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Purpose: Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor. Methods: Using multivariable-adjusted survival analyses and competing risk analyses we evaluated outcomes in patients with neuroendocrine tumor receiving 90Y-DOTATOC, 177Lu-DOTATOC or their combination. Results: 90Y-DOTATOC plus 177Lu-DOTATOC treatment was associated with longer survival than 90Y-DOTATOC (66.1 vs. 47.5months; n = 1,358; p < 0.001) or 177Lu-DOTATOC alone (66.1 vs. 45.5months; n = 390; p < 0.001). 177Lu-DOTATOC was associated with longer survival than 90Y-DOTATOC in patients with solitary lesions (HR 0.3, range 0.1-0.7; n = 153; p = 0.005), extrahepatic metastases (HR 0.5, range 0.3-0.9; n = 256; p = 0.029) and metastases with low uptake (HR 0.1, range 0.05-0.4; n = 113; p = 0.001). 90Y-DOTATOC induced higher hematotoxicity rates than combined treatment (9.5% vs. 4.0%, p = 0.005) or 177Lu-DOTATOC (9.5% vs. 1.4%, p = 0.002). Renal toxicity was similar among the treatments. Conclusions: Using 90Y and 177Lu might facilitate tailoring radiopeptide therapy and improve survival in patients with neuroendocrine tumors.

Purpose: The aim of this study was to compare ST-segment depression (STD) during bicycle ergometry and extent of myocardial ischaemia assessed by myocardial perfusion SPECT (MPS) in a large patient cohort. Methods: Consecutive patients (n = 955) referred for MPS with bicycle ergometry and interpretable stress ECG were evaluated with respect to ECG and MPS findings of ischaemia. The maximal STD was recorded and exercise ECG was considered ischaemic if STD was horizontal or downsloping (≥1mm). MPS was interpreted using a 20-segment model with a scale of 0 to 4. A summed stress (SSS), summed rest (SRS) and summed difference score (SDS = SSS−SRS, e.g. extent of ischaemia) were derived. Ischaemia was defined as an SDS ≥ 2. Results: An exercise-induced STD was present in 215 patients (22%) and myocardial ischaemia on MPS was present in 366 patients (38%). The extent of ST-segment depression and the number of ECG leads with significant STD were each strongly and significantly associated with increasing severity of ischaemia and the number of coronary territories involved (p < 0.01 for all correlations). Conclusion: These data demonstrate a strong correlation between the extent of STD, number of ischaemic leads and severity of myocardial ischaemia as assessed by MPS during bicycle ergometry

Purpose: Carbimazole ameliorates hyperthyroidism but reduces radioiodine uptake and adversely affects the outcome of simultaneous radioiodine therapy. We explored whether withdrawal of carbimazole for 3 days can restore the outcome of radioiodine treatment without concurrent exacerbation of hyperthyroidism. By generating three groups with comparable radioiodine uptake, we also investigated whether the effect of carbimazole depends on the radioiodine uptake. Methods: Stratified by a radioiodine uptake >30%, 227 consecutive adult patients were prospectively assigned to radioiodine therapy (target dose 200Gy) without, on or 3days off carbimazole. Patients were clinically (Crooks-Wayne score) and biochemically (T3, fT4, TSH) followed up after 3, 6 and 12months. Primary endpoint was outcome 12months after radioiodine therapy. Results: A total of 207 patients completed follow-up (toxic nodular goitre, n=117; Graves' disease, n=90). The overall success rate was 71.5%. Patients without and 3days off carbimazole had similar biochemical (81.4% and 83.3%, respectively; p=0.82) and clinical outcomes [median (range) Crooks-Wayne score 0 (0-16) and 1 (0-10), respectively; p=0.73], which were both higher than in patients on carbimazole [42.6%, p<0.001; Crooks-Wayne score 3 (0-30), p<0.03]. Time to achieve cure was delayed on carbimazole. No changes in thyroid hormone levels occurred after 3days' discontinuation of carbimazole. Logistic regression revealed that all observed cure rates were independent of entity, sex, age, thyroid volume, radioiodine uptake, radioiodine half-life, fT4, T3 and TSH. Conclusion: Patients under carbimazole treatment can be referred for radioiodine therapy after withdrawal of carbimazole for only 3days. Three days of carbimazole withdrawal is long enough to restore the success of radioiodine therapy and short enough to avoid the risk of exacerbation of hyperthyroidism

Purpose: Substance P is the main ligand of neurokinin type 1 (NK-1) receptors, which are consistently overexpressed in malignant gliomas. The peptidic vector 111In/90Y-DOTAGA-substance P binds to these receptors and can be used for local treatment of brain tumours. Dosimetry for this interstitial brachytherapy has mainly been done using geometrical models; however, they often do not faithfully reproduce the in vivo biodistribution of radiopharmaceuticals, which is indispensable to correlate the deposited energy with clinical response. The aim of this study was to establish a reproducible dosimetry protocol for intratumoural radiopeptide therapy. Methods: For test and therapeutic injections, 2MBq of 111In-substance P and 370-3,330MBq of 90Y-substance P, respectively, were applied in 12 patients with malignant gliomas. Over a period of 24h, serial SPECT scans were performed on a dual-head SPECT camera. The scans were acquired in a double-energy window technique together with 99mTc-ECD in order to co-register the dose distributions with a separately acquired, contrast-enhanced CT scan. Quantitative voxelwise dose distribution maps (in Gy/GBq) were computed from these data using a mono-exponential decay approach. Pre- and post-therapeutic values were compared. Results: Agreement between pre- and post-therapeutic dosimetry was very good and delivered absolute dose values in Gy per injected GBq. In all patients, the pretherapeutic test injection together with the CT overlay technique could predict the precise localisation of dose deposition in an anatomical context. Conclusion: This protocol allows a precise pretherapeutic computation of the expected three-dimensional dose distribution and is clearly superior to the previously used dosimetry based on planar scintigraphic images. It has become an indispensable tool for planning intratumoural radiopeptide therapy in glioma patients

Purpose: 131I- and 90Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin's lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (<20min) with either 177Lu or 90Y. Materials and methods: Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. Results: The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 105 times excess of diethylenetriaminepentaacetic acid (DTPA, 37°C, 7days). Two patients with relapsed NHL were treated with 740MBq/m2 body surface 177Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314mGy. The administration of 177Lu-DOTA-rituximab was tolerated well. Conclusion: Our results show that DOTA-rituximab (4:1) can be labelled with 177Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. 177Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NHL

Purpose: We aimed to assess the impact of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis. Methods: An international expert panel determined diagnoses and clinical management in patients with suspected large vessel vasculitis, with and without the results of 18F-FDG PET, respectively. The accuracy of the clinical diagnosis and the resulting clinical management with and without the 18F-FDG PET results were compared using logistic regression models. Results: The analysis included 30 patients referred to a tertiary care centre with large vessel vasculitis and 31 controls. 18F-FDG PET had an overall sensitivity of 73.3% [95% confidence interval (CI) 54.1-87.7%], a specificity of 83.9% (95% CI 66.3-94.5%), a positive predictive value of 81.5% (95% CI 61.9-93.7%) and a negative predictive value of 76.5% (95% CI 58.8-89.3%). The diagnostic accuracy of 18F-FDG PET was higher in patients not receiving immunosuppressive drugs (93.3 vs 64.5%, p = 0.006). Taken in context with other available diagnostic modalities, the addition of 18F-FDG PET increased the clinical diagnostic accuracy from 54.1 to 70.5% (p = 0.04). The addition of 18F-FDG PET increased the number of indicated biopsies from 22 of 61 patients (36.1%) to 25 of 61 patients (41.0%) and changed the treatment recommendation in 8 of 30 patients (26.7%) not receiving immunosuppressive medication and in 7 of 31 patients (22.6%) receiving immunosuppressive medication. Conclusion: 18F-FDG PET is a sensitive and specific imaging tool for large vessel vasculitis, especially when performed in patients not receiving immunosuppressive drugs. It increases the overall diagnostic accuracy and has an impact on the clinical management in a significant proportion of patients

Complete surgical resection beyond tumor margins cannot be achieved in glioblastoma multiforme (GBM) because of infiltrative nature. In several cancers, neoadjuvant treatment has been implemented to reduce the risk of tumor cell spreading during resection. In GBM, the objective of a neoadjuvant approach is reduction of tumor cells within the main tumor mass and beyond in the infiltration zone. Such an approach can only be performed if elevated intracranial pressure can be medically controlled. In a previous study with recurrent gliomas, we showed that local intratumoral injection of radiolabeled DOTAGA-substance P substantially inhibited further growth and led to radionecrotic transformation of the tumor (CCR 2006). We have now examined this modality as neoadjuvant treatment for GBM, primarily assessing feasibility, toxicity, the extent of resection, and functional outcome. After diagnosis of GBM, 17 patients were included in a prospective phase I study. Repetitive intratumoral injections of radiolabeled DOTAGA-substance P were performed, followed by surgical resection. Chemical synthesis, radiolabeling, and local injection of the peptidic vector [90Yttrium]-DOTAGA-substance P were described previously. Neoadjuvant injection of [90Y]-DOTAGA-substance P was feasible without decompensation of intracranial pressure. Prolonged application of corticosteroids was identified as the main risk factor for side effects. Fifteen patients stabilized or improved their functional status. The mean extent of resection in subsequent surgery was 96%. Neoadjuvant therapy of GBM using locally injected radiolabeled DOTAGA-substance P was feasible and of low toxicity. The high extent of resection and concomitant irradiation of tumor cells in the infiltration zone may be prognostically relevant