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.

[FDG-PET-CT based imaging of retropharyngeal lymph nodes with its impact on radiotherapy]. / Die Darstellung retropharyngealer Lymphknoten in der FDG-PET/CT und ihre Bedeutung für die Radiotherapie.

BACKGROUND: In about 20% there is an involvement of the retropharyngeal lymph nodes in patients with locally advanced carcinoma of the hypopharynx and cervical esophagus. A case report should demonstrate the diagnostic and therapeutic impact of FDG-PET/CT in the radiotherapeutic management of a locally advanced carcinoma of the hypopharynx in special consideration of the RPLN. PATIENT AND METHOD: A pretherapeutic FDG-PET/CT was performed with the patient fixed in the radiotherapy mask in order to integrate the anatomic and metabolic information into the radiotherapy planning system by an exact matching of the data. RESULTS: Only the FDG-PET could detect a retropharyngeal lymph node involvement (RPLN) by an intensive glucose utilisation with a consecutive modification of the target volume and dose increase in this region. CONCLUSION: This case report demonstrates that FDG-PET/CT facilitates the imaging of metabolic active and otherwise hardly detectable lymph nodes in locally advanced head and neck cancer with consequences on target volume definition and dose application in 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

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.

[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.

Mechanisms of regional wall motion abnormalities in contrast-enhanced dobutamine stress echocardiography.

BACKGROUND: In the diagnosis of coronary artery disease (CAD) with Dobutamine Stress Echocardiography (DSE), regional wall motion abnormalities (RWMA) are assumed to indicate a perfusion deficit. METHODS AND RESULTS: For a more particular examination of RWMAs, we compared simultaneous echo-contrast (Optisone)-enhanced DSE (0-40 microg/kg Dobutamine, 16-segment- model) and MiBi-SPECT in a prospective double-blinded study design in 69 non-selected consecutive patients (44 male, 25 female, age 64+/-12 years). Additionally, all patients were examined by coronary-angiography. The prevalence of significant CAD (stenosis >50% lumen diameter) was 52%. DSE had a sensitivity of 78% and a specificity of 66% for the detection of significant CAD with a positive and negative predictive value of 72 and 73%, respectively. Among 28 patients with significant CAD and positive DSE study (true positive), 78% displayed a corresponding perfusion deficit in MiBi-SPECT. Among 11 patients with a positive DSE study but no current significant coronary stenosis (false positive), 82% showed stress-induced RWMAs in the inferior/posterior region, 73% displayed left ventricular hypertrophy, 54% resting-ECG abnormalities and 45% resting-RWMA (3 previous MI, 2 previous CABG surgery). Among 8 patients with negative DSE study but significant coronary stenosis (false negative), 75% had a stenosis of the LCX, 63% displayed resting- WMA, 63% displayed left bundle branch block or ST-segment depression, 50% displayed only peripheral coronary stenosis, and DSE visualization was suboptimal in 38%. CONCLUSION: This prospective study in non-selected patients shows that the majority of RWMAs in DSE are matched to a perfusion deficit detectable by nuclear imaging. Nevertheless, pre-existing cardiac abnormalities may also lead to stress-induced RWMA not associated with a perfusion deficit or mask a perfusion deficit upon DSE. Particularly in patients with LV hypertrophy, resting-RWMA, bundle branch block or ST segment depression, the predictive value of DSE may, therefore, be limited.

The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.

BACKGROUND: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), or Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in two genes encoding subunits of a cell membrane-associated receptor complex: TREM2 and DAP12. The clinical course of PLOSL has not been characterized in a series of patients with TREM2 mutations. METHODS: The authors compare neurologic and neuroradiologic follow-up data of six patients carrying TREM2 mutations with PLOSL due to defective DAP12 genes. The authors review the known mutations in these two genes. RESULTS: Mutations in DAP12 and TREM2 result in a uniform disease phenotype. In Finnish and Japanese patients with PLOSL, DAP12 mutations predominate, whereas TREM2 is mutated more frequently elsewhere. CONCLUSIONS: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.

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.

[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.

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.

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.

[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.

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.

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.

R peak time prolongation and R peak delay in leads I, V5, or V6. Diagnostic values as signs of myocardial dysfunction in chronic mitral incompetence.

On the assumption that maximum R peak time prolongation in the left-sided leads I, V5, or V6 and its time relationship to the S peak time of the maximum S amplitude in leads V1, V2, or V3 (representing dorsally directed forces of ventricular depolarization) could indicate the extent of left ventricular volume overloading and possibly left ventricular systolic function, these variables and the preoperative findings of angiocardiography were compared between patients with chronic mitral incompetence who, late after corrective valve surgery, had either well-preserved radionuclide left ventricular ejection fraction (group 1, n = 36) or radionuclide left ventricular ejection fraction below 50% (group 2, n = 30). Before surgery, group 2 patients had a highly significant lower mean left ventricular ejection fraction, a highly significant greater mean end-systolic volume index, a significantly greater mean end-diastolic volume index, a significantly greater mean maximum R peak time in leads I, V5, or V6, and a significantly greater prolongation of the maximum R peak time above the S peak time in the right precordial leads, as compared with group 1. R peak times greater than 50 ms or the presence of R peak delay (maximum R peak time greater than the S peak time of the maximum right precordial S amplitude) yields less sensitive but highly reliable results in predicting radionuclide left ventricular ejection fraction below 50% with both specificity and positive predictive values of 100%. Thus, in chronic mitral regurgitation surgery should not be delayed if patients present these signs because they are specific markers of irreversibly impaired chamber function.

[Scintigraphic imaging of head and neck cancers with 99m technetium (v) dimercaptosuccinic acid. A prospective clinical study]. / Szintigraphische Darstellung von Kopf-Hals-Karzinomen mit 99mTechnetium (v) Dimercaptosuccinic acid. Eine prospektive klinische Studie.

In patients with cervical metastases conventional examination by ultrasound, CT or MRI imaging often fails to identify an unknown primary tumor. Also the retrieval of a recurrent malignancy may be difficult. Scintigraphy, utilizing technetium-99m (v) dimercaptosuccinic acid was chosen for a prospective study in 17 patients to evaluate its properties for imaging metastasizing squamous cell carcinoma of the head and neck. Scintigraphic findings were correlated with the results of clinical examination and conventional imaging techniques. In all cases the primary tumor revealed good uptake of 99mTc(v)DMSA. Manifest cervical metastases could only be imaged in some cases. In future, therefore, 99mTc(v)DMSA scanning may be used for the detection of unknown primary tumors. However, it does not appear helpful in the evaluation of cervical nodes.

Octreotide scintigraphy localizes somatostatin receptor-positive islet cell carcinomas.

Tyr-3-Octreotide is a synthetic derivative of somatostatin and a somatostatin-receptor analogue. The iodine-123-labelled compound localizes somatostatin-receptor-positive tumours. In this paper two patients are reported in whom somatostatin receptors were demonstrated in vitro. In a 60-year-old female with an islet cell carcinoma of the pancreas, multiple liver metastases and previously unrecognized bone metastases in the right acetabulum could be diagnosed as the reason for a persistent hypoglycaemia. In a 60-year-old male an islet cell carcinoma of the pancreas was localized with 123I-Tyr-3-octreotide. The somatostatin receptors were demonstrated in vitro and the tumour was successfully treated with somatostatin. These studies demonstrate that 123I-Tyr-3-octreotide offers the possibility of localizing somatostatin-receptor-positive tumours and their metastases. Moreover the method makes it possible to determine the receptor status of a tumour in vivo.