[Importance of preoperative and intraoperative imaging for operative strategies]. / Bedeutung der prä- und intraoperativen Bildgebung für die operative Strategie.

Recent advances in preoperative and postoperative imaging have an increasing influence on surgical decision-making and make more complex surgical interventions possible. This improves the possibilities for frequently occurring challenges and promoting improved functional and oncological outcome. This manuscript reviews the role of preoperative and intraoperative imaging in surgery. Various techniques are explained based on examples from hepatobiliary surgery and neurosurgery, in particular real-time procedures, such as the online use of augmented reality and in vivo fluorescence, as well as new and promising optical techniques including imaging of intrinsic signals and vibrational spectroscopy.

[Acute treatment of patients with severe traumatic brain injury]. / Akutversorgung des Patienten mit schwerem Schädel-Hirn-Trauma.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and permanent disability and a common and important global problem. The contribution of secondary posttraumatic brain damage to overall disability in TBI is significant, underlining the importance of prompt and comprehensive treatment for affected patients. METHODS: This article focuses on current concepts of prehospital and emergency room management of patients with severe TBI to prevent secondary brain injuries. RESULTS AND DISCUSSION: Preclinical prevention and treatment of hypoxia, hypotension and hypercarbia are essential, as they affect the long-term outcome in TBI patients. Prehospital intubation should be critically weighed and in the context of an individual decision. In general, prehospital intubation is more difficult than in the clinical setting. The combination of ketamine and benzodiazepines are commonly used to induce anesthesia before intubation in hemodynamic instable patients. The choice of a muscle relaxant for anesthesia induction is either a non-depolarizing neuromuscular blocking agent or succinylcholine. Administration of mannitol or hypertonic saline is effective to rapidly decrease intracranial pressure. Whenever possible the final destination for transport of TBI patients should be a level I center with round the clock neurosurgical expertise. Trauma-induced coagulopathy should be recognized and immediately treated using a point-of-care testing. CONCLUSION: Hypoxia, hypotension and hypercarbia should strictly be avoided to improve survival and neurological outcome in patients with severe TBI. The prehospital decision to intubate must be made on a case by case basis at the accident site. A level I trauma center should be the destination for this patient group.

Surgery of low-grade gliomas near speech-eloquent regions: brainmapping versus preoperative functional imaging.

The identification of eloquent areas is of utmost importance in the surgery of tumors located near speech-eloquent brain areas, since the classical concept of a constant localization was proven to be untrue and the spatial localization of these areas may show large interindividual differences. Some neurosurgical centers apply intraoperative electrophysiological methods that, however, necessitate the performance of surgery in the awake patient. This might be a severe burden both for the patient and the operating team in a procedure that lasts several hours; in addition, electrical stimulation may generate epileptic seizures. Alternatively, methods of functional brain imaging (e.g., PET, fMRI, MEG) may be applied, which allow individual localization of speech-eloquent areas. Matching of these image data with a conventional 3D-CT or MRI now allows the exact transfer of this information into the surgical field by neuronavigation. Whereas standards concerning electrophysiological stimulation techniques that could prevent a permanent postoperative worsening of language are available, until now it remains unclear whether the resection of regions shown to be active in functional brain imaging will cause a permanent postoperative deficit.

Comparison of functional brain PET images and intraoperative brain-mapping data using image-guided surgery.

OBJECTIVE: Knowledge about the spatial localization of eloquent brain areas is essential for resecting lesions in the vicinity of these areas. The classical approach is to perform surgery on the awake patient under local anesthesia using brain-mapping techniques. As an alternative, the location of eloquent areas can be visualized by preoperative functional brain-imaging techniques, for example, positron emission tomography (PET), functional magnetic resonance imaging (fMRI), or magnetoencephalography (MEG). Using functional activation PET, both methods were combined by integration into a frameless navigation system (BrainLAB) and used to map speech-eloquent areas. PATIENTS AND METHODS: Speech-eloquent areas were localized preoperatively in seven patients with a left-sided glioma using 2-[(18)F]-2-desoxy-D-glucose PET. Patients were scanned under silence conditions (i.e., with the patient remaining silent in a sound-proof cabin), and speech was activated using a verb-generation paradigm. The PET data were transferred to the neuronavigation workstation and matched with a preoperative 3D-MRI using an automatic image-fusion algorithm. Intraoperative speech localization was performed using brain-mapping techniques under local anesthesia with bipolar cortical stimulation. The stimulator position was mapped into the MRI/PET data set by neuronavigational tracking of the instrument. RESULTS: Functional PET images were integrated into the MRI-based neuronavigational system and could be transferred exactly to the operative field. By the additional integration of cortical stimulation, intraoperative electrophysiological findings can be directly compared with preoperative functional images. Seven patients with left-sided glioma were operated on using this protocol, confirming the technical feasibility. In three of seven patients, preoperative PET findings were not supported by intraoperative mapping. CONCLUSIONS: This matching and mapping technique is suitable for monitoring eloquent speech areas during surgical resection of extensive left-sided low-grade gliomas, allowing a direct comparison between intraoperative electrophysiological brain mapping and preoperative functional brain-imaging findings. The sensitivity and specificity of functional imaging techniques can now be evaluated by reconciling the data with the intraoperative stimulation results.

Albright's hereditary osteodystrophy associated with cerebellar pilocytic astrocytoma: coincidence or genetic relationship?

Albright's hereditary osteodystrophy (AHO) is a rare inherited disease characterized by skeletal abnormalities, short stature, and, in some cases, resistance to parathyroid hormone, resulting in pseudohypoparathyroidism (PHP). Heterozygous inactivating mutations of the GNAS1 gene are responsible for reduced activity of the alpha subunit of the Gs protein (G(Salpha)), a protein that mediates hormone signal transduction across cell membranes. G(salpha) is also known to have oncogenic potentials, leading to the development of human pituitary tumors and Leydig cell tumors. Here, we report the 1st case, a 3.5-year-old girl, with classic AHO phenotype and PHP type 1A associated with a cerebellar pilocytic astrocytoma. Coincidence or genetic relationships of both diseases are discussed according to molecular findings and current literature.

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.

Temporary response of localized intracranial mast cell sarcoma to combination chemotherapy.

Cerebral involvement of systemic mastocytosis and intracranial sarcoma of myelogenic origin are well known entities. An 8-year-old girl with an isolated cerebral mast cell tumor is presented. Specific histopathologic stains were used to confirm the diagnosis detecting immunophenotype and proliferative activity. Treatment with irradiation, intrathecal cytarabine, and interferon-alpha2b did not induce regression whereas polychemotherapy did. Systemic combination chemotherapy led to marked transient tumor regression in this proliferating mast cell sarcoma in an unusual intracranial location.

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/STK11 in 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.

Genetic alterations of the tumor suppressor gene PTEN/MMAC1 in human brain metastases.

The high mutation rate in advanced brain tumors, recent functional studies, and the high frequency of mutations in prostate metastases all strongly suggest that PTEN/MMAC1 alterations are involved in the formation of metastases. We searched for genetic alterations in the PTEN/MMAC1 gene in 56 consecutive brain metastases from various primary tumors by loss of heterozygosity (LOH), direct sequence analysis, and differential PCR analysis. The highest LOH rates were detected in metastases deriving from lung (67%) and breast (64%) cancers. Three (25%) of the eight detected inactivating mutations (one nonsense mutation, one splice-site mutation, one 11-bp deletion, and five homozygous deletions) were found in metastases originating from 12 different lung carcinomas, suggesting that PTEN/MMAC1 alterations may play a role in the progression of this tumor. With the exception of lung carcinomas, our findings indicate that genetic abnormalities of the PTENM/MMAC1 gene are only involved in a relatively small subset of brain metastases. However, the discrepancy between the high overall LOH rate (50%) and the low frequency of PTEN/MMAC1 mutation detection rate (14%) suggests the presence of one or more additional tumor suppressor genes on chromosome 10q.

Intraoperative facial nerve monitoring (IFNM) predicts facial nerve outcome after resection of vestibular schwannoma.

Intraoperative facial nerve monitoring (IFNM) is a suitable technique for intraoperative facial nerve identification and dissection, especially in large vestibular schwannomas (VS) (acoustic neuroma). To evaluate its feasibility for estimating functional nerve outcome after VS resection 60 patients underwent surgery using IFNM. Out of this group the last 40 patients were included in a prospective study evaluating the prognostic value of various IFNM parameters (proximal and distal absolute EMG amplitude, stimulation threshold, and proximal-to-distal amplitude ratio) for prediction of initial postoperative facial nerve function and recovery of function. Stimulation threshold and absolute EMG amplitude proximally at the brain stem were both predictive for postoperative nerve function. Good initial facial nerve outcome (modified House Brackmann grading, mHB degree I and degree II) was found in 15/16 patients with a proximal EMG amplitude greater than 800 microV and in 19/22 patients with proximal stimulation threshold less than 0.3 mA. Sixteen of 16 patients with proximal stimulation threshold equal to or greater than 0.3 mA had moderate-to-severe facial palsy (mHB degree III or worse). Six of six patients without evokable proximal amplitude initially had insufficient nerve function (mHB degree IV). Intraoperative decrease of the proximal amplitude was associated with an unfavourable outcome, whereas distal amplitudes usually stayed unchanged. Mean distal EMG amplitudes were also found to be decreased with poor nerve function, which may mean that the tumour had already affected the nerve. A proximal amplitude of 300 microV or less and a proximal-to-distal amplitude ratio below 1:3 were found in the absence of functional recovery in 6/8 (75%) and 5/6 (83%) patients with initial mHB degree IV, respectively. Two patients with initial mHB degree IV improved to mHB degree III despite intraoperative evidence of missing functional nerve integrity. Therefore, functional recovery cannot be predicted by IFNM in all cases of anatomical nerve preservation. We conclude that a minimum follow-up period of 1 year may still be advisable even in certain patients without evidence of intraoperative functional nerve integrity.

Multiple intracerebral haemangioblastomas in identical twins with von Hippel-Lindau disease--a clinical and molecular study.

Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant neoplastic disorder causing central nervous system haemangioblastomas. The VHL gene (3p25-3p26) is known to be a tumour suppressor gene, with its inactivation being responsible for a predisposition to tumour development. As far as we know, the present report of VHL disease manifestation in identical twins is unique. Genetic inquiry into the family background did not reveal this disease among their progenitors. For presymptomatic diagnosis of 17 presently unaffected family members, constitutional DNA of the twins was screened for VHL germline mutations, using loss of heterozygosity studies and exon-specific DNA sequencing. To determine the influence of somatic mutations of the VHL gene in tumourigenesis, DNA of five surgically removed intracerebral haemangioblastomas of the identical twins was analyzed in comparison with their constitutional DNA by DNA sequencing of the complete VHL coding region. However, no allelic losses were found for the VHL gene or for various other tumour suppressor genes (p53, BRCA1, BRCA2, DCC, and MCC). Furthermore, no mutations were found in the constitutional DNA of either twin sister or in the DNA of all five tumour lesions. Based on our observations, we conclude that in certain VHL families, presymptomatic molecular diagnosis of the disease is not feasible and requires close clinical surveillance of all individuals at risk.

Structure-activity relationships of four anti-cancer alkylphosphocholine derivatives in vitro and in vivo.

This study was carried out to investigate whether structure-activity relationships of alkylphosphocholines, a new group of anti-neoplastic agents, which had been detected in methylnitrosourea(MNU)-induced rat mammary carcinoma, can be transferred to in vitro systems. Therefore, the anti-neoplastic activity of 4 alkylphosphocholines (APCs) was compared in 6 tumor cell lines in vitro and in MNU-induced rat mammary carcinoma in vivo. The in vitro system consisted of 2 rat mammary-carcinoma-derived cell lines (1/C2 and 1/C32), as well as 2 human mammary-gland (MDA-MB-231 and MCF-7)- and gastrointestinal tract (HT-29 and KB)-derived tumor cell lines. As assessed by both cell counting and MTT-assay, the ranking of concentrations effecting 50% growth inhibition (IC50) was parallel in all cell lines for octadecylphosphocholine (18:0-PC), octadecenyl-(trans-9.10)-phosphocholine (t-18:1-PC) and octadecenyl-(cis-9.10)-phosphocholine (c-18:1-PC). Only hexadecylphosphocholine (16:0-PC) differed in its activity, being least active in 1/C2, 1/C32 and MDA-MB-231 cells, moderately active in KB and MCF-7 cells, and most active in HT-29 cells. The IC50 concentrations of APCs in the 2 rat mammary carcinoma cell lines significantly correlated with dosages effecting a 50% tumor growth delay in vivo. Remarkably, the 2 gastrointestinal cell lines were more sensitive to APC exposure than the mammary-carcinoma cell lines. In all cell lines except KB cells, growth-stimulation effects were seen in the concentration range preceding the anti-proliferative activity; in vivo, however, no accelerated cancer growth was observed. The in vitro system failed to describe the superior therapeutic ratio of c-18:1-PC, as assessed in vivo, because it does not take the relative sensitivity of tumor vs. normal cells into account. Complementary in vivo trials are therefore indispensable for a final evaluation. Comparison of the 2 in vitro assays shows good agreement of the interrelationship of IC50 values, those obtained by MTT assay being on average 25% higher than those obtained from cell counting.

Assessment of antineoplastic agents by MTT assay: partial underestimation of antiproliferative properties.

In the present study a slightly modified MTT assay was used in conjunction with cell counting to determine the antiproliferative efficacy of N-(2-chloroethyl)-N-nitroso-N'-2-hydroxyethylurea (HECNU), vinblastine, and hexadecylphosphocholine (HPC) in a panel of six tumor cell lines. This panel consisted of two human (MDA-MB231, MCF-7) and two rodents (1/C2, 1/C32) mammary-carcinoma cell lines as well as of two tumor cell lines of gastrointestinal origin (HT-29, KB). It was shown that the use of acid isopropanol as a solvent of the formazan crystals produced correlations between cell number and absorption that were as good as, if not better than, those seen after dimethylsulfoxide (DMSO) application. The optimal period of incubation with the MTT dye was 2 h. A comparison of the antiproliferative activity of HECNU revealed that the HT-29 cell line was most resistant [50% inhibition concentration (IC50), 138.7 mumol/l], followed by MCF-7 cells (IC50, 127.7 mumol/l), whereas MDA-MB231 cells showed the highest sensitivity (IC50, 6 mumol/l). Vinblastine induced the highest (MCF-7 cells; IC50, 0.68 nmol/l) and the lowest (1/C2 cells; IC50, 7.69 nmol/l) degrees of growth inhibition in cell lines derived from mammary carcinoma. This contrasted with the activity of HPC, which was considerably less effective in the four mammary-carcinoma cell lines (IC50 from 29.4 to 69.9 mumol/l) than in the two cell lines of gastrointestinal origin (IC50, 1.9 and 3.1 mumol/l). Interestingly, treatment with HPC stimulated the growth of 1/C32 cells in the lower dose range. After treatment with HECNU, the average IC50 value determined in the MTT assay was 2.4-fold that disclosed by cell counting, whereas the average values found for HPC and vinblastine by both methods corresponded fairly well, with the respective values obtained using the MTT assay being only 26% and 14% higher than those measured by cell counting. A dose-dependent increase in the mean size of MCF-7 cells was observed after exposure to HECNU, which--if taken into account--considerably reduced underestimation of this parameter by the MTT assay. No variation in cell size was noted following treatment with HPC and vinblastine. Thus, depending on the antitumor agent used, the MTT assay can result in slight or even considerable underestimation of the antitumor efficacy of certain compounds and may need correction by consideration of the effect of the drugs on cell size.