Multimodal Imaging of Patients With Gliomas Confirms 11C-MET PET as a Complementary Marker to MRI for Noninvasive Tumor Grading and Intraindividual Follow-Up After Therapy.

The value of combined L-( methyl-[11C]) methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n = 65 patients with histologically verified brain lesions n = 70 MET-PET and MRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2-weighted [FLAIR/T2w]) examinations were performed. The computer software "visualization and analysis framework volume rendering engine (Voreen)" was used for analysis of extent and intersection of tumor compartments. Binary logistic regression models were developed to differentiate between World Health Organization (WHO) tumor types/grades. Tumor sizes as defined by thresholding based on tumor-to-background ratios were significantly different as determined by MET-PET (21.6 ± 36.8 cm3), T1w-Gd-MRI (3.9 ± 7.8 cm3), and FLAIR/T2-MRI (64.8 ± 60.4 cm3; P < .001). The MET-PET visualized tumor activity where MRI parameters were negative: PET positive tumor volume without Gd enhancement was 19.8 ± 35.0 cm3 and without changes in FLAIR/T2 10.3 ± 25.7 cm3. FLAIR/T2-MRI visualized greatest tumor extent with differences to MET-PET being greater in posttherapy (64.6 ± 62.7 cm3) than in newly diagnosed patients (20.5 ± 52.6 cm3). The binary logistic regression model differentiated between WHO tumor types (fibrillary astrocytoma II n = 10 from other gliomas n = 16) with an accuracy of 80.8% in patients at primary diagnosis. Combined PET and MRI improve the evaluation of tumor activity, extent, type/grade prediction, and therapy-induced changes in patients with glioma and serve information highly relevant for diagnosis and management.

Inverse 1,2,3-triazole-1-yl-ethyl substituted hydroxamates as highly potent matrix metalloproteinase inhibitors: (radio)synthesis, in vitro and first in vivo evaluation.

Noninvasive imaging and quantification of matrix metalloproteinase (MMP) activity in vivo are of great (pre)clinical interest. This can potentially be realized by using radiolabeled MMP inhibitors (MMPIs) as positron emission tomography (PET) imaging agents. Triazole-substituted MMPIs, discovered by our group, are highly potent inhibitors of MMP-2, -8, -9, and -13. The triazole ring and its position contribute significantly to the potency of the MMP inhibitor. To evaluate structure-activity relationships (SARs) of the initially discovered triazole-substituted MMPIs, an additional CH2-group between the backbone of the molecule and the triazole core was inserted, and the triazole ring was "inversed" by switching the alkyne and azide groups. Similar to the original triazole-substituted hydroxamates, the inverse triazole MMPIs are excellent inhibitors with promising in vivo properties. Pharmacokinetic properties and metabolic stability of an (18)F-labeled candidate in mice were investigated.

Cerebral metastases from thyroid carcinoma: complete remission following radioiodine treatment.

BACKGROUND: Brain metastases arise in roughly 0.9% of all cases of differentiated thyroid cancer. The median survival of adult patients with thyroid carcinoma that has metastasized to the brain is less than one year. Radioactive iodine treatment is only rarely given because its efficacy is not documented. In children, the situation may be different. METHOD: In 2005, a 15-year-old girl underwent thyroidectomy, and an oxyphilic variant of papillary thyroid carcinoma was found in ectopic thyroid tissue. The patient underwent oral, high-dose radioactive iodine treatment. The post-therapeutic I-131 whole-body scan revealed multiple metastases in the skeleton, lungs, and the soft tissues, along with physiological uptake of the residual thyroid tissue. Magnetic resonance imaging of the head revealed two brain metastases. RESULTS: When the initial treatment was completed, additional age-adapted high-dose radioactive iodine treatment was given, up to a total activity level of 35 GBq. There followed a complete remission of all metastases in the brain, bones, lungs, and soft tissues. Computed tomography of the chest revealed stable residuals. Over the ensuing 7.5 years of follow-up, the thyroglobulin values steadily declined to less than 2 ng/mL. The patient was asymptomatic at her last follow-up in May 2013. She did not develop any delayed reaction to high-dose radioactive iodine treatment (in particular, she did not develop leukemia or any other secondary malignancy). She remained fertile: after completion of the treatment, she had two healthy children. CONCLUSION: In this patient with multifocal thyroid carcinoma, a rare entity, radioactive iodine treatment was successful as the single treatment. This case illustrates the point that a given therapeutic modality might succeed in an individual case despite a total or near-total lack of efficacy for most patients in the same situation.

Small-animal PET: a promising, non-invasive tool in pre-clinical research.

Today, non-invasive imaging techniques are significantly contributing to the understanding of molecular processes in vivo. Positron emission tomography (PET) is a scintigraphic medical imaging modality that uses radiolabelled molecules (tracers), provides quantitative tomographic images and allows non-invasive assessment of the biodistribution of radioactive substances in vivo. The assessment of pathological glucose metabolism is the clinically best-established application of PET today; however, a multitude of different tracers are available to assess diverse physiological processes. The growing interest in pre-clinical imaging studies, in biological and medical basic research, as well as in pharmaceutical research, has fostered the recent growth in small-animal PET. Small-animal PET can be applied to enable the transfer from molecular findings in vitro to in vivo applications in humans, from bench to bed side.

Synthesis and first in vivo evaluation of new selective high affinity beta1-adrenoceptor radioligands for SPECT based on ICI 89,406.

The results of cardiac biopsies suggest that myocardial beta1-adrenoceptor (AR) density is reduced in patients with chronic heart failure, while changes in cardiac beta2-ARs vary. A technique for visualization and quantification of beta1-AR populations rather than total beta-AR densities in the human heart would be of great clinical interest. Molecular imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET), with appropriate radiopharmaceuticals offer the possibility to assess beta-AR density noninvasively in humans, but to date, neither a SPECT nor a PET-radioligand is clinically established for the selective imaging of cardiac beta1-ARs. The aim of this study was to design a high affinity selective beta1-AR radioligand for the noninvasive in vivo imaging of cardiac beta1-AR density in man using SPECT. Based on the well-known selective beta1-AR antagonist, ICI 89,406, both the racemic iodinated target compound 11a and the (S)-enantiomer 15a were synthesized. Competition studies using the nonselective AR ligand, [(125)I]iodocyanopindolol ([(125)I]ICYP), and ventricular membrane preparations from mice showed that 11a and 15a possess higher beta1-AR affinities (up to 265-fold) and beta1-AR selectivities (up to 245-fold) than ICI 89,406. Encouraged by these results, the radioiodinated counterparts of racemic 11a (11b: (125)I, 11c: (123)I) and (S)-configurated 15a (15b: (125)I, 15c: (123)I) were synthesized. The target compounds were evaluated in rats. Biodistribution and metabolism studies in rats indicated that there is a specific heart uptake of 11b-c and especially 15b-c accompanied by rapid metabolism of the radioligands. Therefore, radioiodinated 11c and 15c appeared to be unpromising SPECT-radioligands for assessing beta1-ARs in vivo in the rat. However, the rat may metabolize beta-AR ligands more rapidly than other species as demonstrated for (S)-[(11)C]CGP 12177, a radioligand structurally related to 11a-c and 15a-c. Therefore further studies in a different animal model will be carried out.

Acute toxicity of adjuvant radiotherapy in locally advanced differentiated thyroid carcinoma. First results of the multicenter study differentiated thyroid carcinoma (MSDS).

BACKGROUND AND PURPOSE: The indication for adjuvant postoperative radiotherapy in patients with differentiated thyroid carcinoma (DTC) extending beyond the thyroid capsule has been an issue of controversy during the past 2 decades. No randomized studies evaluating the benefit of radiotherapy have been published so far. In the Multicenter Study Differentiated Thyroid Carcinoma (MSDS), a randomization has been performed concerning external-beam radiotherapy in patients with DTC extending beyond the thyroid capsule (pT4 pN0/1/x cM0, TNM classification, 5th edition, 1997) following surgery and radioiodine therapy. Radiation-associated toxicity has been prospectively evaluated. PATIENTS AND METHODS: Radiotherapy was performed with 50.4 Gy (pN0) or 54.0 Gy (pN1/x) to the cervical, supraclavicular and upper mediastinal lymph nodes. A total dose of 59.4 Gy (R0 resection) or 66.6 Gy (R1) was used to treat the tumor bed. Conventional fractionation was used with 1.8 Gy/d. At the time of the analysis, 36 patients were randomized or allocated to treatment arm A (with external-beam radiotherapy). Of these, 22 were treated with radiotherapy, and documentation of acute toxicity was available. Toxicity was evaluated prospectively according to the RTOG/EORTC criteria. RESULTS: The maximal acute toxicity observed during radiotherapy was grade I in four patients, grade II in 16 patients, and grade III in two patients (9.1%; 95% confidence interval [95% CI] 1.1-29.2%). Toxicity was mainly observed at the pharynx, larynx, and skin. In 19 patients, residual toxicity within 100 days following radiotherapy was evaluated. No residual toxicity was observed in two patients. Maximal residual toxicity was grade I in 13 patients and grade II in four. No further grade III toxicity could be observed. CONCLUSION: The majority of patients experience mild to moderate side effects from adjuvant external-beam radiotherapy. At the first follow-up examination, most side effects have subsided. Acute toxicity is tolerable in these patients.

Prognostic significance of amino acid transport imaging in patients with brain tumors.

OBJECTIVE: To evaluate the prognostic significance of presence, intensity, and extent of amino acid uptake in patients with suspected primary or recurrent brain tumors. METHODS: We retrospectively analyzed 181 consecutive studies of amino acid uptake using single-photon emission computed tomography and the amino acid l-[3-(123)I]iodo-alpha-methyltyrosine (IMT). In a blinded analysis, all studies were evaluated for presence, maximal uptake (IMT(max)), and extent (IMT(ext)) of focal tracer uptake. RESULTS: The most frequent tumors were 53 astrocytomas (World Health Organization Grade I-III), 41 glioblastomas, 16 metastases, 13 oligodendrogliomas (Grade II-III), and 10 medulloblastomas. The other patients exhibited various parenchymal tumors or nonneoplastic lesions. IMT uptake was present in 69% of the patients with IMT(max) ranging from 1.4 to 6.2. IMT(max) and IMT(ext) were significant predictors of survival in the whole group. When the group was divided according to primary versus recurrent tumor, only the primary tumors achieved a high level of significance (P < 0.01). When patients without any IMT uptake were excluded from the analysis, statistical significance for both IMT(max) and IMT(ext) was lost. Multiple regression analysis, including IMT(max), IMT(ext), age, and tumor grade, revealed only extent of IMT uptake as an independent predictor of prognosis. CONCLUSION: Absence of IMT uptake is a significant predictor of long-term survival in patients with suspected primary or recurrent brain tumors. Only the extent of a given lesion provided minor supplementary prognostic information as compared with histopathology and age. These findings suggest caution in relating high amino acid uptake values to poor prognosis, despite the capability of amino acid imaging to help determine the presence and extent of gliomas.