The role of genetic variants of NOD2/CARD15, a receptor of the innate immune system, in GvHD and complications following related and unrelated donor haematopoietic stem cell transplantation.

Previous studies from our group indicated a role of SNPs within the innate immunity receptor NOD2/CARD15 as a risk factor for GvHD and treatment-related mortality allogeneic stem cell transplantation from HLA-identical siblings. We now extended these studies to assess the role of NOD2/CARD15 SNPs in 342 unrelated donor transplants. Overall, presence of any SNPs in patients or donor resulted in an increased risk of severe GvHD (25% in wildtype versus 38% in recipients and donors with variants, P= 0.01), which did not translate in increased mortality. When the analysis was broken down to individual SNPs, the presence of a SNP13 in the donor turned out to be the only highly significant risk factor (GvHD III/IV 22% wt, 42% SNP13 donor, P < 0.004; TRM 33% wt versus 59% SNP13 donor, P= 0.01; overall survival 49% wt versus 26% SNP13 donor, P= 0.007). This association was confirmed in multivariate analysis. Analysis of clinical risk factors suggested that this effect was most prominent in patients receiving any form of T cell depletion. Thus our observation indicates that the presence of a defect in innate immunity signalling in donor monocytes and possibly antigen presenting cells is most prominent in patients having additional T cell deficiency.

Positron emission tomography findings in obstructive sleep apnea patients with residual sleepiness treated with continuous positive airway pressure.

Despite sufficient continuous positive airway pressure (CPAP) therapy, some patients with the obstructive sleep apnea syndrome (OSAS) still suffer from excessive daytime sleepiness (EDS). In some of them, no cause of the persistence of EDS can be found. Brain damage due to nocturnal hypoxemia is a potential cause for this unclear persistent sleepiness (UPS). This study was done to evaluate this hypothesis. Patients with UPS were identified among the OSAS patients, who came for a CPAP therapy checkup to our sleep laboratory. UPS was recognized when no explanation for persistent EDS could be yielded by standard diagnostic procedures. Out of 167 patients under CPAP therapy 13 had UPS. To investigate the brain morphology, positron emission tomography (PET) scanning with the tracer fluorine-18 fluorodeoxyglucose (FDG), called FDG-PET, were performed in 7 of the UPS patients. Abnormal PET findings were concentrated in frontal area (found in 4 patients). The frontal abnormality seems to distinguish the OSAS patients with UPS from the whole OSAS population, examined in previous studies.

The prognostic value of anaemia at different treatment times in patients with locally advanced head and neck cancer treated with surgery and postoperative radiotherapy.

AIMS: We report a retrospective mono-institutional analysis of anaemia (< 12 g/dl) at different treatment times (preoperative, postoperative, before radiotherapy and nadir levels during radiotherapy) in head and neck cancer patients treated with surgery and postoperative radiotherapy. The study objective was to determine whether, and at which time points, anaemia had a significant effect on the end points overall survival and local recurrence-free survival (LRFS). MATERIALS AND METHODS: The end points for the statistical analysis in 130 patients were LRFS and overall survival. A univariate analysis (Log-rank test) was carried out on the following variables with potential end point-related impact: gender, T, N, G, American Joint Committee on Cancer (AJCC) stage, tumour site, resection status, overall treatment time (OTT), radiotherapy treatment time (RTT) and preoperative, postoperative, pre-radiotherapy and nadir levels of haemoglobin during radiotherapy. Individual variables with a significant effect (P=0.05) were then subjected to multivariate Cox regression analysis. RESULTS: The median overall survival was 59 months. The univariate analysis showed that AJCC stage (P=0.0268), resection status (P=0.0407), preoperative haemoglobin level (P=0.0087), postoperative haemoglobin level (P=0.0035), RTT (P=0.0042) and OTT (P=0.0343) significantly influenced overall survival. OTT (P=0.0130) and postoperative haemoglobin (P=0.0243) had a significant effect on LRFS. The multivariate Cox regression analysis showed postoperative haemoglobin < 12 g/dl and OTT>100 days to be independent negative prognostic factors for both end points. CONCLUSIONS: Postoperative acute anaemia < 12 g/dl and an OTT>100 days were independent negative prognostic factors for LRFS and overall survival in patients with head and neck cancer treated with surgery and postoperative radiotherapy.

Papillary microcarcinoma and papillary cancer of the thyroid

AIMS: Major controversies exist regarding the treatment of papillary microcarcinoma of the thyroid (PMC). Prior to 2003 PMC was defined by the WHO as a papillary carcinoma of 1 cm or less in diameter. In 2004 that definition changed, with the new classification requiring that the tumour also must be found incidentally. PATIENTS, METHODS: In this study we reviewed the clinical records of 67 patients with papillary tumours of the thyroid

[Survival with distant metastatic disease in head and neck cancer. A retrospective analysis]. / Uberleben mit hämatogen metastasierten HNO-Tumoren: Eine retrospektive monozentrische Analyse.

QUESTIONS: The objective of this retrospective analysis was to investigate parameters with a potential impact on survival in a collective of 114 patients with distant metastatic disease after head and neck cancer. PATIENTS AND METHODS: The primary endpoint was the survival with distant metastatic disease, the secondary endpoint was overall survival. Primary therapy, local recurrence, second neoplasms, palliative chemotherapy (CHT) and radiotherapy (RT), as well as Karnofsky performance status (KPS) at the time of diagnosis of the metastases were analyzed as potential impact parameters using the log-rank test with subsequent Cox regression analysis. RESULTS: Palliative CHT (P=0.0020) and KPS (P=0.0011) had a significant positive impact on the median survival probability with metastases (8.2 months) using the log-rank test, KPS at the time of diagnosis of metastases remained as an independent prognostic parameter in the Cox regression (P=0.0013). Primary therapy, local tumor control and KPS had a significant positive influence on the median overall survival probability (18.5 months) univariately (P=0.0139, P=0.0106, P= 0.0096) and multivariately (P=0.0123, and P=0.0063, P=0.0197, respectively). CONCLUSIONS: KPS at the time of diagnosis of metastases is an independent prognostic parameter for both endpoints. Lacking evidence for life prolongation, palliative therapies should therefore first and foremost focus on the stabilization of the KPS.

Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells.

CX+/CX- and Colo+/Colo- tumor sublines with stable heat shock protein 70 (Hsp70) high and low membrane expression were generated by fluorescence activated cell sorting of the parental human colon (CX2) and pancreas (Colo357) carcinoma cell lines, using an Hsp70-specific antibody. Two-parameter flow cytometry revealed that Hsp70 colocalizes with Bag-4, also termed silencer of death domain, not only in the cytosol but also on the plasma membrane. After nonlethal gamma-irradiation, the percentage of membrane-positive cells and the protein density of Hsp70 and Bag-4 were found to be strongly upregulated in carcinoma sublines with initially low expression levels (CX-, Colo-). Membrane expression of Hsp70 was also elevated in Bag-4 overexpressing HeLa cervix carcinoma cells when compared to neo-transfected cells. In response to gamma-irradiation, neo-transfected HeLa cells behaved like Hsp70/Bag-4 low-expressing CX- and Colo-, and Bag-4-transfected HeLa cells like Hsp70/Bag-4 high-expressing carcinoma sublines CX+ and Colo+. Immunoprecipitation studies further confirmed colocalization of Hsp70 and Bag-4 but also point to an association of Hsp70 and Hsp40 on the plasma membrane of CX+ and Colo+ cells; on CX- and Colo- tumor sublines, Hsp40 was detectable in the absence of Hsp70 and Bag-4. Other co-chaperones including Hsp60 and Hsp90 were neither found on the cell surface of CX+/CX-, Colo+/Colo- nor on HeLa neo-/HeLa Bag-4-transfected tumor cells. Functionally, Hsp70/Bag-4 and Hsp70/Hsp40 membrane-positive tumor cells appeared to be better protected against radiation-induced effects, including G2/M arrest and growth inhibition, on the one hand. On the other hand, membrane-bound Hsp70, but neither Bag-4 nor Hsp40, served as a recognition site for the cytolytic attack mediated by natural killer cells.

[Integration of PACS and HIS into the workflow of a nuclear medicine department. Experience in Regensburg]. / Integration von PACS und KIS in den Workflow einer nuklearmedizinischen Abteilung: Regensburger Erfahrungen.

AIM: The development of new diagnostic techniques and the implementation of a modern quality control management system requires the continuous adaptation of existing data processing tools to the nuclear medicine diagnostic workflow. Furthermore, PACS connected to HIS facilitates and enhances the transfer of data and pictures, and satisfies the legal requirements for data retention as regulated by law. Therefore, the aim of this work is to present the architecture, structure and results of such a system newly installed in a department of nuclear medicine. METHODS: Initially, the nuclear medicine workflow was carefully analyzed and each step was correlated to the corresponding module. The standard SAP R/3 and IS-H/IS-H(*)med based software used for patient administration at the University of Regensburg Hospital was adapted to the needs of the Nuclear Medicine Department. The networking of the imaging systems was done by integration of a PACS. Finally, the PACS was connected to the HIS to allow the attachment of images to the medical report. RESULTS, CONCLUSION: By connecting the HIS to the nuclear medicine PACS, the workflow was significantly improved. The data management sequence starting at the reception desk, continuing through the nuclear medical examination, to the physician's final written and image report is clearly structured. Although high demands exist on technical support and administration the integration of PACS and HIS into the nuclear medicine workflow leads to enhanced efficiency and reduction in hospital costs. Patient and data management are considerably improved in this way.

[The therapeutic impact of (18)F-FDG whole body PET. A radiooncologist's view]. / Der Einfluss der (18)F-FDG-Ganzkörper-PET auf das therapeutische Management onkologischer Patienten aus strahlentherapeutischer Sicht.

AIMS: An explorative analysis of the diagnostic as well as therapeutic impact of (18)F-FDG whole body PET on patients with various tumours in the setting of an university hospital radiation therapy was performed. PATIENTS AND METHODS: 222 FDG PET investigations (148 initial stagings, 74 restagings) in 176 patients with diverse tumour entities (37 lung carcinoma, 15 gastrointestinal tumours, 38 head and neck cancer, 30 lymphoma, 37 breast cancer, 19 sarcoma and 16 other carcinomas) were done. All PET scans were evaluated in an interdisciplinary approach and consecutively confirmed by other imaging modalities or biopsy. Unconfirmed PET findings were ignored. Proportions of verified PET findings, additional diagnostic information (diagnostic impact) and changes of the therapeutic concept intended and documented before PET with special emphasis on radiooncological decisions (therapeutic impact) were analysed. RESULTS: 195/222 (88%) FDG-PET findings were verified, 104/222 (47%) FDG-PET scans yielded additional diagnostic information (38 distant, 30 additional metastasis, 11 local recurrencies, 10 primary tumours and 15 residual tumours after chemoptherapy). The results of 75/222 (34%) scans induced changes in cancer therapy and those of 58/222 (26%) scans induced modifications of radiotherapeutic treatment plan (esp. target volumes). CONCLUSION: (18)F-FDG whole body PET is a valuable diagnostic tool for therapy planning in radiooncology with a high impact on therapeutic decisions in initial staging as well as in restaging. Especially in a curative setting it should be used for definition of target volumes.

Cardiovascular risk estimates and risk factors in renal transplant recipients.

Cardiovascular morbidity, including coronary artery disease and left ventricular hypertrophy, and mortality are high in patients following renal transplantation. Cardiovascular disease is thought to be due to traditional (hypertension, hyperlipidemia, diabetes mellitus and smoking) as well as nontraditional cardiovascular risk factors (microinflammation). Furthermore, immunosuppressive drugs, namely, calcineurin inhibitors, sirolimus, and steroids, have been reported to adversely affect cardiovascular risk factors (e.g., hypertension, hyperlipidemia, hyperglycemia). Evidence from comparative trials and from conversion studies suggest that blood pressure, hyperlipidemia, and hyperglycemia after renal transplantation may be differentially affected by the calcineurin inhibitors cyclosporine and tacrolimus. In the European Tacrolimus versus Cyclosporin A Microemulsion Renal Transplantation Study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) versus cyclosporine (n = 271). In addition, to blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose, we estimated the 10-year risk of coronary heart disease (Framingham risk score). Tacrolimus resulted in a significantly lower time-weighted average of serum cholesterol (P < .001), and mean arterial blood pressure (P < .05), but a higher time-weighted average of blood glucose (P < .01) than cyclosporine. Mean 10-year coronary artery disease risk estimate was significantly lower in men treated with tacrolimus, (10.0% versus 13.2%; P < .01) but was unchanged in women (4.7% versus 7.0%). Tacrolimus and cyclosporine microemulsion have compound-specific effects on cardiovascular risk factors that differentially affect the predicted rate of coronary artery disease.

Implantation of stimulation electrodes in the subretinal space to demonstrate cortical responses in Yucatan minipig in the course of visual prosthesis development.

PURPOSE: During the course of the development of visual prostheses, subretinal stimulation films were implanted in micropigs in order to prove the feasibility of subretinal electrical stimulation with subsequent cortical response. One aim was to demonstrate that epidural recording of visual evoked potentials is possible in the micropig. METHODS: Film-bound stimulation electrode arrays were placed in the subretinal space of micropigs. This enabled the retina to be stimulated subretinally. Since conventional visual evoked potential (VEP) measuring is virtually impossible in the pig from the neurosurgical point of view, epidural recording electrode arrays were positioned over the visual cortex as permanent electrodes. RESULTS: The feasibility of temporary implantation of film-bound stimulation electrode arrays was successfully demonstrated in the micropig model. On stimulation with monopolar voltage pulses (1000 to 3000 mV), reproducible epidural VEP measurements (5 to 10 micronV) were detected. CONCLUSIONS: The feasibility of subretinal stimulation of the retina was demonstrated in a retinal model that is similar to the human retina. This animal model therefore offers a suitable means of studying the tolerability of stimulation situations in the course of visual prosthesis development.

Cholinergic innervation of cerebral cortex in organotypic slice cultures: sustained basal forebrain and transient striatal cholinergic projections.

Slices of entire forebrain hemispheres were taken from early postnatal rat pups and maintained as organotypic slice cultures. Basal forebrain cholinergic neurons, identified by histochemical staining for acetylcholinesterase, develop axons that grow rapidly into cerebral cortex. Ingrowth occurs by two routes: some axons course laterally from the basal forebrain region to reach lateral neocortex; others course dorsally from the septum to reach medial cortex. By one to two weeks in vitro, acetylcholinesterase-positive axons have extended throughout most of the cortical territory. In addition to basal forebrain cholinergic axons, the normally local circuit cholinergic neurons of the striatum also send axons into cerebral cortex. These striatum-derived axons can be distinguished from basal forebrain axons by their distinct morphological characteristics and by their different response to excision of the striatum or basal forebrain. Further, acetylcholinesterase-positive axons in cortex that originate from striatum appear to retract or degenerate after about one week in culture, while those from basal forebrain remain present and apparently healthy beyond two weeks. These data document the basal forebrain cholinergic ingrowth into cerebral cortex using this whole hemisphere slice culture system and also demonstrate different degrees of maintenance of cortical afferents that are derived from different subcortical sources.

Electrocardiographic characteristics indicating a risk of irreversibly impaired myocardial function in chronic aortic regurgitation.

In order to define which of selected ECG variables could indicate irreversibly impaired myocardial function in chronic aortic regurgitation 54 patients were stratified according to normal (> or = 50%; Group A, n = 41) or subnormal radionuclide left ventricular ejection fraction (LVEF < 50%; Group B, n = 13) late after aortic valve replacement. Preoperatively, Group B patients had a significantly greater QRS duration, greater R-peak time (RPT) prolongation in I, V5 or V6, greater RPT relative to the S-peak time of the maximum S in V1, V2 or V3 (R-peak delay) and a greater negative T-wave in I or V6, as compared with Group A. These ECG variables together with preoperative angiocardiographic LVEF and end-systolic volume index were subjected to stepwise linear discriminant analysis. The maximum RPT, angio-LVEF and the maximum RPT relative to the S-peak time of the maximum S in V1, V2 or V3 emerged as the most promising variables. Of of Group A patients 82.9% and 84.6% of Group B patients were correctly classified by the three variables. If applied separately, APT prolongation or the presence of the R-peak delay in the left-sided leads, although less sensitive, have reasonably high specificity as risk indicators of irreversibly impaired chamber function, their positive predictive value being 60 and 62.5%, respectively. In conjunction with preoperative LVEF the diagnostic contribution of the two ECG variables amounts to the greatest overall separation of postoperatively preserved from irreversibly impaired systolic function.

Sonographic parenchymal and brain perfusion imaging: preliminary results in four patients following decompressive surgery for malignant middle cerebral artery infarct.

To investigate new methods of diagnostic transcranial sonography for brain parenchymal, vascular and perfusion imaging, we performed 3-D native tissue harmonic transcranial sonography (3D-nthTCS), 3-D transcranial color-coded duplex sonography (3D-TCCS), and "loss-of-correlation" imaging (LOC-TCCS) in four patients following early hemicraniectomy due to space-occupying "malignant" middle cerebral artery infarction (MMCAI). Three-dimensional datasets, utilizing 3D-nthTCS and 3D-TCCS, were created and up to 10 axial 2-D B-mode image planes, similar to CCT, reconstructed in each patient. Three-dimensional reconstructions of the circle of Willis documented one persistent carotid-T occlusion and three recanalizations of the MCA. LOC-TCCS, based on stimulated acoustic emission from an ultrasound (US) contrast agent, demonstrated a perfusion deficit in 2 of 3 patients, with regard to their infarcts. Concluding, 3D-nthTCS, 3D-TCCS and LOC-TCCS are promising tools for bedside monitoring, early prognosis and treatment evaluation for MMCAI in the postoperative period. Further studies should be performed to standardize these new methods and evaluate their applications through the intact calvarina.

Somatostatin receptor scintigraphy in thymoma imaging method and clinical application.

Somatostatin receptor scintigraphy with 111In-[DTPA-D-Phe1]-octreotide has the potential for visualizing primary and recurrent thymomas in patients with myasthenia gravis, whereas thymic hyperplasias fail to accumulate somatostatin analog peptides. We demonstrate somatostatin receptor imaging findings in a patient with a mixed encapsulated thymoma which exhibited intense 111In-[DTPA-D-Phe1]-octreotide uptake in early and late scans. In another patient with a history of malignant thymoma 111In-[DTPA-D-Phe1]-octreotide accumulation was clearly seen in a mass suspected to be a recurrence. This paper describes the imaging protocol including Single Photon Emission Computed Tomography (SPECT) and discusses the clinical applications of this feasible functional imaging method in patients with thymomas.

[Critical appraisal of diagnostic studies in nuclear medicine]. / Evidenzbasierte Bewertung von Diagnosestudien in der Nuklearmedizin.

The conceptual ideas of evidence based critical appraisal of diagnostic studies are described in this survey. In this context special attention is given to biases in study design such as verification- as well as information-bias limiting the validity of diagnostic studies. The practice of critical appraisal is demonstrated in an application to an example of a nuclear medicine scenario. The impact of evidence based medicine on nuclear medicine as a diagnostic discipline is discussed in detail.

Quantitative whole body scintigraphy--a simplified approach.

In this paper we present investigations on a simplified method of quantitative whole body scintigraphy by using a dual head LFOV-gamma camera and a calibration algorithm without the need of additional attenuation or scatter correction. Validation of this approach to the anthropomorphic phantom as well as in patient studies showed a high accuracy concerning quantification of whole body activity (102.8% and 97.72%, resp.), by contrast organ activities were recovered with an error range up to 12%. The described method can be easily performed using commercially available software packages and is recommendable especially for quantitative whole body scintigraphy in a clinical setting.

[Brain SPECT using Tc-99m-bicisate (ECD) in rapidly progressive dementia syndrome]. / Hirn-SPECT mit Tc-99m-Bicisat (ECD) bei rasch progredientem dementiellen Syndrom.

We present a 61-year-old male patient with progressive dementia. A brain SPECT with Tc-99m-bicisate was performed for confirmation of clinically suspected Alzheimer-dementia. At the time of the SPECT-investigation marked apraxia and aphasia besides severe dementia were present. Electrophysiological as well as anatomical neuroimaging findings showed non-diagnostic alterations. SPECT revealed distinct perfusion defects, which made Alzheimer Dementia unlikely. The further course of the patient was determined by rapidly progressive deterioration with development of akinetic mutism. Thereafter, increased levels of neuron-specific enolase as well as 14-3-3 proteins were found in the cerebro-spinal fluid (CSF). The patient finally died with signs of cerebral decortication. Due to the clinical course and the CSF-findings the patient's final diagnosis was Creutzfeldt-Jakob-disease, nevertheless no autopsy was performed. The presented case report underscores the clinical utility of perfusion brain SPECT in the differential diagnosis of dementias.

Follow-up findings in regional cerebral blood flow (r-CBF)-SPECT in a case of idiopathic childhood hemidystonia. Functional neuroimaging and pathophysiological implications.

A 9 1/2-year-old girl suffered from intermitting tremor and jitteriness of her left hand and oral muscles every 4 to 6 weeks with long lasting episodes. Clinically myoclonias and dystonic positioning of the left arm, hand and facial muscles were seen. No evidence of trauma, infection or inborn errors of metabolism was found. Successful therapy with carbamazepine was initiated while L-DOPA failed. An ictal 99m-Tc-HMPAO-SPECT showed severe asymmetry with focal hyperperfusion of the contralateral right thalamus and basal ganglia as well as of the bifrontal cortex, whereas no anatomical lesions were found by MRI. In contrast, an interictally performed 99m-Tc-HMPAO SPECT showed hypoperfusion of the right thalamus and normalisation of the frontal perfusion under medical treatment. These 99m-Tc-HMPAO-SPECT findings may provide new insights into the localisation and pathophysiological pathways of idiopathic childhood dystonia.

111In-oxine labelling of tumour-cytotoxic macrophages generated in vitro from circulating blood monocytes: an in vitro evaluation.

The labelling of ex-vivo activated macrophages with doses of 111In-oxine sufficient for gamma camera imaging does not damage cell viability or the functional competence of cells (secretion of tumour necrosis factor-alpha and interleukin-6). The mean labelling efficiency was about 84%. Release of 111In equivalent to 15% occurred over 24 h under cell culture conditions, indicating good stability of the radioactive cell label. 111In-oxine-labelled macrophages are a suitable tool for biokinetic studies of adoptive immunotherapy.

Vocal stability in functional dysphonic versus healthy voices at different times of voice loading.

Functional (nonorganic) dysphonia is often characterized by vocal instability. The purpose of the prospective study was to examine whether there is a difference in vocal instability of functional dysphonic voices compared with healthy ones, this means whether electroglottographic perturbation values differ (1) between healthy and dysphonic voices and (2) between two subgroups of the dysphponic voices (hypertonic and hypotonic dysphonic voices). Twenty-three patients with hypertonic functional dysphonia, 9 with hypotonic functional dysphonia and 31 healthy nonsmokers, were each examined electroglottographically before (Ex 1), immediately after (Ex 2), and 1 hour after (Ex 3) voice loading. Perturbations of frequency, amplitude, quasi-open-quotient, and contact-index were calculated from the EGG signal. At all three times of examination, hypertonic dysphonic voices showed higher perturbations than healthy voices, and they had higher perturbations than hypotonic dysphonic voices before and 1 hour after voice loading. Hypotonic dysphonic voices showed higher perturbations than healthy voices only 1 hour after voice loading. Voice loading induced different reactions in dysphonic voices: Some voices showed increased perturbations, and others exhibited normal or even decreased perturbation immediately after voice loading. Examination of electroglottographic-derived perturbations immediately after voice loading seems not to be useful. Differentiation of hypertonic and hypotonic dysphonic voices was possible with an estimated sensitivity of 88.9% and a specificity of 87.0% by using the sum of the amplitude-perturbation and the quasi-open-quotient-perturbation measured before voice loading.