CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival.

Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.

Post-Surgical Language Reorganization Occurs in Tumors of the Dominant and Non-Dominant Hemisphere.

PURPOSE: Surgical resection of brain tumors may shift the location of cortical language areas. Studies of language reorganization primarily investigated left-hemispheric tumors irrespective of hemispheric language dominance. We used functional magnetic resonance imaging (fMRI) to investigate how tumors influence post-surgical language reorganization in relation to the dominant language areas. METHODS: A total of, 17 patients with brain tumors (16 gliomas, one metastasis) in the frontotemporal and lower parietal lobes planned for awake surgery underwent pre-surgical and post-surgical language fMRI. Language activation post-to-pre surgery was evaluated visually and quantitatively on the statistically thresholded images on patient-by-patient basis. Results were qualitatively compared between three patient groups: temporal, with tumors in the dominant temporal lobe, frontal, with tumors in the dominant frontal lobe and remote, with tumors in the non-dominant hemisphere. RESULTS: Post-to-pre-surgical distributions of activated voxels changed in all except the one patient with metastasis. Changes were more pronounced in the dominant hemisphere for all three groups, showing increased number of activated voxels and also new activation areas. Tumor resection in the dominant hemisphere (frontal and temporal) shifted the activation from frontal towards temporal, whereas tumor resection in the non-dominant hemisphere shifted the activation from temporal towards frontal dominant areas. CONCLUSION: Resection of gliomas in the dominant and in the non-dominant hemisphere induces postsurgical shifts and increase in language activation, indicating that infiltrating gliomas have a widespread influence on the language network. The dominant hemisphere gained most of the language activation irrespective of tumor localization, possibly reflecting recovery of pre-surgical tumor-induced suppression of these activations.

Decision-making in a patient with cardiac arrest due to venous thromboembolism within 24 h after glioblastoma resection.

In the fulminant VTE form with cardiac arrest, systemic thrombolysis remains the most effective therapy. However, several contraindications restrict the use such as intracranial neoplasm or a recent history of intracranial surgery. Here, we report the case of a 59-year-old man who underwent glioblastoma resection and suffered from a fulminant pulmonary embolism with cardiac arrest. After CPR, continuous tPA infusion via an endovascularly placed pulmonary catheter was maintained over a period of 8 h. In this case, we report on our decision-making process and the use of local thrombolysis as a successful therapy in a patient with multiple contraindications.

Intra-operative subcortical electrical stimulation: a comparison of two methods.

OBJECTIVE: For intra-operative subcortical electrical stimulation of the corticospinal tract, two techniques - originally described for cortical stimulation - have evolved: the 50-Hz-stimulation first described by Penfield in 1937 and the high-frequency multipulse train stimulation technique first described by Taniguchi in 1993. Motor thresholds of both methods in combination with a bipolar and monopolar stimulation technique and their reliability for eliciting motor evoked potentials (MEPs) were studied. METHODS: Data were obtained in 20 patients (50±17 years; 10 females) undergoing tumour resection under general anaesthesia. Both 50-Hz-stimulation of 1-s duration and a multipulse stimulation (5 pulses interstimulus interval 4 ms, 0.5-Hz repetition rate) were applied with a bipolar probe (1.5-mm ball tip, 8-mm interelectrode distance) and a monopolar probe (1.5-mm-diameter tip). MEPs were recorded in muscles contralateral to the stimulated hemisphere. Comparison of different stimulation modalities was performed at the site where monopolar multipulse stimulation technique elicited MEPs with the lowest stimulation intensity (constant current monophasic cathodal stimulation, individual pulse width 0.5 ms, max. 25 mA). RESULTS: MEPs were elicited by monopolar multipulse stimulation with an intensity of 8±3.9 mA (21/21 stimulation sites); monopolar 50-Hz stimulation with 12±5.4 mA (18/21 stimulation sites); bipolar multipulse stimulation with 14±8.1 mA (12/21 stimulation sites) and bipolar 50-Hz stimulation with 15±6.3 mA (11/21 stimulation sites). CONCLUSIONS: Stimulation intensities for eliciting MEPs are significantly lowest for the monopolar multipulse stimulation (p<0.025). Monopolar compared to bipolar stimulation resulted in eliciting MEPs in a higher number of tested patients (Fisher's p<0.0001). SIGNIFICANCE: Subcortical stimulation with a monopolar probe and a multipulse stimulation is most efficient for the purpose of identifying the corticospinal tract. This is explained by the more radiant electric field properties of the monopolar probe compared to the bipolar probe.

The influence of preoperative anticoagulation on outcome and quality of life after surgical treatment of chronic subdural hematoma.

The main aim of this study was to investigate the influence of perioperative anticoagulation on the clinical course and outcome of 144 patients who underwent surgery for chronic subdural hematoma (CSDH). The outcome was categorized according to the modified Rankin Scale (mRS), Barthel Index and postoperative quality of life (QoL) scale. There was a significant correlation between preoperative aspirin medication and reoperation (Mann-Whitney U-test, p<0.05). Moreover, dosage and duration of postoperative low-molecular-weight heparin (LMWH) administration were associated with a higher risk of reoperation (Mann-Whitney U-test, p<0.01) and a worse outcome on the mRS (Mann-Whitney U-test, p<0.05). Intraoperative treatment with prothrombin complex concentrate led to a poor outcome on the mRS (Craddock-Flood test, p<0.05). Reoperation is the strongest predictive factor of a poor QoL after surgical treatment of CSDH. Both preoperative and postoperative anticoagulation treatment may affect reoperation rate and, thus, postoperative QoL.

Virtual endoscopy is a useful device for training and preoperative planning of transsphenoidal endoscopic pituitary surgery.

Virtual endoscopy (vE) allows simulated three-dimensional (3-D) visualisation of anatomical structures by computerised reconstruction of radiological images. The aim of this study was to evaluate the feasibility of vE and its potential benefits for endoscopic transsphenoidal pituitary surgery. vE was realised using a commercially available ray-casting software plugin of a picture archiving and communications system (PACS). For this study, the vE system was enhanced with volume segmentation, transparency and cutting tools. The data for vE were derived from high resolution computed tomography (CT) scans of 22 patients with pituitary pathology (20 pituitary adenomas, 2 Rathke's cleft cysts) preoperatively. Anatomic structures were identified on vE images and compared with the intraoperative endoscopic views. The simulated 3-D vE images were found to be comparable to the intraoperative endoscopic anatomy in terms of distortion and angle of view. vE was found to be particularly useful for the preoperative depiction of 1) the nasal anatomy and its variations for choosing the side of the approach, 2) the sphenoid sinus septae and chambers for improved intraoperative orientation, 3) the transparent 3-D simulated visualisation of the pituitary gland, tumour and adjacent anatomic structures in relation to the sphenoid sinus landmarks for planning the opening of the sellar floor. We conclude that vE harbours the potential to become a valuable tool in endoscopic pituitary surgery for training purposes and preoperative planning. Furthermore, vE may add to the safety of interventions in case of anatomic variations.

Natriuresis and renal Na-K-ATPase activity in kidneys of normotensive and spontaneously hypertensive rats.

The isolated perfused kidneys of spontaneously hypertensive (SHR) rats aged 10-12 weeks (early hypertensive phase) exhibited pressure natriuresis curves already shifted to the right, as compared with kidneys of the normotensive Wistar rats and Wistar-Kyoto rats. Sodium excretion in relation to tubular sodium load was higher in kidneys of SHR rats as compared with those of the normotensive controls. Renal Na-K-ATPase activity was significantly lowered only in the cortex during chronic hypertension but not in the outer medulla. In both parts of the kidney no differences could be detected in the apparent Km value for sodium stimulation or the apparent activation energies. Mg-ATPase activity was lowered in SHR rats during chronic hypertension. Protein content was significantly decreased in the outer medulla of SHR rats in the early hypertensive phase as well as during chronic hypertension. The results suggest that the functional changes observed in kidneys of young SHR rats are not due to a genetically determined defect in renal Na-K-ATPase.

Inhibition of calcium release of diazoxide studied in the isolated rat kidney.

Isolated kidneys of normotensive Wistar rats (NWR) and of genetically hypertensive Kyoto rats (SHR) were perfused. Contraction of intrarenal vascular smooth muscle cells were induced by barium ions (0.1 to 1.0 mmol) as well as by high potassium concentrations (40 mmol). It was shown that barium stimulates intracellular calcium stores to release activator calcium. Repeated stimulation with barium under calcium-free perfusion conditions resulted in depletion of these stores. In kidneys of SHR rats the tension development in response to barium was stronger as compared with NWR rats and the time needed to deplete the stores was prolonged. This suggests that smooth muscle cells of SHR rats contain more sequestered calcium. Diazoxide inhibited the barium contracture rapidly, reversibly and dose dependently. The inhibition was non-competitive. Percentual inhibition was equal in NWR and in SHR rat kidneys. Moreover, diazoxide did not block the calcium influx across the sarcolemma membrane. The magnitude of the potassium contractures depended entirely upon the extracellular calcium concentration. In the range of 0.1 to 1.0 mmol calcium, tension development varied linearly with log calcium concentration. Diazoxide also inhibited the potassium contractures, provided normally filled calcium stores were available. The combined results strongly suggest that diazoxide prevents intracellular calcium stores to release calcium and, furthermore, that this action is the basic mechanism of the vasodilating activity of diazoxide in smooth muscle cells of rat intrarenal vessels.

Absence of effect of diazoxide on sodium and water handling in the isolated perfused rat kidney.

The effect of the thiazide derivative diazoxide on water and sodium handling of the isolated perfused rat kidney was studied. In kidneys of normotensive rats no influence on diuresis, glomerular filtration rate or sodium and potassium excretion rates could be detected whereas hydrochlorothiazide showed the anticipated effects. The diuretic effect of the latter compound was not inhibited nor potentiated by pretreatment with diazoxide. In kidneys of hypertensive rats, studied at different ages: 10, 20, 30, and 45 weeks respectively, no acute effects of diazoxide on tubular function were found either. Diazoxide and hydrochlorothiazide both resulted into a small drop of renal perfusion pressure indicating that renal vascular resistance was lowered. The results suggest that the water and sodium retention frequently observed in patients treated with diazoxide are not caused by a direct effect of the drug on tubular function but are mediated by its peripheral and/or intrarenal vascular effects.