11)C]Acetate uptake was highest in spleen and pancreas while [(11)C]choline uptake was predominant in liver and kidney parenchyma. However, interindividual variation was high. The potential of both radiotracers to detect known bone lesions, lymph node metastases, and imaging of the primary tumour was identical. However, both failed to detect a small local recurrence in two patients as well as to demonstrate lymph node involvement in one patient, which was confirmed by surgery. CONCLUSIONS: In this preliminary study, uptake of both radiotracers in prostate cancer or its metastases was nearly identical and none of them should be favoured. At present, both radiotracers influence patient management by detection of local recurrence, lymph node, or bone metastases of PCA.

[Implementation of a measurement protocol to evaluate system parameters in positron emission tomography]. / Implementation of a measurement protocol to evaluate system parameters in positron emission tomography.

To evaluate system parameters in PET measurements, several different activity ratios of the investigated phantom must be analyzed. The aim of this study was to develop a measurement protocol which requires just one filling of the phantom to measure adequate image contrasts and count ranges. We used 11C for the hollow spheres and 18F for the background of the whole-body PET phantom. Because of the different half-lives of the radionuclides, the dynamic acquisition of the frames (duration compensated for 18F decay) realizes various activity ratios between the spheres and the constant background. By summing up different frames, the counts in the background can also be varied. The presented method reduces the radiation exposure of the staff and economizes the use of the tomograph.

[Assessment of image reconstruction parameters in PET using physical and statistical figures of merit]. / Assessment of image reconstruction parameters in PET using physical and statistical figures of merit.

The aim of this study was to analyze the recommended OSEM image reconstruction parameters in positron emission tomography (PET). Spatial resolution, signal-to-noise ratio, and contrast were used as physical figures of merit (FOM). For statistical FOMs, the t-value and the area under the receiver operating characteristic (ROC) were employed. The spatial resolution was measured with 21 point sources. The signal-to-noise ratio, the contrast, and the t-value were investigated with a whole-body phantom with hollow spheres inserted. A phantom containing line sources was used for ROC analysis. As result, the reconstruction parameters recommended for visual evaluation lead to images with an adequate lesion detectability. The quantitative reconstruction, however, needs improvement.

Simultaneous iterative reconstruction of emission and attenuation images in positron emission tomography from emission data only.

For quantitative image reconstruction in positron emission tomography attenuation correction is mandatory. In case that no data are available for the calculation of the attenuation correction factors one can try to determine them from the emission data alone. However, it is not clear if the information content is sufficient to yield an adequate attenuation correction together with a satisfactory activity distribution. Therefore, we determined the log likelihood distribution for a thorax phantom depending on the choice of attenuation and activity pixel values to measure the crosstalk between both. In addition an iterative image reconstruction (one-dimensional Newton-type algorithm with a maximum likelihood estimator), which simultaneously reconstructs the images of the activity distribution and the attenuation coefficients is used to demonstrate the problems and possibilities of such a reconstruction. As result we show that for a change of the log likelihood in the range of statistical noise, the associated change in the activity value of a structure is between 6% and 263%. In addition, we show that it is not possible to choose the best maximum on the basis of the log likelihood when a regularization is used, because the coupling between different structures mediated by the (smoothing) regularization prevents an adequate solution due to crosstalk. We conclude that taking into account the attenuation information in the emission data improves the performance of image reconstruction with respect to the bias of the activities, however, the reconstruction still is not quantitative.

Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer.

UNLABELLED: Previous studies have shown that vertebral bone metastases (BM) not seen on planar bone scintigraphy (BS) might be present on (18)F-fluoride PET scans or at MRI. Therefore, we evaluated the effect of SPECT or (18)F-labeled NaF PET ((18)F PET) imaging on the management of patients with newly diagnosed lung cancer. METHODS: Fifty-three patients with small cell lung cancer or locally advanced non-small cell lung cancer were prospectively examined with planar BS, SPECT of the vertebral column, and (18)F PET. MRI and all available imaging methods, as well as the clinical course, were used as reference methods. BS with and without SPECT and (18)F PET were compared using a 5-point scale for receiver operating characteristic (ROC) curve analysis. RESULTS: Twelve patients had BM. BS produced 6 false-negatives, SPECT produced 1 false-negative, and (18)F PET produced no false-negatives. The area under the ROC curve was 0.779 for BS, 0.944 for SPECT, and 0.993 for (18)F PET. The areas under the ROC curve of (18)F PET and BS complemented by SPECT were not significantly different, and both tomographic methods were significantly more accurate than planar BS. As a result of SPECT or (18)F PET imaging, clinical management was changed in 5 patients (9%) or 6 patients (11%), respectively. CONCLUSION: As indicated by the area under the ROC curve analysis, (18)F PET is the most accurate whole-body imaging modality for screening for BM. Routinely performed SPECT imaging is practicable, is cost-effective, and improves the accuracy of BS.

Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation.

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (188Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2+/-2.1 (range 6.9-15.8) GBq 188Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4+/-5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.