Stephan B. Sobottka

Near infrared Raman spectroscopic mapping of native brain tissue and intracranial tumors

This study assessed the diagnostic potential of Raman spectroscopic mapping by evaluating its ability to distinguish between normal brain tissue and the human intracranial tumors gliomas and meningeomas. Seven Raman maps of native specimens were collected ex vivo by a Raman spectrometer with 785 nm excitation coupled to a microscope with a motorized stage. Variations within each Raman map were analyzed by cluster analysis. The dependence of tissue composition on the tissue type in cluster averaged Raman spectra was shown by linear combinations of reference spectra. Normal brain tissue was found to contain higher levels of lipids, intracranial tumors have more hemoglobin and lower lipid to protein ratios, meningeomas contain more collagen with maximum collagen content in normal meninges. One sample was studied without freezing. Whereas tumor regions did not change significantly, spectral changes were observed in the hemoglobin component after snap freezing and thawing to room temperature. The results constitute a basis for subsequent Raman studies to develop classification models for diagnosis of brain tissue.

Analysis of human brain tissue, brain tumors and tumor cells by infrared spectroscopic mapping

This study uses infrared (IR) spectroscopic, point detection, mapping procedures to examine tissue samples from normal brain specimens and from astrocytic gliomas, the most frequent human brain tumors. Model systems were derived from cultured glioma cell lines. IR spectra of normal tissue sections distinguished white matter from gray matter by increased spectral contributions from lipids and cholesterol. Qualitatively the same differences were found in IR spectra of low and high grade glioma tissue sections pointing to a significant reduction of brain lipids with increasing malignancy. Whereas spectral contributions of proteins and lipids were similar in IR spectra of glioma cells and tissues, nucleic acid bands were more intense for cells suggesting higher proliferative activities. For statistical analyses of IR spectroscopic maps from 71 samples, a parameter for the lipid to protein ratio was introduced involving the CH(2) symmetric stretch band with lipids as main contributors and the amide I band of proteins. As this parameter correlated with the grade of gliomas obtained from standard histopathological examination, it was applied to classify brain tissue sections based on IR spectroscopic mapping.

Surgical Management of Single and Multiple Brain Metastases: Results of a Retrospective Study

Background: Advancement in diagnosis and treatment of various cancer entities led to an increasing incidence of brain metastases in the last decades. Surgical excision of single and multiple brain metastases is one of the central treatment options beside radiotherapy, radiosurgery and chemotherapy. To evaluate the benefit of surgery with/without whole-brain radiation therapy (WBRT) in single brain metastases and the influence of image guidance for brain metastases resection, 104 patients were retrospectively evaluated for post-operative outcome. Patients and Methods: Between January 1994 and December 1999 150 patients were surgically treated for brain metastases at the Department of Neurosurgery at the Technical University of Dresden. Outcome could be evaluated in 104 patients with respect to special treatment strategies and survival time (69 patients with single and 35 patients with multiple lesions). Results: Most metastases originated from primary lung and breast tumours. Karnofsky performance score improved on average by 10 after surgery. The extent of the extracerebral tumour burden was the main influence on survival time. Patients’ age below 70 years was combined with prolonged survival time (median survival time, MST: 4.5 months vs. 7 months). Patients with solitary cerebral metastasis had a MST of 16 months, whereas patients with singular lesions had a MST of 7 and 4 months, depending on the extent of the extracerebral tumour growth. Additional post-operative WBRT with 30 Gy was combined with an increase in MST in patients with single brain metastasis (surgery + WBRT: MST 13 months; surgery only: MST 8 months). In addition, the rate of recurrent cerebral tumour growth was distinctly higher in the non-WBRT group. Neuronavigation did not significantly improve post-operative survival time. In 80% of patients extracerebral tumour growth limited patients’ survival. Conclusion: Surgery is an initial treatment option in patients with single and multiple brain metastases especially with large tumours (> 3 cm). Post-operative WBRT seems to prolong survival time in patients with single brain metastasis by decreasing local and distant tumour recurrence. Neuronavigational devices permit a targeted approach. Multiple processes can be extirpated in one session without prolonging the hospitalisation time for the patient. However, neuronavigational devices cannot assure complete tumour resection.

Identification of Primary Tumors of Brain Metastases by Infrared Spectroscopic Imaging and Linear Discriminant Analysis

This study applies infrared (IR) spectroscopy to distinguish normal brain tissue from brain metastases and to determine the primary tumor of four frequent brain metastases such as lung cancer, colorectal cancer, breast cancer, and renal cell carcinoma. Standard methods sometimes fail to identify the origin of brain metastases. As metastatic cells contain the molecular information of the primary tissue cells and IR spectroscopy probes the molecular fingerprint of cells, IR spectroscopy based methods constitute a new approach to determine the primary tumor of a brain metastasis. IR spectroscopic images were recorded by a FTIR spectrometer equipped with a macro sample chamber and coupled to a focal plane array detector. Unsupervised cluster analysis of IR images revealed variances within each sample and between samples of the same tissue type. Cluster averaged IR spectra of tissue classes with known diagnoses were selected to develop a metric with eight variables. These data trained a supervised classification model based on linear discriminant analysis that was used to identify the origin of 20 cryosections including one brain metastasis with an unknown primary tumor.

Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain.

Inactivating germline mutations of the novel putative tumor-suppressor gene LKB1/STK11 at 19p13.3 have been shown to cause Peutz-Jeghers syndrome (PJS), an autosomal dominantly inherited disease characterized by a predisposition to mucocutaneous pigmentations, as well as various benign and malignant neoplasms. To elucidate the role of LKB1/STK11in the carcinogenesis of primary and secondary human brain tumors, a total of 309 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, DI9S878, and D19S565. Low LOH rates were observed for glioma (17.3%, n = 139), meningioma (5.3%, n = 57), schwannoma (0%, n = 21), pituitary adenoma (18.8%, n = 16), primary CNS lymphoma, neuroblastoma, plasmocytoma, medulloblastoma, germinoma, and papilloma of the choroid plexus (6.6%, n = 15). In contrast, brain metastases exhibited a mean LOH frequency of 42.6% (n = 61), with breast (56.3%) and lung cancer metastases (58.3%) being most frequently affected. Genomic DNA sequencing of the complete coding region of LKB1/STK11 was performed in all brain metastases exhibiting LOH (n = 26); no mutation was revealed, but we did find a germline mutation in a PJS patient. Despite high LOH fiequencies at the 19p13.3 locus in carcinoma metastases to the brain and occasional mutations reported for certain primary carcinomas, there are no mutations in LKB1/STK11. This fact suggests that alterations of LKB1/STK11 occur relatively early in tumorigenesis and are rarely involved in the development of carcinoma metastases. Based on these findings, the genes adjacent to LKB1/STK11 may be relevant for the development of metastases to the brain from certain carcinomas.

Procedure for Neonatal Screening for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

The value of screening of neonates for congenital adrenal hyperplasia is not universally accepted. Procedures for screening are recommended here in order to provide a structure to the testing and ultimately bring together data that will allow the effect of screening to be judged for benefit or dismissed as no better than clinical recognition of the disease state.

Open vs retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome: a retrospective cohort study.

BACKGROUND Both open ulnar nerve decompression and retractor-endoscopic ulnar nerve decompression have been shown to yield good results. However, a comparative evaluation of the techniques is lacking. OBJECTIVE To compare the results of open and endoscopic surgery in cubital tunnel syndrome. METHODS One hundred fourteen patients undergoing open (n = 59) or endoscopic (n = 55) decompression of the ulnar nerve for cubital tunnel syndrome were retrospectively compared. The long- and short-term outcomes were compared with respect to the time until return to full activity and the duration of postoperative pain. Additionally, matched pairs between the 2 groups were chosen for analysis (n = 34). RESULTS Long-term results in the open vs endoscopic groups were as follows: excellent results, 54.2% vs 56.4%; good results, 23.8% vs 32.7%; fair results, 20.3% vs 9.1%; and poor results, 1.7% vs 1.8%, respectively. For the matched pairs, the results had similar significance levels (P = .84). The times until return to full activity in the open vs the endoscopic groups were as follows: 2 to 7 days, 18.6% vs 76.4%; 7 to 14 days, 55.9% vs 10.9%; and > 14 days, 25.4% vs 12.7% (P < .001 between nonmatched and matched pairs). The durations of postoperative pain in the open vs the endoscopic groups were as follows: 1 to 3 days, 45.8% vs 67.3%; 3 to 10 days, 42.5% vs 25.4%; and > 10 days, 11.7% vs 7.3% (P =.04 for nonmatched and P = .05 for matched pairs). CONCLUSION There are no significant differences in long-term outcomes after open and retractor-endoscopic in situ decompression of the ulnar nerve in cubital tunnel syndrome. The short-term results are significantly better in endoscopic surgery.

Suitability of infrared spectroscopic imaging as an intraoperative tool in cerebral glioma surgery

AbstractInfrared spectroscopic imaging is a promising intraoperative tool which enables rapid, on-site diagnosis of brain tumors during neurosurgery. A classification model was recently developed using infrared spectroscopic images from thin tissue sections to grade malignant gliomas, the most frequent class of primary brain tumor. In this study the model was applied to 54 specimens from six patients with inhomogeneous gliomas composed of regions with different tumor density and morphology. The resection was controlled using neuronavigation which transfers the findings obtained by preoperative magnetic resonance imaging (MRI) into the operating field. For comparison, all specimens were independently evaluated by histopathology after hematoxylin and eosin staining. The infrared-derived grading agreed with histopathology and MRI findings for almost all specimens. With regard to histopathological assessment, sensitivities of 100% (22/22) and 93.1% (27/29) and specificities of 96.9% (31/32) and 88.0% (22/25) were achieved, depending on whether the classification was based on the predominant or maximal tumor grade, respectively, in the specimen. Altogether, in 98% (53/54) of all specimens the decision to continue or not continue tumor resection could have been made according to the infrared spectroscopic classification. This retrospective study clearly demonstrates that infrared spectroscopic imaging may help to define tumor margins intraoperatively and to detect high-grade tumor residues for achieving more radical tumor resection. MRT-guided tumor resection (left) is combined with infrared spectroscopy-based tissue classification (middle, right). With regard to histopathological assessment, sensitivities of 100% and 93.1% and specificities of 96.9% and 88.0% were achieved for 54 specimens. (TIF 47.1 KB)

Intraoperative imaging of cortical cerebral perfusion by time-resolved thermography and multivariate data analysis

A new approach to cortical perfusion imaging is demonstrated using high-sensitivity thermography in conjunction with multivariate statistical data analysis. Local temperature changes caused by a cold bolus are imaged and transferred to a false color image. A cold bolus of 10 ml saline at ice temperature is injected systemically via a central venous access. During the injection, a sequence of 735 thermographic images are recorded within 2 min. The recorded data cube is subjected to a principal component analysis (PCA) to select slight changes of the cortical temperature caused by the cold bolus. PCA reveals that 11 s after injection the temperature of blood vessels is shortly decreased followed by an increase to the temperature before the cold bolus is injected. We demonstrate the potential of intraoperative thermography in combination with multivariate data analysis to image cortical cerebral perfusion without any markers. We provide the first in vivo application of multivariate thermographic imaging.

Restoration of ankle movements with the ActiGait implantable drop foot stimulator: a safe and reliable treatment option for permanent central leg palsy

OBJECT The ActiGait drop foot stimulator is a promising technique for restoration of lost ankle function by an implantable hybrid stimulation system. It allows ankle dorsiflexion by active peroneal nerve stimulation during the swing phase of gait. In this paper the authors report the outcome of the first prospective study on a large number of patients with stroke-related drop foot. METHODS Twenty-seven patients who experienced a stroke and with persisting spastic leg paresis received an implantable ActiGait drop foot stimulator for restoration of ankle movement after successful surface test stimulation. After 3 to 5 weeks, the stimulator was activated, and gait speed, gait endurance, and activation time of the system were evaluated and compared with preoperative gait tests. In addition, patient satisfaction was assessed using a questionnaire. RESULTS Postoperative gait speed significantly improved from 33.9 seconds per 20 meters to 17.9 seconds per 20 meters (p < 0.0001), gait endurance from 196 meters in 6 minutes to 401 meters in 6 minutes (p < 0.0001), and activation time from 20.5 seconds to 10.6 seconds on average (p < 0.0001). In 2 patients with nerve injury, surgical repositioning of the electrode cuff became necessary. One patient showed a delayed wound healing, and in another patient the system had to be removed because of a wound infection. Marked improvement in mobility, social participation, and quality of life was confirmed by 89% to 96% of patients. CONCLUSIONS The ActiGait implantable drop foot stimulator improves gait speed, endurance, and quality of life in patients with stroke-related drop foot. Regarding gait speed, the ActiGait system appears to be advantageous compared with foot orthosis or surface stimulation devices. Randomized trials with more patients and longer observation periods are needed to prove the long-term benefit of this device.