Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

[Success and complication rate of CT-guided marking of pulmonary nodules with coil wires for video-assisted thoracoscopic surgery (VATS)]. / Erfolgs- und Komplikationsrate der CT-gesteuerten Markierung pulmonaler Rundherde mittels Spirale vor videoassistierter thorakoskopischer chirurgischer Resektion (VATS).

PURPOSE: To assess the success and complication rate of the CT-guided marking of pulmonary nodules for video-assisted thoracoscopic surgery (VATS). MATERIALS AND METHODS: Pulmonary nodules (mean diameter 9 +/- 5 mm, mean pleural distance 7 +/- 5 mm) were marked with a coil wire in 30 patients (20 males, mean age 57.6 +/- 15.5 years, 22 patients with a history of malignancy). The intended coil-nodule distance was < or = 10 mm. RESULTS: 81 % of nodules were not visible by thoracoscopy. The technical success rate of CT-guided marking was 86.7 %. The projected nodule-coil distance was achieved in 90 % of cases. The procedure had to be changed from thoracoscopy to thoracotomy in 4 patients due to coil wire marking problems: 2 x coil displacement, 1 x coil-nodule distance > 10 mm, unfavorable direction of wire. Histology was determined in all patients (70 % malignant, 30 % benign). Complications requiring therapy were not observed. CONCLUSIONS: The CT-guided marking of pulmonary nodules is a precondition for VATS if the nodule does not involve the visceral pleura in the majority of cases. The success rate is high with a low complication rate.

[Digital X-ray mammography: comparison of the image quality achievable with a wet laser imager, a dry infrared laser imager and a dry laser imager using direct thermography]. / Digitale Röntgenmammographie: Bildqualitativer Vergleich eines Nasslaserdruckers, eines infrarotbasierten Trockenlaserdruckers und eines thermographiebasierten Trockendruckers.

PURPOSE: To compare the image quality of digital X-ray mammographies obtained with wet imagers with that of standard dry imaging technology. MATERIAL AND METHODS: Beginning 03/08/2003, 200 X-ray mammographies with a digital fullfield mammography system (Lorad Selenia, Lorad/Hologic) were prospectively and consecutively documented with a wet laser imager (Scopix LR 5200, Agfa), a dry infrared laser imager (DryView 8610, Kodak) and a dry imager using the principle of direct thermography (Drystar 4500M, Agfa, N = 166). One X-ray exposure was systematically chosen from each examination and was presented in an anonymous and randomized form to three radiologists who evaluated the films using a structured questionnaire. RESULTS: The visualization of normal anatomic structures was considered being good to excellent for all imagers with the mean assessments 1.0 - 2.4 for the Drystar 4500M, 1.0 - 2.1 for the DryView 8610 and 1.1 - 2.0 for the Scopix LR 5200. The mean assessments were 0.1 - 0.6 points lower in dense than in normal parenchyma, thus, the parenchymal density is the predominant factor for image quality. CONCLUSION: In view of the comparable image quality obtained with the different imagers used in the study, individual decisions to purchase a specific imager will be based on economics rather than on diagnostic points of view.

Clinical applications of functional MRI at 1.0 T: motor and language studies in healthy subjects and patients.

In this article we describe clinical applications of functional MRI (fMRI) at 1.0 T. All experiments were performed on a commercially available 1.0-T system (Magnetom Impact Expert, Siemens AG, Erlangen, Germany) using a blood oxygen level-dependent (BOLD)-sensitive multi-slice EPI technique (TE 66 ms, 4 mm slice thickness, 210 mm field of view, 64 x 64 acquisition matrix). Different paradigms for localization of the motor cortex and for language lateralization were tested in healthy subjects and patients. Methodological considerations concerning the development of the paradigms are also described. In all healthy subjects, motor activation elicited BOLD signal changes in the sensorimotor cortex, permitting identification of primary motor and sensory cortical areas. Furthermore, focal activation of different cortical areas by a language task was possible in 6 of 10 subjects. Nineteen motor studies were performed in 18 patients with supratentorial lesions, in most cases prior to neurosurgical procedures. In 14 studies, fMRI results demonstrated the localization of the motor hand areas relative to the lesion. The results proved valuable for preoperative planning and contributed to therapeutical decisions. We conclude that functional MRI for clinically relevant applications, such as localization of motor and language function, is feasible even at a field strength of 1.0 T without dedicated equipment.

High amino acid uptake in a low-grade desmoplastic infantile ganglioglioma in a 14-year-old patient.

Amino acid uptake is higher in high-grade than in low-grade gliomas; this is the rationale for using radioactively labelled amino acids for the non-invasive grading of brain neoplasms. We present a 14-year-old boy with a low-grade desmoplastic infantile ganglioglioma (DIG) that exhibited marked contrast enhancement on magnetic resonance imaging (MRI), but no signs of infiltration and only minimal surrounding edema. In this benign neoplasm the relative uptake of the radioactively labelled amino acid I-123-alpha-methyl tyrosine (IMT), determined using single-photon emission computed tomography (SPECT), was 3.24; it was considerably higher than that of eleven other pretherapeutic low-grade gliomas where it ranged from 1.06 to 1.94 and also markedly above that average value of 2.37 found in 20 high-grade gliomas. This case report illustrates that results from emission tomography with radioactively labelled amino acids must be interpreted with caution, particularly when rare tumor entities are considered in view of uncommon clinical or radiological findings.

MR-monitored LITT as a palliative concept in patients with high grade gliomas: preliminary clinical experience.

The purpose of this study was to evaluate the clinical utility of laser-induced thermotherapy (LITT) as a palliative treatment for patients with high-grade gliomas. Four consenting patients with recurrent high grade III/IV gliomas near the primary language or motor areas were palliatively treated with LITT (2-5 W, 3-13 minutes; Neodym YAG Laser, Dornier, Friedrichshafen, Germany). Temperature monitoring was performed by T1-weighted turbo-fast low-angle shot (FLASH) imaging at 1.5 T (Siemens Magnetom SP 4000, Siemens, Erlangen, Germany). MRI studies before LITT included contrast-enhanced conventional scans and functional activation studies to localize the primary motor cortex or language areas using an echo-planar imaging (EPI) spin-echo (SE) sequence. Follow-up studies consisted of contrast-enhanced conventional scans as well as diffusion studies (contrast-enhanced Fourier-acquired steady-state technique and EPI-SE) and perfusion studies (EPI-SE with .2 mmol of gadolinium (Gd)/kg body weight) to differentiate post-therapeutic effects from residual or recurrent tumor growth. Local tumor control was achieved in areas with laser energy deposition with clinically stable conditions > or = 6 months. Conventional contrast-enhanced scans demonstrated strong enhancement surrounding ablated tumor components, which showed a reduction in CBV/CBF. Perfusion studies were useful to discriminate granulomatous tissue enhancement from residual or recurrent tumor growth. Careful application of LITT may evolve as an alternative palliative concept for patients with end-stage high-grade cerebral gliomas reducing clinical symptoms from circumscribed areas of pathology.

Diagnosis of recurrent glioma with SPECT and iodine-123-alpha-methyl tyrosine.

UNLABELLED: Iodine-123-alpha-methyl tyrosine (IMT) allows the investigation of amino acid transport rate in brain neoplasms. It was the aim of this study to evaluate the potential of IMT-SPECT to diagnose the recurrence of gliomas after primary therapy. METHODS: Using a triple-headed SPECT camera, the cerebral uptake of IMT was determined in 27 patients 22 mo, on average, after surgical removal of a primary brain tumor. Eighteen patients had suffered from high-grade gliomas, and nine had suffered from low-grade tumors. Four patients were examined before and after surgical revision of a presumed tumor recurrence. A total of 31 studies were evaluated. The final diagnosis was based on prospective clinicopathological follow-up. Recurrence was diagnosed in 23 cases, with marked clinical deterioration occurring 3.1 mo, on average, after SPECT, and was confirmed by histopathology in 14 instances. Eight cases were free of recurrence, as evidenced by inconspicuous clinical follow-up, ranging from 6 mo to 17 mo after SPECT in seven cases, and by clinical course and histopathology in the remaining subject. RESULTS: Patients with recurrence had significantly higher ratios of IMT uptake in the tumor area to that in a background region than did patients without recurrence (2.27 +/- 0.59 compared to 1.47 +/- 0.29; p < 0.002). The best cutoff level of the IMT uptake ratio in the differentiation between recurrence and benign posttherapeutic lesion was 1.8. Using this study-specific discrimination threshold, the sensitivity and specificity of IMT-SPECT for detecting glioma recurrence were 18 of 23 (78%) and 8 of 8 (100%), respectively. The area under the binormal receiver operating characteristic curve, fitted to the data, was 0.90 +/- 0.06. CONCLUSION: Iodine-123-alpha-methyl tyrosine-SPECT is a promising new tool in the follow-up of patients with gliomas after primary therapy.

Iodine-123-alpha-methyl tyrosine in gliomas: correlation with cellular density and proliferative activity.

UNLABELLED: Amino acid transport rate in gliomas can be assessed using SPECT and the amino acid L-123I-alpha-methyl tyrosine (IMT). This study attempted to correlate the uptake of IMT by gliomas with the proliferative activity and cellular density of these neoplasms. METHODS: The study used 27 patients with gliomas, including 18 patients with high-grade tumors and nine patients with low-grade neoplasms. Amino acid transport rate was determined using IMT and the triple-headed SPECT camera. Proliferative activity was immunohistochemically assessed as the relative number of cells expressing the Ki-67 nuclear antigen; cellular density was evaluated using light microscopy. RESULTS: Relative IMT uptake correlated significantly with the proliferative fraction of tumor cells (r = 0.6, p < 0.001). There was no significant correlation between IMT uptake and cellular density (r = 0.25, p > 0.05). CONCLUSION: The uptake of the SPECT radiopharmaceutical IMT is related to proliferative activity rather than to the cellular density of gliomas.

Non-invasive grading of primary brain tumours: results of a comparative study between SPET with 123I-alpha-methyl tyrosine and PET with 18F-deoxyglucose.

Use of iodine-123-alpha-methyl tyrosine (123I-IMT) allows investigation of the amino acid transport rate in gliomas. It was the aim of this study to compare the value of measurement of glucose metabolism with that of measurement of 123I-IMT uptake for the non-invasive grading of brain tumours. The study population comprised 23 patients with histopathologically proven primary brain tumours; 14 had high-grade gliomas, and nine low-grade brain neoplasms. Glucose metabolism was studied using an ECAT EXACT 47 positron emission tomography (PET) camera and fluorine-18 fluorodeoxyglucose (18F-FDG); 123I-IMT uptake was measured with the triple-headed single-photon emission tomography (SPET) camera, MULTISPECT 3. 18F-FDG and 123I-IMT uptake was quantified as ratios between the uptake by the tumour and contralateral regions of reference. Glucose metabolism and amino acid uptake of the brain tumours correlated significantly (r=0.71, P <0.001). Assuming discrimination thresholds between high-grade and low-grade tumours of 0.8 for 18F-FDG uptake and 1.8 for 123I-IMT uptake, the accuracy values of 18F-FDG PET and 123I-IMT SPET for differentiating between high-grade and low-grade tumours were 21/23 (91%) and 19/23 (83%), respectively. The difference in diagnostic performance was not significant on receiver operating characteristic analysis (P >0.4). It is concluded that there is no major difference between the PET investigation of glucose metabolism and the less expensive SPET measurement of amino acid uptake in terms of their accuracy in evaluating the malignancy grade of primary brain tumours. This encourages the performance of further studies to analyse the potential impact of 123I-IMT SPET on the therapeutic management of patients with brain tumours.

Uptake of iodine-123-alpha-methyl tyrosine by gliomas and non-neoplastic brain lesions.

Using single-photon emission tomography (SPET), the radiopharmaceutical l-3-iodine-123-alpha-methyl tyrosine (IMT) has been applied to the imaging of amino acid transport into brain tumours. It was the aim of this study to investigate whether IMT SPET is capable of differentiating between high-grade gliomas, low-grade gliomas and non-neoplastic brain lesions. To this end, IMT uptake was determined in 53 patients using the triple-headed SPET camera MULTISPECT 3. Twenty-eight of these subjects suffered from high-grade gliomas (WHO grade III or IV), 12 from low-grade gliomas (WHO grade II), and 13 from non-neoplastic brain lesions, including lesions after effective therapy of a glioma (five cases), infarctions (four cases), inflammatory lesions (three cases) and traumatic haematoma (one case). IMT uptake was significantly higher in high-grade gliomas than in low-grade gliomas and non-neoplastic lesions. IMT uptake by low-grade gliomas was not significantly different from that by non-neoplastic lesions. Diagnostic sensitivity and specificity were 71% and 83% for differentiating high-grade from low-grade gliomas, 82% and 100% for distinguishing high-grade gliomas from non-neoplastic lesions, and 50% and 100% for discriminating low-grade gliomas from non-neoplastic lesions. Analogously to positron emission tomography with radioactively labelled amino acids and fluorine-18 deoxyglucose, IMT SPET may aid in differentiating high-grade gliomas from histologically benign brain tumours and non-neoplastic brain lesions; it is of only limited value in differentiating between non-neoplastic lesions and histologically benign brain tumours.

Influence of size of regions of interest on the measurement of uptake of 123I-alpha-methyl tyrosine by brain tumours.

The aim of this study was to assess the influence of variations in the size of regions of interest (ROIs) on uptake values in brain tumours of L-3-iodine-123-alpha-methyl tyrosine (IMT). In addition, we attempted to establish the influence of size of ROIs on levels of significance assessing differences in mean IMT uptake between high-grade and low-grade tumours. Relative IMT uptake was determined in 19 patients with brain tumours using a MULTISPECT 3 triple-headed camera. Reconstructed image resolution was 14 mm at FWHM. Ten of the subjects suffered from high-grade gliomas (WHO grade III or IV) and nine from benign brain tumours, including eight patients with low-grade gliomas (WHO grade II). ROIs were defined by selecting those pixels within the tumour that exhibited uptake values above predefined threshold values. Using threshold values of 100, 95, 90, 85 and 80% of the mean, transaxial ROI size was approximately 0.1, 2.8, 4.3, 6.2 and 8.8 cm2, respectively. Over this range, mean, IMT uptake values decreased significantly from 2.4 to 1.9. High-grade tumours exhibited significantly higher IMT uptake than low-grade tumours at each of the threshold values. The corresponding levels of significance calculated using the Mann-Whitney U-test were between 0.01 and 0.02. Although IMT uptake values in brain tumours are significantly dependent on ROI size, levels of significance assessing differences in IMT uptake between high-grade and low-grade tumours are relatively insensitive to variations in this parameter.

[Intraoperative radiotherapy (IORT) in malignant brain tumors]. / Intraoperative Strahlentherapie (IORT) maligner Hirntumoren.

PURPOSE: Feasibility and morbidity of IORT for malignant brain tumors as well as value of innovative imaging for diagnosis of rest tumors and recurrences were examined. METHODS AND MATERIALS: Between May 1992 and November 1993, 23 patients with malignant brain tumors were treated in Münster with IORT. The patient collective was heterogeneous and negatively selected, i.e. beside of primary treatments, also patients with extensive previous treatment, recurrent tumors or metastases were included. Therapy consisted of radical surgical resection and intraoperative electron radiotherapy using total doses from 15 Gy to 25 Gy relative to the 90% isodose. Afterwards, patients without prior treatment underwent percutaneous irradiation with a maximum dose of 60 Gy, related to the small volume of the tumor area plus a safety margin of 2 cm. RESULTS: No increase of peri-operative morbidity or subacute sequelae was observed. Overall 1-year survival was 67% for grade III gliomas (WHO), and 56% for glioblastoma multiforme. When the Matsutani selection criteria (primary therapy of a supratentorial, peripheral astrocytoma grade III or glioblastoma smaller than 5 cm in diameter with a Karnofsky performance index of more than 60% and possible wide resection) were applied, 1-year survival increased to 75%. Nuclear medical diagnostics using 123I-alpha-methyltyrosin SPECT proved a valuable method for imaging of non-resectable tumor tissue and diagnosis of recurrences. CONCLUSIONS: The results of this study indicate that IORT can contribute to successful tumor treatment while neither increasing peri-operative morbidity nor subacute sequelae.

Comparative immunohistochemical study of the presence of glial fibrillary acidic protein in the pituitary of several vertebrates.

The presence and distribution of the astrocytic marker protein GFAP (glial fibrillary acidic protein) in the pituitaries of several mammalian as well as of some submammalian vertebrates were examined immunohistochemically. Our study revealed that GFAP-immunoreactive pituicytes, probably reflecting the presence of the filament-rich fibrous type of pituicyte, are a common feature of the mammalian neural lobe. Moreover, interspecific and interindividual differences of the neurohypophyseal immunostaining could be observed. In the distal neurohypophysis of some submammalian vertebrates, processes of ependymal glia showed GFAP-like immunoreactivity. Our results are in agreement with the well established evolutionary stability of GFAP elsewhere in the brain. In contrast to the neurohypophysis, GFAP-positive cells within the intermediate lobe were inconstantly present in only some species. They may be derived from neurohypophyseal glia. Folliculo-stellate cells of the adenohypophyseal pars distalis were not stained.