Predictive factors of [11C]choline PET/CT in patients with biochemical failure after radical prostatectomy

Purpose

Detection of recurrence in prostate cancer patients with biochemical failure after radical prostatectomy by [¹¹C]choline PET/CT depends on the prostate-specific antigen (PSA) level. The role of other clinical and pathological variables has not been explored.

Methods

A total of 2,124 prostate cancer patients referred to our Institution for [¹¹C]choline PET/CT from December 2004 to January 2007 for restaging of disease were retrospectively considered for this study. Inclusion criteria were: previous treatment by radical prostatectomy, and biochemical failure, defined as at least two consecutive PSA measurements of >0.2 ng/ml. These criteria were met for 358 patients. Binary logistic analysis was used to investigate the predictive factors of [¹¹C]choline PET/CT. PET/CT findings were validated using criteria based on histological analysis, and follow-up clinical and imaging data. Receiver operating characteristic (ROC) analysis was used to assess the performance of [¹¹C]choline PET/CT in relation to PSA levels.

Results

The mean PSA level was 3.77?±?6.94 ng/ml (range 0.23–45 ng/ml; median 1.27 ng/ml). PET/CT was positive for recurrence in 161 of 358 patients (45%). On an anatomical region basis, [¹¹C]choline pathological uptake was observed in lymph nodes (107/161 patients, 66%), prostatectomy bed (55/161 patients, 34%), and in the skeleton (46/161 patients, 29%). PET/CT findings were validated using histological criteria (46/358, 13%), and follow-up clinical and imaging criteria (312/358, 87%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were, respectively, 85%, 93%, 91%, 87%, and 89%. In multivariate analysis, high PSA levels, advanced pathological stage, previous biochemical failure and older age were significantly (P?<?0.05) associated with an increased risk of positive PET/CT findings. The percentage of positive scans was 19% in those with a PSA level between 0.2 and 1 ng/ml, 46% in those with a PSA level between 1 and 3 ng/ml, and 82% in those with a PSA level higher than 3 ng/ml. ROC analysis showed that PET/CT-positive and PET/CT-negative patients could be best distinguished using a PSA cut-off value of 1.4 ng/ml.

Conclusions

In addition to PSA levels, pathological stage, previous biochemical failure and age should be considered by physicians when referring prostate cancer patients with biochemical failure after radical prostatectomy to [¹¹C]choline PET/CT.     

Comparison of integrated whole-body [11C]choline PET/MR with PET/CT in patients with prostate cancer

Purpose

To evaluate the performance of conventional [¹¹C]choline PET/CT in comparison to that of simultaneous whole-body PET/MR.

Methods

The study population comprised 32 patients with prostate cancer who underwent a single-injection dual-imaging protocol with PET/CT and subsequent PET/MR. PET/CT scans were performed applying standard clinical protocols (5 min after injection of 793?±?69 MBq [¹¹C]choline, 3 min per bed position, intravenous contrast agent). Subsequently (52?±?15 min after injection) PET/MR was performed (4 min per bed position). PET images were reconstructed iteratively (OSEM 3D), scatter and attenuation correction of emission data and regional allocation of [¹¹C]choline foci were performed using CT data for PET/CT and segmented Dixon MR, T1 and T2 sequences for PET/MR. Image quality of the respective PET scans and PET alignment with the respective morphological imaging modality were compared using a four point scale (0–3). Furthermore, number, location and conspicuity of the detected lesions were evaluated. SUVs for suspicious lesions, lung, liver, spleen, vertebral bone and muscle were compared.

Results

Overall 80 lesions were scored visually in 29 of the 32 patients. There was no significant difference between the two PET scans concerning number or conspicuity of the detected lesions (p not significant). PET/MR with T1 and T2 sequences performed better than PET/CT in anatomical allocation of lesions (2.87?±?0.3 vs. 2.72?±?0.5; p?=?0.005). The quality of PET/CT images (2.97?±?0.2) was better than that of the respective PET scan of the PET/MR (2.69?±?0.5; p?=?0.007). Overall the maximum and mean lesional SUVs exhibited high correlations between PET/CT and PET/MR (ρ?=?0.87 and ρ?=?0.86, respectively; both p?<?0.001).

Conclusion

Despite a substantially later imaging time-point, the performance of simultaneous PET/MR was comparable to that of PET/CT in detecting lesions with increased [¹¹C]choline uptake in patients with prostate cancer. Anatomical allocation of lesions was better with simultaneous PET/MR than with PET/CT, especially in the bone and pelvis. These promising findings suggest that [¹¹C]choline PET/MR might have a diagnostic benefit compared to PET/CT in patients with prostate cancer, and now needs to be further evaluated in prospective trials.     

Preoperative lymph node staging in patients with primary prostate cancer: comparison and correlation of quantitative imaging parameters in diffusion-weighted imaging and 11C-choline PET/CT

Purpose

To compare the diagnostic performance of DWI and 11C-choline PET/CT in the assessment of preoperative lymph node status in patients with primary prostate cancer.

Material and methods

Thirty-three patients underwent DWI and 11C-choline PET/CT prior to prostatectomy and extended pelvic lymph node dissection. Mean standardised uptake value (SUV_mean) and mean apparent diffusion coefficient (ADC) of 76 identified lymph nodes (LN) were measured and correlated with histopathology. ADC values and SUVs were compared using linear regression analysis.

Results

A significant difference between benign and malignant LN was observed for ADC values (1.17 vs. 0.96?×?10^-3 mm²/s; P?<?0.001) and SUV_mean (1.61 vs. 3.20; P?<?0.001). ROC analysis revealed an optimal ADC threshold of 1.01?×?10^-3 mm²/s for differentiating benign from malignant LN with corresponding sensitivity/specificity of 69.70 %/78.57 % and an area under the curve (AUC) of 0.785. The optimal threshold for SUV_mean was 2.5 with corresponding sensitivity/specificity of 69.72 %/90.48 % and with an AUC of 0.832. ADC values and SUV_mean showed a moderate significant inverse correlation (r?=?-0.63).

Conclusion

Both modalities reveal similar moderate diagnostic performance for preoperative lymph node staging of prostate cancer, not justifying their application in routine clinical practice at this time. The only moderate inverse correlation between ADC values and SUV_mean suggests that both imaging parameters might provide complementary information on tumour biology.

Key Points

? Conventional imaging shows low performance for lymph node staging in prostate cancer. ? DWI and 11C-choline PET/CT both provide additional functional information ? Both functional modalities reveal only moderate diagnostic performance.     

Tumour volume delineation in prostate cancer assessed by [11C]choline PET/CT: validation with surgical specimens

Purpose

PET has been proven to be helpful in the delineation of gross tumour volume (GTV) for external radiation therapy in several tumour entities. The aim of this study was to determine if [¹¹C]choline PET could be used to localize the carcinomatous tissue within the prostate in order to specifically target this area for example with high-precision radiation therapy.

Methods

Included in this prospective study were 20 patients with histological proven prostate carcinoma who underwent [¹¹C]choline PET/CT before radical prostatectomy. After surgical resection, specimens were fixed and cut into 5-mm step sections. In each section the area of the carcinoma was delineated manually by an experienced pathologist and digitalized, and the histopathological tumour volume was calculated. Shrinkage due to resection and fixation was corrected using in-vivo and ex-vivo CT data of the prostate. Histopathological tumour location and size were compared with the choline PET data. Different segmentation algorithms were applied to the PET data to segment the intraprostatic lesion volume.

Results

A total of 28 carcinomatous lesions were identified on histopathology. Only 13 (46 %) of these lesions had corresponding focal choline uptake. In the remaining lesions, no PET uptake (2 lesions) or diffuse uptake not corresponding to the area of the carcinoma (13 lesions) was found. In the patients with corresponding PET lesions, no suitable SUV threshold (neither absolute nor relative) was found for GTV segmentation to fit the volume to the histological tumour volume.

Conclusion

The choline uptake pattern corresponded to the histological localization of prostate cancer in fewer than 50 % of lesions. Even when corresponding visual choline uptake was found, this uptake was highly variable between patients. Therefore SUV thresholding with standard algorithms did not lead to satisfying results with respect to defining tumour tissue in the prostate.     

[11C]Choline as pharmacodynamic marker for therapy response assessment in a prostate cancer xenograft model

Purpose

[¹¹C]Choline has been established as a PET tracer for imaging prostate cancer. The aim of this study was to determine whether [¹¹C]choline can be used for monitoring the effects of therapy in a prostate cancer mouse xenograft model.

Methods

The androgen-independent human prostate cancer cell line PC-3 was implanted subcutaneously into the flanks of 13 NMRI (nu/nu) mice. All mice were injected 4–6 weeks after xenograft implantation with 37 MBq [¹¹C]choline via a tail vein. Dynamic imaging was performed for 60 min with a small-animal PET/CT scanner (Siemens Medical Solutions). Six mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. Seven mice were treated with PBS as a control. [¹¹C]Choline imaging was performed prior to and 1, 2 and 3 weeks after treatment. To determine choline uptake the images were analysed in terms of tumour-to-muscle (T/M) ratios. Every week the size of the implanted tumour was determined with a sliding calliper.

Results

The PC-3 tumours could be visualized by [¹¹C]choline PET. Before treatment the T/M_mean ratio was 1.6±0.5 in the control group and 1.8±0.4 in the docetaxel-treated group (p=0.65). There was a reduction in the mean [¹¹C]choline uptake after docetaxel treatment as early as 1 week after initiation of therapy (T/M ratio 1.8±0.4 before treatment, 0.9±0.3 after 1 week, 1.1±0.3 after 2 weeks and 0.8±0.2 after 3 weeks). There were no decrease in [¹¹C]choline uptake in the control group following treatment (T/M ratio 1.6±0.5 before treatment, 1.7±0.4 after 1 week, 1.8±0.7 after 2 weeks and 1.7±0.4 after 3 weeks). For analysis of the dynamic data, a generalized estimation equation model revealed a significant decrease in the T/M_dyn ratios 1 week after docetaxel treatment, and the ratio remained at that level through week 3 (mean change ?0.93±0.24, p<0.001, after 1  week; ?0.78±0.21, p<0.001, after 2 weeks; ?1.08±0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/M_dyn ratios (mean change 0.085±0.39, p=0.83, after 1 week; 0.31±0.48, p=0.52, after 2 weeks; 0.11±0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy.

Conclusion

Our results demonstrate that [¹¹C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer.     

18F-fluorodeoxyglucose positron emission tomography and computed tomography in anaplastic thyroid cancer

Purpose

Our aim was to evaluate in anaplastic thyroid carcinoma (ATC) patients the value of ¹⁸F-FDG PET/CT compared with total body computed tomography (CT) using intravenous contrast material for initial staging, prognostic assessment, therapeutic monitoring and follow-up.

Methods

Twenty consecutive ATC patients underwent PET/CT for initial staging. PET/CT was performed again during follow-up. The gold standard was progression on imaging follow-up (CT or PET/CT) or confirmation with another imaging modality.

Results

A total of 265 lesions in 63 organs were depicted in 18 patients. Thirty-five per cent of involved organs were demonstrated only with PET/CT and one involved organ only with CT. In three patients, the extent of disease was significantly changed with PET/CT that demonstrated unknown metastases. Initial treatment modalities were modified by PET/CT findings in 25% of cases. The volume of FDG uptake (≥300 ml) and the intensity of FDG uptake (SUV_max ≥18) were significant prognostic factors for survival. PET/CT permitted an earlier assessment of tumour response to treatment than CT in 4 of the 11 patients in whom both examinations were performed. After treatment with combined radiotherapy and chemotherapy, only the two patients with a negative control PET/CT had a confirmed complete remission at 14 and 38 months; all eight patients who had persistent FDG uptake during treatment had a clinical recurrence and died.

Conclusion

FDG PET/CT appears to be the reference imaging modality for ATC at initial staging and seems promising in the early evaluation of treatment response and follow-up.     

[<Superscript>68</Superscript>Ga]DOTATATE PET/MRI and [<Superscript>18</Superscript>F]FDG PET/CT are complementary and superior to diffusion-weighted MR imaging for radioactive-iodine-refractory differentiated thyroid cancer

Purpose

The purpose of this study was to determine whether [⁶⁸Ga]DOTATATE PET/MRI with diffusion-weighted imaging (DWI) can replace or complement [¹⁸F]FDG PET/CT in patients with radioactive-iodine (RAI)-refractory differentiated thyroid cancer (DTC).

Methods

The study population comprised 12 patients with elevated thyroglobulin and a negative RAI scan after thyroidectomy and RAI remnant ablation who underwent both [¹⁸F]FDG PET/CT and [⁶⁸Ga]DOTATATE PET/MRI within 8 weeks of each other. The presence of recurrent cancer was evaluated on a per-patient, per-organ and per-lesion basis. Histology, and prior and follow-up examinations served as the standard of reference.

Results

Recurrent or metastatic tumour was confirmed in 11 of the 12 patients. [⁶⁸Ga]DOTATATE PET(/MRI) correctly identified the tumour burden in all 11 patients, whereas in one patient local relapse was missed by [¹⁸F]FDG PET/CT. In the lesion-based analysis, overall lesion detection rates were 79/85 (93 %), 69/85 (81 %) and 27/82 (33 %) for [¹⁸F]FDG PET/CT, [⁶⁸Ga]DOTATATE PET/MRI and DWI, respectively. [¹⁸F]FDG PET(/CT) was superior to [⁶⁸Ga]DOTATATE PET(/MRI) in the overall evaluation and in the detection of pulmonary metastases. In the detection of extrapulmonary metastases, [⁶⁸Ga]DOTATATE PET(/MRI) showed a higher sensitivity than [¹⁸F]FDG PET(/CT), at the cost of lower specificity. DWI achieved only poor sensitivity and was significantly inferior to [¹⁸F]FDG PET in the lesion-based evaluation in the detection of both extrapulmonary and pulmonary metastases.

Conclusion

[¹⁸F]FDG PET/CT was more sensitive than [⁶⁸Ga]DOTATATE PET/MRI in the evaluation of RAI-refractory DTC, mostly because of its excellent ability to detect lung metastases. In the evaluation of extrapulmonary lesions, [⁶⁸Ga]DOTATATE PET(/MRI) was more sensitive and [¹⁸F]FDG PET(/CT) more specific. Furthermore, DWI did not provide additional information and cannot replace [¹⁸F]FDG PET for postoperative monitoring of patients with suspected RAI-refractory DTC.

     

Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer

Purpose

Positron emission tomography (PET) with choline tracers has found widespread use for the diagnosis of prostate cancer (PC). However, choline metabolism is not increased in a considerable number of cases, whereas prostate-specific membrane antigen (PSMA) is overexpressed in most PCs. Therefore, a ⁶⁸Ga-labelled PSMA ligand could be superior to choline tracers by obtaining a high contrast. The aim of this study was to compare such a novel tracer with standard choline-based PET/CT.

Methods

Thirty-seven patients with biochemical relapse of PC [mean prostate-specific antigen (PSA) 11.1?±?24.1 ng/ml, range 0.01–116] were retrospectively analysed after ¹⁸F-fluoromethylcholine and ⁶⁸Ga-PSMA PET/CT within a time window of 30 days. Radiotracer uptake that was visually considered as PC was semi-quantitatively analysed by measuring the maximum standardized uptake values (SUV_max) of the scans acquired 1 h after injection of ⁶⁸Ga-PSMA complex solution (median 132 MBq, range 59–263 MBq) and ¹⁸F-fluoromethylcholine (median 237 MBq, range 114–374 MBq), respectively. In addition, tumour to background ratios were calculated.

Results

A total of 78 lesions characteristic for PC were detected in 32 patients using ⁶⁸Ga-PSMA PET/CT and 56 lesions were detected in 26 patients using choline PET/CT. The higher detection rate in ⁶⁸Ga-PSMA PET/CT was statistically significant (p?=?0.04). In five patients no lesion was found with both methods. All lesions detected by ¹⁸F-fluoromethylcholine PET/CT were also seen by ⁶⁸Ga-PSMA PET/CT. In ⁶⁸Ga-PSMA PET/CT SUV_max was clearly (>10 %) higher in 62 of 78 lesions (79.1 %) and the tumour to background ratio was clearly (>10 %) higher in 74 of 78 lesions (94.9 %) when compared to ¹⁸F-fluoromethylcholine PET/CT.

Conclusion

⁶⁸Ga-PSMA PET/CT can detect lesions characteristic for PC with improved contrast when compared to standard ¹⁸F-fluoromethylcholine PET/CT, especially at low PSA levels.     

Diagnostic usefulness of an amino acid tracer, α-[N-methyl-11C]-methylaminoisobutyric acid (11C-MeAIB), in the PET diagnosis of chest malignancies

Objectives

Although positron emission tomography (PET) using [¹⁸F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) is established as one of the first-choice imaging modalities in the diagnosis of chest malignancies, there are several problems to solve in clinical practice, such as false positive uptake in inflammatory diseases. The aim of this study was to evaluate the clinical usefulness of an amino acid tracer, α-[N-methyl-¹¹C]-methylaminoisobutyric acid (¹¹C-MeAIB), in the diagnosis of chest malignancies, in combination with ¹⁸F-FDG.

Setting

Fifty-nine cases (57 patients, 66 ± 12 years old) who consulted to our institution for the wish to receive differential diagnosis of chest diseases were included. Purpose of the studies were as follows: differential diagnosis of newly developed lung nodules, n = 22; newly developed mediastinal lesions, n = 20; and both, n = 17 (including lung cancer: n = 19, lymphoma: n = 1, other cancers: n = 2, sarcoidosis: n = 15, non-specific inflammation: n = 18, other inflammatory: n = 4, respectively). Whole-body static PET or PET/CT scan was performed 20 and 50 min after the IV injection of ¹¹C-MeAIB and ¹⁸F-FDG, respectively.

Results

¹¹C-MeAIB uptake of malignant and benign lesions was statistically different both in pulmonary nodules (p < 0.005) and in mediastinal lesions (p < 0.0005). In visual differential diagnosis, ¹¹C-MeAIB showed higher results (specificity: 73 %, accuracy: 81 %), compared to those in ¹⁸F-FDG (60, 73 %, respectively). In cases of sarcoidosis, ¹¹C-MeAIB showed higher specificity (80 %) with lower uptake (1.8 ± 0.7) in contrast to the lower specificity (60 %) with higher uptake of ¹⁸F-FDG (7.3 ± 4.5).

Conclusions

¹¹C-MeAIB PET/CT was useful in the differential diagnosis of pulmonary and mediastinal mass lesions found on CT. ¹¹C-MeAIB PET or PET/CT showed higher specificity than that of ¹⁸F-FDG PET/CT in differentiating between benign and malignant disease. Our data suggest that the combination of ¹⁸F-FDG and ¹¹C-MeAIB may improve the evaluation of chest lesions, when CT and ¹⁸F-FDG PET/CT are equivocal.     

Detection of internal mammary lymph node metastasis with 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with stage III breast cancer

Purpose

The present study assessed the positive predictive value (PPV) of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for the detection of internal mammary node (IMN) metastasis in patients with clinical stage III breast cancer.

Methods

Patients who were diagnosed with clinical stage III breast cancer and underwent pretreatment ¹⁸F-FDG PET/CT were retrospectively analyzed. The ¹⁸F-FDG PET/CT scans were prospectively reviewed by two board-certified nuclear medicine physicians in a blinded manner. The intensities of IMNs were graded into four categories (no activity and lower, similar, and higher activities than that of the mediastinal blood pool). IMNs were measured from the combined CT (largest diameter of the short axis). Histologic data of the IMNs were obtained by ultrasonography-guided fine-needle aspiration biopsy or surgical excision. The PPV was calculated for pathologically confirmed IMNs. Visual grade, maximum standardized uptake values (SUV_max), and sizes were analyzed according to the pathology results.

Results

There were 249 clinical stage III breast cancer patients (age 48.0?±?10.1 years, range 26–79 years) who had undergone initial ¹⁸F-FDG PET/CT prior to treatment. Excluding 33 cases of stage IV breast cancer, 62 of 216 patients had visible IMNs on ¹⁸F-FDG PET/CT, and histologic confirmation was obtained in 31 patients. There were 27 metastatic and four nonmetastatic nodes (PPV 87.1 %). Metastatic nodes mostly presented with visual grade 3 (83.9 %), and SUV_max and size were 3.5?±?4.3 and 5.6?±?2.0 mm, respectively.

Conclusion

¹⁸F-FDG PET/CT has a high PPV for IMN metastasis in clinical stage III breast cancer, indicating the possibility of metastasis in IMNs with FDG uptake similar to/lower than that of the blood pool or small-sized nodes.     

Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury

Objective

[¹¹C]Flumazenil ([¹¹C]FMZ) positron emission tomography (PET) can be used as a measure of neuronal loss. The purpose of this study was to validate reference tissue kinetic modelling of [¹¹C]FMZ PET within a group of patients with head injury.

Methods

Following earlier studies, the pons was used as the reference region. PET scans were performed on 16 controls and 11 patients at least 6 months following injury, each of whom also had arterial blood sampling to provide whole blood and metabolite-corrected plasma input functions. Regional non-displaceable binding potentials (BP_ND) were calculated from five reference tissue models and compared to BP_ND from arterial input models. For the patients, the regions included a peri-lesional region of interest (ROI).

Results

Total distribution volume of the pons was not significantly different between control and patient groups (P = 0.24). BP_ND from all the reference tissue approaches correlated well with BP_ND from the plasma input models for both controls (r ² = 0.98–1.00; P < 0.001) and patients (r ² = 0.99–1.00; P < 0.001). For the peri-lesional regions (n = 11 ROI values), the correlation was also high (r ² = 0.91).

Conclusions

These results indicate that reference tissue modelling with the pons as the reference region is valid for [¹¹C]FMZ PET in head-injured patients at 6 months following injury within both normal appearing and peri-lesional brain regions.     

Diagnostic value of diffusion-weighted magnetic resonance imaging (DWI) compared to FDG PET/CT for whole-body breast cancer staging

Purpose

The aim of the study was to prospectively compare the diagnostic value of whole-body diffusion-weighted imaging (DWI) and FDG PET/CT for breast cancer (BC) staging.

Methods

Twenty BC patients underwent whole-body FDG PET/CT and 1.5-T DWI. Lesions with qualitatively elevated signal intensity on DW images (b?=?800 s/mm²) were rated as suspicious for tumour and mapped to individual lesions and different compartments (overall 552 lesions). The apparent diffusion coefficient (ADC) value was determined for quantitative evaluation. Histopathology, MRI findings, bone scan findings, concordant findings between FDG PET/CT and DWI, CT follow-up scans and plausibility served as the standards of reference defining malignancy.

Results

According to the standards of reference, breasts harboured malignancy in 11, regional lymph nodes in 4, M1 lymph nodes in 3, bone in 7, lung in 2, liver in 3 and other tissues in 3 patients. On a compartment basis, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for the detection of malignancies were 94, 99, 98, 97 and 98% for FDG PET/CT and 91, 72, 76, 50 and 96% for DWI, respectively. Of the lesions seen on DWI only, 348 (82%) turned out to be false-positive compared to 23 (11%) on FDG PET/CT. The average lesion ADC was 820?±?300 with true-positive lesions having 929?±?252 vs 713?±?305 in false-positive lesions (p?<?0.0001).

Conclusion

Based on these initial data DWI seems to be a sensitive but unspecific modality for the detection of locoregional or metastatic BC disease. There was no possibility to quantitatively distinguish lesions using ADC. DWI alone may not be recommended as a whole-body staging alternative to FDG PET(/CT). Further studies are necessary addressing the question of whether full-body MRI including DWI may become an alternative to FDG PET/CT for whole-body breast cancer staging.     

Erratum to: Radiation dosimetry of N-([11C]methyl)benperidol as determined by whole-body PET imaging of primates

Purpose

N-([¹¹C]Methyl)benperidol ([¹¹C]NMB) can be used for PET measurements of D₂-like dopamine receptor binding in vivo. We report the absorbed radiation dosimetry of i.v.-administered [¹¹C]NMB, a critical step prior to applying this radioligand to imaging studies in humans.

Materials and methods

Whole-body PET imaging with a CTI/Siemens ECAT 953B scanner was done in a male and a female baboon. Following i.v. injection of 370-555 kBq of [¹¹C]NMB, sequential images taken from the head to the pelvis were collected for three hours. Volumes of interest (VOIs) were identified that entirely encompassed small organs (whole brain, striatum, eyes, and myocardium). Large organs (liver, lungs, kidneys, lower large intestine, and urinary bladder) were sampled by drawing representative regions within the organ volume. Time-activity curves for each VOI were extracted from the PET and organ residence times were calculated by analytical integration of a multi-exponential fit of the time-activity curves. Human radiation doses were estimated using OLINDA/EXM 1.0 and the standard human model.

Results

Highest retention was observed in the blood and liver, each with total residence times of 1.5 min. The highest absorbed radiation doses were to the heart (10.5 μGy/MBq) and kidney (9.10 μGy/MBq), making these the critical organs for [¹¹C]NMB. A heart absorption of 0.5 μGy would result from an injected dose of 4847 kBq [¹¹C]NMB.

Conclusions

Thus, up to 3700 kBq of [¹¹C]NMB can be safely administered to human subjects for PET studies. Total body dose and effective dose for [¹¹C]NMB are 2.8 μGy/MBq and 3.7 μSv/MBq, respectively.     

Synthesis and evaluation of a new vesamicol analog <Emphasis Type="Italic">o</Emphasis>-[<Superscript>11</Superscript>C]methyl-<Emphasis Type="Italic">trans</Emphasis>-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter

Introduction

We focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer’s diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (σ-1 and σ-2), o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [¹¹C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation.

Method

[¹¹C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [¹¹C]methyl iodide, with a radiochemical yield of 60–75 %, a radiochemical purity of greater than 98 %, and a specific activity of 5–10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [¹¹C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET–CT imaging study were performed to check the binding selectivity of [¹¹C]OMDV for VAChT.

Results

In vivo studies demonstrated [¹¹C]OMDV passage through the blood–brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [¹¹C]OMDV was significantly inhibited by co-administration of vesamicol. In contrast, brain accumulation of [¹¹C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective σ-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP], a σ-1 and σ-2 receptor ligand. PET–CT imaging revealed inhibition of [¹¹C]OMDV accumulation in the brain by co-administration of vesamicol.

Conclusion

[¹¹C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [¹¹C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.

     

PET imaging of focal demyelination and remyelination in a rat model of multiple sclerosis: comparison of [11C]MeDAS, [11C]CIC and [11C]PIB

Purpose

In this study, we compared the ability of [¹¹C]CIC, [¹¹C]MeDAS and [¹¹C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake.

Methods

Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group).

Results

The kinetics of [¹¹C]CIC, [¹¹C]MeDAS and [¹¹C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [¹¹C]CIC make this tracer less suitable for in vivo PET imaging. [¹¹C]PIB showed good uptake in the white matter in the cerebrum, but [¹¹C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [¹¹C]MeDAS distribution correlated well with myelin density in different brain regions.

Conclusion

This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [¹¹C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [¹¹C]CIC and [¹¹C]PIB.     

Whole-body [18F]FDG PET/MRI vs. PET/CT in the assessment of bone lesions in oncological patients: initial results

Objectives

To compare [¹⁸?F]FDG PET/MRI with PET/CT for the assessment of bone lesions in oncologic patients.

Methods

This prospective study included 67 patients with solid tumours scheduled for PET/CT with [¹⁸?F]FDG who also underwent a whole-body PET/MRI scan. The datasets (PET/CT, PET/MRI) were rated by two readers regarding lesion conspicuity (four-point scale) and diagnostic confidence (five-point scale). Median scores were compared using the Wilcoxon test.

Results

Bone metastases were present in ten patients (15 %), and benign bone lesions in 15 patients (22 %). Bone metastases were predominantly localized in the pelvis (18 lesions, 38 %) and the spine (14 lesions, 29 %). Benign bone lesions were exclusively osteosclerotic and smaller than the metastases (mean size 6 mm vs. 23 mm). While PET/CT allowed identification of 45 of 48 bone metastases (94 %), PET/MRI allowed identification of all bone metastases (100 %). Conspicuity of metastases was high for both modalities with significantly better results using PET/MRI (p?<?0.05). Diagnostic confidence in lesion detection was high for both modalities without a significant difference. In benign lesions, conspicuity and diagnostic confidence were significantly higher with PET/CT (p?<?0.05).

Conclusions

[¹⁸?F]FDG PET/MRI shows high potential for the assessment of bone metastases by offering superior lesion conspicuity when compared to PET/CT. In hypersclerotic, benign bone lesions PET/CT still sets the reference.

Key Points

? PET/MRI and PET/CT are of equal value for the identification of disease-positive patients ? PET/MRI offers higher lesion conspicuity as well as diagnostic confidence ? PET/MRI is an attractive new alternative for the assessment of bone metastases     

Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET

Objective

XR9576 (tariquidar) is an anthranilic acid derivative and potent P-glycoprotein (P-gp) inhibitor. XR9576 has undergone phase I and II studies as combined chemotherapy against cancer. XR9576 has been developed as a useful therapeutic agent but not as a PET probe. We therefore developed [¹¹C]XR9576 as a PET probe and assessed whether PET studies using [¹¹C]XR9576 are a promising approach to assess P-gp function primarily.

Methods

We synthesized [¹¹C]XR9576 by methylation of 7-O-desmethyl XR9576 with [¹¹C]methyl iodide. In in vivo tissue distribution, the effects of co-injection with XR9576 on the uptake of [¹¹C]XR9576 in mice were investigated. PET studies using [¹¹C]XR9576 were performed in P-gp and/or Bcrp knockout mice as well as in wild-type mice. Metabolites of [¹¹C]XR9576 were measured in the brain and plasma of mice.

Results

[¹¹C]XR9576 was successfully synthesized with suitable radioactivity for injection as well as appropriate radiochemical purity and stability. In in vivo tissue distribution, the brain uptake of [¹¹C]XR9576 significantly increased about tenfold of control on co-injection with >10 mg/kg of XR9576. In PET studies, the AUC_{brain [0–60 min]} in P-gp and P-gp/Bcrp knockout mice was 2- and 11-fold higher than that in wild-type mice. [¹¹C]XR9576 showed a high metabolic stability (>90% unchanged form) in the brain and plasma of mice 30 min after injection. These results suggest that a tracer amount of [¹¹C]XR9576 behave as the P-gp and Bcrp substrate, and the increased brain uptake or AUC_brain of [¹¹C]XR9576 correlates with P-gp and Bcrp functions.

Conclusions

PET studies using [¹¹C]XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors.     

18F-FDOPA PET/CT for detection of recurrence in patients with glioma: prospective comparison with 18F-FDG PET/CT

Purpose

Differentiation between recurrence and radiation necrosis in patients with glioma is crucial, since the two entities have completely different management and prognosis. The purpose of the present study was to compare the efficacies of ¹⁸F-FDG PET/CT and 3,4-dihydroxy-6-[¹⁸F]fluoro-phenylalanine (¹⁸F-FDOPA) PET/CT in detection of recurrent gliomas.

Methods

A total of 28 patients (age 38.82?±?1.25 years; 85.7 % men) with histopathologically proven glioma with clinical/imaging suspicion of recurrence were evaluated using ¹⁸F-FDG PET/CT and ¹⁸F-FDOPA PET/CT. ¹⁸F-FDG PET/CT and ¹⁸F-FDOPA PET/CT images were evaluated qualitatively and semiquantitatively. The combination of clinical follow-up, repeat imaging and/or biopsy (when available) was taken as the reference standard.

Results

Based on the reference standard, 21 patients were positive and 7 were negative for tumour recurrence. The sensitivity, specificity and accuracy of ¹⁸F-FDG PET/CT were 47.6 %, 100 % and 60.7 %, respectively, and those of ¹⁸F-FDOPA PET/CT were 100 %, 85.7 % and 96.4 %, respectively. The results of ¹⁸F-FDG PET/CT and ¹⁸F-FDOPA PET/CT were concordant in 57.1 % of patients (16 of 28) and discordant in 42.9 % (12 of 28). The difference in the findings between ¹⁸F-FDG PET/CT and ¹⁸F-FDOPA PET/CT was significant (P?=?0.0005, McNemar’s test). The difference was significant for low-grade tumours (P?=?0.0039) but not for high-grade tumours (P?=?0.250).

Conclusion

¹⁸F-FDOPA PET/CT is highly sensitive and specific for detection of recurrence in glioma patients. It is superior to ¹⁸F-FDG PET/CT for this purpose and is especially advantageous in patients with low-grade gliomas.     

11C-Choline PET/CT as a guide to radiation treatment planning of lymph-node relapses in prostate cancer patients

Purpose

To evaluate, in prostate cancer (PCa) patients the potential of ¹¹C-choline PET/CT as a guide to helical tomotherapy (HTT) of lymph-node (LN) relapses with simultaneous integrated boost (SIB). The efficacy and feasibility of HTT in terms of acute toxicity were assessed.

Methods

We enrolled 83 PCa patients (mean age 68 years, range 51 – 82 years) with biochemical recurrence after radical primary treatment (mean serum PSA 7.61 ng/ml, range 0.37 – 187.00 ng/ml; PSA₀) who showed pathological findings on ¹¹C-choline PET/CT only at the LN site. ¹¹C-Choline PET/CT was performed for restaging and then for radiation treatment planning (PET/CT₀). Of the 83 patients, 8 experienced further LN relapse, of whom 5 were retreated once and 3 were retreated twice (total 94 radiotherapy treatments). All pelvic and/or abdominal LNs positive on PET/CT₀ were treated with high doses using SIB. Doses were in the range 36 – 74 Gy administered in 28 fractions. After the end of HTT (mean 83 days, range 16 – 365 days), serum PSA was measured in all patients (PSA₁) and compared with PSA₀ to evaluate early biochemical response. In 47 patients PET/CT was repeated (PET/CT₁) to assess metabolic responses at the treated areas. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) were used to assess acute toxicity.

Results

PET/CT₀ revealed pathological LNs in the pelvis in 49 patients, pathological LNs in the abdomen in 15 patients pathological LNs in both the pelvis and abdomen in 18 patients, and pathological LNs in the pelvis or abdomen and other sites in 12 patients. All these sites were treated with HTT. With respect to PSA₀, PSA₁ (mean 6.28 ng/ml, range 0.00 – 220.46 ng/ml) showed a complete biochemical response after 66 of the 94 HTT treatments, a partial response after 12 treatments, stable disease after 1 treatment and progression of disease after 15 treatments. Of the 47 patients receiving PET/CT₁, 20 showed a complete metabolic response at the treated area, 22 a partial metabolic response, 3 progression of disease and 2 stable disease. HTT with SIB was well tolerated in all patients. Grade 3 acute toxicity in the genitourinary tract was observed in two patients.

Conclusion

¹¹C-Choline PET/CT is a valuable tool for planning and monitoring HTT in LN relapse after primary treatment. High-dose hypofractionated ¹¹C-choline PET/CT-guided HTT with SIB is well tolerated and is associated with a high early biochemical response rate.