Treatment strategies of space-occupying intradural metastases of the cauda equina of nonneurogenic origin.

BACKGROUND: Compressive intradural metastases of the cauda equina are a rare site of metastatic spread in systemic cancer. So far, only few reports have been published with conflicting statements concerning a surgical versus nonsurgical approach. METHOD: Five patients with symptomatic space-occupying intradural metastases of the cauda equina were analyzed retrospectively, focusing on the influence of surgical intervention on pain relief, neurological outcome and thus the patients' quality of life. FINDINGS: At the time of diagnosis, all patients were in an advanced metastatic state. Surgical resection was the primary treatment in four patients and radiotherapy in one. Despite infiltration of the cauda rootlets, gross total tumour resection could be achieved in two of the four patients treated surgically. Functional outcome was beneficial in these patients with marked and immediate relief of pain and improvement of motor function even following incomplete tumour resection. CONCLUSIONS: Surgical treatment of compressive intradural metastases of the cauda equina seems to be feasible with low operative risk and with the potential benefit of an immediate relief of pain and improvement in motor function and thus an increase in quality of life.

Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors.

We investigated the variability in infectivity of cells in primary brain tumor samples from different patients using an HSV-1 amplicon vector. We studied the infectivity of HSV-1 amplicon vectors in tumor samples derived from neurosurgical resections of 20 patients. Cells were infected with a definite amount of HSV-1 amplicon vector HSV-GFP. Transduction efficiency in primary tumor cell cultures was compared to an established human glioma line. Moreover, duration of transgene expression was monitored in different tumor cell types. All primary cell cultures were infectable with HSV-GFP with variable transduction efficiencies ranging between 3.0 and 42.4% from reference human Gli36 Delta EGFR glioma cells. Transduction efficiency was significantly greater in anaplastic gliomas and meningiomas (26.7+/-17.4%) compared to more malignant tumor types (glioblastomas, metastases; 11.2+/-8.5%; P=0.05). To further investigate the possible underlying mechanism of this variability, nectin-1/HevC expression was analyzed and was found to contribute, at least in part, to this variability in infectability. The tumor cells expressed the exogenous gene for 7 to 61 days with significant shorter expression in glioblastomas (18+/-13 d) compared to anaplastic gliomas (42+/-24 d; P<0.05). Interindividual variability of infectivity by HSV-1 virions might explain, at least in part, why some patients enrolled in gene therapy for glioblastoma in the past exhibited a sustained response to HSV-1-based gene- and virus therapy. Infectivity of primary tumor samples from respective patients should be tested to enable the development of efficient and safe herpes vector-based gene and virus therapy for clinical application.

Loss of BRCA2 correlates with reduced long-term survival of sporadic breast cancer patients.

BACKGROUND: The present study was undertaken to analyze the prognostic value of loss of heterozygosity (LOH) at 13q12-13, 17q21 and 17p13, harboring BRCA2, BRCA1 and p53 to predict the clinical course of sporadic breast cancer patients. MATERIALS AND METHODS: LOH analysis was performed by PCR amplification of genomic DNA using nine microsatellite markers. Fifty-three sporadic breast cancer patients were followed clinically for a median of 55 months. Disease-free and overall survival was documented as the endpoint for statistical evaluation. RESULTS: Patients presenting with LOH in their tumor samples at at least one of the loci examined were found to have a reduced overall survival time compared to those retaining heterozygosity (61% versus 48%). Focusing on the three target regions, patients with LOH at the BRCA2 locus died earlier compared to patients retaining heterozygosity (69% versus 50%) and, in addition, BRCA2 LOH-positive patients showed a shorter metastasis-free interval (30 versus 37 months). In a multivariate analysis, LOH at the 13q12-13 locus was found to be a significant predictor for reduced long-term survival (risk ratio 2.33, 95% C.I., 1.0-5.3; p<0.05) and earlier metastases manifestation (risk ratio 2.32, 95% C.I., 1.0-5.3, p<0.05). CONCLUSION: Allelic loss at the BRCA2 locus may be of use as a negative predictor for metastases-free and overall survival.

Rifampin-impregnated silicone catheters: a potential tool for prevention and treatment of CSF shunt infections.

BACKGROUND: Infection continues to be one of the major complications of cerebro-spinal fluid shunting procedures. Recent insights in the pathophysiological mechanism of these foreign body infections have elucidated the difficulty of achieving successful treatment without device removal. The development of a rifampin-impregnated silicone catheter yielded excellent results in infection prevention and treatment in vitro as well as in an animal model. PATIENTS AND METHODS: Here, we describe the application of this device in two patients with a complicated course of shunt infection. RESULTS: In one patient the rifampin-impregnated shunt system was implanted after external drainage to prevent further infection. The shunt infection of the second patient was treated by replacement of the infected shunt system with a rifampin-impregnated device. Both patients recovered immediately without any signs of adverse effects and the two shunt systems have now been working properly for more than 36 and 21 months, respectively. CONCLUSION: These results suggest that rifampin-impregnated silicone catheters could become a valuable tool in the treatment and prevention of shunt infections.

Use of scanning electron microscopy to investigate the prophylactic efficacy of rifampin-impregnated CSF shunt catheters.

Infection continues to be one of the major complications of cerebrospinal fluid (CSF) shunting procedures, and is caused mainly by skin-derived bacteria. Production of an extracellular biofilm plays an important role in the pathogenesis of shunt-associated infections by protecting bacteria from immune mechanisms and antibiotics. So far, removal of the original shunt and implantation of a new shunting device has been the only successful treatment for most patients. As an alternative strategy to prevent CSF infections, a rifampin-impregnated silicone catheter was designed to provide high initial and long-lasting (>60 days) release of bactericidal drug. To investigate the pathophysiological mechanism of its function, this new device was investigated both in vitro and in a rodent model of CSF infection by scanning electron microscopy (SEM) and bacterial culture. Staphylococcus epidermidis (10(8) cfu/ml) and S. aureus (10(4) cfu/ml) served as test strains. SEM demonstrated that, in contrast to the unloaded catheters, initial bacterial adherence on the catheter surface could be reduced to a few single cells, which did not show visible signs of proliferation. Bacterial cultures obtained simultaneously were all sterile, showing that adherent bacteria were killed immediately by the rifampin released from the catheter. Although rifampin incorporation into silicone polymers was not able to prevent initial bacterial adhesion completely, subsequent colonisation could be prevented.

An easy and safe method to store and disinfect explanted skull bone.

In our department extensive decompression craniectomies became the treatment of choice for patients with massive cerebral oedema following either trauma or acute cerebral infarction. The remarkable survival rates of this neurosurgical technique created the problem of adequate vault defect reconstruction. To evaluate the biological safety of using stored autologous skull flaps for this purpose, we compared three different disinfection methods. Skull bone fragments stored at -21 degrees C for different periods of time were artificially contaminated with clinically relevant strains of Serratia marcescens, Enterococcus faecium and Staphylococcus aureus. As potential methods for disinfection we tested immersion in 3% H2O2, boiling in normal saline for 15 and 30 minutes and a special process of steam disinfection at a temperature of 75 degrees C for 20 minutes. We were able to demonstrate that only steam disinfection completely eliminated the bacterial strains tested. Refrigeration plus steam disinfection of autologous skull bone prior to re-implantation seems to offer reliable safety for its use for defect closure. It is available at reasonable cost in many hospitals and does not require a bone bank.

Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome.

The occurrence of distant metastases is the most feared manifestation of breast cancer, often occurring years after the primary surgery and associated with poor survival. The dominant metastatic clone is characterized by an accumulation of genetic alterations, but it is not actually known at what stage of the metastatic cascade these alterations have occurred. We investigated allelic losses during breast cancer progression in a series of 17 primary breast carcinomas and 22 corresponding brain, liver, lung, and bone metastases (mean metastasis-free interval, 31 months) by analyzing 19 microsatellite markers on seven breast cancer- or metastasis-related chromosomal regions and correlated the incidence of combined loss of heterozygosity (LOH) with metastasis-free and postmetastatic survival. We found that, in comparison with the corresponding primary tumor, additional LOH events are frequently found in metastases and that the incidence of combined LOH in the primary tumor, plus the occurrence of additional LOH events in the distant metastases, correlated significantly with decreased postmetastatic survival. Combined LOH of the three breast cancer-related chromosomal regions alone or in combination with allelic loss at the p53 gene region seems to have a specific influence on the aggressive behavior of metastases. We hypothesize that the occurrence of additional LOH events is either involved in termination of dormancy of micrometastatic tumor cells at distant organ sites or acquired during further progression of metastases.

Accumulation of genetic alterations in brain metastases of sporadic breast carcinomas is associated with reduced survival after metastasis.

Tumor progression is characterized by stepwise accumulation of genetic alterations. To identify alterations associated with breast cancer metastasis, an analysis of comparative loss of heterozygosity (LOH) was performed on 38 primary sporadic breast carcinomas and 16 distant metastases. Two loci at 5q21 and 18q21 were chosen because of their reported increased deletion frequency in metastatic tumors. LOH at 17q21, 13q12-13, 17p13.1 and 11q22-23 was analyzed to determine whether there is a specific involvement of these breast cancer-associated gene loci in the metastatic process. Our data show that distant metastases are characterized by markedly increased LOH frequency at all loci examined. In both gene locus groups, significantly more distant metastases are affected by combined LOH. Furthermore, a significantly reduced postmetastatic survival time has been observed in patients with brain metastases affected by synchronous allelic loss at the four breast cancer-associated gene loci. Our results suggest that cumulative LOH of breast cancer-related gene loci is associated with a more aggressive phenotype of metastatic breast tumors.