Translational imaging of the fibroblast activation protein (FAP) using the new ligand [68Ga]Ga-OncoFAP-DOTAGA.

PURPOSE: The fibroblast activation protein (FAP) is an emerging target for molecular imaging and therapy in cancer. OncoFAP is a novel small organic ligand for FAP with very high affinity. In this translational study, we establish [68Ga]Ga-OncoFAP-DOTAGA (68Ga-OncoFAP) radiolabeling, benchmark its properties in preclinical imaging, and evaluate its application in clinical PET scanning. METHODS: 68Ga-OncoFAP was synthesized in a cassette-based fully automated labeling module. Lipophilicity, affinity, and serum stability of 68Ga-OncoFAP were assessed by determining logD7.4, IC50 values, and radiochemical purity. 68Ga-OncoFAP tumor uptake and imaging properties were assessed in preclinical dynamic PET/MRI in murine subcutaneous tumor models. Finally, biodistribution and uptake in a variety of tumor types were analyzed in 12 patients based on individual clinical indications that received 163 ± 50 MBq 68Ga-OncoFAP combined with PET/CT and PET/MRI. RESULTS: 68Ga-OncoFAP radiosynthesis was accomplished with high radiochemical yields. Affinity for FAP, lipophilicity, and stability of 68Ga-OncoFAP measured are ideally suited for PET imaging. PET and gamma counting-based biodistribution demonstrated beneficial tracer kinetics and high uptake in murine FAP-expressing tumor models with high tumor-to-blood ratios of 8.6 ± 5.1 at 1 h and 38.1 ± 33.1 at 3 h p.i. Clinical 68Ga-OncoFAP-PET/CT and PET/MRI demonstrated favorable biodistribution and kinetics with high and reliable uptake in primary cancers (SUVmax 12.3 ± 2.3), lymph nodes (SUVmax 9.7 ± 8.3), and distant metastases (SUVmax up to 20.0). CONCLUSION: Favorable radiochemical properties, rapid clearance from organs and soft tissues, and intense tumor uptake validate 68Ga-OncoFAP as a powerful alternative to currently available FAP tracers.

[Uncommon manifestation of prostate cancer : Sister Mary Joseph's nodule]. / Ungewöhnliche Manifestation eines Prostatakarzinoms : Sister-Mary-Joseph-Knoten.

We report on the case of an 81-year-old man suffering from prostate cancer for several years. In recent months, PSA levels increased, and 68Ga-PSMA-PET-CT (PSMA: prostate-specific membrane antigen) imaging demonstrated suspicious lesions in the paravesical area and an umbilical tumor mass. Local excision was performed. Histologically, the tumor mass was diagnosed as metastasis of the prostate cancer, which is also designated as Sister Mary Joseph's nodule. Umbilical metastases of primary prostate cancer are extremely rare; however, they are of clinical importance since they are commonly associated with tumor progress and with a particularly poor prognosis.

Specific biomarkers of receptors, pathways of inhibition and targeted therapies: clinical applications.

A deeper understanding of the role of specific genes, proteins, pathways and networks in health and disease, coupled with the development of technologies to assay these molecules and pathways in patients, promises to revolutionise the practice of clinical medicine. In particular, the discovery and development of novel drugs targeted to disease-specific alterations could benefit significantly from non-invasive imaging techniques assessing the dynamics of specific disease-related parameters. Here we review the application of imaging biomarkers in the management of patients with brain tumours, especially malignant glioma. This first part of the review focuses on imaging biomarkers of general biochemical and physiological processes related to tumour growth such as energy, protein, DNA and membrane metabolism, vascular function, hypoxia and cell death. These imaging biomarkers are an integral part of current clinical practice in the management of primary brain tumours. The second article of the review discusses the use of imaging biomarkers of specific disease-related molecular genetic alterations such as apoptosis, angiogenesis, cell membrane receptors and signalling pathways. Current applications of these biomarkers are mostly confined to experimental small animal research to develop and validate these novel imaging strategies with future extrapolation in the clinical setting as the primary objective.

PET surveillance of patients with Ewing sarcomas of the trunk: Must the lower legs be included?

AIM: FDG-PET(/CT) is frequently used in surveillance of Ewing sarcoma (ES) patients. Since ES and PNET (primitive neuroectodermal tumours) may cause peripheral metastases some centers routinely recommend whole body PET acquisition from head to toe what may necessitate repositioning of the patient and thus extending examination time. It is not clear yet whether inclusion of lower leg adds to the diagnostic accuracy of PET scanning, especially in primary tumors of the trunk. PATIENTS, METHOD: 40 patients with ES and PNET of the trunk who were referred for surveillance after primary therapy with complete remission, were evaluated retrospectively: 27 men, 13 women; mean age at diagnosis 16.3 (3-35) years. At the time of diagnosis 28 patients had localized and 12 metastatic disease. Almost all of the patients had undergone a combined chemotherapy with surgery or/and radiotherapy. 156 follow-up PET scans of the legs of these patients were evaluated retrospectively. RESULTS: only in three (1.9%) of 156 scans a pathologic FDG accumulation was attributed to metastatic disease of the lower extremities. In these cases the observation of metastatic disease in the legs did not alter therapy, since in all three cases a multifocal disease progression was observed. CONCLUSION: scanning of the lower legs may be omitted during follow-up in patients in whom the primary tumor was located in the trunk and in whom no clinical signs pointing to metastases in the lower legs are present. This provides a sufficient diagnostic power and a shorter examination time, thus increasing patient comfort and scanner availability.

Lesion concordance, image quality and artefacts in PET/CT: results of a multicenter study.

AIM: This study had three major objectives: 1.) to record the number of concordant (both in PET and CT) pathological lesions in different body regions/organs, 2.) to evaluate the image quality and 3.) to determine both, the quantity and the quality of artefacts in whole body FDG PET/CT scans. PATIENTS, METHODS: Routine whole body scans of 353 patients referred to FDG-PET/CT exams at 4 university hospitals were employed. All potentially malignant lesions in 13 different body regions/organs were classified as either concordant or suspicious in FDG-PET or CT only. In the latter case the diagnostic relevance of this disparity was judged. The image quality in PET and CT was rated as a whole and separately in 5 different body regions. Furthermore we investigated the frequency and site of artefacts caused by metal implants and oral or intravenous contrast media as well as the subjective co-registration quality (in 4 body regions) and the diagnostic impact of such artefacts or misalignment. In addition, the readers rated the diagnostic gain of adding the information from the other tomographic method. RESULTS: In total 1941 lesions (5.5 per patient) were identified, 1094 (56%) out of which were concordant. 602 (71%) out of the 847 remaining lesions were detected only with CT, 245 (29%) were only PET-positive. As expected, CT particularly depicted the majority of lesions in the lungs and abdominal organs. However, the diagnostic relevance was greater with PET-only positive lesions. Most of the PET/CT scans were performed with full diagnostic CT including administration of oral and intravenous contrast media (> 80%). The image quality in PET and CT was rated excellent. Artefacts occurred in more than 60% of the scans and were mainly due to (dental) metal implants and contrast agent. Nevertheless there was almost no impact on diagnostic confidence if reading of the non attenuation corrected PET was included. The co-registration quality in general was also rated as excellent. Misalignment mostly occurred due to patient motion and breathing and led to diagnostic challenges in about 4% of all exams. The diagnostic gain of adding PET to a CT investigation was rated higher than vice versa. CONCLUSIONS: As the image quality in both PET and CT was more than satisfying, CT-artefacts almost never led to diagnostic uncertainties and serious misalignment rarely occurred, PET/CT can be considered as suitable for routine use and may replace single PET- and CT-scans. However, additional reading of the non attenuation corrected PET is mandatory to assure best possible diagnostic confidence in PET. Since approximately half of all lesions found in PET/CT were not concordant, at least in a setting with a diagnostic CT the exams need to be reported by both a nuclear medicine physician and a radiologist in consensus.

Prediction of lymph node metastases in NSCLC. Three dimensional anatomical parameters do not substitute FDG-PET-CT.

PURPOSE: To distinguish between benign and malignant mediastinal lymph nodes in patients with NSCLC by comparing 2D and semi-automated 3D measurements in FDG-PET-CT. PATIENTS, MATERIAL, METHODS: FDG-PET-CT was performed in 46 patients prior to therapy. 299 mediastinal lymph-nodes were evaluated independently by two radiologists, both manually and by semi-automatic segmentation software. Longest-axial-diameter (LAD), shortest-axial-diameter (SAD), maximal-3D-diameter, elongation and volume were obtained. FDG-PET-CT and clinical/FDG-PET-CT follow up examinations and/or histology served as the reference standard. Statistical analysis encompassed intra-class-correlation-coefficients and receiver-operator-characteristics-curves (ROC). RESULTS: The standard of reference revealed involvement in 87 (29%) of 299 lymph nodes. Manually and semi-automatically measured 2D parameters (LAD and SAD) showed a good correlation with mean intraclass coefficients of .80 and .72, respectively. Semi-automated prediction revealed the highest areas-under-the-ROC-curve for volume (.75, 95%CI: .69-81) and SAD (.75, 95%CI: .70-.81). AUC for LAD and maximal-3D diameter were about .68. Substantially lower accuracies were found for elongation (.57, 95%CI: .50-.64). CONCLUSION: Optimized semi-automated three dimensional parameters by CT cannot approximate reported data on FDG-PET-CT for lymph node assessment in NSCLC. SAD remains the most accurate and at the same time simple to achieve anatomical criterion for definition of NSCLC target lesions.

Whole-body imaging of oncologic patients using 16-channel PET-CT. Evaluation of an i.v. contrast enhanced MDCT protocol.

AIM: This study evaluated a MDCT protocol for contrast-enhanced 16-channel PET-CT with regard to scan range and duration of a whole-body (18)F-FDG PET-CT examination, the occurrence of contrast-material induced artefacts and quantitative assessment of CT attenuation. PATIENTS, METHODS: 205 patients (51.9+/-12.4 years) with different malignant tumours underwent whole-body PET-CT; the study protocol had been approved by the institutional review board. Contrast-enhanced MDCT (16 x 1.5 mm; 120 ml Iomeprol 3 ml/s, 50 ml saline chaser bolus, scan delay 70 s; oral contrast) was also used for attenuation correction. From MDCT data mean scan range and duration, occurrence of contrast media-induced artefacts, and mean CT densities of jugular (jv) and subclavian (scv), superior (vcs) and inferior (vci) caval, portal (pv), and bilateral external iliac veins, pulmonary (ap) and iliac arteries, descending thoracic and abdominal aorta, all cardiac chambers, as well as both liver lobes, spleen, adrenal glands and kidneys were determined. RESULTS: Attenuation corrected PET images were free of contrast media-related image artefacts. Homogeneous contrast enhancement was found in the mediastinal veins (right/left jv 171+/-34/171+/-35, scv 127+/-50/127+/-40, vcs 153+/-36 HU) and arteries (e.g. ap 145+/-26/151+/-26). Cardiac chambers, abdominal vessels (e.g. vci 138+/-24, pv 159+/-25 HU), and parenchymal organs revealed sufficient and homogenous contrast-enhancement in all cases. No beam-hardening artefacts occurred in the neighbourhood of the subclavian veins. CONCLUSION: The chosen whole-body (18)F-FDG 16-slice PET-CT protocol allowed for craniocaudal CT scanning with high vessel and parenchymal contrast revealing no IV contrast-media induced artefacts in attenuation-corrected PET data sets.

Intramedullary spinal cord metastasis as initial presentation of systemic cancer--report of a rare case.

We report the rare case of a 74-year-old man who was admitted to our hospital with rapid progression of tetraparesis, which was most apparent in the lower right limb, sensory disturbances from C3 to S1 on the left side and recent onset of constipation and urinary retention. There was no known history of cancer. As MRI of the neck disclosed a cervical intramedullary mass lesion at C 4/5 level suspicious for a primary glial tumour, the patient underwent surgery. After microsurgical excision the histological analysis of the lesion unexpectedly revealed an intramedullary spinal cord metastasis (ISCM) of a poorly differentiated carcinoma, immunohistochemically consistent with a bronchial carcinoma. As intramedullary spinal cord metastases are generally associated with poor survival, a palliative irradiation of the levels C1-6 was additionally performed. Unfortunately tetraparesis and numbness remained. The very rare occurrence of intramedullary spinal cord metastasis and the absence of pathognomonic symptoms often lead to a delay until an underlying malignancy is discovered. Although rare, intramedullary spinal cord metastasis should be considered as a differential diagnosis of a spinal intramedullary lesion. Surgery and radiation are both options in the controversially discussed treatment of ISCM.

Influence of PET/CT-introduction on PET scanning frequency and indications. Results of a multicenter study.

AIM: To evaluate the influence of the introduction of combined PET/CT scanners into clinical routine. This investigation addresses the quantitative changes between PET/CT and stand alone PET. METHODS: The study included all examinations performed on stand alone PET- or PET/CT-scanners within 12 month prior to and after implementation of PET/CT. The final data analysis included five university hospitals and a total number of 15 497 exams. We distinguished exams on stand alone tomographs prior to and after installation of the combined device as well as PET/CT scans particularly with regard to disease entities. Various further parameters were investigated. RESULTS: The overall number of PET scans (PET and PET/CT) rose by 146% while the number of scans performed on stand alone scanners declined by 22%. Only one site registered an increase in stand alone PET. The number of exams for staging in oncology increased by 196% while that of cardiac scans decreased by 35% and the number of scans in neurology rose by 47%. The use of scans for radiotherapy planning increased to 7% of all PET/CT studies. The increase of procedures for so-called classic PET oncology indications was moderate compared to the more common tumors. An even greater increase was observed in some rare entities. CONCLUSIONS: The introduction of PET/CT led to more than a doubling of overall PET procedures with a main focus on oncology. Some of the observed changes in scanning frequency may be caused by a rising availability of new radiotracers and advancements of competing imaging methods. Nevertheless the evident increase in the use of PET/CT for the most common tumour types demonstrates its expanding role in cancer staging. The combination of molecular and morphologic imaging has not only found its place but is still gaining greater importance with new developments in technology and radiochemistry.

High diagnostic value of 18F-FDG-PET in pediatric patients with chronic inflammatory bowel disease.

Diagnosis of chronic inflammatory bowel disease (IBD) in children requires noninvasive, atraumatic diagnostic tools that depict localization and acuity of inflammation and yield only a low radiation dose. This retrospective analysis evaluates the diagnostic potential of FDG-PET. Twenty-six consecutive FDG-PET scans of 23 patients (age: 2-16, years, 14 M, 9 F) with suspected IBD were analyzed in this retrospective study. Results were compared to endoscopic, histologic, and abdominal ultrasound (US) finding. In these examinations, presence of inflammation was evaluated in each patient in 8 bowel segments (score 1-4). Standardized uptake values (SUVs) for FDG-PET were measured for all segments. Sensitivity, specificity, and accuracy were calculated using histology as the standard of reference on a segment-based analysis (pathologic if inflammation score > or = 3 or SUV(max)/SUV(liver)>1.2). With histology as the standard of reference, FDG-PET showed a sensitivity/specificity/accuracy of 98%/68%/8%/3 as compared to endoscopy (90%/75%/82%) and US (56%/92%/75%). For the small bowel, FDG-PET was even more reliable (100%/86%/90%). Because of its high sensitivity and accuracy,FDG-PET is an excellent, noninvasive diagnostic tool for IBD. Depicting inflammation in the whole bowel, while being not traumatic, it is attractive for use especially in children. FDG-PET is especially reliable for the small bowel and can inform application of topical therapy.

Tumor staging using whole-body high-resolution 16-channel PET-CT: does additional low-dose chest CT in inspiration improve the detection of solitary pulmonary nodules?

For optimal image fusion between CT and F-18-FDG-PET, the acquisition of CT images is performed in mild expiratory suspension, which might compromise the detection of lung metastases. This study aimed at evaluating the influence of expiration on the detection of solitary pulmonary nodules (SPN) and at assessing if additional inspiratory low-dose CT (I-LDCT) of the chest can improve the detection of potential lung metastases performing whole-body 16-channel PET-CT. Sixty-six patients with malignant tumors underwent PET-CT: contrast-enhanced CT was acquired during mild expiration and was used for fusion with PET images; additionally, chest I-LDCT was performed at deep inspiration. Two radiologists reported all SPN detected at I-LDCT and the expiratory CT scan independently. Overall, 53% of 128 SPN (mean: 3.8+/-0.2 mm) were detected at both respiratory states: 51 SPN only at I-LDCT, and 9 nodules only at expiratory CT. Of the SPN, 117/128 were classified as certain; 45 of those were additionally detected at I-LDCT, and 6 nodules at expiratory CT. A 100% detection rate was reached in SPN >4 mm at I-LDCT versus >8 mm at expiratory CT (all P<0.001). Additional I-LDCT of the chest significantly improves the detection of SPN at whole-body F-18-FDG-PET-CT and thus is recommended as part of the standard protocol for oncological patients.

Correlation between respiration-induced thoracic expansion and a shift of central structures.

The fusion of computed tomography (CT) and positron emission tomography (PET) may improve diagnostic accuracy, but is limited by different breathing protocols. This study aimed at quantifying respiration-induced alignment errors. PET-CT was acquired in 24 patients. Contrast-enhanced whole-body CT was obtained in a single breath hold in the expiratory state of a normal breathing cycle. An inspiratory low-dose CT of the thorax was acquired in the same session, and comparison of the two CT scans was used to assess the potential mismatch of PET and CT fusion. The largest craniocaudal expansion was found in the area of the diaphragm. A considerable sagittal expansion was found in the anterior parts of the lungs. Central tracheo-bronchial structures were displaced during inspiration mainly in the anterior and caudal directions. The craniocaudal shift of central structures showed a linear correlation with the diaphragmatic expansion, whereas the sagittal shift correlated with the sagittal pleural expansion. There was, however, no correlation between craniocaudal and sagittal respiratory motion. Alignment errors are most severe in the base of the lung, but central structures are affected, too. Understanding of the main vectors of respiratory motion may help in image interpretation when PET and CT are acquired separately.

[Clinical value of amino acid imaging in paediatric brain tumours. Comparison with MRI]. / Der klinische Wert der Darstellung kindlicher Hirntumore mit Aminosäuren: Vergleich mit MRT.

PURPOSE: To evaluate single photon emission computed tomography (SPECT) using the amino acid l-3-[123I]-alpha-methyl tyrosine (IMT) and contrast enhanced magnetic resonance imaging (MRI) as diagnostic tools in primary paediatric brain tumours in respect of non-invasive tumour grading. Patients, materials, methods: 45 children with primary brain tumours were retrospectively evaluated. IMT uptake was quantified as tumour/nontumour-ratio, a 4-value-scale was used to measure gadolinium enhancement on contrast enhanced MRI. Statistical analyses were performed to evaluate IMT uptake and gadolinium enhancement in low (WHO I/II) and high (WHO III/IV) grade tumours and to disclose a potential relationship of IMT uptake to disruption of blood brain barrier as measured in corresponding MRI scans. RESULTS: IMT uptake above background level was observed in 35 of 45 patients. IMT uptake was slightly higher in high grade tumours but the difference failed to attain statistical significance. Grading of individual tumours was neither possible by IMT SPECT nor by gadolinium enhanced MRI. CONCLUSION: IMT is accumulated in most brain tumours in children. Tumour grading was not possible using IMT or contrast enhancement as determined by MRI. Neither morphological nor functional imaging can replace histology in paediatric brain tumours.

O-(2-[18F]fluorethyl)-L-tyrosine PET in the clinical evaluation of primary brain tumours.

PURPOSE: The aim of this study was to evaluate the differential uptake of O-(2-[18F]fluorethyl)-L-tyrosine (FET) in suspected primary brain tumours. METHODS: Positron emission tomography (PET) was performed in 44 patients referred for the evaluation of a suspected brain tumour. Acquisition consisted of four 10-min frames starting upon i.v. injection of FET. Tumour uptake was calculated as the ratio of maximal tumour intensity to mean activity within a reference region (FETmax). RESULTS: FET uptake above the cortical level was observed in 35/44 lesions. All histologically confirmed gliomas and many other lesions showed FET uptake to a variable extent. No uptake was observed in nine lesions (one inflammatory lesion, one dysembryoplastic neuroepithelial tumour, one mature teratoma, six lesions without histological confirmation). An analysis of uptake dynamics was done in the patients with increased FET uptake (22 gliomas, three lymphomas, three non-neoplastic lesions, three lesions with unknown histology and four other primaries). Upon classification of tumours into low (i.e. WHO I and II) and high grade (i.e. WHO III and IV), a significant difference in FETmax between the two categories was observed only in the first image frame (0-10 min p.i.), with FETmax=2.0 in low-grade and 3.2 in high-grade tumours (p<0.05); no significant differences were found in frame 4 (30-40 min p.i.), with FETmax=2.4 vs 2.7. Similar results were obtained when the analysis was applied only to astrocytic tumours (2.0 vs 3.1 in the first frame; 2.4 vs 2.6 in the fourth frame). CONCLUSION: These initial results indicate that FET PET is a useful method to identify malignant brain lesions. It appears that high- and low-grade brain tumours exhibit a different uptake kinetics of FET. A kinetic analysis of FET PET may provide additional information in the differentiation of suspected brain lesions.

[PET/CT in radiotherapy]. / PET-CT in der Strahlentherapie.

Combining positron emission tomography (PET) and X-ray computed tomography (CT) with simultaneous acquisition may improve diagnostic accuracy in oncology. Moreover this combination holds considerable promise in radiotherapy. Metabolic information may be used in decision making in radiotherapy and in planning target volumes. Furthermore early evaluation of treatment efficacy becomes possible. New tracers for the assessment of tumour hypoxia or apoptosis in clinical routine are currently being developed. These tracers may yield high relevance in radiotherapy. Hybrid scanners facilitate patient handling and shorten the duration of acquisition. Furthermore fusion accuracy is optimal. Prospective studies have to be conducted to show that the new technology improves patient care in terms of efficiency and quality.