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.

Neurobehavioral and neurometabolic (SPECT) correlates of paranormal information: involvement of the right hemisphere and its sensitivity to weak complex magnetic fields.

Experiments were designed to help elucidate the neurophysiological correlates for the experiences reported by Sean Harribance. For most of his life he has routinely experienced "flashes of images" of objects that were hidden and of accurate personal information concerning people with whom he was not familiar. The specificity of details for target pictures of people was correlated positively with the proportion of occipital alpha activity. Results from a complete neuropsychological assessment, Single Photon Emission Computed Tomography (SPECT), and screening electroencephalography suggested that his experiences were associated with increased activity within the parietal lobe and occipital regions of the right hemisphere. Sensed presences (subjectively localized to his left side) were evoked when weak, magnetic fields, whose temporal structure simulated long-term potentiation in the hippocampus, were applied over his right temporoparietal lobes. These results suggest that the phenomena attributed to paranormal or "extrasensory" processes are correlated quantitatively with morphological and functional anomalies involving the right parietotemporal cortices (or its thalamic inputs) and the hippocampal formation.

Remote viewing with the artist Ingo Swann: neuropsychological profile, electroencephalographic correlates, magnetic resonance imaging (MRI), and possible mechanisms.

In the present study, the artist Ingo Swann, who helped develop the process of remote viewing (awareness of distant objects or places without employing normal senses), was exposed during a single setting of 30 min. to specific patterns of circumcerebral magnetic fields that significantly altered his subjective experiences. Several times during subsequent days, he was asked to sit in a quiet chamber and to sketch and to describe verbally distant stimuli (pictures or places) beyond his normal senses. The proportions of unusual 7-Hz spike and slow wave activity over the occipital lobes per trial were moderately correlated (rho=.50) with the ratings of accuracy between these distal, hidden stimuli and his responses. A neuropsychological assessment and Magnetic Resonance Imaging indicated a different structural and functional organization within the parieto-occipital region of the subject's right hemisphere from organizations typically noted. The results suggest that this type of paranormal phenomenon, often dismissed as methodological artifact or accepted as proofs of spiritual existence, is correlated with neurophysiological processes and physical events. Remote viewing may be enhanced by complex experimentally generated magnetic fields designed to interact with the neuromagnetic "binding factor" of consciousness.

Cortisol metabolism in the postoperative period after cardiac surgery.

Relative 11beta-hydroxysteroid dehydrogenase deficiency has been shown previously to arise from endogenous hypercortisolism in diseases of the hypothalamic/pituitary/adrenocortical system; whether stress induced hypercortisolism may also result in substrate overload of 11beta-hydroxysteroid dehydrogenase has not yet been studied. We therefore studied the characteristics of cortisol metabolisation during the postoperative period of cardiac surgery, representing a well standardized surgical procedure. In a prospective, observational, consecutive case study, 14 patients undergoing cardiac surgery were investigated. During the first two days after cardiac surgery urine was collected from the patients during two 10 hour overnight periods (8 p.m. (day of surgery) until 6 a.m., and during the following night). Using capillary gas-chromatography, main urinary cortisol metabolites were quantified (tetrahydrocortisone, tetrahydrocortisol, allo-tetrahydrocortisol, cortolones, cortols as sum of cortisol metabolites (CM)). Free urinary cortisol (FUC) was determined by an automated immunoassay after extraction. The ratio of cortisol metabolites (tetrahydrocortisol, allo-tetrahydrocortisol, cortols) to cortisone metabolites (tetrahydrocortisone, cortolones) was calculated to characterize the overall activity of 11beta-hydroxysteroid dehydrogenase, an enzyme system catalyzing the conversion of cortisol to inactive cortisone (CMR, cortisol metabolisation ratio). Total cortisol metabolisation (including hepatic ring A-reduction and conjugation) was estimated by a cortisol turnover quotient (CM/FUC). In all urinary samples the ratio of cortisol to cortisone metabolites was markedly elevated compared to controls (patients: median 1.9, interquartile range 1.5-2.4, absolute range 1.0-3.2; controls: median 0.45, interquartile range 0.36-0.52); this ratio was positively correlated to FUC (r2 = 0.30; p = 0.003). The cortisol turnover quotient was markedly reduced (patients: median 38.0, interquartile range 20.0-103.9, absolute range 8.3-211.9; controls: median 259, interquartile range 176-415) and inversely correlated to FUC (r2 = 0.64, p < 0.001). It is concluded that major surgical trauma results in a marked relative reduction of cortisol inactivation probably consequent to substrate overload of the metabolizing enzymes; as the activity of these enzymes (mainly 11beta-hydroxysteroid dehydrogenase) is crucial for the modulation of cortisol receptor access, tissue corticoid sensitivity in the postoperative period may vary substantially from physiological conditions.

Corticosteroid-binding globulin and free cortisol in the early postoperative period after cardiac surgery.

OBJECTIVES: To characterize concentrations of corticosteroid-binding globulin (CBG), total and free serum cortisol, and free urinary cortisol in patients during the postoperative period of cardiac surgery. DESIGN AND METHODS: In 24 patients serum was sampled on the first and second postoperative day after cardiac surgery (21 procedures with thoracotomy, 3 thoracoscopic procedures); urine was collected for two 10-h periods (8 P.M. until 6 A.M.) on the respective postoperative days. Total serum cortisol and free urinary cortisol were measured with an automated chemiluminescence assay (analysis of urine after extraction with dichloromethane), and CBG using a coated-tube RIA. Free serum cortisol was calculated from the concentrations of total serum cortisol and CBG as described previously. Thirty healthy volunteers were studied as controls. RESULTS: CBG was reduced to about one-half of the normal concentration on both postoperative days. Whereas total cortisol was about two-fold increased on the first postoperative day compared to controls extremely high concentrations of free serum cortisol were calculated from CBG and total cortisol [median 136 nmol/L (interquartile range 100-185); controls 21.8 nmol/L (interquartile range 16.9-29.8)]. On the second postoperative day, median total serum cortisol was within the interquartile range of the controls, free serum cortisol in contrast was still two-fold increased. Free serum cortisol and free urinary cortisol were significantly correlated (r = 0.60). CONCLUSIONS: Extremely high concentrations of free serum cortisol are typically found in the postoperative period of cardiac surgery; under these conditions the mere consideration of total cortisol does not appropriately display the activation of the adrenal cortex.

Homosexual inmates in the Buchenwald Concentration Camp.

The treatment of homosexual inmates in Nazi concentration camps is a subject which was largely ignored by historians in both West and East Germany after the war. Not until the 1980s, when research began to focus on some of the lesser-known victims of Nazi terror, did attention shift to the fate of homosexuals. This process can be seen clearly at the Buchenwald Memorial in the former GDR, the site of the persecution and also the death of considerable numbers of prisoners identified by the pink triangle on their clothing. The persecution of homosexuals in Nazi Germany began in 1933, even before Buchenwald was built in 1937. The Nazis aimed to eradicate homosexuality, which they saw as a threat to the survival of the German people. Incarceration in concentration camps like Buchenwald marked a stage in the radicalization of Nazi policy against homosexuals. There they were subjected to the harshest conditions and treated as the lowest of the low in the camp hierarchy. They were continually exposed to the terror of the SS but also the latent prejudices of the rest of the camp population. The culminating points of their maltreatment in Buchenwald were the use of homosexuals in experiments to develop immunization against typhus fever and the attempt by an SS doctor to "cure" homosexuality through the implantation of sexual hormones.

[Initial experience with the NOVACOR left heart assist system in transition for heart transplantation at the Grosshadern Clinic]. / Erste Anwendung des Linksherzunterstützungssystems NOVACOR als Uberbrückung zur Herztransplantation am Klinikum Grosshadern.

We recently used an electrically powered left ventricular assist device (NOVACOR Corp., Oakland, Calif.) to support the circulation of a 17-year-old man with profound circulatory impairment. He had been regularly listed for cardiac transplantation previously because of dilated cardiomyopathy, and decompensated acutely with severe biventricular failure before a suitable donor heart became available. Isolated left ventricular support with the NOVACOR system provided adequate haemodynamics and recovery of right ventricular, hepatic and renal function. After 2 days of support, orthotopic heart transplantation could be performed successfully. Five days after transplantation he developed a massive cerebral haemorrhage during a hypertensive crisis of which he recovered completely after neurosurgery without any residuals. He ist currently doing extremely well some 14 months after transplantation.