Successful Chimeric Antigen Receptor (CAR) T-Cell Treatment in Aggressive Lymphoma Despite Coronavirus Disease 2019 (CoVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication - Case Report.

In patients with compromised immune function, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (CoVID-19) impose particular challenges. Especially in hematological malignancies, including lymphoma, the demands by this novel virus disease are further enhanced during sophisticated treatments, such as chimeric antigen receptor (CAR) T-cell therapy. Here, we present the first case of a patient with refractory diffuse-large B-cell lymphoma, who underwent CAR T-cell treatment in the context of SARS-CoV-2. Irrespective of prolonged and active SARS-CoV-2 infection, T cells were successfully isolated by apheresis and processed to anti-CD19 CAR T cells (axicabtagene-ciloleucel). In light of the aggressive lymphoma course, lymphodepleting chemotherapy and CAR-T cells were administered in early recovery after oxygen-dependent CoVID-19 pneumonia. Except for moderate cytokine release, this cellular immunotherapy was well tolerated. Notably, there is no deterioration of the SARS-CoV-2 infection; however, complete lymphoma response and full clinical recovery were observed. In conclusion, CAR T-cell treatment in aggressive lymphoma in the setting of SARS-CoV-2 infection is feasible and may offer significant therapeutic activity in refractory disease.

Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors.

PURPOSE: Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET. PATIENTS AND METHODS: Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma. RESULTS: Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 ± 6.8 versus 22.1 ± 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 ± 2.6 versus 12.6 ± 2.7). CONCLUSIONS: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors.

Association between sentinel lymph node excision with or without preoperative SPECT/CT and metastatic node detection and disease-free survival in melanoma.

CONTEXT: Malignant melanoma has become an increasing interdisciplinary public health challenge worldwide. Sentinel lymph node excision (SLNE) is considered the most sensitive and specific staging test for the detection of micrometastatic melanoma in regional lymph nodes. OBJECTIVE: To compare metastatic node detection and disease-free survival using single-photon emission computed tomography/computed tomography (SPECT/CT)-aided SLNE vs standard SLNE in patients with melanoma. DESIGN, SETTING, AND PATIENTS: A prospective, computerized melanoma patient database at the University Hospital Essen, Skin Cancer Center, Essen, Germany, was used to identify a cohort of 464 patients eligible for SLNE between March 2003 and April 2011. A total of 403 patients with clinically negative lymph nodes, who underwent SLNE with or without preoperative SPECT/CT, qualified for subsequent analysis. MAIN OUTCOME MEASURES: Metastatic node detection and disease-free survival. RESULTS: Between March 2003 and October 2008, 254 patients underwent the standard SLNE technique. After November 2008, 149 patients underwent the SPECT/CT technique. Patients who did not receive SNLE in both intervals (46/300 [15.34%] for standard cohort vs 15/164 [9.15%] for SPECT/CT cohort; P = .06) did not differ in either age (difference, 69.20 years; 95% CI, 62.84-72.07 years; P = .38), tumor depth (difference, 2.90 mm; 95% CI, 2.87-4.54 mm; P = .54), or ulceration of the primary tumor (difference, -8.00%; 95% CI, -35.74% to 19.81%; P = .59). However, using SPECT/CT allowed SLNE in the head and neck area more frequently (2.0% for standard vs 23.5% for SPECT/CT; difference, 21.1%; 95% CI, 14.1%-28.2%; P < .001). In the SPECT/CT cohort, more sentinel lymph nodes per patient were detected than in the standard cohort (2.40 vs 1.87; 95% CI, 1.93-2.18; P < .001). The number of positive sentinel lymph nodes per patient was significantly higher in the SPECT/CT cohort than in the standard cohort (0.34 vs 0.21; 95% CI, 0.21-0.31; P = .04). The local relapse rate in the SPECT/CT cohort was lower than in the standard cohort (6.8% vs 23.8%, P = .03), which prolonged 4-year disease-free survival (93.9% vs 79.2%; P = .02). CONCLUSION: Among patients with clinically lymph node-negative melanoma, the use of SPECT/CT-aided SLNE compared with SLNE alone was associated with a higher frequency of metastatic involvement and a higher rate of disease-free survival.

Indocyanine green fluorescence-guided sentinel lymph node biopsy in dermato-oncology.

BACKGROUND: Sentinel lymph node biopsy (SLNB) for cutaneous malignancies usually carried out with radioactive nanocolloids (Tc-99m). The SLNE is controversially discussed internationally. This is especially given to the high false-negative rate up to 44 %. An alternative could be the fluorescent dye indocyanine green (ICG). MATERIAL AND METHODS: We investigated the advantage of intraoperative fluorescence detection of lymphatic vessels and SLN with a Near-Infrared (NIR) camera in comparison to conventional methods using preoperative lymphoscintigraphy and SPECT/CT in 22 patients with malignant melanoma. RESULTS: A total of 61 SLNs were removed in 22 operative procedures. In 7 SLN (10.3 %; 7/68) the histopathological assessment could demonstrate a metasta-tic involvement. 11 additional SLN (19.1 %) in 8 patients were only identified using the fluorescent labeling. Two of these additional SLN (9.1 %; 2/22) showed metastatic involvement. CONCLUSION: The ICG fluorescence-guided SLNB is an innovative imaging technique for dermato-oncology, reliable and providing additional information in the detection of SLN. Therefore SLNB with fluorescence-dye is an attractive option with intraoperative real-time lymphoscintigraphy to improve the detection of SLN in cutaneous malignancies and potential reduction of the false negative rate in SLN.

68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors.

UNLABELLED: Radiolabeled somatostatin analogs represent valuable tools for both in vivo diagnosis and therapy of neuroendocrine tumors (NETs) because of the frequent tumoral overexpression of somatostatin receptors (sst). The 2 compounds most often used in functional imaging with PET are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately 10-fold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in the detection of NET lesions because it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same NET patients. METHODS: Forty patients with metastatic NETs underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the work-up before prospective peptide receptor radionuclide therapy. The performance of both imaging methods was analyzed and compared for the detection of individual lesions per patient and for 8 defined body regions. A region was regarded positive if at least 1 lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUVmax) was compared for concordant lesions and renal parenchyma. RESULTS: Seventy-eight regions were found positive with (68)Ga-DOTATATE versus 79 regions with (68)Ga-DOTATOC (not significant). Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE than with (68)Ga-DOTATOC (254 vs. 262, P < 0.05). Mean (68)Ga-DOTATATE SUVmax across all lesions was significantly lower than (68)Ga-DOTATOC (16.0 ± 10.8 vs. 20.4 ± 14.7, P < 0.01). Mean SUVmax for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.7 ± 3.0 vs. 13.2 ± 3.3). CONCLUSION: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess a comparable diagnostic accuracy for the detection of NET lesions, with (68)Ga-DOTATOC having a potential advantage. The approximately 10-fold higher affinity for the sst2 of (68)Ga-DOTATATE does not prove to be clinically relevant. Quite unexpectedly, SUVmax of (68)Ga-DOTATOC scans tended to be higher than their (68)Ga-DOTATATE counterparts.

Comparison of FDG-PET/CT and bone scintigraphy for detection of bone metastases in breast cancer.

BACKGROUND: Bone scintigraphy is the standard procedure for the detection of bone metastases in breast cancer patients. FDG-PET/CT has been reported to be a sensitive tool for tumor staging in different malignant diseases. However, its accuracy for the detection of bone metastases has not been compared to bone scintigraphy. PURPOSE: To compare whole-body FDG-PET/CT and bone scintigraphy for the detection of bone metastases on a lesion basis in breast cancer patients. MATERIAL AND METHODS: Twenty-nine consecutive women (mean age 58 years, range 35-78 years) with histologically proven breast cancer were assessed with bone scintigraphy and whole-body FDG-PET/CT. Twenty-one patients (72%) were suffering from primary breast cancer and eight patients (28%) were in aftercare with a history of advanced breast cancer. Both imaging procedures were assessed for bone metastases by a radiologist and a nuclear medicine physician. Concordant readings between bone scintigraphy and FDG-PET/CT were taken as true. Discordant readings were verified with additional MRI imaging in all patients and follow-up studies in most patients. RESULTS: A total of 132 lesions were detected on bone scintigraphy, FDG-PET/CT or both. According to the reference standard, 70/132 lesions (53%) were bone metastases, 59/132 lesions (45%) were benign, and three lesions (2%) remained unclear. The sensitivity of bone scintigraphy was 76% (53/70) compared to 96% (67/70) for FDG-PET/CT. The specificity of bone scintigraphy and FDG-PET/CT was 95% (56/59) and 92% (54/59), respectively. According to the reference standard bone metastases were present in eight out of the 29 patients (28%), whereas 20 patients (69%) were free of bone metastases. One (3%) patient had inconclusive readings on both modalities as well as on MRI and follow-up studies. Bone scintigraphy and FDG-PET/CT correctly identified seven out of eight patients with bone metastases and 20 out of 20 patients free of metastases. CONCLUSION: On a lesion-basis whole-body FDG-PET/CT is more sensitive and equally specific for the detection of bone metastases compared with bone scintigraphy.

Response and long-term control of bone metastases after peptide receptor radionuclide therapy with (177)Lu-octreotate.

UNLABELLED: Peptide receptor radionuclide therapy (PRRT) is an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP NETs), with outstanding overall response rates and survival. However, little is known about the particular efficacy regarding bone metastasis (BM). METHODS: We retrospectively analyzed a consecutive subgroup of 42 patients with BM of GEP NETs treated with PRRT ((177)Lu-octreotate, 4 intended cycles at 3 monthly intervals [10-14 wk]; mean activity per cycle, 8.1 GBq). Availability of restaging and outcome data was required for patient inclusion. Baseline characteristics, including age, tumor origin, performance score, Ki-67 index, tumor load, tumor uptake, plasma chromogranin A, and neuron-specific enolase, were analyzed regarding impact on tumor regression (modified M.D. Anderson criteria) and time to progression. Survival analyses were performed using Kaplan-Meier curves, log-rank test at a significance level of P less than 0.05, and Cox proportional hazards model for uni- and multivariate analyses. RESULTS: Median follow-up was 32 mo. The observed response of BMs consisted of complete remission in 2 (4.8%), partial remission in 14 (33.3%), minor response in 5 (11.9%), stable disease in 16 (38.1%), and progressive disease in 5 (11.9%) patients. Median progression-free survival and overall survival (OS) were 35 mo (26-44, 95% confidence interval) and 51 mo (37-65, 95% confidence interval), respectively. Patients with responding BMs (complete remission, partial remission, or minor response) exhibited a trend toward better OS (median OS not reached after 53 mo) when compared to nonresponding patients (39 mo, P = 0.076). Only Ki-67 index (>10%) and chromogranin A level (>600 ng/mL) contributed to regression analysis. CONCLUSION: BM of GEP NETs is effectively controlled by PRRT, with long progression-free survival and OS. Poor patient condition and multifocality of BMs do not clearly affect treatment efficacy, possibly encouraging the use of PRRT in advanced bone metastatic disease. Larger studies are needed to assess predictors of treatment outcome in these patients.

68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax.

PURPOSE: By targeting somatostatin receptors (sst) radiopeptides have been established for both diagnosis and therapy. For physiologically normal human tissues the study provides a normative database of maximum standardized uptake value (SUV(max)) and sst mRNA. METHODS: A total of 120 patients were subjected to diagnostic (68)Ga-DOTATOC positron emission tomography (PET)/CT (age range 19-83 years). SUV(max) values were measured in physiologically normal tissues defined by normal morphology, absence of surgical intervention and absence of metastatic spread during clinical follow-up. Expression of sst subtypes (sst1-sst5) was measured independently in pooled adult normal human tissue by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: SUV(max) revealed a region-specific pattern (e.g., mean ± SD, spleen 31.1 ± 10.9, kidney 16.9 ± 5.3, liver 12.8 ± 3.6, stomach 7.0 ± 3.1, head of pancreas 6.2 ± 2.3, small bowel 4.8 ± 1.8, thyroid 4.7 ± 2.2, bone 3.9 ± 1.3, large bowel 2.9 ± 0.8, muscle 2.1 ± 0.5, parotid gland 1.9 ± 0.6, axillary lymph node 0.8 ± 0.3 and lung 0.7 ± 0.3). SUV(max) was age independent. Gender differences were evident within the thyroid (female/male: 3.7 ± 1.6/5.5 ± 2.4, p < 0.001; Mann-Whitney U test) and the pancreatic head (5.5 ± 1.9/6.9 ± 2.2, p < 0.001). The sst mRNA was widely expressed and heterogeneous, showing sst1 to be most abundant. SUV(max) values exclusively correlated with sst2 expression (r = 0.846, p < 0.001; Spearman rank correlation analysis), whereas there was no correlation of SUV(max) with the expression of the other four subtypes. CONCLUSION: In normal human tissues (68)Ga-DOTATOC imaging has been related to the expression of sst2 at the level of mRNA. The novel normative database may improve diagnostics, monitoring and therapy of sst-expressing tumours or inflammation on a molecular basis.

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas.

Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-life, striatal and extrastriatal binding potentials could be determined in one single scan. Receptor occupancy was calculated as percent reduction in binding potential relative to age-matched medication-free patients suffering from schizophrenia. Quetiapine occupied 44+/-18% in the temporal cortex and 26+/-17% in the putamen, a difference significant at the level of p=0.005 (Student's t test). Quetiapine showed a mean occupancy of 36+/-16% and in the thalamus. In the caudate nucleus there was an occupancy of 29+/-16% (p=0.0072). Individual occupancy levels did not exceed 59% in any of the striatal volumes of interest. The time-interval between scan and last drug ingestion did not influence the relationship between plasma concentration and central D2/3R occupancy. Taken together, quetiapine shows preferential extrastriatal binding at D2/3Rs; the extent of this difference is comparable to that previously described for clozapine. Both antipsychotics show very low affinity for D2/3Rs.

The quantification of dynamic FET PET imaging and correlation with the clinical outcome in patients with glioblastoma.

The PET tracer O-(2-[18F]Fluoroethyl)-l-tyrosine (FET) has been shown to be valuable for different roles in the management of brain tumours. The aim of this study was to evaluate several quantitative measures of dynamic FET PET imaging in patients with resected glioblastoma. We evaluated dynamic FET PET in nine patients with histologically confirmed glioblastoma. Following FET PET, all subjects had radiation and chemotherapy. Tumour ROIs were defined by a threshold-based region-growing algorithm. We compared several standard measures of tumour uptake and uptake kinetics: SUV, SUV/background, distribution volume ratio (DVR), weighted frame differences and compartment model parameters. These measures were correlated with disease-free and overall survival, and analysed for statistical significance. We found that several measures allowed robust quantification. SUV and distribution volume did not correlate with clinical outcome. Measures that are based on a background region (SUV/BG, Logan-DVR) highly correlated with disease-free survival (r = -0.95, p < 0.0001), but not overall survival. Some advanced measures also showed a prognostic value but no improvement over the simpler methods. We conclude that FET PET probably has a prognostic value in patients with resected glioblastoma. The ratio of SUV to background may provide a simple and valuable predictive measure of the clinical outcome. Further studies are needed to confirm these explorative results.

Striatal and extrastriatal D2/D3-receptor-binding properties of ziprasidone: a positron emission tomography study with [18F]Fallypride and [11C]raclopride (D2/D3-receptor occupancy of ziprasidone).

To elucidate the "atypicality" of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. [F]fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel [C]raclopride-PET study, striatal D2/D3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol. Ziprasidone plasma concentrations correlated significantly with D2/D3-receptor occupancies in all volumes of interests. Occupancy in extrastriatal regions was approximately 10% higher than in striatal regions. Half maximal effective concentration values were consistently higher in striatal than in extrastriatal regions (temporal cortex: 39 ng/mL; putamen: 64 ng/mL), irrespective of the time between last dosing and scan. Single ziprasidone doses resulted in higher occupancies exceeding the 95% prediction limits of the occupancy versus plasma concentrations for chronic dosing. Ziprasidone shares moderate preferential extrastriatal D2/D3-receptor binding with some other atypicals. D2/D3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels, suggesting relatively high intraday variations of D2/D3-receptor binding. The discrepancies between single-dose and steady-state results are important for the future design of dose-finding PET occupancy studies of novel antipsychotics. Single-dose studies may not be totally relied on for final dose selection.

Postinfectious focal necrotizing myopathy.

A 37-year-old woman was admitted to our department with general fatigue, fever, and asymmetric pain in her lower legs, 2 weeks after a common cold. Dynamic skeletal scintigraphy with 780 MBq (20 mCi) Tc-99m HDP revealed increased perfusion and tracer uptake in the soft tissue of the lower legs, suggesting an inflammatory etiology. A muscle biopsy revealed a vasculitic necrotizing myopathy predominantly affecting the small vessels of the lower legs. We diagnosed it as a postinfectious immunologic reaction.

Brain and plasma pharmacokinetics of aripiprazole in patients with schizophrenia: an [18F]fallypride PET study.

OBJECTIVE: Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia. METHOD: Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole. RESULTS: Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142). CONCLUSIONS: Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

Cerebral A1 adenosine receptors (A1AR) in liver cirrhosis.

PURPOSE: The cerebral mechanisms underlying hepatic encephalopathy (HE) are poorly understood. Adenosine, a neuromodulator that pre- and postsynaptically modulates neuronal excitability and release of classical neurotransmitters via A(1) adenosine receptors (A(1)AR), is likely to be involved. The present study investigates changes of cerebral A(1)AR binding in cirrhotic patients by means of positron emission tomography (PET) and [(18)F]CPFPX, a novel selective A(1)AR antagonist. METHODS: PET was performed in cirrhotic patients (n = 10) and healthy volunteers (n = 10). Quantification of in vivo receptor density was done by Logan's non-invasive graphical analysis (pons as reference region). The outcome parameter was the apparent binding potential (aBP, proportional to B (max)/K (D)). RESULTS: Cortical and subcortical regions showed lower A(1)AR binding in cirrhotic patients than in controls. The aBP changes reached statistical significance vs healthy controls (p < 0.05, U test with Bonferroni-Holm adjustment for multiple comparisons) in cingulate cortex (-50.0%), precentral gyrus (-40.9%), postcentral gyrus (-38.6%), insular cortex (-38.6%), thalamus (-32.9%), parietal cortex (-31.7%), frontal cortex (-28.6), lateral temporal cortex (-28.2%), orbitofrontal cortex (-27.9%), occipital cortex (-24.6), putamen (-22.7%) and mesial temporal lobe (-22.4%). CONCLUSION: Regional cerebral adenosinergic neuromodulation is heterogeneously altered in cirrhotic patients. The decrease of cerebral A(1)AR binding may further aggravate neurotransmitter imbalance at the synaptic cleft in cirrhosis and hepatic encephalopathy. Different pathomechanisms may account for these alterations including decrease of A(1)AR density or affinity, as well as blockade of the A(1)AR by endogenous adenosine or exogenous xanthines.

Effect of aging on cerebral A1 adenosine receptors: A [18F]CPFPX PET study in humans.

Cerebral A(1) adenosine receptors (A(1)AR) fulfill important neuromodulatory and homeostatic functions. The present study examines possible age-related A(1)AR changes in living humans by positron emission tomography (PET) and the A(1)AR ligand [(18)F]CPFPX. Thirty-six healthy volunteers aged 22-74 years were included. The apparent binding potential (BP'2) of [(18)F]CPFPX in various cerebral regions was calculated non-invasively using the cerebellum as reference region. In addition, the total distribution volume (DV't) was assessed in 10 subjects undergoing arterial blood sampling. There was no significant association between regional DV't and age, gender, caffeine consumption or sleep duration. BP'2 showed a significant age-dependent decrease in all regions except cingulate gyrus (p=0.062). The BP'2 decline ranged from -17% (striatum) to -34% (postcentral gyrus), the average cortical decline being -23%. There was no significant effect of gender, caffeine consumption and sleep duration on BP'2. In line with in vitro animal studies, the present in vivo PET study detected an age-dependent A(1)AR loss in humans that may be of pathophysiological importance in various neurological diseases associated with aging. Because of the discrepant results of the invasive (DV't) and the non-invasive (BP'2) analyses the present study needs further validation.

Neural signatures of body ownership: a sensory network for bodily self-consciousness.

Body ownership refers to the special perceptual status of one's own body, which makes bodily sensations seem unique to oneself. We studied the neural correlates of body ownership by controlling whether an external object was accepted as part of the body or not. In the rubber hand illusion (RHI), correlated visuotactile stimulation causes a fake hand to be perceived as part of one's own body. In the present study, we distinguished between the causes (i.e., multisensory stimulation) and the effect (i.e., the feeling of ownership) of the RHI. Participants watched a right or a left rubber hand being touched either synchronously or asynchronously with respect to their own unseen right hand. A quantifiable correlate of the RHI is a shift in the perceived position of the subject's hand toward the rubber hand. We used positron emission tomography to identify brain areas whose activity correlated with this proprioceptive measure of body ownership. Body ownership was related to activity in the right posterior insula and the right frontal operculum. Conversely, when the rubber hand was not attributed to the self, activity was observed in the contralateral parietal cortex, particularly the somatosensory cortex. These structures form a network that plays a fundamental role in linking current sensory stimuli to one's own body and thus also in self-consciousness.

Positron emission tomography study of regional cerebral metabolism during general anesthesia with xenon in humans.

BACKGROUND: The precise mechanism by which the gaseous anesthetic xenon exerts its effects in the human brain remains unknown. Xenon has only negligible effects on inhibitory gamma-aminobutyric acid receptors, one of the putative molecular targets for most general anesthetics. Instead, xenon has been suggested to induce anesthesia by inhibiting excitatory glutamatergic signaling. Therefore, the authors hypothesized that xenon, similar to ketamine and nitrous oxide, increases global and regional cerebral metabolism in humans. METHODS: The regional cerebral metabolic rate of glucose (rcMRGlu) was sequentially assessed in two groups of six volunteers each, using F-fluorodeoxyglucose as tracer. In the xenon group, rcMRGlu was determined at baseline and during general anesthesia induced with propofol and maintained with 1 minimum alveolar concentration xenon. In the control group, rcMRGlu was measured using the identical study protocol but without administration of xenon. rcMRGlu was assessed after the plasma concentration of propofol had decreased to subanesthetic levels (< 1.0 microg/ml). rcMRGlu was quantified in 10 cerebral volumes of interest. In addition, voxel-wise changes in rcMRGlu were analyzed using statistical parametric mapping. RESULTS: Xenon reduced whole-brain metabolic rate of glucose by 26 +/- 7% (from 43 +/- 5 micromol x 100 g x min to 31 +/- 3 micromol x 100 g x min; P < 0.005) and significantly decreased rcMRGlu in all volumes of interest compared with the control group receiving propofol only. Voxel-based analysis revealed metabolic depression within the orbitofrontal, frontomesial, temporomesial, occipital, dorsolateral frontal, and lateral temporal cortices and thalami. No increases in rcMRGlu were detected during xenon anesthesia. CONCLUSIONS: Xenon induces metabolic depression in the human brain, suggesting that the inhibition of the glutamatergic system is likely to be of minor significance for the anesthetic action of xenon in vivo.

Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia.

The brain serotonin-2A receptor (5-HT(2A)R) has been implicated in both the pathology of schizophrenia and the therapeutic action of atypical antipsychotics. However, little is known about the 5-HT(2A)R status before the onset of schizophrenia and before the exposure to antipsychotics. We used [18F] altanserin and positron emission tomography (PET) in a pilot study of 6 individuals suspected to be at elevated risk for schizophrenia and seven age-matched controls to test the hypothesis that regional 5-HT(2A)R binding is altered in the prodromal stages of schizophrenia. Distribution volume ratios (DVRs) as a proxy for 5-HT(2A)R availability were significantly reduced in prefrontal cortex regions of at-risk subjects, implicating early abnormalities of serotonergic neurotransmission that antecede the onset of schizophrenia.