[Peptide receptor radionuclide therapy for patients with somatostatin receptor expressing tumours. German Guideline (S1)]. / Peptidrezeptor-Radionuklidtherapie Somatostatinrezeptor-exprimierender Tumore. DGN-Leitlinie (S1).

This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.

[Neuroendocrine neoplasms of the distal jejunum and ileum]. / Neuroendokrine Neoplasien des distalen Jejunums und Ileums.

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.

[Neuroendocrine tumours of the GI tract--data from the German NET Registry]. / Neuroendokrine Tumoren des Verdauungstrakts - Daten des deutschen NET-Registers.

BACKGROUND: Neuroendocrine tumours (NET) are rare and heterogeneous neoplasia. To obtain valid data on epidemiology, diagnostics, therapy, prognosis and risk factors is the aim of the German NET registry. PATIENTS AND METHODS: Data from 2009 histologically proven NET were collected from 35 NET centres between 1999 and 2010. Data collection has been performed prospectively since 2004. Results: Median follow-up was 34.5 months and median age at diagnosis 56.4 years. Primary tumour localisations were pancreas (34.2%), midgut (5.8%), stomach (6.5%), bowel (6.9%), duodenum (4.8%) and neuroendocrine CUP (12.6%). Synchronous metastases were seen in 46% and second malignancies in 12%. From 860 patients, 402 (46.7%) had functional tumours with the following hormone excess syndromes: carcinoid syndrome (19.1%; n = 164), persistent hyperinsulinaemic hypoglycaemia (17.7%; n = 152), Zollinger- Ellison syndrome (7.1%; n = 61), glucagonoma (0.7%; n = 15), Verner-Morrison syndrome (0.4%; n = 8) and somatostatinoma syndrome(0.1%; n = 2). Surgical therapy was performed in 78%, therapy with somatostatin receptor analogues(SSA) in 28%, peptide radioreceptor therapy (PRRT) in 19%, chemotherapy in 18% and interferon therapy in 6.5%. Only surgery was done in 47%, whereas 53% received a second therapy. General mortality rate during follow-up was 14.9%. The tumour-specific survival rates for 2, 5 and 10 years were 94, 85 and 70%. The 5-year survival is dependent on the surgical or non-surgical therapy (82 versus 61%, p < 0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p < 0.001). Grading (G1, G2, G3) based on proliferation index Ki-67 recommended by the ENETS guidelines and WHO classification is highly correlated to the 5-year survival rate (88, 82, 33%, p < 0.001). CONCLUSION: The German NET registry provides valid multicentric data on NET in Germany. Surgical therapy is the most frequent and important therapy with good clinical outcome. In non-resectable, metastatic tumours, systemic therapies are common. Continuation and evaluation of the new WHO and TNM classifications for NET and their therapies will be a future focus of the registry.

An unusual case of ectopic ACTH syndrome.

Ectopic ACTH-syndrome is a rare cause of Cushing's disease. Despite extensive diagnostic procedures the source of ACTH secretion often remains occult. This case describes a 45-year old woman with an ectopic Cushing's syndrome. Extensive imaging procedures including CT scan of chest and abdomen, octreotide scan and MRI of the chest and pituitary did not reveal the source of ACTH secretion. In consideration of an occult source of ACTH secretion we started a therapeutic trial with cabergoline (0.5 mg/d), a dopamine receptor agonist, which has been shown to be effective in ectopic Cushing's syndrome. 2 months after cabergoline treatment had been initiated, ACTH and cortisol levels normalized in association with significant improvement of the clinical symptoms. During follow-up a [(68)Ga-DOTA-dPhe(1), Tyr(3)]-octreotate ([(68)Ga-DOTA]-TATE) PET-CT was performed revealing a somatostatin receptor positive lesion in the right sphenoidal sinus suggesting the source of ACTH secretion. The patient was cured by transnasal resection of the polypoid lesion, which was immunohistochemically characterized as an ACTH-positive neuroendocrine tumor. This case report demonstrates the management of ectopic ACTH-syndrome by molecularly -targeted therapy with dopamine receptor -agonists as well as improved detection of the ectopic ACTH source by novel imaging modalities, such as [(68)Ga-DOTA]-TATE PET specifically targeting somatostatin receptor subtype-2 with high affinity.

Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas.

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

The positive predictive value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment.

OBJECTIVE: To explore prospectively the positive predictive value of O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET)-PET in selected patients with a magnetic resonance imaging (MRI)-based suspicion of a glioma recurrence or progression. Methods Patients with a supratentorial glioma (initial World Health Organization (WHO) grade II, III or IV) were considered eligible if they had both an MRI-(new/progressive contrast-enhancing lesion) and FET-PET-based diagnosis of a recurrence/progression after various forms and combinations of irradiation and chemotherapy. Criterion for tumour recurrence/progression in FET-PET was a standardized uptake value (SUVmax)/Background (BG) ratio of >2.0 in the late uptake phase. All patients underwent multimodal (MRI, FET-PET) imaging-guided stereotactic biopsy. The positive predictive value was defined as the proportion of MRI and FET-PET findings indicating glioma recurrence/progression that also tested positive for tumour recurrence/progression after stereotactic biopsy. RESULTS: Thirty-one patients with initially WHO grade II (17), WHO grade III (6), and grade IV glioma (8) were included. In 26 patients FET-PET results indicating tumour recurrence/progression were concordant with the biopsy results. In five patients histopathologic evaluation failed to reveal a "vital" tumour. FET-PET findings were also discordant with the radiographic and clinical follow-up in these five patients. The positive predictive value of FET-PET was 84%. CONCLUSION: The positive predictive value of FET-PET using the standard ratio method is high, but not high enough to replace stereotactic biopsy in this highly selected study cohort. Whether the calculation of FET uptake in the early phase and/or the evaluation of uptake kinetics will improve the positive predictive value of FET-PET deserves prospective evaluation.

Brain imaging and neuropsychology in late-onset dementia due to a novel mutation (R93C) of valosin-containing protein.

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD, MIM 167320) is a recently identified autosomal dominant disorder due to mutations in the valosin-containing protein (VCP) that affects muscle, bone and brain. Brain involvement and neuropsychological findings of IBMPFD have not been described in detail. A patient carried a novel heterozygous base pair change, 47832C>T, in the VCP gene that resulted in substitution of an arginine residue by cysteine at position 93 (R93C). He presented first with myopathy while bone involvement remained subclinical. The patient developed behavioral abnormalities in his 60s and showed frank personality change with fluent empty speech at the age of 74 years. This syndrome was best classified as semantic dementia. Magnetic resonance imaging disclosed slight but progressive cerebral atrophy with prominent callosal and frontal white matter loss. Positron emission tomography demonstrated glucose hypometabolism of the frontal and temporal lobes disproportionate to their structural involvement. This first comprehensive clinical and neuroimaging study in IBMPFD may raise the awareness among clinicians as well as basic scientists for this exemplary genetic model of dementia.

Equipment-independent reference values for dopamine transporter imaging with 123I-FP-CIT.

AIM: Reliable reference values are helpful to interpret and compare the results of dopamine transporter imaging with SPECT. Since semi-quantitative reference values cannot be easily transferred between imaging equipments, this study aimed to establish equipment independent normal values for the true striatal binding of 123I-FP-CIT. PATIENTS, METHODS: Specific striatal FP-CIT binding of 6 healthy volunteers and 26 patients with essential tremor were used to generate a reference range by applying an equipment specific resolution dependent factor to compensate for recovery effects. This factor has been determined previously by a series of standardized phantom measurements of an anthropomorphic basal ganglia phantom. Herewith, the resulting DAT binding values represent the expected true specific binding in the striatum. RESULTS: On average, true specific striatal binding was 5.83 +/- 0.96 in healthy controls, 5.25 +/- 0.67 in patients with essential tremor and 5.36 +/- 0.75 in the entire study cohort. CONCLUSION: These preliminary results may serve as a basis for the generation of a generally accepted equipment independent reference range for dopamine transporter imaging with 123I-FP-CIT. By a simple phantom measurement that can be accomplished within one day factors related to specific imaging equipment and processing can be corrected for, resulting in specific binding values which may enable a more standardized interpretation of dopamine transporter scans.

O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma.

PURPOSE: Convection-enhanced delivery (CED) of paclitaxel is a new locoregional approach for patients with recurrent glioblastoma. The aim of this study was to evaluate O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) in monitoring the effects of this type of direct drug delivery. METHODS: Eight patients with recurrent glioblastoma underwent CED of paclitaxel, which was infused over stereotactically placed catheters into the tumour. FET PET and MRI were performed before and 4 weeks after therapy and then at 3-month intervals to document follow-up. For quantitative evaluation, SUV(max)(tumour)/SUV(mean)(background) ratios were calculated. RESULTS: At baseline all tumours showed gadolinium enhancement and high FET uptake (SUV(max)/BG 3.2+/-0.8). Four weeks after CED, a statistically significant decrease in FET uptake was seen (SUV(max)/BG-17%; p<0.01). During follow-up, no recurrence was observed within the CED area. Two out of eight patients with extended tumours died 4 and 5 months after treatment, most probably from local complications. Temporarily stable disease with stable FET uptake was observed in six of eight patients; this was followed by progression and increasing FET uptake ratios (+46%) distant from the CED area in five of the six patients 3-13 months after CED. One patient still presents stable FET uptake 10 months after CED. MRI showed unchanged/increasing contrast enhancement and oedema without ability to reliably assess disease progression. CONCLUSION: FET PET is a valuable tool in monitoring the effects of CED of paclitaxel. In long-term follow-up, stable or decreasing FET uptake, even in contrast-enhancing lesions, is suggestive of reactive changes, whereas increasing ratios appear always to be indicative of recurrence. Therefore, FET PET is more reliable than MRI in differentiating stable disease from tumour regrowth.

[Radionuclide techniques in the diagnosis of parkinsonian syndromes]. / Den klinischen Experten voraus? Frühdiagnostik von Parkinson-Syndromen mit PET und SPECT.

The differential diagnosis of most parkinsonian syndromes can be adequately established on the basis of clinical criteria alone. The characterization of the dopaminergic system using nuclear imaging techniques such as PET and SPECT, is gaining in importance, in particular for the diagnosis of clinically unclear cases. For the first time, these techniques permit the investigation of the presynaptic and postsynaptic dopaminergic system in vivo, and thus the establishment of the differential diagnosis of parkinsonian syndromes at an early stage. Furthermore, the severity and progression of the disease can be assessed and the effect of putative neuroprotective drugs can be documented.

Comparison of alpha-dihydroergocryptine and levodopa monotherapy in Parkinson's disease: assessment of changes in DAT binding with [123I]IPT SPECT.

Putative neurotoxic actions of levodopa and neuroprotective effects of dopamine agonists, as indicated by laboratory and animal studies, provide the rationale to study their effect on the progression of Parkinson's disease. Aim of this pilot study was to compare the effects of monotherapy with the dopamine agonist alpha-dihydroergocryptine (DEC) versus monotherapy with levodopa on nigrostriatal dopaminergic neurons as measured with dopamine transporter (DAT) SPECT. 25 PD patients (H&Y stages 1 to 2.5) entered this study and were treated in a randomized fashion either with DEC (101+/-39 mg) or levodopa (369+/-51 mg) monotherapy. 16/25 patients (8 per group) terminated the study after 52 weeks. In each patient SPECT investigations with [123I]IPT were performed at baseline and after 52 weeks to assess changes of specific DAT binding over time. Changes in clinical symptoms were assessed by UPDRS score. The mean annual decline rate in striatal IPT-binding was lower in the DEC group (8.4%) compared to the levodopa group (10.4%). The difference was most accentuated in the putamen (DEC: 7.3%; levodopa: 16.2%; p = 0.16). Due to the small sample size and the relatively short observation period, however, group differences did not reach a statistical significant level. The results of this pilot study suggest that as compared to levodopa monotherapy DEC may have beneficial effects on decline of dopamine transporter binding similar to those recently described for pramipexole.

[Initial experiences with adjuvant locoregional radioimmunotherapy using 131I-labeled monoclonal antibodies against tenascin (BC-4) for treatment of glioma (WHO III and IV)]. / Initiale Erfahrungen mit der adjuvanten lokoregionalen Radioimmuntherapie mit 131I-markierten monoklonalen Tenascin-Antikörpern (BC-4) bei Patienten mit Gliom (WHO III und IV).

AIM: None of the established treatments (surgery, radiotherapy, chemotherapy) for malignant glioma has improved its very poor prognosis. Adjuvant locoregional radio-immunotherapy (RIT) represents a new therapeutic approach. We present our initial experience with this therapeutic tool with respect to adverse effects, biokinetics and clinical follow-up. METHODS: Following surgery and radiotherapy, 12 patients with glioma (4, WHO stage III; 8, WHO stage IV) underwent 1-5 RIT-cycles (average dose 1100 MBq 131labelled monoclonal BC-4 antibodies) at six week intervals. Follow-up included serial FDG-PET and MRI investigations. Evaluation of biokinetics included whole body scans, together with analysis of blood, urine and fluid from the tumor cavity. RESULTS: Following RIT, four patients experienced temporary seizures, which, in one case, were associated with temporary aphasia. Eight patients developed HAMA (human anti-mouse antibodies) during follow-up. Mean biologic half-life of the radiopharmaceutical in the resection cavity was 3.9 d (range: 1.0-10.2 d) and remained stable intraindividually during further RIT-cycles. The antibody/radionuclide conjugate remained stable in the tumor cavity for at least 5 d. Median survival presently stands at 18.5 months compared to 9.7 months in a historical patient group (n = 89) undergoing conventional therapeutic strategies. Five patients show no signs of recurrence. In three patients with post-surgical evidence of residual tumor, one patient showed partial remission, one stable disease, and one progressive disease during RIT. Four patients without evidence of residual tumor mass at the beginning of RIT developed recurrence during therapy. CONCLUSIONS: Initial experience demonstrates that locoregional RIT is a well tolerated treatment modality that may represent a promising new approach in the management of patients with malignant glioma. Advantages of local application include passage of the blood-brain barrier, high concentration of activity within the resection cavity and low systemic toxicity.

[Correlation of FDG-PET and MRI/CT with histopathology in primary diagnosis, lymph node staging and diagnosis of recurrency of head and neck cancer]. / Korrelation von FDG-PET und MRT/CT mit der Histopathologie in Primärdiagnostik, Lymphknotenstaging und Rezidivdiagnostik von Kopf-Hals-Tumoren.

AIM: Correct staging of head and neck cancer is important for the patient's prognosis and further therapeutic strategies. Aim of the present study was to investigate the diagnostic value of FDG-PET regarding the pre-surgical diagnosis of primary tumor and cervical lymph node metastases, the diagnosis of tumour recurrence, and the localisation of unknown primary, further to compare the results to those of morphological imaging modalities (CT/MRI) and to correlate the results of both methods with histopathological findings. PATIENTS/METHODS: 115 patients (pts) (72 x primary diagnosis, 37 x recurrence, and 6 x unknown primary) underwent FDG-PET (ECAT EXACT HR+) and CT or MRI. Results were correlated with histopathological findings in terms of detection of primary and recurrent tumors as well as lymph node metastases. RESULTS: Regarding the pre-surgical diagnosis, sensitivity and specificity for identifying primary tumors were 85 % and 100 % for PET and 88 % and 75 % for CT/MRI, respectively. Accuracy was 86 % for PET and 87 % for CT/MRI. Sensitivity and specificity for detecting primary lymph node involvement were 71 %/86 % for PET and 74 %/57 % for CT/MRI, resulting in an accuracy of 77 % with PET and 68 % with morphological imaging. In 23 pts histopathology revealed pT1 stages with tumor diameters < 12 mm. In 8 pts CT/MRI and in 10 pts PET failed to identify these small primary lesions. Detecting tumor recurrence (n = 37) PET showed a higher sensitivity (83 %), specificity (76 %) and accuracy (78 %) compared to CT/MRI (sensitivity: 67 %; specificity: 52 %; accuracy: 57 %). In 4/6 pts with unknown primary, imaging was able to identify a primary lesion (3/4 in FDG-PET, 2/4 in CT/MRI), in 2/6 patients even in the follow-up no primary tumor was found. CONCLUSIONS: FDG-PET provides only minor additional information to morphological imaging concerning diagnosis of primary tumors. At a similar level of sensitivity, however, it seems to be more specific regarding the lymph node involvement. PET seems to be superior to CT/MRI in detecting tumor recurrence as well as occult primary tumors in pts with known cervical lymph node metastases.

[[F-18]FDG imaging of head and neck tumors: comparison of hybrid PET, dedicated PET and CT]. / [F-18]FDG-Bildgebung bei Kopf-Hals-Tumoren: vergleichende Untersuchungen mit Hybrid-PET, Ring-PET und CT.

AIM: Aim of the study was to evaluate [F-18]FDG imaging of head and neck tumors using a Hybrid-PET device of the 2nd or 3rd generation. Examinations were compared to dedicated PET and Spiral-CT. METHODS: 54 patients suffering from head and neck tumors were examined using dedicated PET and Hybrid-PET after injection of 185-350 MBq [F-18]FDG. Examinations were carried out on the dedicated PET first followed by a scan on the Hybrid-PET. Dedicated PET was acquired in 3D mode, Hybrid-PET was performed in list mode using an axial filter. Reconstruction of data was performed iteratively on both, dedicated PET and Hybrid-PET. All patients received a CT scan in multislice technique. All finding have been verified by the goldstandard histology or in case of negative histology by follow up. RESULTS: Using dedicated PET the primary or recurrent lesion was correctly diagnosed in 47/48 patients, using Hybrid-PET in 46/48 patients and using CT in 25/48 patients. Metastatic disease in cervical lymph nodes was diagnosed in 17/18 patients with dedicated PET, in 16/18 patients with Hybrid-PET and in 15/18 with CT. False positive results with regard to lymph node metastasis were seen with one patient for dedicated PET and Hybrid-PET, respectively, and with 18 patients for CT. In a total of 11 patients unknown metastatic lesions were seen with dedicated PET and with Hybrid-PET elsewhere in the body. Additional malignant disease other than the head and neck tumor was found in 4 patients. CONCLUSION: Using Hybrid-PET for [F-18]FDG imaging reveals a loss of sensitivity and specificity of about 1-5% as compared to dedicated PET in head and neck tumors. [F-18]FDG PET with both, dedicated PET and Hybrid-PET is superior to CT in the diagnosis of primary or recurrent lesions as well as in the assessment of lymph node involvement.

Determination of calcaneal ultrasound properties ex situ: reproducibility, effects of storage, formalin fixation, maceration, and changes in anatomic measurement site.

The objective of this study was to determine the reproducibility of ultrasonic bone properties with a system for measuring calcanei ex situ; the influence of changes of the measurement site; and the effects of fixation, storage, and maceration. We examined 14 fixed calcanei and 12 fresh bones. Ultrasonic measurements were performed ex situ after degassing, using an Achilles+ system and a special positioning device. The instrument precision was 0.16% for speed of sound (SOS), 1.4% for broadband ultrasonic attenuation (BUA), and 1. 8% for the stiffness index (SI). The short-term precision was 0.54%, 1.9%, and 2.8%, respectively. A defined shift of the measurement site (5 mm distal of the middle) led to unpredictable changes in ultrasound (US) properties (r = 0.65 for SOS, 0.82 for BUA, and 0.75 for SI). Embalment with 4% formalin/96% alcohol caused a systematic decrease in SOS, an increase in BUA, and a decrease in SI (mean = -12.7 units; P < 0.001), the effect increasing with time. However, values at 6 months of fixation and later were highly correlated with those in fresh specimens (r = 0.95 for the SI). Two weeks storage in degassed and normal solution had only modest effects on ultrasound properties. Maceration did not lead to a systematic increase or decrease of ultrasound variables, but introduced unpredictable changes (r = 0.64-0.94). We conclude that in comparative biomechanical studies it is feasible to measure calcaneal specimens embalmed in formalin/alcohol ex situ, if the primary interest is not in the absolute values but in the correlation with mechanical failure loads at other skeletal sites.