Helmut Dittmann

PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study

The aim of this study was to evaluate the use of [18F]fluorothymidine (FLT) as a positron emission tomography (PET) tracer for the diagnosis of breast cancer. To this end, 12 patients with 14 primary breast cancer lesions (T2–T4) were studied by FLT-PET. For comparison, [18F]fluorodeoxyglucose (FDG) PET scans were performed in six patients. Thirteen of the 14 primary tumours demonstrated focally increased FLT uptake (SUVmean=3.4±1.1). Seven out of eight patients with histologically proven axillary lymph node metastases showed focally increased FLT uptake in the corresponding areas (SUVmean=2.4±1.2). The lowest SUV (mean =0.7) was observed in one of two inflammatory cancers. The contrast between primary tumours or metastases and surrounding tissue was high in most cases. In direct comparison to FDG-PET, the SUVs of primary tumours (5/6) and axillary lymph node metastases (3/4) were lower in FLT-PET (SUVFLT: 3.2 vs SUVFDG: 4.7 in primary tumours and SUVFLT: 2.9 vs SUVFDG: 4.6 in lymph node metastases). Since FLT uptake in surrounding breast tissue was also lower, tumour contrast was comparable to that with FDG. It is of note that normal FLT uptake was very low in the mediastinum, resulting in a higher tumour-to-mediastinum ratio as compared to FDG (P=0.03). FLT-PET is suitable for the diagnosis of primary breast cancer and locoregional metastases. High image contrast may facilitate the detection of small foci, especially in the mediastinum.

Is standardised 18F-FDG uptake value an outcome predictor in patients with stage III non-small cell lung cancer?

PurposeRecent studies have demonstrated the relevance of 18F-FDG uptake as an independent prognostic factor for recurrence of operable non-small cell lung cancer (NSCLC). This corresponds with the experimental finding that FDG uptake correlates with the proliferative activity of tumour cells (Higashi et al., J Nucl Med 2000;41:85-92). On the basis of these observations, we studied the influence of FDG uptake on prognosis and occurrence of distant metastases in patients with advanced NSCLC.MethodsOne hundred and fifty-nine patients with NSCLC of UICC stage IIIA or IIIB were included in the study. In all patients, neoadjuvant treatment was planned to achieve operability. FDG PET was performed as an additional staging procedure prior to the initiation of therapy. Clinical outcome data in terms of overall survival, disease-free survival and incidence of distant metastases could be obtained for 137 patients and were correlated with the average standardised uptake value of the tumour (SUVavg). Furthermore, other factors influencing SUVavg and patient outcome (histological tumour type, grading, UICC stage, tumour size) were analysed.ResultsSUVavg was significantly influenced by tumour histology, UICC stage and tumour size. No significant difference could be shown for grading. In 38 out of the 159 patients (24%), FDG PET revealed previously unsuspected distant metastases. The incidence of distant metastases significantly correlated with SUVavg. Overall survival tended to decrease with increasing SUVavg; however, significance was only reached when a cut-off of 12.0 was applied (p=0.05).ConclusionFDG uptake is an independent prognostic factor in patients with UICC stage III NSCLC, although less distinctively so than has been reported for stage I/II tumours.

Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced- intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-Hodgkin lymphoma: results of a phase 2 study

Forty patients were enrolled in this phase 2 study combining radioimmunotherapy (RIT) using yttrium-90-ibritumomab-tiuxetan (15 MBq [0.4 mCi]/kg) with reduced-intensity conditioning (RIC) using fludarabine (90 mg/m(2)) and 2 Gy total body irradiation followed by allogeneic hematopoietic cell transplantation (HCT) from related (n = 13) or unrelated (n = 27) donors for the treatment of advanced non-Hodgkin lymphoma. Diagnoses were follicular lymphoma (n = 17), chronic lymphocytic leukemia (n = 13), mantle cell lymphoma (n = 8), marginal zone lymphoma (n = 1), and lymphoplasmacytic lymphoma (n = 1). Median age was 55 years (range, 34-68 years). All patients were high risk with refractory disease or relapse after preceding autologous HCT. No additional toxicities attributable to RIT were observed. Engraftment was rapid and sustained. Incidences of acute graft-versus-host disease 2-4 and chronic graft-versus-host disease were 43% and 53%, respectively. Kaplan-Meier-estimated nonrelapse mortality was 45% at 2 years. Twenty-two of 40 patients (55%) are alive, resulting in a Kaplan-Meier-estimated 2-year survival of 51% for all, 67% for follicular lymphoma, 49% for chronic lymphocytic leukemia, and 37% for mantle cell lymphoma patients. The combined use of RIT with RIC is feasible with acceptable toxicity, even in elderly and heavily pretreated patients. This study is registered at www.clinicaltrials.gov as #NCT00302757.

PET/CT for the assessment and quantification of 90Y biodistribution after selective internal radiotherapy (SIRT) of liver metastases

Dear Sir, We read with great interest the recently published Image of the Month by Lhommel et al. “Yttrium-90 TOF PET scan demonstrates high-resolution biodistribution after liver SIRT” [1]. The authors used a high-end time-of-flight (TOF) PET/CT in order to detect the annihilation photons that occur after internal pair formation in Y [2–4]. The authors show that Y PET/CT is feasible and potentially yields a better spatial resolution than bremsstrahlung scintigraphy or SPECT typically used for the evaluation of Y biodistribution after selective internal radiotherapy (SIRT) [5]. The authors used a 2.5-mm copper ring to prevent saturation of the PET detectors arising from the bremsstrahlung photons. In our department we had initiated similar measurements albeit with a non-TOF PET/CT (biograph Hi-Rez 16, Siemens Healthcare, Erlangen, Germany). Our results indicate that, in addition to the findings of Lhommel et al., Y PET/CT can be performed even without an advanced TOF mode (Fig. 1a). Saturation of the detectors did not seem to be an issue with our scanner, so an additional shielding of Y bremsstrahlung with a copper ring was not essential. We would like to add to the results presented by Lhommel and colleagues data from phantom studies performed using an International Electrotechnical Commission (IEC) hotsphere phantom with a Y concentration of 3.6 MBq/ml and an acquisition time of 40 min/bed position (Fig. 1c). Our studies using non-TOF PET/CT with 4×4 mm lutetium oxyorthosilicate (LSO) detector elements revealed a recovery coefficient (RC) of 0.6–1.0 with spheres 17 mm or larger in diameter. Recovery increased with the sphere diameter (Fig. 1d). Assuming a hot background (healthy liver tissue receiving a minor Y dose), a lesion size of approximately 17 mm seems to be the limit for reliable detectability with our PET/CT system. Using ordered subset expectation maximization (OSEM) reconstruction, a resolution of 5.2±0.6 mm (336×336 matrix, 8 iterations, 16 subsets) and 7.8±0.5 mm (128×128 matrix, 4 iterations, 8 subsets) was achieved. Our studies suggest a minimum concentration of 1MBq/ml of Y for PET imaging, which is easily obtained in SIRT. The sensitivity for Y PET is reduced by a factor of 3.4e-5 in comparison to F PET. Although bremsstrahlung scans (Fig. 1b) will probably remain the method of choice for the assessment of Y biodistribution in most applications, PET/ CT is possible in cases of sufficient radioactivity concentration in the target tissue as achieved in SIRT. Y PET/CT could become a versatile adjunct as we see combined PET/ M. K. Werner (*) :K. Brechtel :C. Pfannenberg Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University Medical Center, Tübingen, Germany e-mail: Matthias.Werner@med.uni-tuebingen.de

Accuracy of parathyroid imaging: a comparison of planar scintigraphy, SPECT, SPECT-CT, and C-11 methionine PET for the detection of parathyroid adenomas and glandular hyperplasia.

PURPOSE To compare the accuracy of planar scintigraphy, single photon emission computed tomography (SPECT), SPECT-CT, and positron emission tomography (PET) with C-11 methionine for the pre-operative detection of parathyroid adenomas. MATERIALS AND METHODS We retrospectively evaluated the pre-operative studies of 60 patients with primary (n=56) and secondary (n=4) hyperparathyroidism. In 25/60 patients (Group 1), only planar scans were obtained, and additional SPECT and SPECT-CT were carried out in 35/60 patients (Group 2). PET or PET-CT with C-11 methionine was conducted in 8/60 patients (Group 3). RESULTS The results of the planar scans (Group 1) were true positive in 19/25 patients and false negative in 6/25 patients (sensitivity per patient, 76%). Histopathology confirmed 27 adenomas and two hyperplasia. Planar imaging identified 20/29 of these pathologies, whereas 9/29 were missed (sensitivity per adenoma, 69%). SPECT (Group 2) results were true positive in 34/35 patients and false negative in only one case (sensitivity per patient, 97%). On a lesion-based analysis, 38 adenomas were identified, and two were missed (sensitivity per adenoma, 95%). The sensitivities of SPECT and SPECT-CT were equal; however, SPECT-CT provided superior topographic information. C-11 methionine PET (Group 3) results were true positive in all eight patients. In one case, surgery confirmed two ipsilateral adenomas, only one of which was identified by PET (sensitivity per patient, 100%; per adenoma, 88.9%). CONCLUSION SPECT is superior to planar imaging. SPECT-CT has identical sensitivity compared to SPECT alone, but it provides additional topographic information. The sensitivity of PET appears to be even higher compared to SPECT. In the case of negative scintigraphic findings and proven hyperparathyroidism, additional C-11 methionine PET or PET-CT is recommended.

In vitro studies on the cellular uptake of melanoma imaging aminoalkyl-iodobenzamide derivatives (ABA)

The cellular uptake of 11 radioiodinated aminoalkyl-iodobenzamides (ABA) was studied using cultivated murine melanoma cells (B16/C3). All derivatives showed a high uptake (up to about 80%) of radioactivity in melanotic melanoma cells; hence, accumulation of all compounds radioiodinated in the ortho position was reduced by approximately 30%. Using the compound para-[131I]iododiethyl-aminoethylbenzamide (p-131I-ABA-2-2) a close correlation of the cellular melanin content with the tracer uptake (R2 = 0.95) was verified. The presence of extracellular melanin, however, had no effect on the cellular tracer uptake. Because the accumulation was independent of the specific activity of p-131I-ABA-2-2, a significant contribution to the uptake process by binding to receptor sites could be excluded.

PET/CT with 18F-FLT: Does It Improve the Therapeutic Management of Metastatic Germ Cell Tumors?

Because 18F-FDG PET alone has only limited value in metastatic germ cell tumors (GCTs), we investigated the addition of 3′-deoxy-3′-18F-fluorothymidine (FLT) to 18F-FDG for early response monitoring and prediction of the histology of residual tumor masses in patients with metastatic GCT. Methods: Eleven patients with metastatic GCT were examined with both 18F-FDG PET/CT and 18F-FLT PET/CT before chemotherapy, after the first cycle of chemotherapy (early response), and 3 wk after completion of chemotherapy. In 1 patient with negative 18F-FLT PET/CT results before chemotherapy, no further 18F-FLT scanning was performed. PET images were analyzed visually and, using standardized uptake values (SUVs), semiquantitatively. The results were compared with the findings of CT and tumor marker levels and validated by histopathologic examination of resected residual masses, including Ki-67 immunostaining (7 patients), or by clinicoradiologic follow-up for at least 6 mo (4 patients). A responder was defined as a patient showing the presence of necrosis, a complete remission, or a marker-negative partial remission within a minimum progression-free interval of 6 mo. Early treatment response was judged according to the criteria of the European Organization for Research and Treatment of Cancer. Results: Before chemotherapy, reference lesions showed increased 18F-FDG uptake (mean SUV, 8.8; range, 2.9–15.0) in all patients and moderate 18F-FLT uptake (mean SUV, 3.7; range, 1.7–9.7) in 10 of 11 patients. After 1 cycle of chemotherapy, mean SUV decreased in responders and nonresponders by 64% and 60%, respectively, for 18F-FDG (P = 0.8) and by 58% and 48%, respectively, for 18F-FLT (P = 0.5). After the end of chemotherapy, mean SUV decreased in responders and nonresponders by 85% and 73%, respectively, for 18F-FDG (P = 0.1) and by 68% and 65%, respectively, for 18F-FLT (P = 0.8). The results of early and final PET were inconsistent in 6 of 11 patients for 18F-FDG and in 4 of 10 patients for 18F-FLT. Both patients with teratoma had false-negative results on both 18F-FDG and 18F-FLT. The sensitivity, specificity, positive predictive value, and negative predictive value for detection of viable tumor after 1 cycle of chemotherapy were 60%, 33%, 43%, and 50%, respectively, for 18F-FDG and 60%, 80%, 75%, and 67%, respectively, for 18F-FLT PET/CT. The respective values after the end of chemotherapy were 20%, 100%, 100%, and 60% for 18F-FDG and 0%, 100%, 0%, and 50% for 18F-FLT PET/CT. Conclusion: PET-negative residual masses after chemotherapy of metastatic GCT still require resection, since the low negative predictive value of 18F-FDG PET for viable tumor cannot be improved by application of 18F-FLT.

Peptide receptor radionuclide therapy of neuroendocrine tumors with 90Y-DOTATOC: Is treatment response predictable by pre-therapeutic uptake of 68Ga-DOTATOC?

PURPOSE PET with (68)Ga-DOTATOC allows for imaging and quantitative assessment of somatostatin receptor expression in neuroendocrine tumors (NET). The aim of this retrospective study was to analyze whether pre-therapeutic (68)Ga-DOTATOC PET/CT is able to predict response to Peptide Receptor Radionuclide Therapy (PRRT). PATIENTS AND METHODS Forty patients with advanced stage NET were treated with a fixed dose of (90)Y-DOTATOC (5550 or 3700MBq). Prior to PRRT, each patient received (68)Ga-DOTATOC PET/CT. Treatment results were evaluated after 3months by CT, tumor marker levels and clinical course and correlated with (68)Ga-DOTATOC uptake (SUVmax) and the assumed uptake of (90)Y-DOTATOC in tumor manifestations (MBq/g). ROC analysis and pairwise comparison of area under the curve (AUC) were performed with pre-treatment uptake of (68)Ga-DOTATOC, assumed uptake of (90)Y-DOTATOC and treatment activity alone and in relation to body weight as continuous variables, and response/no response as classification variable. RESULTS According to conventional criteria (tumor shrinkage, decrease of tumor markers, improved or stable clinical condition), 20 patients were classified as responders, 16 as non-responders and in four patients findings were equivocal. Using a SUV more than 17.9 as cut-off for favorable outcome, PET was able to predict treatment response of all responders and 15 out of 16 non-responders. All four patients with equivocal findings showed SUV less than or equal to 17.9 and soon experienced tumor progression. The assumed uptake of (90)Y-DOTATOC in tumor manifestations using a cut-off more than 1.26MBq/g as predictor of response was able to correctly classify 19 out of 20 responders, and 14 out of 16 non-responders. In all patients with equivocal findings, the assumed uptake of (90)Y-DOTATOC was below 1.26MBq/g. CONCLUSION Pre-therapeutic (68)Ga-DOTATOC tumor uptake as well as assumed uptake of (90)Y-DOTATOC are strongly associated with the results of subsequent PRRT. The defined cut-off values should be confirmed by prospective studies and may then provide the rationale for individual dosing and selecting patients with high likelihood of favorable treatment outcome.

Comprehensive assessment of renal function and vessel morphology in potential living kidney donors: an MRI-based approach.

Objectives:To test the feasibility of a single MR-based examination allowing for the comprehensive assessment of renal anatomy, function, and vascular status in candidates for kidney transplantation. Materials and Methods:Twelve healthy potential kidney donors (mean age: 47 ± 14 [standard deviation] years, 3 men and 9 women) participated in the study, which was approved by the local ethics committee. MR-nephrography was performed using a navigator-gated T1-weighted saturation-recovery sequence (TrueFISP: TR/TE = 621.31 milliseconds/1.27 milliseconds, Flip angle = 70 degrees, TI = 300 milliseconds, BW = 977 Hz/Px, or TurboFLASH: TR/TE = 528 milliseconds/1.15 milliseconds, Flip angle = 8 degrees, TI = 300 milliseconds, BW = 600 Hz/Px). Images were acquired up to 60 minutes after the injection of 4 mL of gadobutrol. The glomerular filtration rate (GFR) was evaluated from the renal clearance of gadobutrol within the extra cellular fluid volume by exponential fitting of time-signal curves measured over the liver. MR-angiography was performed using a T1-weighted 3D-Flash sequence. The overall measuring time was 70 to 80 minutes. For each subject, GFR data were compared with the results of renal scintigraphy with 99mTc-labeled DTPA from the same day. Results:Kidney anatomy and vascular status were successfully assessed in all subjects. The results of MR-angiography were in excellent accordance with the surgical findings. MR-nephrography presented a good agreement to the scintigraphy (mean GFR from MR-nephrography = 117 ± 24 mL/min per 1.73 m2; mean GFR from scintigraphy = 116 ± 26 mL/min per 1.73 m2). The Bland-Altman-plot showed a mean difference in measurements pairs of −1 ± 12 mL/min per 1.73 m2. The absolute paired difference ranged between 0 and 22 mL/min per 1.73 m2. Conclusions:The study showed the feasibility of the comprehensive assessment of renal anatomy, function, and vascular morphology, using 1 single MR examination. The proposed protocol may find immediate clinical application in the preoperative assessment of potential kidney donors.

Uptake of mIBG and catecholamines in noradrenaline- and organic cation transporter-expressing cells: potential use of corticosterone for a preferred uptake in neuroblastoma- and pheochromocytoma cells

For imaging of neuroblastoma and phaeochromocytoma, [(123)I]meta-iodobenzylguanidine ([(123)I]mIBG) is routinely used, whereas [(18)F]6-fluorodopamine ([(18)F]6-FDA) is sporadically applied for positron emission tomography in pheochromocytoma. Both substances are taken up by catecholamine transporters (CATs). In competition, some other cell types are able to take up catecholamines and related compounds probably by organic cation (OCT) [extraneuronal monoamine (EMT)] transporters (OCT1, OCT2, OCT3=EMT). In this study, we investigated the uptake of radioiodine-labeled meta-iodobenzylguanidine (mIBG) as well as [(3)H]dopamine (mimicring 6-fluorodopamine) and [(3)H]noradrenaline. SK-N-SH (neuroblastoma) and PC-12 (phaeochromocytoma) cells were used and compared with HEK-293 cells transfected with OCT1, OCT2 and OCT3, respectively. In order to gain a more selective uptake in CAT expressing tumor cells, different specific inhibitors were measured. Uptake of mIBG into OCT-expressing cells was similar or even better as into both CAT-expressing cell lines, whereas dopamine and noradrenaline uptake was much lower in OCT-expressing cells. In presence of corticosterone (f.c. 10(-4) M], catecholamine and mIBG uptake into SK-N-SH and PC-12 cells was only slightly reduced. In contrast, this process was significantly inhibited in OCT2 and OCT3 transfected HEK-293 as well as in Caki-1 cells, which naturally express OCT3. We conclude that the well-known corticosteroid corticosterone might be used in combination with [(18)F]6-FDA or [(123)I]mIBG to improve specific imaging of neuroblastoma and pheochromocytoma and to reduce irradiation dose to nontarget organs in [(131)I]mIBG treatment.