Johannes Meller

Early diagnosis and follow-up of aortitis with [18F]FDG PET and MRI

The aim of this prospective study was to compare fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) with magnetic resonance imaging (MRI) in patients with early aortitis, at the time of initial diagnosis and during immunosuppressive therapy. The study population consisted of 15 patients (nine females and six males; median age 62 years, range 26–76 years) who presented with fever of unknown origin or an elevated erythrocyte sedimentation rate or elevated C-reactive protein and who showed pathological aortic [18F]FDG uptake. Fourteen of these patients had features of early giant cell arteritis (GCA), while one had features of early Takayasu arteritis. During follow-up, seven PET scans were performed in six patients with GCA 4–30 months (median 19 months) after starting immunosuppressive medication. The results of [18F]FDG imaging were compared with the results of MRI at initial evaluation and during follow-up and with the clinical findings. At baseline, abnormal [18F]FDG uptake was present in 59/104 (56%) of the vascular regions studied in 15 patients. Seven follow-up PET studies were performed in six patients. Of 30 regions with initial pathological uptake in these patients, 24 (80%) showed normalisation of uptake during follow-up. Normalisation of [18F]FDG uptake correlated with clinical improvement and with normalisation of the laboratory findings. All except one of the patients with positive aortic [18F]FDG uptake were investigated with MRI and MRA. Thirteen of these 14 patients showed inflammation in at least one vascular region. Of 76 vascular regions studied, 41 (53%) showed vasculitis on MRI. Of 76 vascular regions studied with both PET and MRI, 47 were concordantly positive or negative on both modalities, 11 were positive on MRI only and 18 were positive on PET only. MRI was performed during follow-up in six patients: of 17 regions with inflammatory changes, 15 regions remained unchanged and two showed improvement. Whole-body [18F]FDG PET is valuable in the primary diagnosis of early aortitis. The results of [18F]FDG PET and MRI in the diagnosis of aortitis in this study were comparable, but FDG imaging identified more vascular regions involved in the inflammatory process than did MRI. In a limited number of patients [18F]FDG PET was more reliable than MRI in monitoring disease activity during immunosuppressive therapy.

Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With 131I-Labetuzumab After Salvage Resection of Colorectal Metastases in the Liver: Five-Year Safety and Efficacy Results

PURPOSE Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM. PATIENTS AND METHODS Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined. RESULTS With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade < or = 3 neutropenia and/or thrombocytopenia. CONCLUSION Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.

High Rates of Durable Responses With Anti-CD22 Fractionated Radioimmunotherapy: Results of a Multicenter, Phase I/II Study in Non-Hodgkin's Lymphoma

PURPOSE Fractionated radioimmunotherapy targeting CD22 may substantially improve responses and outcome in non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS A multicenter trial evaluated two or three weekly infusions of yttrium-90 ((90)Y) epratuzumab tetraxetan (humanized anti-CD22 antibody) in 64 patients with relapsed/refractory NHL, including 17 patients who underwent prior autologous stem-cell transplantation (ASCT). Objective (OR) and complete responses (CR/complete response unconfirmed [CRu]), as well as progression-free survival (PFS), were determined. RESULTS At the maximum total (90)Y dose of 45 mCi/m(2) (1,665 MBq/m(2)), grade 3 to 4 hematologic toxicities were reversible to grade 1 in patients with less than 25% bone marrow involvement. The overall OR rate and median PFS for all 61 evaluable patients was 62% (CR/CRu, 48%) and 9.5 months, respectively. Patients without prior ASCT obtained high OR rates of 71% (CR/CRu, 55%) across all NHL subtypes and (90)Y doses, even in poor-risk categories (refractory to last anti-CD20-containing regimen, 73% [CR/CRu, 60%]; bulky disease: 71% [CR/CRu, 43%]). Patients with prior ASCT received lower doses, but achieved an OR rate of 41% (CR/CRu, 29%). For patients with follicular lymphoma (FL), OR rates and median PFS increased with total (90)Y-dose, reaching 100% (CR/CRu, 92%) and 24.6 months, respectively, at the highest dose levels (> 30 mCi/m(2) total (90)Y-dose [1,110 MBq/m(2)]). Further, patients with FL refractory to prior anti-CD20-containing regimens achieved 90% (nine of 10 patients) OR and CR/CRu rates and a median PFS of 21.5 months. CONCLUSION Fractionated anti-CD22 radioimmunotherapy provides high total doses of (90)Y, yielding high rates of durable CR/CRus in relapsed/refractory NHL, resulting in 20 mCi/m(2) x 2 weeks as the recommended dose for future studies.

Dynamic lymphoscintigraphy and image fusion of SPECT and pelvic CT-scans allow mapping of aberrant pelvic sentinel lymph nodes in malignant melanoma

To date, there are no reliable criteria to identify those patients with melanoma-infiltrated sentinel lymph nodes (SLNs) of the groin who might benefit from an extended lymphadenectomy, including the pelvic lymph nodes. We hypothesised that there are pelvic lymph nodes that receive lymph directly from the primary tumour, thus being at an increased risk for metastasis. In order to determine the frequency of radioactively labelled pelvic lymph nodes and the kinetics of their appearance, we introduce here a combination of dynamic lymphoscintigraphy, single photon emission computed tomography (SPECT) and image fusion of SPECT and pelvic Computed Tomography (CT)-scans. By dynamic lymphoscintigraphy and intraoperative gamma probe detection, superficially located inguinal SLNs (median 2 nodes) could be identified in all of the 51 patients included in this analysis. The histological search for micrometastases was positive in 16 patients (median Breslow thickness of the primary melanoma 2.5 mm). In 29 patients, SPECT and the image fusion technique were additionally performed. Radioactively labelled pelvic lymph nodes were detected in 20 individuals, 6 of them presenting aberrant pelvic SLNs that, on dynamic lymphoscintigraphy, had appeared simultaneously with the superficial SLN(s). Of the 6 patients in whom radioactive pelvic lymph nodes were excised together with the superficial SLN(s), only one had positive superficial SLNs. In this patient, the aberrant pelvic SLN proved to be tumour-positive. In 9 patients, there was no radiotracer uptake in the pelvic lymph nodes at all. Image fusion of SPECT and pelvic CT-scans is an excellent tool to localise exactly the pelvic tumour-draining nodes. The significance of radioactively labelled pelvic lymph nodes for the probability of pelvic metastases should be analysed further.

Association of daytime sleepiness with nigrostriatal dopaminergic degeneration in early Parkinson's disease

IntroductionMany patients with Parkinsons disease (PD) report daytime sleepiness. Its etiology, however, is still not fully understood. The aim of this study was to examine if the amount of nigrostriatal dopaminergic degeneration is associated with subjective daytime sleepiness in patients with PD.Patients and methodsWe investigated 21 patients with PD clinically and by means of [123I] FP-CIT-SPECT (DaTSCANR). Each patient filled in the Epworth sleepiness scale (ESS), the Parkinsons Disease Sleep Scale (PDSS), and the self-rating depression scale according to Zung (SDS) to assess sleepiness, sleep quality, and depressive symptoms.ResultsThe mean specific dopamine transporter binding in the 21 PD patients (60.8 ± 10.4 years, nine females, median Hoehn and Yahr stage 2.0) was decreased. Nine patients were in Hoehn and Yahr stage 1 (58.7 ± 6.6 years, four females; ESS score 7.4 ± 4.5; PDSS score 105.1 ± 30.9), the other 12 patients were in Hoehn and Yahr stage 2 (62.4 ± 12.6 years, five females; ESS score 6.7 ± 4.7, PDSS score 97.1 ± 25.6). Age, gender, ESS, and PDSS scores were not significantly different in both groups. However, ESS scores showed an inverse correlation with mean DAT binding in the striatum (r = -0.627, p = 0.03), the caudate nucleus (r = -0.708, p = 0.01), and the putamen (r = -0.599, p = 0.04) in patients with Hoehn and Yahr stage 2. There was no correlation of the ESS score with age, disease duration, UPDRS motor score, PDSS score, or depression score.ConclusionSubjective daytime sleepiness seems to be associated with dopaminergic nigrostriatal degeneration in early PD.

67Ga-citrate and 99Tcm-MDP for estimating the severity of vertebral osteomyelitis.

The aim of this study was to evaluate the roles of 67Ga-citrate and 99Tcm-methylene diphosphonate (99Tcm-MDP) planar and single photon emission tomographic (SPET) imaging in patients with vertebral osteomyelitis. Thirty patients (22 females, 8 males) aged 62.7±16.4 years (mean±s) were enrolled prospectively between May 1995 and May 1998. The patients had been on antibiotics for 7±4 weeks prior to the study. Histology was available for all but nine patients with mild infections, who were evaluated by a combination of magnetic resonance imaging (MRI), clinical and laboratory tests. 67Ga-citrate (185 MBq) and three-phase bone (555 MBq 99Tcm-MDP) planar and SPET imaging were performed in all patients, together with MRI as a comparison. In total, 67 infectious foci were detected. Based on histology, there were four cases of severe, 13 cases of moderate and four cases of mild osteomyelitis; nine mild infections were also classified by the combination of MRI, clinical and laboratory results. Combined MRI and 67Ga-citrate SPET correctly classified all patients; MRI detected all 67 infectious foci, whereas 67Ga-citrate SPET identified 54 only. False-negative results were seen with all other modalities, especially in cases of mild and moderate infection. 67Ga-citrate SPET identified unsuspected cases of endocarditis (n = 2), paravertebral abscess (n = 1), subaxillary soft tissue abscess (n = 1) and rib osteomyelitis (n = 1). For 67Ga-citrate SPET, the target-to-background ratio was 2.24±0.31, 1.76±0.07 and 1.30±0.18 for severe, moderate and mild osteomyelitis, respectively. Significant differences were noted between severe and moderate infection (P = 0.0051) and between severe and mild infection (P<0.0001); that between moderate and mild infection was non-significant. For 99Tcm-MDP planar and SPET imaging, and for planar 67Ga-citrate imaging, there was no correlation with severity. We conclude that 67Ga-citrate SPET is able to identify vertebral osteomyelitis and detect additional sites of infection. It can also aid in determining the severity of infection and, potentially, the response to therapy.

Normal hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with Huntington's disease

A significant atrophy and loss of hypocretin neurons in the brains of human patients with Huntingtons disease (HD) and in R6/2 mice have been reported. We included 10 patients with HD and 12 patients with chorea-like hyperkinetic movement disorders (non-HD). All patients of the HD group and eleven patients of the non-HD group showed normal hypocretin-1 levels. Thus, hypocretin-1 may not serve as an additional diagnostic marker for HD.

Imaging in the Dialysis Patient: Nuclear Medicine Studies in the Dialysis Patient

Nuclear medicine (scintigraphy) studies that are performed in patients being prepared for regular dialysis treatment include the measurement of renal clearance and dynamic studies of renal perfusion and function. Static scintigraphy with 99mTc‐DMSA may be used in the evaluation of children at risk of renal damage and further functional deterioration. In patients on peritoneal dialysis, nuclear medicine procedures enable the diagnosis of structural complications such as intra‐abdominal herniations and leaks. Diagnosis of infections of the vascular access sites in patients on hemodialysis and of the catheter tunnel in patients on peritoneal dialysis can be made with high diagnostic accuracy using radiolabeled, autologous leukocytes. Scintigraphy is valuable in delineating the extent of deposits of amyloid and parenchymal microcalcifications, and may be helpful in the functional evaluation of organs and tissues involved in the pathophysiology of renal impairment and dialysis. If radioiodine therapy with 131I is performed in patients on hemodialysis with benign or malignant thyroid disease, then pretherapeutic dosimetry is necessary to avoid over‐ and undertreatment. Radioiodine therapy in the dialysis patient leads to only insignificant contamination of dialysis equipment and marginal exposure to the medical staff.

Increased Radioiodine Uptake of Thyroid Cell Cultures after External Irradiation

Background:Radioiodine uptake (RIU) is one of the main prognostic factors for curative results of radioiodine therapy in patients with differentiated thyroid cancer. Some days after application of 131I, the uptake of a subsequent administration of radioiodine was found to be reduced. In contrast, early after irradiation with high-energy photons glucose and amino acid uptake were observed to be increased. Effects of external irradiation on RIU of thyrocytes using high-energy photons have not been investigated so far.Material and Methods:Two different cell lines (FRTL-5 and ML-1 cells) derived from thyroid tissue were studied in vitro. Cell lines were either incubated with 131I only (controls) or additionally irradiated with single doses of 6 or 10 Gy of high-energy photons using a linear accelerator. Cell number and RIU were determined 24–96 h after 131I application. RIU measurements were repeated after application of sodium perchlorate in excess to investigate specificity of the uptake. Statistical analyses were performed using non-parametric tests.Results:Incubation with radioiodine as well as irradiation with high-energy photons slowed down proliferation in investigated cell lines significantly. Irradiation with solely 131I resulted in stable or slightly decreased iodide uptake. Compared to those cells, the RIU increased significantly in externally irradiated cells, i. e., additional irradiation with 10 Gy resulted in an almost threefold increase of RIU in FRTL-5 after 72 h. The increase of RIU after irradiation was dose-dependent in both cell lines and could be blocked by perchlorate excess.Conclusion:It could be demonstrated that external irradiation increases RIU in thyroid cell cultures early after irradiation. The increase was dose-dependent and specific, as it could be blocked by perchlorate. This effect appears to be similar to the increase of other actively transported substances after irradiation with high-energy photons. Therefore, the results of this study may contribute to the knowledge of a generalized irradiation-induced mechanism which causes the activation of different cellular transporters. The clinical impact of these findings on combined therapy concepts has to be investigated in further experiments.Hintergrund:Der Radioiod-Uptake (RIU) ist ein wesentlicher prognostischer Faktor für den kurativen Erfolg der Radioiodtherapie bei Patienten mit differenziertem Schilddrüsenkarzinom. Es konnte gezeigt werden, dass einige Tage nach 131I-Gabe der Uptake bei einer erneuten Radioiodapplikation deutlich vermindert war. Im Gegensatz dazu wurde eine Zunahme des Glukose- und Aminosäure-Uptakes kurz nach der Bestrahlung mit hochenergetischen Photonen beschrieben. Effekte einer externen Bestrahlung mit hochenergetischen Photonen auf den RIU von Thyreozyten sind bisher noch nicht untersucht worden.Material und Methodik:Die Untersuchungen wurden in vitro an zwei unterschiedlichen Zelllinien (FRTL-5- und ML-1-Zellen) thyreoidalen Ursprungs durchgeführt. Die Zellkulturen wurden entweder nur mit Radioiod inkubiert (Kontrollen) oder zusätzlich einzeitig mit Hilfe eines Linearbeschleunigers mit 6 oder 10 Gy bestrahlt. Die Bestimmung der Zellzahl und des RIU erfolgte 24–96 h nach der 131I-Applikation. Die Messungen wurden nach Zugabe von Natriumperchlorat im Überschuss wiederholt. Statistische Analysen erfolgten mittels nichtparametrischer Tests.Ergebnisse:Die Proliferation der untersuchten Zelllinien wurde sowohl durch die Inkubation mit Radioiod als auch durch die Bestrahlung signifikant vermindert. Die Bestrahlung mit 131I allein führte zu gleichbleibendem oder leicht vermindertem Iodid-Uptake. Verglichen mit diesen Zellen erhöhte die externe Bestrahlung den RIU signifikant. So konnte bei FRTL-5-Zellen durch die zusätzliche Bestrahlung mit 10 Gy der RIU nach 72 h beinahe verdreifacht werden. Der Anstieg des RIU nach Bestrahlung war bei beiden Zelllinien dosisabhängig und konnte durch einen Überschuss an Perchlorat blockiert werden.Schlussfolgerung:In dieser Studie konnte gezeigt werden, dass eine externe Bestrahlung mit hochenergetischen Photonen zu einem Anstieg des RIU von Schilddrüsen-Zellkulturen führt. Dieser Anstieg war dosisabhängig und spezifisch, da er durch Perchlorat geblockt werden konnte. Dieser Effekt weist Ähnlichkeiten zum Anstieg anderer aktiv transportierter Substanzen nach Bestrahlung auf. Die Ergebnisse dieser Studie liefern einen Beitrag zur Kenntnis eines generalisierten Mechanismus, welcher auf eine Aktivierung unterschiedlicher zellulärer Transporter nach Bestrahlung mit hochenergetischen Photonen hinweist. Die klinische Relevanz dieser Ergebnisse für kombinierte Therapieverfahren sollte in weiteren Untersuchungen geklärt werden.

Aβ peptide1–42, Tau protein and S-100B protein level in cerebrospinal fluid of three patients with primary progressive aphasia

Abstract Primary progressive aphasia (PPA) is a clinical syndrome characterized by a slowly progressive aphasia in the absence of accompanying signs of generalized dementia. While non-fluent PPA tends to progress frontally and is usually linked to frontotemporal degeneration, fluent PPA might be associated with both, frontotemporal degeneration or Alzheimers disease. Although recent reports suggest that PPA belongs neuropathologically to the group of tauopathias, cerebrospinal fluid analysis has not been established as a means of diagnosis in PPA so far. In this paper we investigated Aβ peptide1–42 (Aβ1–42), Tau protein and S-100B protein level in the cerebrospinal fluid of three patients with PPA. In all patients Tau protein and S-100B level were slightly elevated, however, Aβ1–42 was found to be in normal range. Thus, our first results point to PPA being neurochemically linked to frontotemporal degeneration.