Daniel Putzer

Bone Metastases in Patients with Neuroendocrine Tumor: 68Ga-DOTA-Tyr3-Octreotide PET in Comparison to CT and Bone Scintigraphy

Somatostatin receptor scintigraphy is an accurate imaging modality for the diagnosis of neuroendocrine tumor. Because detection of distant metastases has a major impact on treatment, early diagnosis of metastatic spread is of great importance. So far, no standard procedure has become established for the early diagnosis of bone metastases from neuroendocrine tumor. We compared the diagnostic value of CT with that of the novel somatostatin analog 68Ga-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′′′-tetraacetic acid-d-Phe1-Tyr3-octreotide (68Ga-DOTATOC) in the detection of such metastases. Methods: Fifty-one patients (22 women and 29 men; age range, 32–87 y) with histologically verified neuroendocrine tumor were included in this study. PET scans were fused with CT scans using a vacuum fixation device. 18F-NaF or 99mTc-dicarboxypropane diphosphonate bone scans or clinical follow-up served as the reference standard. Results: Twelve of the 51 patients had no evidence of bone metastases on any of the available imaging modalities, and 37 patients had 68Ga-DOTATOC PET results true-positive for bone metastases. 68Ga-DOTATOC PET results were true-negative for 12 patients, false-positive for one, and false-negative for another, resulting in a sensitivity of 97% and a specificity of 92%. 68Ga-DOTATOC PET detected bone metastases at a significantly higher rate than did CT (P < 0.001). Furthermore, conventional bone scans confirmed the results of somatostatin receptor PET but did not reveal additional tumors in any patients. Conclusion: 68Ga-DOTATOC PET is a reliable, novel method for the early detection of bone metastases in patients with neuroendocrine tumor. Our results show that CT and conventional bone scintigraphy are less accurate than 68Ga-DOTATOC PET in the primary staging or restaging of neuroendocrine tumor.

O-(2-18F-fluoroethyl)-L-tyrosine PET predicts failure of antiangiogenic treatment in patients with recurrent high-grade glioma.

The objective of this study was to compare MRI response assessment with metabolic O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET response evaluation during antiangiogenic treatment in patients with recurrent high-grade glioma (rHGG). Methods: Eleven patients with rHGG were treated biweekly with bevacizumab–irinotecan. MR images and 18F-FET PET scans were obtained at baseline and at follow-up 8–12 wk after treatment onset. MRI treatment response was evaluated by T1/T2 volumetry according to response assessment in neurooncology (RANO) criteria. For 18F-FET PET evaluation, an uptake reduction of more than 45% calculated with a standardized uptake value of more than 1.6 was defined as a metabolic response (receiver-operating-characteristic curve analysis). MRI and 18F-FET PET volumetry results and response assessment were compared with each other and in relation to progression-free survival (PFS) and overall survival (OS). Results: At follow-up, MR images showed partial response in 7 of 11 patients (64%), stable disease in 2 of 11 patients (18%), and tumor progression in 2 of 11 patients (18%). In contrast, 18F-FET PET revealed 5 of 11 metabolic responders (46%) and 6 of 11 nonresponders (54%). MRI and 18F-FET PET showed that responders survived significantly longer than did nonresponders (10.24 vs. 4.1 mo, P = 0.025, and 7.9 vs. 2.3 mo, P = 0.015, respectively). In 4 patients (36.4%), diagnosis according to RANO criteria and 18F-FET PET was discordant. In these cases, PET was able to detect tumor progression earlier than was MRI. Conclusion: In rHGG patients undergoing antiangiogenic treatment, 18F-FET PET seems to be predictive for treatment failure in that it contributes important information to response assessment based solely on MRI and RANO criteria.

[18F]-fluoro-ethyl-l-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma

BACKGROUND To assess the sensitivity and specificity of [(18)F]-fluoro-ethyl-l-tyrosine ((18)F-FET) PET in brain tumors and various non-neoplastic neurologic diseases. METHODS We retrospectively evaluated (18)F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). (18)F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense). RESULTS Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed (18)F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher (18)F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). (18)F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions. CONCLUSIONS (18)F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood-brain barrier and (18)F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.

Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and 123I-metaiodobenzylguanidine: a clarification

Purpose 68Ga-DOTA-Tyr3-octreotide positron emission tomography (68Ga-DOTA-TOC PET) has proven to be superior to 111In-DTPA-D-Phe1-octreotide (111In-octreotide) planar scintigraphy and SPECT imaging in neuroendocrine tumours (NETs). Because of these promising results, we compared the accuracy of 123I-metaiodobenzylguanidine (123I-MIBG) imaging with PET in the diagnosis and staging of metastatic phaeochromocytoma and neuroblastoma, referring to radiological imaging as reference standard.

Virtual neck exploration: a new method for localizing abnormal parathyroid glands.

Background Data:Computed tomography (CT) together with 99mTc-sestamibi single photon emission computed tomography (MIBI-SPECT) image fusion (CT-MIBI-SPECT image fusion) allows virtual exploration of the neck. The aim of this study was to evaluate whether CT-MIBI-SPECT image fusion is superior to MIBI-SPECT and CT in detecting abnormal parathyroid glands in patients with primary hyperparathyroidism. Methods:CT-MIBI-SPECT image fusion for preoperative localization was performed in 116 patients with primary hyperparathyroidism (pHPT). Both investigations were performed with reproducible fixation of the patient on a vacuum mattress. At a special work station the neck was virtually explored by viewing the CT images in all 3 dimensions. The MIBI-SPECT images were superimposed on underlying CT images. Only patients with single-gland disease were evaluated (pHPT: 112, persistent pHPT: 1, recurrent pHPT: 1, persistent secondary hyperparathyroidism: 1, tertiary HPT after kidney transplantation: 1). CT-MIBI-SPECT image fusion results were compared with those obtained with CT alone and MIBI-SPECT alone. The predicted positions were correlated with the intraoperative findings. Results:CT-MIBI-SPECT image fusion was able to predict the exact position of the abnormal gland in 102 (88%) of the 116 patients, whereas CT alone showed in 75 (65%) patients and MIBI-SPECT alone in 64 (55%) patients the exact position of the abnormal gland. Sixty-two patients underwent minimally invasive surgery, namely in 21 patients with a unilaterally focused approach and in 33 patients with a bilateral approach (27 of these underwent simultaneous thyroid resection). Sensitivity for CT-MIBI-SPECT image fusion was 88%, for CT alone 70%, and for MIBI-SPECT alone 59%. Specificity for CT-MIBI-SPECT image fusion was 99%, for MIBI-SPECT alone 95%, for CT alone 94%. Overall accuracy for CT-MIBI-SPECT image fusion was 97%, for CT alone 89%, for MIBI-SPECT 87%. Conclusions:This study provides evidence that CT-MIBI-SPECT image fusion is superior to CT or MIBI-SPECT alone for preoperative localization of enlarged parathyroid glands in patients with single-gland primary hyperparathyroidism.

An Intra-Individual Comparison of MRI, [18F]-FET and [18F]-FLT PET in Patients with High-Grade Gliomas

Objectives Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [18F]-FET and the nucleoside PET tracer [18F]-FLT in high-grade gliomas (HGG). Methods MRI, [18F]-FET and [18F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for [18F]-FET and [18F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearmans rank correlation coefficient and the Mann-Whitney U test. Results [18F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [18F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [18F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [18F]-FET PET detected 22 of 23 (96%) HGG. [18F]-FET uptake beyond areas of cT1 was found in 61% of cases and [18F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [18F]-FET compared to [18F]-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001). Conclusion In HGG [18F]-FET but not [18F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [18F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [18F]-FLT tracer uptake.

CT-MIBI-SPECT image fusion predicts multiglandular disease in hyperparathyroidism

BackgroundTo perform focused or minimally invasive surgery for hyperparathyroidism (HPT) exact preoperative localization is mandatory. Computed tomography–99mTc-sestamibi–single photon emission computed tomography image fusion (CT-MIBI-SPECT) serves this difficult task in single gland HPT to a large extent. The aim of this study was to evaluate whether CT-MIBI-SPECT image fusion is superior to MIBI-SPECT alone and CT alone in detecting abnormal parathyroid tissue in patients with multiglandular disease.Patients and methodsCT-MIBI-SPECT image fusion for preoperative localization was performed in 30 patients with multiglandular disease. There were six patients with primary hyperparathyroidism (four MEN I syndromes and two double adenomas; one of these patients has HRPT2 gene mutation), 14 with secondary, and eight with tertiary HPT, further one patient each suffering from persistent primary and persistent secondary hyperparathyroidism. In both persistent patients only one remaining gland was left from primary surgery. The results of MIBI-SPECT, CT, and CT-MIBI-SPECT image fusion were compared in these patients. The outcome and the exact predicted positions were correlated with intraoperative findings.ResultsIn five out of six patients with multiglandular primary hyperparathyroidism more than one gland was detected, thus multiglandular disease could be suspected preoperatively. Overall CT-MIBI-SPECT image fusion was able to predict the exact position of all abnormal glands per patient in 14 of 30 (46.7%) cases, whereas CT alone was successful in 11 (36.7%), and MIBI-SPECT alone just in four (13.3%) of 30 patients.ConclusionMultiglandular disease in primary hyperparathyroidism can be suspected preoperatively in a high percentage of patients. Additionally, this study shows that CT-MIBI-SPECT image fusion is superior to CT or MIBI-SPECT alone in preoperative localization of all pathologic glands in patients suffering from multiglandular disease.

Differentiated Thyroid Cancer: A New Perspective with Radiolabeled Somatostatin Analogues for Imaging and Treatment of Patients

BACKGROUND The expression of somatostatin receptors (SSTR) in thyroid cells may offer the possibility to identify metastatic lesions and to select patients for peptide receptor radionuclide therapy (PRRT). We investigated (68)Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) to select patients with progressive differentiated thyroid cancer (DTC) for PRRT as well as treatment response and toxicity in treated patients. METHODS We enrolled 41 patients with progressive radioiodine-negative DTC (24 women and 17 men; mean age=54.3 years, median=59 years, range=19-78 years). In all patients, [(18)F]FDG-PET/CT was performed to determine recurrent disease with enhanced glucose metabolism, and (68)Ga-DOTATOC PET/CT was used to identify SSTR expression. Dosimetric evaluation was performed with (111)In-DOTATOC scintigraphy. Eleven patients were treated with PRRT receiving a fractionated injection of 1.5-3.7 GBq (90)Y-DOTATOC/administration. Serial (68)Ga-DOTATOC PET/CT scans were performed in all treated patients to evaluate treatment response. Parameters provided by (68)Ga-DOTATOC PET/CT were analyzed as potential therapeutic predictors to differentiate responding from nonresponding. In all treated patients, adverse events and toxicity were recorded. RESULTS (68)Ga-DOTATOC PET/CT were positive in 24/41 of radioiodine-negative DTC patients. Based on the high expression of SSTR detected by (68)Ga-DOTATOC PET/CT, 13 patients were suitable for PRRT. Two out of 13 patients were not treated due to the lack of fulfillment of other study inclusion criteria. PRRT induced disease control in 7/11 patients (two partial response and five stabilization) with a duration of response of 3.5-11.5 months. Objective response was associated with symptoms relief. Functional volume (FV) over time obtained by PET/CT was the only parameter demonstrating a significant difference between lesions responding and nonresponding to PRRT (p=0.001). Main PRRT adverse events were nausea, asthenia, and transient hematologic toxicity. One patient experienced permanent renal toxicity. CONCLUSIONS In our series, SSTR imaging provided positive results in more than half of the cases with radioiodine-negative DTC, and about one third of patients were eligible for PRRT. (68)Ga-DOTATOC PET/CT seems a reliable tool both for patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to better define its role.

Role of radiopharmaceuticals in the diagnosis and treatment of neuroendocrine tumours.

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms characterised by their endocrine metabolism and histological pattern, originating mainly from the gastroenteropancreatic tract (GEP NETs). As opposed to other tumour entities GEP NETs are relatively rare tumours and their diagnosis requires a high index of suspicion. NETs characteristically synthesise, store and secrete a variety of peptides and neuroamines which may lead to clinical syndromes such as the carcinoid syndrome, the Zollinger Ellison syndrome, or the Verner Morrison syndrome [1,2]. However, most GEP NETs are clinically silent until late presentation with metastases. In fact, a delayed diagnosis of NET is typical, resulting in excessive morbidity and mortality and increased probability of metastatic disease. A multidisciplinary approach for therapeutic intervention is necessary. On initial clinical presentation, NETs may be difficult to diagnose because of the large variability in tumour location and the high frequency of small lesions. The proliferation marker Ki-67 (MIB-1) is important in determining tumour grade and prognosis. Once metastasised, the therapeutic options for patients with NETs are limited. Treatment with long-acting somatostatin (SST) analogues results in reduced hormonal (over)production, and thus, relief of symptoms. Surgery is the therapy of choice in localised disease. Chemoembolisation of primary tumour/liver metastases can be attempted in order to reduce the tumour mass for subsequent therapy with radiolabelled peptide analogues in patients with slowgrowing tumours. In patients with poorly differentiated tumours chemotherapy may be considered [3]. However, the management options are manifold, and there are only a few evidence-based controlled studies available. Furthermore, formal guidelines are required. One should be aware that not all centres have the same treatment approach. For example, some believe that the long-acting SST analogues exert a beneficial effect even when the patient does not have symptoms. Positive effects of long-acting octreotide on tumour progression were assessed in the PROMID study recently [4]. In addition, there is not a general agreement as to the scope and timing of tumour debulking surgery and/or chemoembolisation [1]. The assessment of the location and extent of NETs is crucial for clinical management. Although being a heterogeneous group of neoplasms, NETs are characterised by their ability to over-express SST receptors (SSTR) at the cell surface. For localisation, conventional SSTR scintigraphy/positron emission tomography (PET), computed tomograhpy (CT)/magnetic resonance imaging (MRI), fused PET/CT or PET/MRI imaging, endoscopic ultrasound, arterial stimulation and venous sampling are used [5–8]. Other nuclear medicine techniques are also available for rare NETs. Here, we give an overview of the clinical value of radiopharmaceuticals used for diagnosis and treatment of NET patients.

[18F]choline positron emission tomography in prostate cancer patients with biochemical recurrence after radical prostatectomy: influence of antiandrogen therapy - a preliminary study.

ObjectiveOur purpose was to evaluate whether antiandrogen therapy (AAT) influences [18F]choline PET results in patients with biochemical recurrence after radical prostatectomy (RPE). MethodsThrough a retrospective study we evaluated two groups of patients, both with histologically proven carcinoma of the prostate, who had undergone RPE and a subsequent [18F]choline PET because of biochemical failure (<4 ng/dl). One group consisted of 13 patients under AAT at the time of the PET examination (age range, 55–80 years; median, 68). The other group who had not undergone AAT consisted of 22 patients (age range, 48–72 years; median, 67). Our results were correlated with follow-up information related to histopathology, changes in prostate-specific antigen levels, other imaging modalities and clinical examination. Mean follow-up was 27 months. ResultsIn patients who had undergone AAT, [18F]choline PET was true positive in eight out of 10 patients. The overall sensitivity in this group was 80%. In two cases [18F]choline PET turned out to be false negative, missing local relapse. Of the patients treated only with RPE, 10 out of 20 turned out to be true positive, resulting in a sensitivity of 50%.In all, in four patients biochemical recurrence could not be correlated to pathological findings in any of the available modalities. The difference in sensitivity between patients with and without AAT was statistically not significant (P=0.235). ConclusionIn patients with biochemical recurrence during AAT after RPE, [18F]choline PET can yield true-positive findings, even at prostate-specific antigen values of less than 4 ng/dl, and is an accurate technique for the detection of recurrence.