Sandra Rosenbaum-Krumme

PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status

Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided.

Clinical applications of 124I-PET/CT in patients with differentiated thyroid cancer

Abstract124I-PET/CT has a high clinical potential in patients with differentiated thyroid cancer (DTC). Two aspects deserve special mention: staging of recurrent or residual disease and pretherapy dosimetry. Used in combination 124I-PET and CT allows foci of highly specific 124I uptake to be localized with a low radiation dose, which is specifically important in pretherapy diagnostics. In addition in the combination of FDG-PET and CT non-iodine-avid lesions may be detected and may be discriminated from simultaneously occurring iodine-positive lesions. In clinical applications, the pretherapy 124I-PET dosimetry may result in a significant alteration in the therapeutic procedure compared to standard therapy using fixed therapeutic activities. In this context, 124I-PET dosimetry is a useful procedure especially in advanced DTC, and allows the administration of safer and more effective radioiodine activities as well as earlier multimodal interventions compared to standard empirical protocols. This review summarizes the clinical data on 124I-PET/CT in patients with DTC, and addresses future prospects.

Assessment of Lesion Response in the Initial Radioiodine Treatment of Differentiated Thyroid Cancer Using 124I PET Imaging

124I PET/CT images from differentiated thyroid cancer patients were retrospectively analyzed to assess the relationship between absorbed radiation dose (AD) to lesions and their response after radioiodine therapy. Methods: Patients received serial 124I PET/CT scans before and after their first radioiodine treatment. The pretherapy PET data were used to segment the lesion volumes and to predict the therapy-delivered ADs after administration of the therapeutic 131I activity. The segmentation method’s lower volume limit of determinability was a sphere of 0.80 mL, which classified the lesions into a known-volume group (>0.80 mL) or a small-volume group (≤0.80 mL) with their respective average and minimum ADs. The posttherapy PET data were used to assess the lesion-based therapy success. In the known-volume group, the response rate was calculated on the basis of lesions that received average ADs above the generally accepted threshold of 85 Gy for metastases and 300 Gy for thyroid remnants (TRs) and was expressed as the percentage of completely responding lesions. In the small-volume group, the metastasis and TR responses were evaluated for 3 minimum-AD groups: 5 to 10 Gy (TR, 5 to 30 Gy), >10 to 85 Gy (TR, >30 to 300 Gy), and >85 Gy (TR, >300 Gy). Their response rates were calculated in terms of the percentage of completely responding lesions in each minimum-AD group. Results: In total, 59 lesions in 17 patients were amenable to reliable volume estimation. The response rates were 63%, 88%, and 90% for lymph node metastases (LMs), pulmonary metastases, and TRs, respectively. The response rates of 168 small lesions in 34 patients were more than 82% for LMs and more than 91% for TRs in each of the 3 minimum-AD groups; all small pulmonary metastases responded completely. Conclusion: In the known-volume group, the response rate for TRs matched well with historical data derived using 131I scintigraphy imaging, whereas the response rate for LMs was not as high as expected, which may be explained by too short a follow-up time for a few LMs and a higher sensitivity of PET imaging. Small lesions were treated effectively, suggesting that they are considerably smaller than 0.80 mL.

Malignant Pheochromocytoma Imaging with [124I]mIBG PET/MR

Pheochromocytoma localized in the adrenal medulla (in 85%) or in the thoracic/abdominal sympathetic trunk (paraganglioma) has malignant potential in about 10% of cases. Metaiodobenzylguanidine (mIBG) can be labeled with 123-iodine (for scintigraphy), 131-iodine (basically for therapy), or 124-iodine [excellent positron emission tomography (PET) imaging and tumor dosimetry based on high spatial resolution] and has high sensitivity for the diagnosis of primary/metastatic pheochromocytoma (1–3). Thiscasereportsontheworldwidefirst [I]-mIBG-PET/ magnetic resonance imaging (MRI) performed with an integrated PET/MR (Biograph mMR; Siemens Healthcare, Erlangen, Germany) in a malignant pheochromocytoma. The addition of MRI to mIBG-PET is promising as it improves tumor delineation because of the high soft tissue contrast in MRI that is especially relevant in pretherapeutic dosimetry. Compared with conventional [I]mIBG scintigraphy, [I]mIBG-PET provides high-resolution images. A 24-yr-old woman suffering from progressive malignant pheochromocytoma (primary right adrenal) underwent dosimetry with [I]mIBG PET/computed tomography (CT) (50 MBq) for treatment planning before therapy with [I]mIBG. An additional whole-body PET/ MRI (48 h after [I]mIBG administration) was performed with the following examination parameters (entire acquisition time, 40 min): four bed positions (head to upper thigh); PET, 8-min list mode per bed position; MRI, DIXON (T1-weighted sequences in-/opposed phases) for acquiring the -map for attenuation correction, simultaneous with PET non-contrast-enhanced coronal T1, transversal fat-saturated T2, and diffusionweighted imaging non-simultaneous followed by coronal and axial fat-saturated T1 after administration of gadolinium-based contrast agent. The PET/MRI (Fig. 1A, PET maximum intensity projection (MIP); B, fused PET/MRI coronal T1; C, fused PET/CT coronal) revealed local tumor recurrence (right adrenal bed) and multiple metastases (liver, lymph nodes, abdominal muscles, peritoneal) with intense tracer uptake, hyperintense signal on T2, hypointense on nonen-

Impact of whole-body imaging on treatment decision to radio-frequency ablation in patients with malignant liver tumors: comparison of [18F]fluorodeoxyglucose-PET/computed tomography, PET and computed tomography.

ObjectiveThe correct staging of patients with malignant liver tumors before radio-frequency ablation (RFA) is mandatory for successful treatment. Our study aimed to compare the influence on decision to perform RFA of whole-body fluorodeoxyglucose (FDG)-PET/computed tomography (CT) with whole-body contrast-enhanced CT (CE-CT) and PET alone. MethodsFifty-eight patients with known hepatic malignancies (23, liver metastases 35) received FDG-PET/CT before RFA planned with curative intention. CT and PET data were each read separately, PET/CT fusion data were read in consensus afterward by a third reader group. The diagnostic accuracy of CE-CT, PET alone, and PET/CT to identify patients eligible for RFA was compared and the impact on decision was analyzed. The McNemar test with Bonferroni correction was used to test for significant differences. ResultsThe accuracy and sensitivity to detect correctly intrahepatic and extrahepatic tumor were 94 and 97% for CT, 75 and 54% for PET, and 97 and 95% for PET/CT. The differences between CT and PET, as well as between PET/CT and PET, were statistically significant, but there was no significant difference between PET/CT and CT alone (P>0.65). PET alone, CE-CT, and PET/CT correctly identified 32, 55, and 57 patients, respectively. Again, PET/CT showed no significant advantage over CE-CT. Both imaging methods performed significantly better than PET alone (P<0.0001). Forty-three (74%) of 58 patients underwent RFA with curative intention. ConclusionWhole-body imaging changed patient management in 26% of the patients planned for curative intended RFA, yet there was no significant difference between CE-CT and PET/CT.

Imaging of Prostate-Specific Membrane Antigen Expression in Metastatic Differentiated Thyroid Cancer Using 68Ga-HBED-CC-PSMA PET/CT.

Purpose The prostate-specific membrane antigen (PSMA) was shown to be overexpressed on the neovasculature of several malignancies. Here, the role of 68Ga-HBED-CC-PSMA PET/CT for the detection of PSMA expression in patients with metastasized differentiated thyroid cancer (DTC) was evaluated. Methods Six patients with iodine-negative and 18F-FDG–positive metastasized DTC (mean TG, 1616 ng/mL) received 71–93 MBq of the 68Ga-labeled PSMA ligand and underwent PET/CT at 62 ± 7 minutes p.i.. Tumor accumulation capacity of the tracer and the detection rate of local recurrences and metastases were compared with 18F-FDG. Tracer uptake was quantified in terms of the SUVmax. Results In 5 of 6 patients, sites of putative metastatic disease could be identified using 68Ga-HBED-CC-PSMA PET/CT. All lesions detected with 68Ga-HBED-CC-PSMA PET/CT (n = 42) were confirmed by 18F-FDG PET/CT or conventional CT imaging. Using 68Ga-HBED-CC-PSMA PET/CT, all tumor lesions identified with 18F-FDG PET/CT imaging could be visualized in 3 of 5 patients. In 2 patients, only the most prominent lesions detected with 18F-FDG PET/CT imaging were visualized by 68Ga-HBED-CC-PSMA PET/CT. 68Ga-HBED-CC-PSMA uptake ranged from low in 1 patient (mean SUVmax 3.3) to intermediate (1 patient; mean SUVmax, 6.1) to intense (3 patients; mean SUVmax, 12.8, 16.2, and 18.3). The highest SUVmax values were observed for a bone lesion, reaching 39.7. Conclusions These preliminary results indicate that 68Ga-HBED-CC-PSMA PET/CT might be suitable for staging of patients with metastasized DTC. 68Ga-HBED-CC-PSMA PET/CT could be useful for the identification of patients who might qualify for PSMA-targeted radionuclide therapy because of high PSMA uptake.

High Level of Agreement Between Pretherapeutic 124I PET and Intratherapeutic 131I Imaging in Detecting Iodine-Positive Thyroid Cancer Metastases

The aim of this retrospective study was to assess the level of agreement between PET and scintigraphy using diagnostic amounts of 124I and therapeutic amounts of 131I, respectively, in detecting iodine-positive metastases in patients with differentiated thyroid carcinoma. Methods: The study included patients who underwent PET/CT 24 and 120 h after administration of approximately 25 MBq of 124I and subsequently underwent imaging 5–10 d after administration of 1–10 GBq of 131I. For each patient, the intratherapeutic 131I imaging comprised a whole-body scintigraphy scan and a SPECT/CT scan of the neck to distinguish between metastatic and thyroid remnant tissues. Iodine uptake was rated as a metastatic focus if located outside the thyroid bed. Lesion- and patient-based analyses were performed. Results: The study included 137 patients with 227 metastases iodine-positive on both functional imaging modalities. In the lesion-based analysis, 124I PET and 131I imaging detected 98% (223/227) and 99% (225/227) of the iodine-positive metastases, respectively; the level of agreement between 124I PET and 131I imaging was 97% (221/227). Four metastases (3 lymph node and 1 bone) in 4 patients were 124I-negative but 131I-positive, and 2 lymph node metastases in 2 patients were 131I-negative but 124I-positive. In the patient-based analysis, 61 of the 137 patients presented with iodine-positive metastases. 124I PET and 131I imaging detected at least one iodine-positive metastasis in 97% (59/61) and 98% (60/61) of the patients, respectively. The level of agreement was 95% (58/61). Both imaging modalities concordantly identified 76 of 137 patients without pathologic iodine uptake. Conclusion: Because of the high level of agreement, pretherapeutic 124I PET/CT is an adequate methodology in the detection of iodine-positive metastases and can be used as a reliable tool for staging of thyroid cancer patients and individualized treatment planning.

Effects of rosiglitazone on radioiodine negative and progressive differentiated thyroid carcinoma as assessed by ¹²⁴I PET/CT imaging.

Aim: The aim of this study was to evaluate the redifferentiative and antiproliferative effects of rosiglitazone in patients with progressive differentiated thyroid cancer (DTC) without or with negligible overall radioiodine uptake. Materials and Methods: A total of 9 patients with progressive DTC with either no or only negligible radioiodine accumulation were enrolled in this study. Oral rosiglitazone treatment was applied for 6 months (4 mg per day for 2 weeks followed by 8 mg per day). The compatibility of the medication was initially checked twice weekly and then weekly by laboratory tests and clinical evaluation of side effects. The assessments of alterations in the doses absorbed by the tumor and in lesion sizes over the course of rosiglitazone treatment were performed using serial 124I positron emission tomography and computed tomography imaging. The assessment time points were before enrollment and 3 and 6 months posttreatment initiation. Results: Lesion dosimetry indicated that 5 of 9 patients had an improved lesion absorbed dose per administered activity (LDpA), yielding in radioiodine therapy treatment in 4 patients. One third of the patients (3/9) were unchanged with regard to LDpA, and 1 of 9 had deteriorated LDpA. Volumetric analyses revealed that lesion sizes were regredient in 3 of 9 patients, stable in 4 of 9, and was progressive in 1 of 9. The medication was well-tolerated, and no patient developed clinically important toxicity associated with rosiglitazone treatment. In 2 of 9 of the patients, the medication was terminated after 3 months as a precaution due to progressive heart disease in one patient and bone fracture within a known osteolytic bone lesion in another patient. It is not clear that these complications were caused by rosiglitazone. Conclusion: Rosiglitazone appears to be suitable as off-label therapy in radioiodine-negative and progressive DTC that lacks therapy alternatives. In Europe, rosiglitazone was removed for label use because of reported side effects during diabetes treatment. Further investigations of other available glitazone compounds are necessary.

Does 18F-FDG PET/MRI reduce the number of indeterminate abdominal incidentalomas compared with 18F-FDG PET/CT?

ObjectiveIncidental masses of abdominal organs are a relevant problem in radiological examinations. The aim of this study was to evaluate whether simultaneous 18F-fluorodeoxyglucose (18F-FDG) PET/MRI, because of its higher soft-tissue contrast and the diversity of available pulse sequences, can reduce the number of indeterminate abdominal incidentalomas compared with 18F-FDG PET/computed tomography (CT). Materials and methodsIn this retrospective study, we enrolled 173 patients (91 women and 82 men, mean age 55.8±14.6 years) who underwent contrast-enhanced 18F-FDG PET/CT on the same day for oncological indications. Data sets were examined in a random order by two readers noting incidentalomas and incidental tracer uptake of the liver, kidneys, spleen, pancreas, adrenal glands, and gallbladder. Findings were categorized into three categories: most likely malignant, indeterminate, and most likely benign. In addition, the most relevant MR sequence for the final decision was recorded for each incidentaloma. The numbers of benign, indeterminate, and malignant findings on 18F-FDG PET/CT and 18F-FDG PET/MRI were compared. A subgroup analysis was carried out to detect potential differences with respect to lesion location (organwise) and lesion consistency (solid vs. cystic). ResultsA total of 649 upper abdominal incidentalomas were found. 18F-FDG PET/MRI detected more incidentalomas (n=635) than contrast-enhanced 18F-FDG PET/CT (n=407, P<0.001). Using 18F-FDG PET/MRI, significantly fewer incidentalomas were categorized as indeterminate compared with 18F-FDG PET/CT (n=27 vs. 91, P<0.001). This was true for cystic (P<0.001) as well as solid masses (P<0.001). Seventy incidentalomas categorized as indeterminate on contrast-enhanced 18F-FDG PET/CT could be clarified as most likely benign by 18F-FDG PET/MRI, whereas only six lesions rated as benign by 18F-FDG PET/CT were classified as indeterminate in 18F-FDG PET/MRI. 18F-FDG PET/MRI compared with contrast-enhanced 18F-FDG PET/CT had significantly fewer indeterminate findings in the liver (P<0.001), kidneys (P=0.012), and adrenal glands (P=0.002); differences for the spleen (P=0.5) were not significant. Conclusion18F-FDG PET/MRI identifies more incidentalomas than 18F-FDG PET/CT, but significantly reduces the number of indeterminate incidental findings of abdominal organs.

Diagnostic Accuracy of Virtual 18 F-FDG PET/CT Bronchoscopy for the Detection of Lymph Node Metastases in Non-Small Cell Lung Cancer Patients

The aim of this study was to determine the diagnostic accuracy of 18F-FDG PET/CT bronchoscopy for the detection of regional lymph node metastases in non–small cell lung cancer (NSCLC) patients; potential differences in the maximum standardized uptake value (SUVmax), mean SUV (SUVmean), short-axis diameter, and distance to the airways when comparing true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) lymph nodes; the smallest bronchus diameter accessible by virtual bronchoscopy; and the duration from the start of the virtual 18F-FDG PET/CT bronchoscopy viewing tool until the images were displayed. Methods: Sixty-one consecutive NSCLC patients (mean age ± SD, 58 ± 10 y) underwent whole-body 18F-FDG PET/CT. From these data, virtual 18F-FDG PET/CT bronchoscopies were reconstructed. The duration from the start of the tool until the display of virtual bronchoscopy images was determined. The diagnostic accuracy of 18F-FDG PET/CT bronchoscopy for the detection of regional lymph node metastases was evaluated on a lesion basis. Axial 18F-FDG PET/CT scans served as the standard of reference. The SUVmax, SUVmean, short-axis diameter, and distance to the airways of regional lymph nodes were measured. Lymph nodes were classified as TP, FP, TN, and FN. The smallest bronchus diameter accessible by 18F-FDG PET/CT bronchoscopy was measured. Results: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of virtual 18F-FDG PET/CT bronchoscopy for the detection of lymph node metastases were 76%, 87%, 85%, 79%, and 81%, respectively. The differences between the SUVmax, SUVmean, short-axis diameter, and distance to the airways of TP and FP as well as TN and FN lymph nodes were statistically significant (P < 0.05). The mean smallest diameter of accessible bronchi by 18F-FDG PET/CT bronchoscopy was 3 mm. The mean time duration from the start of the virtual 18F-FDG PET/CT bronchoscopy tool until the display of the images was 22 ± 7 s. Conclusion: Virtual fly-through 3-dimensional 18F-FDG PET/CT bronchoscopy yields a high diagnostic accuracy for the detection of regional lymph node metastases and has access to bronchi even in the periphery of the lung. High SUVmax, high SUVmean, large small-axis diameter, and short distance to the airways aid detection of lymph node metastases with 18F-FDG PET/CT bronchoscopy.