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The present guideline is focused on quality assurance of somatostatin receptor PET/CT (SSTR-PET/CT) in oncology patients. The document has been developed by a multidisciplinary board of specialists providing consensus of definitions, prerequisites, methodology, operating procedures, assessment, and standardized reporting. In particular, imaging procedures for the two most commonly used radioligands of human SSTR, i. e. 68Ga-DOTATOC and 68Ga-DOTATATE are presented. Overall, SSTR-PET/CT requires close interdisciplinary communication and cooperation of referring and executing medical disciplines, taking into account existing guidelines and recommendations of the European and German medical societies, including the European Association of Nuclear Medicine (EANM), German Society for Endocrinology (DGE), German Society for Nuclear Medicine (DGN) and German Society for Radiology (DRG)., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Schattauer GmbH.)

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.

Diffuse localised neuroendocrinal cells represent the largest population of endocrinally active cells and can degenerate to malignant neuroendocrine tumours (NET). In this review the most important hereditary syndromes that predispose for endocrine and neuroendocrine tumours are presented and discussed. NET occur mainly as sporadic tumours. Current investigations on the pathogenesis of sporadic neuroendocrine tumours have revealed a close relationship between hereditary and sporadic neuroendocrine tumours. In the course of hereditary syndromes, such as multiple endocrine neoplasia, endocrine and neuroendocrine tumours as well as non-endocrine neoplasias can occur. In order to recognise these syndromes in good time a knowledge of the predisposing syndromes and their cardinal symptoms is essential. In this way not only individualised diagnosis and therapy can be planned but also an appropriate early management of first degree relatives can be initiated., (Georg Thieme Verlag KG Stuttgart · New York.)

The pulmonary neuroendocrine neoplasms originate from the enterochromaffin cells which are diffusely distributed in the body. The incidence of these tumors has increased significantly in recent decades due to the available diagnostics. They make up about 1-2% of all lung tumors and 20-30% of all neuroendocrine neoplasms. The current WHO classification from 2004 divides them into typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell carcinomas (SCLC). The major neuroendocrine biomarkers are chromogranin A, synaptophysin and CD56. TC have a low mitotic rate of <2 mitoses/2mm(2) (10 HPF), whereas the mitotic rate of the AC is 2-10 mitoses/2 mm(2) (10 HPF). The Ki-67 staining is helpful to distinguish typical and atypical carcinoids from the highly malignant LCNEC and SCLC. Clinically, the patient presents usually with cough, hemoptysis or bronchial obstruction. The occurrence of a carcinoid or Cushing's syndrome and a tumor-associated acromegaly are rare. Surgical resection with radical lymph node dissection is the treatment of choice for achieving long-term survival. Endoscopic resection of the endobronchial tumor growth is a good alternative for inoperable endobronchially localized tumors. Peptide receptor radionuclide therapy (PRRT) is a promising treatment option for patients with metastatic or unresectable pulmonary neuroendocrine tumors. New targeted therapies using angiogenesis inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors are being tested for their effectiveness in many previous studies. Typical carcinoid tumors metastasize less frequently than AC, the 5-year survival rate of patients with TC being over 90%. Patients with AC have a 5-year survival rate between 35% and 87%. The highly malignant LCNEC and SCLC, on the other hand, have a 5-year survival rate between 15% and 57%, and <5% respectively. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach and decision-making in multidisciplinary tumor conferences to ensure a personalized treatment approach. Therefore patients with a neuroendocrine neoplasm of the lung should be treated in specialized centers., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Neuroendocrine tumours of the lung exhibit an increasing incidence and prevalence. However, data on the diagnosis of and therapy for these tumours are sparse compared to neuroendocrine tumours of the gastroenteropancreatic system., Methods: The present article reflects a dialogue between experts on neuroendocrine tumors of the lung and the gastroenteropancreatic system held on February 25th and 26th in Weimar, Germany., Results: Many similarities exist between neuroendocrine tumours of the lung and the gastroenteropancreatic system but there are also significant differences. Similarities exist mainly concerning pathology, diagnosis and therapy. Differences exist regarding the systemic therapy and the significantly lower incidence of paraneoplastic syndromes. Somatostatin receptor PET/CT with gallium-68 labelled somatostatin analogues and peptide receptor radiotherapy are innovative methods for the diagnosis of and therapy for neuroendocrine tumours of the lung. The first treatment option remains complete resection of the tumour. Small molecules like everolimus (Afinitor®) have been tested in clinical trials and have been shown to prolong progression-free survival., Conclusions: Additional studies are necessary and efforts should be undertaken to establish a registry to increase data on methods suitable for he diagnosis of and therapy for neuroendocrine tumours of the lung., (© Georg Thieme Verlag KG Stuttgart · New York.)

A 33 years old woman presented with cramp-like abdominal pain. Ultrasound examination revealed multiple lesions in the liver of hyper- and hypoechoic echogenicity which in accordance to subsequently performed computed tomography and dynamic hepatobiliary scintigraphy were considered to be a focal nodular hyperplasia (FNH). A severe increase of the serum lipase concentration, suspected to be an acute pancreatitis, was treated conservatively and led to a short improvement of symptoms. Some months later, a severe progression of the pain symptoms occurred, along with a measurable expansion of the abdominal circumference and palpable tumors of the liver. The dynamic hepatobiliary imaging and the static liver scan showed a decreased perfusion and function of the nodes as well as a reduced RES activity, respectively. A subsequently performed Positron Emission Tomography (PET) with F-18-Fluorodeoxyglucose (FDG) showed a massively increased glucose metabolism of the liver tumors. The histologic result of several biopsies of the tumors revealed metastases of an acinus cell carcinoma of the pancreas. Under systemic and local chemotherapy, a temporary remission could be obtained that was clearly detectable in a second FDG-PET. Nevertheless, during the further course of the disease, a progression occurred being detectable in an additional control PET-study by an increase in tumor size as well as in tumor glucose metabolism. The patient died in liver coma 15 months after the histologic diagnosis was obtained.

Aim: The differentiation of HCC from liver metastasis or benign disorders by imaging studies based upon morphological aspects may be difficult., Method: In order to evaluate the role of tumour metabolism, we performed FDG-PET (whole-body PET and transmission-corrected regional scans of the liver as well as the SUV determined 60 min after injection of FDG) in ten consecutive patients with HCV-associated focal liver lesions. Definite diagnosis was established after ultrasound-guided liver biopsy followed by histopathological examination. These results were compared with ultrasound, computed tomography, serum anti-p53, and p53 protein expression., Results: The histologic examination revealed a HCC in five patients, regenerative nodules in three patients, and liver metastasis (primary malignancy: one adenocarcinoma and one neuroendocrine tumour) in the remaining two patients. Three of ten lesions were detectable by FDG-PET: two HCCs and one metastatic adenocarcinoma. Seven lesions were not distinguishable by FDG-PET (three HCCs, three regeneration nodules and one metastatic neuroendocrine tumour). In each patient hepatic lesions were visible either by ultrasound or CT. Both tumours (metastatic adenocarcinoma, moderately well-differentiated HCC) with the strongest expression of p53 also presented with highly increased FDG uptake., Conclusions: FDG-PET is not superior to ultrasound or CT and therefore does not allow the non-invasive differentiation of HCV-associated focal liver lesions. Tissue-diagnosis by means of liver-biopsy followed by histopathological examination remains the gold-standard for the differentiation of HCV-related liver lesions. The finding of the relationship of p53 protein overexpression with the SUV needs further confirmation.

A 82-year-old male patient had developed a suffering from an unusual unilateral growing bone metastases of a prostate-carcinoma D2 (Histological diagnosis: indifferent, partly cribiform growing prostate-carcinoma, T3N x M1, G3; first diagnosis 7/1988), which suggests a sufferring from M. Paget. In October 1988, the patient underwent a subcapsular orchiectomy, followed by androgene therapy with fugurel. Due to ongoing osseous metastases, in November/December 1992 a radiotherapy of the right hip (50 Gy) was performed. Beginning from October 1994, severe progression of bone metastases was observed with distinct pain-symptoms, leading to an increasing use of analgetics.

A three-year-old male patient presented already at his birth a disproportion macrosomia of the left foot and a large, nodular nevus flammeus in the left hip region, which led to the tentative diagnosis of a Klippel-Trenaunay syndrome. In the following years, both changes showed a continuous progression, with distinct soft-tissue swelling as well as papillomatous and verruciform vegetations of the nevus. Additionally, large, plain subcutaneous masses developed under the right shoulder, and a macrodactyly of the first and second left toe could be observed. Although several examinations had been performed in the meantime, the tentative diagnosis could not be confirmed up to that time. On the occasion of a severe local infection in the hip region, which led to the consideration of a surgical therapy, a radionuclide lymphography, a blood pool scintigraphy including dynamic phlebography and ventriculography as well as a bone scintigraphy were performed. These examinations were done simultaneously at one day in order to avoid a longer period of immobilization. The findings led to the diagnosis of a large lymphangioma, which could be confirmed histologically after surgery. In consideration of all results, the basic disorder seems to be the rare proteus syndrome rather than a Klippel-Trenaunay syndrome.

In this report we discuss the abilities of intercorrelative cardiovascular nuclear medicine to detect and characterize myocardial perfusion anomalies and viable myocardium in a 58-year-old patient before revascularization.

The present study was undertaken to evaluate the correlation of the favorable in vitro characteristics of the anti-mucin Mabs 12H12 and BM-7 with high tumor accumulation in vivo. They were labeled with 99mTc; their biodistribution in nude mice bearing mammary tumor xenograft AR was examined and immunoscintigraphy was performed after 24 h. 99mTc-labeling of the Mabs 12H12 and BM-7 led to tumor uptakes of 20.7% and 8.8% ID/g, respectively, after 48 h. Tumor-to-muscle ratios were 31 (12H12) and 18 (BM-7). Tumor xenografts were clearly visualized in immunoscintigrams. Combination of Mab 12H12 and 99mTc provides high tumor-to-tissue ratios shortly after administration.

A 50-y-old male patient with prostate cancer showed two suspicious lesions in bone scintigrams. They were assessed to be bone metastases by biopsy of the os ilium. After i.v. injection of 99mTc-HMDP a probe-guided localization permitted optimal surgical treatment. A bone metastasis in the os ilium was confirmed. The intraoperative detection with a hand-held gamma probe permitted accurate and complete excision of the tumour; the bone defect could thus be reduced to a minimum.

In a 61-year old female with a history of breast cancer the whole-body scan (4 h p.i.) after intravenous injection of 576 MBq 99mTc-HMDP showed an accumulation of activity in the stomach and the whole intestines. The reason was an oral urine intake ("uropotia") taking place between the injection and the whole-body bone scan.

The high incidence of deep venous thrombosis requires for successful therapy a timely and accurate diagnosis. We report early clinical results with a 99mTc-labelled anti-platelet antibody (BW 4) for the diagnosis of thrombosis or for studying platelet kinetics. 10 patients were studied of whom 7 were imaged for the detection of thrombi. 3 deep venous thromboses were diagnosed. 3 patients were sent for diagnosing pathological platelet kinetics; 2 demonstrated a markedly changed platelet biodistribution (increased spleen uptake compared to thrombosis patients). The simple and safe handling of the labelling kit enables early studies (within 30 min). The short physical half-life of 99mTc allows a favourable target (thrombus) to non-target (blood-pool) ratio for diagnosis within 2-6 h after injection. Human anti-mouse antibodies were not found in the serum of 4 patients (blood drawn until 4 weeks after administration). There were no side effects.

Murine monoclonal antibodies (MAb) are applied on a growing scale in radioimmunoscintigraphy (IS) for diagnostic and therapeutic purposes. This increasing use of xenogeneic substances in rapidly growing numbers of patients raises questions of accuracy and reliability of the MAb and also the problem of potential human immunoreaction (human anti-mouse IgG antibodies--HAMA). The aim of this study was to evaluate the clinical relevance of HAMA following IS regarding allergic complications and in vivo effects on IS after repeated applications of MAbs. Out of over 800 immunoscintigraphic examinations performed during the last 5 years in our department 289 studies (in 190 patients) with up to 10 applications (13 different MAbs all together) were considered. Only 1 patient with a high HAMA titer developed a mild allergic reaction (local urticaria) after the 3rd application of an anti-CEA MAb. In 171 intensively documented serum courses following IS, 50 (29%) showed elevated HAMA [1st application: 25/108 (23%); 2nd application: 20/41 (49%): 3rd application: 5/11 (45%); 4th-10th application: no HAMA/11 (2 anti-CEA, 9 Antimyosin)]. Only with strongly increased HAMA values (five times the value before 1st application) there was an altered biodistribution of the MAbs in IS with partially inhibited (8/25 studies with repeated applications) tumor localization. Some patients still demonstrated positive tumor localization despite a HAMA reaction. The problem of HAMA in the diagnostic work-up using MAbs is not the allergic reaction but the potential effects on IS in repeated studies. HAMA should be measured prior to repeated immunoscintigraphic studies.

We studied the effect of thyroxine (T4 0.050 mg/kg/d, i.p.), TSH (0.08 U/kg/d, i.p.) and hypothalamic peptide (HF; 1 mg protein/kg/d, i.p.) given alone or in combination, on the growth of murine (NB C-1300) and human (NB Park) neuroblastoma transplanted onto the nude mouse (nu/nu). Both T4 and TSH caused a significant increase (perchlorate a decrease) of the serum T3. Histologically, the T4 treatment was followed by partial tumor necrosis and a marked growth of connective tissue within the tumors; there was no significant change in tumor weight as compared to the control group. Treatment with HF alone or in combination with T4 inhibited in 30% the invasive growth of the neuroblastoma transplants and a fatty degeneration was found in 25% of the human NB-TX after 28 days of treatment. The measurement of the intratumoral content of the cyclic nucleotides showed a significant increase of the cAMP and a decrease of the cGMP. The morphological and biochemical alteration observed under treatment with thyroid hormone or analogues could possibly be applied for therapeutic purposes.

The effect of triiodothyronine (T3) on the differentiation of cultured neuroblastoma (NB) cells was studied after 9 days of treatment with a dose of 10(-4) M/10(6) cells per day. Using phase contrast microscopy, 30-50% of NB cells showed formation of neurites as a morphological sign of cellular differentiation. The initial rise of the mitosis rate was followed by a plateau. Changes in cyclic nucleotide content, in the triphosphates and in the activity of the enzyme ornithine decarboxylase (ODC) were assessed in 2 human and 2 murine cell lines to serve as biochemical parameters of the cell differentiation induced by T3. Whereas the cAMP level increased significantly (3 to 7 fold compared with its initial value), the cGMP value dropped to 30 to 50% of that of the control group. ATP and GTP increased about 200%, the ODC showed a decrease of about 50%. The present studies show a biphasic effect of T3 on neuroblastoma cells: the initial rise of mitotic activity is followed by increased cell differentiation starting from day 4 of the treatment.

The present study was done in order to examine if the use of 111In-DTPA-labeled MAb fragments in place of 131I-labeled MAb fragments increases the sensitivity of tomographic immunoscintigraphy to reach the level of that of planar imaging techniques. In 11 patients with various primary tumors, local recurrences or metastases [colorectal carcinoma (n = 7), ovarian carcinoma (n = 2), papillary thyroid carcinoma (n = 1), undifferentiated carcinoma of the lung (n = 1)], immunoscintigraphy (IS) was carried out using 111In-DTPA-labeled F(ab')2 fragments of various MAbs (anti-CEA, OC 125, anti-hTG) and planar and tomographic imaging were compared intra-individually. By conventional diagnostic procedures, the presence of a tumor mass was confirmed (transmission computer tomography, ultrasound) or verified (131I whole-body scintigraphy, histology) in all cases. Immunoscintigraphy was positive in 9 out of 11 cases by ECT and in 10 out of 11 cases by planar imaging. When using 111In-labeled MAb fragments, intra-individual comparison of ECT and planar imaging resulted in a similar sensitivity. The increased sensitivity of ECT using this tracer in contrast to 131I-labeled MAb fragments may be attributed to the fact that the physical properties of 111In are much more suitable for the gamma cameras most commonly used (single detector, 3/8'' crystal); using 111In-labeled MAb fragments, count rates sufficient for ECT can be obtained within a reasonable acquisition time. This allows to combine IS with the advantages of ECT regarding tumour localization and prevention of artefacts due to superposition of background.

In vitro studies of tumor tissue have shown that 131I-IBG is specifically bound to the plasma membrane-enriched fraction of two neuroblastoma cell lines (NA-2 and C-1300). NB C-1300 showed a slightly higher binding capacity than NB NA-2. It may be inferred from experiments performed with activators of the adrenergic and dopaminergic systems that binding of IBG to proteins on the plasma membrane which is physiologically important for binding of this guanidine derivative, is probable.

In 255 patients (normals: group I, n = 30; nontoxic goitres: group II, n = 134; toxic goitres without ophthalmopathy: group III, n = 63; Graves' disease: group IV, n = 28) a TSH-receptor-autoantibody-assay (TRAK assay) for detection of thyrotropin-binding inhibiting antibodies (TBIAb) was tested and 99mTcO4-uptake (TcTU) was measured. Normal TcTU (range: 1.5-5.5%) and normal TRAK values (normal limit: F less than 11%) were only found in group I. An increased TcTU was found in group II in 22.4% (increased TRAK values only in 2.2%). In group III an increased TcTU was measured in 34.9% of the patients (all with normal TRAK titers). The stimulation of the TSH-receptor in immunogenic hyperthyroidism by TBIAb could be demonstrated by increased TRAK values in 71.4% of the patients with Graves' disease. In correlation, TcTU was also increased in 82.1% of the patients in group IV. As the measurement of TcTU can be helpful in differential diagnosis, the functional imaging with gamma camera and computer is today a conditio sine qua non, especially in suspected hyperthyroidism.

21 patients with LAD-stenoses of at least 70% and 21 patients with LAD-stenoses and additional intramural anterior wall infarctions were studied. 20 patients without heart disease or after successful transluminal coronary angioplasty and 18 patients with intramural anterior wall infarction after successful transluminal dilatation of the LAD (remaining stenosis maximal 30%) served as controls. The normal range of global and regional left ventricular ejection fraction response to exercise was defined based on the data of 25 further patients without relevant coronary heart disease. Thus, a decrease in global ejection fraction and regional wall motion abnormalities were judged pathological. All patients were comparable with respect to age, ejection fraction at rest and work load. Myocardial ischemia could be detected by the exercise ECG in 81% of all patients without infarction and in 71% of patients with infarction. The corresponding values for global left ventricular ejection fraction were 76% and 81%, respectively, and for regional ejection fraction 95% in both groups. No false-positive exercise ECGs were observed in the healthy controls and 2 (11%) in the corresponding group with intramural infarction. The global ejection fraction was pathological in 1 (5%) healthy subject without infarction and in 3 (17%) corresponding patients with infarction. Sectorial analysis revealed 5 and 22%, respectively. Our findings suggest that the exercise ECG has a limited sensitivity to detect myocardial ischemia in patients with isolated LAD-stenoses and intramural myocardial infarction. Radionuclide ventriculography yields pathological values more often; however, false-positive results also occur more frequently.

A new tumor marker (CA 19-9) was investigated. CA 19-9 is a tumor-associated antigen which is detected by a monoclonal antibody. CA 19-9 (CIS-Centocor) was compared simultaneously with CEA (carcinoembryonic antigen) in 347 patients. 123 patients with gastrointestinal tumors showed a sensitivity of 31% for CA 19-9 (CEA 49%), combination increased sensitivity to 58%. The highest sensitivity was found in pancreas carcinoma (CA 19-9 75%, CEA 66%, combination 92%); it was lower in gastric, colon, and oesophagus carcinomas. In relapsed colorectal carcinomas sensitivity was 53% (CEA 78%, combination 85%). In cases of relapse, tumor markers may become positive even if they were not detectable before resection of the primary tumor. Specificity for CA 19-9 was 100% (CEA 84%) compared to a group of non-malignant diseases including patients with inflammations and patients with nicotin abuse (n = 102). Because of its high specificity and superior sensitivity to CEA in pancreas carcinomas CA 19-9 should be determined in primary and relapse diagnosis in combination with CEA.