Abundance of Flt3 and its ligand in astrocytic tumors.

BACKGROUND: Molecular targeted therapies for astrocytic tumors are the subject of growing research interest, due to the limited response of these tumors, especially glioblastoma multiforme, to conventional chemotherapeutic regimens. Several of these approaches exploit the inhibition of receptor tyrosine kinases. To date, it has not been elucidated if fms-like tyrosine kinase-3 (Flt3) and its natural ligand (Flt3L) are expressed in astrocytic tumors, although some of the clinically intended small-molecule receptor tyrosine kinase inhibitors affect Flt3, while others do not. More importantly, the recent proof of principle for successful stimulation of the immune system against gliomas in preclinical models via local Flt3L application requires elucidation of this receptor tyrosine kinase pathway in these tumors in more detail. This therapy is based on recruitment of Flt3-positive dendritic cells, but may be corroborated by activity of this signaling pathway in glioma cells. METHODS: Receptor and ligand expression was analyzed by real-time polymerase chain reaction in 31 astrocytic tumors (six diffuse and 11 anaplastic astrocytomas, 14 glioblastomas) derived from patients of both genders and in glioblastoma cell lines. The two most common activating mutations of the Flt3 gene, ie, internal tandem duplication and D835 point mutation, were assessed by specific polymerase chain reaction. RESULTS: A relatively high abundance of Flt3L mRNA (4%-6% of the reference, b2 microglobulin) could be demonstrated in all tumor samples. Flt3 expression could generally be demonstrated by 40 specific polymerase chain reaction cycles and gel electrophoresis in 87% of the tumors, including all grades, although the small quantities of the receptor did not allow reliable quantification. Expression of both mRNAs was verified in the cell lines, excluding a derivation solely from contaminating lymphocytes or macrophages. No activating mutations were found. CONCLUSION: Our results warrant further analysis of endogenous Flt3 signaling in these tumors prior to application of immunotherapy in human patients.

Lumbar arachnoiditis and thecaloscopy: brief review and proposed treatment algorithm.

The term arachnoiditis describes the inflammation of the meninges and subarachnoid spaces. Lumbar arachnoiditis is characterized by obliterated nerve root sleeves and the adherence of nerve roots to each other in the proximity of the cauda equina, and may be secondary to infectious diseases or tumors, iatrogenic (subsequent to spinal surgery) or idiopathic. It is not very clearly defined epidemiologically or clinically, and various theories regarding its pathophysiology have been proposed; furthermore, its treatment is difficult because there is a lack of evidence-based diagnostic and therapeutic gold standards. Thecaloscopy has been recently described as a novel technique for retrograde transcutaneous neuroendoscopic inspection of the subarachnoid structures of the lumbar thecal sac; it has also been suggested for the treatment of lumbar arachnoiditis. We here review the most modern techniques for the treatment of this disease such as thecaloscopy and neurostimulation.

The PFKFB3 splice variant UBI2K4 is downregulated in high-grade astrocytomas and impedes the growth of U87 glioblastoma cells.

AIMS: Fructose-2,6-bisphosphate, a key regulator of glycolysis, is synthesized and degraded by four different isozymes of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1-4). The PFKFB3 isozyme is upregulated in several human tumours. Six alternatively spliced variants of PFKFB3 mRNA are known in humans (UBI2K1-6). Here, we studied the role of the PFKFB3 splice variants in human astrocytic gliomas. METHODS: We analysed the PFKFB3 splice variants in 48 astrocytic gliomas by RT-PCR and real-time PCR. The effect of transient and stable overexpression of the PFKFB3 isoforms was studied in U87 glioblastoma cells by MTT, cell counting, clone formation assay and metabolic measurements. RESULTS: UBI2K5 and UBI2K6 are the predominant splice variants in rapidly proliferating high-grade astrocytomas while the expression of UBI2K3 and UBI2K4 is mainly restricted to low-grade astrocytomas and nonneoplastic brain tissue. Overexpression of UBI2K5 or UBI2K6 in the U87 glioblastoma cell line enhances the glycolytic flux but does not affect cell growth. In contrast, overexpression of UBI2K4 reduces cell viability and anchorage-independent growth of U87 cells. The UBI2K4 mRNA level is downregulated in astrocytic gliomas with increasing malignancy grade. Moreover, the UBI2K4 mRNA level correlates with growth rate of several human cancer cell lines derived from different tissue types. CONCLUSIONS: Our results demonstrate that the splice variant UBI2K4 impedes the tumour cell growth and might serve as a tumour suppressor in astrocytic tumours.

Sectioning of filum terminale externum using a rigid endoscope through the sacral hiatus. Cadaver study.

AIM: Tethered cord syndrome (TCS) is a stretch-induced functional disorder of the spinal cord, which is directly related to filum fixation. Classic surgical approaches to the filum involve open surgery and include varying amounts of spinal bone removal. In an effort to reduce the morbidity and mortality of these procedures, the authors explored a less invasive method. They evaluated the ability, safety and feasibility for endoscopic sectioning of the filum terminale externum by performing upward orientated navigation in the extradural sacral spinal canal through the sacral hiatus using a rigid endoscope. METHODS: Four adult, phenol-formalin embalmed cadavers were used for endoscopic section of the filum terminale externum at the tip of thecal sac. After preparing the anatomical area of sacral hiatus, a rigid endoscope (Storz, of 3.8 mm external diameter with two working channels, of 1 mm each, one for suction-irrigation and one as working) was inserted into the extradural sacral spinal canal and the filum terminale externum was identified and cut easily at the distal end of thecal sac at the level of S2. In all cases, it was possible to manipulate the rigid endoscope and inspect the full length of the extradural sacral spinal canal, especially at the S1-S2 level. RESULTS: The results indicate that the tested transhiatal approach for upward orientated extradural endoscopy represents a minimally invasive procedure that provides an appropriate and feasible route to the extradural sacral spinal canal. CONCLUSION: Such approach is an attractive alternative for filum terminale externum sectioning in cases where tethered cord syndrome is not accompanied by any other pathology. Moreover if filum terminale internum sectiong is indicated, it can be performed in second stage.

Percutaneous approach for thecaloscopy of the lumbar subarachnoidal space.

INTRODUCTION: Endoscopy of the lumbar subarachnoidal space is named thecaloscopy, which has been used for diagnostic and therapeutic purposes. However, the insertion of the endoscope required microsurgical assistance from the skin into thecal sac in the lumbar region. The current study was applied to explore the possibility of a percutaneous approach for lumbar thecaloscopy insertion, transferring from the previous microsurgical procedure. METHOD: A 2.8-mm fiberoptic endoscope (Storz and Co., Tuttlingen, Germany) was used in the study. In two fresh human cadavers, a thecaloscope was first inserted through a transsacral approach and the tip was advanced inside the thecal sac to the lumbar region for observation. A percutaneous endoscopic approach was performed with the Seldinger technique under fluoroscopic control into the lumbar subarachnoid space. After completing the endoscopic procedure, the lumbar subarachnoid space was exposed microsurgically for morphological investigation of rootlets and surrounding structures. RESULTS: By the observation through a live video in the thecal sac, the percutaneous insertion of a 2.8-mm endoscope into the lumbar subarachnoidal space is feasible without any neural structural damage seen. CONCLUSION: The percutaneous approach for flexible endoscopes into the lumbar subarachnoidal space is a practical option for the future of thecaloscopy.

Endoscopic anatomy of the thecal sac using a flexible steerable endoscope.

In this study the ability for upward-orientated endoscopic visualization of thecal subarachnoid space using a flexible steerable endoscope was evaluated in order to compare endoscopic anatomical findings with the already known macroscopic ones of the incontained structures and to test the approach for clinical employment. For this purpose, four adult phenol-formalin embalmed cadavers were used and the approach selected was through a laminectomy window at the S1-S2 level. The dura mater was opened and a flexible steerable endoscope (Storz, of 2.8 mm external diameter with one working channel) was inserted subarachnoidally for upward-orientated observation of the content of thecal sac. By using this approach filum terminale, lower lumbar, sacral and coccygeal nerve rootlets were identified and observed in detail. By moving the endoscope even more upwards, inspection of the upper part of the thecal subarachnoid space and conus medullaris was also possible. The findings collected from the study indicate that this approach for upward-orientated intradural subarachnoid endoscopy gives an appropriate working and inspecting window to the lower, as well as to the upper part of the thecal subarachnoid space and even of the conus medullaris. Furthermore, inspection and identification of lower lumbar, sacral and coccygeal nerve rootlets is possible and efficient and the endoscopic anatomical observations coincide with the already known gross-anatomical ones.

Endoscopic treatment of lumbar arachnoiditis.

OBJECTIVE: The diagnosis of lumbar arachnoiditis remains complex and often inconclusive. Using the technique of lumbar subarachnoidal endoscopy (thecaloscopy), the pathology can be identified and the patient treated with long-term effects on the symptoms. METHOD: Endoscopic operations were performed on 23 patients suffering from varying symptoms with an enlarged lumbar subarachnoidal space. Having confirmed the diagnosis of lumbar arachnoiditis, a number of endoscopic operations ranging from adhesiolysis to subarachno-epidurostomy were carried out. RESULTS: Radicular symptoms in lumbar arachnoiditis were successfully relieved by various endoscopic dissection techniques, such as restoration of the improved CSF flow by subarachno-epidurostomy along the rootlet. This has been identified as one of the causal factors of the clinical symptoms. In cases where lumbar pain persists in spite of a previous thecaloscopy, further treatment with a lumboperitoneal shunt device has proved most successful.

[Adhesive lumbar arachnoiditis. Endoscopic subarachnoepidurostomy as a new treatment]. / Lumbale adhäsive Arachnoiditis. Endoskopische Subarachnoepidurostomie als neue Behandlungsmöglichkeit.

BACKGROUND: Adhesive lumbar arachnoiditis is essentially an unknown, unreported, and unrecognised disease. It was better known at a time when oil-based dye was used for myelography. The factors causing this pathogenesis remain unknown. In addition, diagnosis is hard to achieve and frequently attained only by an exclusion process. Only in severe cases, using high-resolution MRI, is evidence for the diagnosis obtainable. METHOD/PATIENTS: Modern neuroendoscopic techniques allow diagnosis at a reasonable risk (comparable with lumbar tap) and enable us substantially to treat the pain. Taken together, this means a radical new method of treatment for adhesive arachnoiditis. The treatment of a 23-patient research group suffering from adhesive lumbar arachnoiditis is monitored and described. RESULTS: Various endoscopic manoeuvres were carried out. Endoscopic reduction of adhesions and internal shunting for CSF flow between subarachnoidal and epidural space improved both the biomechanical abilities of rootlets and restoration of blocked CSF pathways. Its main result is the significant reduction of long-term pain registered by a visual analogue pain scale. No bad side effect other than temporary headache was found. No CSF leak syndrome was observed. DISCUSSION: The success of the method was directly influenced by the interventional procedure on the disturbed CSF circulation and its partial restoration (subarachnoepidurostomy). In cases of severe lumbar adhesive arachnoiditis, it was found very beneficial to implant special gravity-controlled valve systems for subarachnoid-peritoneal shunts. CONCLUSION: Adhesive lumbar arachnoiditis is no longer a devastating diagnosis. Due to a novel endoscopic treatment of the local CSF disturbances that restores physiologic pathways, the chance exists for long-lasting improvement of the clinical condition.

Thecaloscopy through sacral bone approaches, cadaver study: further anatomic landmarks.

Endoscopy of the spinal canal, for interventional studies, diagnosis and therapy, is a scientific topic that has attracted the interest of neurosurgeons, anesthesiologists and orthopedic surgeons for the past twenty years. Endoscopy of the thecal sac was assumed to be less important than endoscopy of the ventricular system by neurosurgeons. Nevertheless, during the last years it has attained increasing scientific interest, firstly because of the introduction of small diameter flexible endoscopes and secondly due to the growing interest for minimal invasive diagnostic and therapeutic procedures in modern neurosurgery. Until now thecaloscopy was performed by the ISGT (International Study Group for Thecaloscopy) using co-axial downward orientated approaches. We have examined transsacral approaches to facilitate the navigation of flexible scopes in the lumbosacral subarachnoid space, and thus we now introduce further recognizable endoscopic anatomic landmarks.

Thecaloscopy part III: first clinical application.

PURPOSE: We have already dealt with the technical and anatomical basics for thecaloscopy. The first results of clinical application are presented and the indications for its diagnostic and therapeutic use are described. The aetiology of aseptic arachnitis and the term "Wide spinal canal syndrome" are discussed. PATIENTS AND METHODS: Twelve patients who fulfilled the criteria for entry to the study were selected and the criteria were chosen according to German medical and legal rules. All patients underwent an endoscopic inspection and, if necessary, therapeutic manipulation under general anaesthesia. RESULTS: In all cases the procedure was safely and successfully performed. The pathomorphology of the arachnoid was detected and endoscopically treated in almost all cases. Arachnoid cysts were successfully fenestrated and an intraspinal meningocoele treated with endoscopic assistance. CONCLUSION: Thecaloscopy is a safe procedure if skilfully performed. It provides an opening for a wide range of new diagnostic and therapeutic options.

Thecaloscopy: the endoscopy of the lumbar subarachnoid space, part I: historical review and own cadaver studies.

Since 1931 only a few efforts have been made for direct visualization of the neural structures of the spinal canal. Given current technologies and minimally invasive techniques it is now possible to effectively view these structures. We describe here a new technique for inspection of the subarachnoid space of the lumbar spinal canal by using a flexible endoscope in ten fresh post-mortem adult human cadavers. According to the anatomical structures, namely the thecal sac and its anatomical position, the procedure is called thecaloscopy and the instrument is a thecaloscope. It was proven that the procedure is safe and easy to perform.

Thecaloscopy part II: anatomical landmarks.

Endoscopic anatomy differs from microsurgical anatomy. Topographical orientation as well as the proportion of objects, is different as they depend on the lens/object distance. Orientation under endoscopic conditions requires structures with defined positions or recognisable structures previously identified radiolologically. Structures are anatomical landmarks if the topographical relation to their surroundings is constant and they are easy and reliable to recognise. The contents of the dural sack are nerve roots with their supplying vessels, arachnoid trabeculars, filum terminale, and CSF. Safe navigation of a thecaloscope in relation to the bony structures is only possible with the simultaneous use of intraoperative fluoroscopy. To facilitate the navigation of scopes and instruments in the subarachnoid space we attempted to identify and describe reliable, and therefore constant recognisable anatomical landmarks.

Pharmacokinetics of ampicillin/sulbactam in patients undergoing spinal microneurosurgical procedures.

The fixed combination of ampicillin (2 g)/sulbactam (1 g) was administered as perioperative prophylaxis at induction of anesthesia in 20 patients undergoing spinal microneurosurgery. It was noteworthy that after the short infusion ampicillin and sulbactam penetrated rapidly from blood into the different tissues affected by the surgical procedures. The following mean concentrations were measured in tissues: muscle 32.3+/-6.5 mg/kg ampicillin and 18.6+/-2.9 mg/kg sulbactam (11.1 min), ligament 39.5+/-11.1 mg/kg ampicillin and 25+/-6.5 mg/kg sulbactam (13.8 min), bone 12+/-3.6 mg/kg ampicillin and 7+/-0.8 mg/kg sulbactam (20.6 min), disk 10.2+/-3.3 mg/kg ampicillin and 7.3+/-1.8 mg/kg sulbactam (44.2 min). The mean time of sampling is given in brackets. For a period of at least 2 h the levels of both drugs measured in serum and in the different tissues were above the MICs for bacteria involved in postoperative wound infections. The administration of ampicillin/sulbactam apparently achieved sufficiently, high antibiotic concentrations, even in bradytrophic tissues such as ligament, bone, and disk, and seemed to meet the pharmacological criteria for perioperative prophylaxis in spinal microneurosurgery.

Lysis of basal ganglia haematoma with recombinant tissue plasminogen activator (rtPA) after stereotactic aspiration: initial results.

In a series of 10 patients with stereotactically treated basal ganglia haematoma rtPA was used to dissolve remaining clots. Pre-operative haematoma volume ranged between 39 and 111 cm3 (average 56 cm3). Stereotactic aspiration alone yielded an average volume reduction of 60% (range 23 to 78%). Haematoma cavity was instillated with rtPA repeatedly beginning 24 hours after the stereotactic intervention. At the end of rtPA therapy between 2 and 4 days after onset of the haemorrhage 67 to 92% (average 84%) of the initial haematoma was removed in all patients. More than 80% of the pre-operative clot could be removed in 8 out of 10 patients between day 2 and 4. There were no signs of rtPA related toxicity. At the end of the follow-up period (between 4 and 17 months--mean 8 months) 6 patients were awake, oriented and with a residual hemiparesis able to live in their familiar environment. It is concluded that local rtPA instillation is an effective additional treatment to further resolution of deep seated intracerebral haematomas after stereotactic aspiration.

[Erroneous laterality marking in CT of the head. A case report]. / Fehlerhafte Seitenbezeichnung im Kopf-CT. Fallbericht.

Erroneous left/right side marker during CT-scanning of the head is an extremely rare event. We report a case occurred in emergency situation and present a simple device to avoid such an error.

[Surgical management of perinatal damage of the brachial plexus]. / Die operative Versorung der perinatalen Schädigung des Plexus brachialis.

The etiology of the plexus brachialis palsy is in generally well known. The dimensions of clinical signs is correlating with the severeness of the birth trauma and therefore with the degree of morphological damage, as well. In our remained after conservative therapy in 5% a severe lesion of the plexus. An improvement of motorical functions could be observed. The paper presents 5 cases with severe plexus brachialis lesions which had been operated on and gives a look to the postoperative results.