Infection rates of external ventricular drains are reduced by the use of silver-impregnated catheters.

BACKGROUND: External ventricular drainage (EVD) placement for temporary cerebrospinal fluid (CSF) diversion is a frequent therapeutic procedure. Several types of EVD catheters are currently available, some of which have an antibacterial effect. This study compares the rates of CSF infections in patients with different types of EVD catheters. METHODS: This is a retrospective study of 403 patients with a total of 529 implanted EVDs. We analyze the occurrence of EVD-associated infections, microbiological diagnosis, type of EVD catheter (plain polyurethane vs. silver-impregnated), duration of CSF diversion, primary disease, and outcome. RESULTS: There were a total of 29 patients with EVD infections in the whole study group (7.1 %). A pathogen was detected in all cases. Coagulase-negative staphylococci were detected most frequently (20 out of 29 cases, 70 %). The rate of infections by catheter type was 7.6 % (11 of 145) and 13.8 % (4 out of 29) for two different types of non-coated polyurethane catheters. Silver-impregnated polyurethane catheters became infected in 6.1 % (14 out of 228). The differences between non-coated and silver-coated catheters were statistically significant. CONCLUSIONS: This study provides comparative data on EVD infections with regard to the type of catheter. Silver-impregnated catheters showed significantly lower infection rates when compared to non-impregnated catheters. The results are critically discussed and compared with the published literature.

Clinical trials with intracerebral convection-enhanced delivery of targeted toxins in malignant glioma.

Currently used targeted toxins are recombinant molecules specifically binding to surface receptors overexpressed on tumor cells. These recombinant proteins consist of a tumor-selective ligand coupled to a truncated peptide toxin. Ligands may bind to tumor-associated molecules with receptor signaling properties, such as epidermal growth factor receptor, transferrin receptor, and interleukin-13 or interleukin-4 receptors. The toxin part of the molecule in all clinically used toxins is a modified bacterial polypeptide fused to one of the above ligands. Targeted toxins are very effective against tumor cells resistant to radiation and chemotherapy. They are far more potent than any known chemotherapy drug. Targeted toxins have shown an acceptable profile of toxicity and safety in early clinical studies and have demonstrated some evidence for tumor response. Currently, phase 3 trials with some targeted toxins are underway and final results are still pending. This review summarizes the study protocols and key findings of the most important clinical studies with targeted toxins in malignant glioma patients. It offers in addition an outlook into future areas of development of targeted toxins, such as improved delivery modes and non-invasive imaging of toxin distribution.

Intervertebral disc replacement for cervical degenerative disease--clinical results and functional outcome at two years in patients implanted with the Bryan cervical disc prosthesis.

BACKGROUND: This is a prospective study of patients with degenerative cervical disease who underwent ventral discectomy and disc replacement with the Bryan((R)) cervical disc prosthesis. The objective was to investigate clinical outcome at 2 years of patients implanted with the Bryan disc and to evaluate function of the implant itself. METHODS: Fifty-four consecutive patients with cervical disc herniation and/or spondylosis with preserved mobility in the affected spinal segments were enrolled. Patients presented clinically with cervical radiculopathy and/or myelopathy with or without neck pain. A standard anterior cervical discectomy was carried out and a Bryan disc was implanted in the affected levels. A total of 59 prosthetic discs were implanted, in 49 patients at a single level and in 5 at two adjacent levels. The neurological status was evaluated pre-operatively and at one and two years thereafter. Plain X-rays, CT, and MRI were used for pre-operative diagnostics. Post-operative follow-up was done by X-rays. FINDINGS: All patients had an excellent or good neurological outcome according to the Odom criteria. Loss of function (motion range <3 degrees) was found in 7 (12%) out of 59 Bryan discs at two years after surgery. Heterotopic ossification (HO) of the McAffee grades 1-4 was seen in a total of 17 (29%) segments. There were no implant dislocations or migrations. CONCLUSIONS: Implantation of the Bryan disc resulted in excellent or good neurological outcome in all patients. The surgical technique was safe and without complications. Twelve percent of the implanted Bryan discs lost mobility at two years, mainly due to HO. A trend was seen towards development of HO in the operated segments. Further investigations with longer follow-up periods and with a control group (e.g. fusion with intervertebral cage) will be necessary for a definitive assessment of the long-term functionality and benefits of artificial cervical discs.

Management of chronic back and leg pain by intrathecal drug delivery.

Intrathecal delivery of analgesic drugs by implantable pump systems has been recognized as a treatment option for patients with chronic pain of benign or malignant origin that is resistant to oral or parenteral medication. Patients with chronic back and leg pain (CBLP), a benign but severely disabling condition of the lumbar spine with multifactorial genesis, have been demonstrated in a number of retrospective and in some prospective clinical studies to benefit from intrathecal delivery of opioid and/or non-opioid substances, either as single drugs or in combinations. In addition, intrathecal therapy for CBLP has been proven safe and less expensive that conventional medical therapy. This chapter summarizes the clinical and experimental evidence and the personal experience of the authors with long-term intrathecal infusion therapy for CBLP. It discusses important clinical issues such as drug selection, drug combinations, and side effects and complications of intrathecal infusion. It is concluded that further clinical research is needed in order to provide stronger evidence for the usefulness of a number of drugs currently used for intrathecal therapy on a mostly empirical basis.

Dual electrode spinal cord stimulation in chronic leg and back pain.

Patients with chronic back and leg pain (CBLP) suffer from a disabling spinal condition of multifactorial origin and are often resistant to medical therapy. Spinal cord stimulation (SCS) is a minimally invasive option for treatment of chronic pain in these patients, which involves placement of epidural electrodes close to the midline of the spinal cord. SCS was originally introduced and used for decades with a single electrode. The development of fully implantable dual channel pulse generators connected to dual multicontact electrodes has given pain clinicians a more versatile tool to treat axial low back pain accompanied by radicular neuropathic pain with irregular and asymmetric distribution, a feature which is found in most CBLP patients. It has been hypothesized that using dual electrodes may improve long term outcome for CBLP patients compared with single electrodes. Current evidence however does not lend strong support to this assumption. Given the high cost of treatments for CBLP and of SCS itself, there is an urgent need for high-quality evidence for the effectiveness of dual electrode SCS in relieving pain and/or improving function in patients with CBLP.

Hardware failures in spinal cord stimulation (SCS) for chronic benign pain of spinal origin.

Spinal cord stimulation (SCS) has become an established clinical option for treatment of refractory chronic pain not related to cancer. Current hardware and implantation techniques for SCS are already highly developed and continuously improving, however equipment failures over the course of the long-term treatment are still encountered in a relatively high proportion of treated cases. Percutaneous SCS electrodes seem to be particularly prone to dislocation and insulation failures. This review summarizes the experience of the authors with management of hardware failures and their causes in patients treated with SCS for chronic pain of benign origin. The published literature is critically surveyed and discussed.

Experimental therapies for chronic pain.

Chronic pain, an underestimated but complex medical and social phenomenon, is often resistant to currently used analgesic drugs. The effect of these substances is frequently self-limiting, with increasing level of unwanted side effects caused by increased doses. Moreover, most pharmacological therapies for pain are administered systemically, either via the enteral or the parenteral route, and exert their effects on a multitude of organs and structures in the body regardless of their involvement in chronic pain pathways. Unlike pharmacological agents, biological pain therapies provide a means to target single molecules or specific types of neural cells in spatially limited areas in the central nervous system. Biological therapies utilize externally administered natural or synthetic agents acting at specific receptors on the spinal or supraspinal level, or virus or cell vectors allowing the expression and secretion of such agents in small compartments. By targeting a particular receptor or other specific protein involved in signal transmission, biological approaches to the treatment of chronic pain may provide greater analgesic efficacy without the limitations associated with current pharmacological therapies. This review summarizes published data on the most important of the currently known targets for biological therapy of chronic pain, and focuses on therapeutic approaches for modulation of these targets and on results from preclinical and clinical trials. Biological therapies for chronic pain hold great promise and are rapidly developing, but currently still are in a very early stage and therefore deemed experimental and not suitable for routine clinical use.

Experimental treatments for human transmissible spongiform encephalopathies: is there a role for pentosan polysulfate?

Human transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are caused by the accumulation of an abnormal isoform of the prion protein in the CNS. Creutzfeldt-Jakob disease in its sporadic form is the most frequent type of human TSE. At present, there is no proven specific or effective treatment available for any form of TSE. Pentosan polysulfate (PPS) has been shown to prolong the incubation period when administered to the cerebral ventricles in a rodent TSE model. Cerebroventricular administration of PPS has been carried out in 26 patients with TSEs and has been shown to be well tolerated in doses < or = 220 microg/kg/day. Proof of efficacy has been difficult because the specific and objective criteria for measurement of response have not been established yet. Preliminary clinical experience confirms extended survival in patients with variant Creutzfeldt-Jakob disease receiving intraventricular PPS; however, it is still not clear if this is due to PPS itself. Further prospective investigations of long-term intraventricular PPS administration are essential for the assessment of its effects.

Nontraumatic spinal epidural hematoma associated with clopidogrel.

A 73-year-old female treated with clopidogrel for vascular disease presented with sudden onset of back pain, urinary retention and paraplegia. MRI scans demonstrated a thoracolumbar epidural hematoma and the patient underwent emergency laminectomy for evacuation of the hematoma. A possible causal link between clopidogrel and occurrence of the hemorrhage is discussed and the literature on spontaneous spinal hematomas is reviewed.

Expression of survivin, platelet-derived growth factor A (PDGF-A) and PDGF receptor alpha in primary central nervous system lymphoma.

PURPOSE: Primary central nervous system lymphomas (PCNSL) are rare tumours occurring in the brain. Their biology and the factors predicting survival are not well known. This study investigated expression of the antiapoptotic protein survivin and platelet-derived growth factor A (PDGF-A) and receptor (PDGFRalpha) in PCNSL. EXPERIMENTAL DESIGN: A total of 44 patients with histologically confirmed PCNSL treated between 1992 and 2004 were included in this study, and tumour specimens were investigated immunohistochemically for expression of survivin, PDGF-A and PDGFRalpha. Protein expression and clinical variables were analyzed statistically. RESULTS: Of the 44 tumours 43(98%) were diffuse large B-cell non-Hodgkin's lymphomas (NHL) and one was a T-cell NHL. Around 37 (84%) of the examined PCNSL specimens showed expression of survivin, 16 (36%) of PDGF-A and 34 (77%) of PDGFRalpha. Tumours expressing surviving co-expressed PDGFRalpha frequently and PDGF-A occasionally. Expression of the above proteins was not predictive for survival in this patient group. Except for age and therapy, no other clinical variables correlated significantly with overall survival. CONCLUSIONS: PCNSL express survivin and PDGFRalpha in the majority of investigated cases. PDGF-A is expressed less frequently. Immunohistochemical detection of these proteins does not correlate with overall survival and cannot be used as a prognostic factor.

Cerebroventricular infusion of pentosan polysulphate in human variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy believed to be caused by the bovine spongiform encephalopathy agent, an abnormal isoform of the prion protein (PrP(sc)). At present there is no specific or effective treatment available for any form of CJD. Pentosan polysulphate (PPS), a large polyglycoside molecule with weak heparin-like activity, has been shown to prolong the incubation period of the intracerebral infection when administered to the cerebral ventricles in a rodent scrapie model. PPS also prevents the production of further PrP(sc) in cell culture models. These properties of PPS prompted its cerebroventricular administration in a young man with vCJD. Long-term continuous infusion of PPS at a dose of 11 microg/kg/day for 18 months did not cause drug-related side effects. Follow-up CT scans demonstrated progressive brain atrophy during PPS administration. Further basic and clinical research is needed in order to address the issue of efficacy of PPS in vCJD and in other prion diseases.

Vanishing contrast enhancement in malignant glioma after corticosteroid treatment.

Malignant gliomas of the brain typically exhibit on CT or MRI a strong peripheral contrast enhancement area with a variable central zone of necrosis. These tumours are not known to change their radiological appearance and contrast enhancement pattern under systemic steroid treatment--a feature usually associated with primary CNS lymphoma. We report two cases of adult patients with glioblastoma multiforme and atypical hemispherical contrast enhancement initially demonstrated on MRI or CT, which disappeared after dexamethasone administration. At the same time, however, another tumour focus became visible, in both cases localised in the corpus callosum. Histological diagnosis was confirmed by stereotactic biopsy in both cases. This unusual changing pattern of contrast enhancement seems to be associated with multifocal malignant glioma with partial blood-brain barrier disruption modified by dexamethasone, and may present diagnostic difficulties in respect to neuroimaging and selection of target areas for tumour biopsy.

Long term survival in a patient with recurrent malignant glioma treated with intratumoral infusion of an IL4-targeted toxin (NBI-3001).

Intratumoral infusion of a recombinant targeted toxin (NBI-3001) consisting of the receptor binding domain of human interleukin 4 (IL-4) and Pseudomonas aeruginosa exotoxin A is an investigational treatment for malignant brain tumors. This 27-year-old male patient presented with a recurrent malignant glioma WHO grade IV after surgery and adjuvant radiation and chemotherapy. The recurrence was treated with intratumoral infusion of NBI-3001 at a dose of 9 microg/ml in 66 ml of infusate. Treatment resulted in long-term survival for 3 years after toxin infusion with a durable tumor response. There were some permanent neurological side effects resulting from toxin infusion. The patient eventually died after a late local recurrence of the known brain tumor. Such clinical evolution of a malignant glioma after a single round of immunotoxin infusion is rather unusual. The late local recurrence may suggest that repeated courses rather than a single infusion of intratumoral toxin are possibly needed for successful long-term tumor control.

Results and outcome of neurosurgical treatment for extradural metastases in the cervical spine.

Metastatic lesions are the most common spinal extradural tumours. Significant advances in their neurosurgical management have been made in the last two decades. This retrospective study was undertaken to summarise the long-term results of surgery and the outcome of patients with cervical spine metastases. Sixty-two patients with cervical spine metastases who underwent instrumented spinal surgery at a single centre in an 12-year period (1989-2000) were analysed. All patients presented with local pain and with either neurological deficits, spinal instability, or a combination of both. A standard anterior approach to the cervical spine was chosen, and a partial or total vertebrectomy and vertebral body replacement with subsequent anterior instrumented fusion were carried out in all cases. General and neurological status was evaluated at baseline and in regular intervals thereafter. Plain X-rays, CT, and MRI were used for preoperative planning. Postoperative follow-up was done by X-rays. The mean follow-up time for all patients was 1.5 years. A stable bony fusion of the cervical spine was achieved in 60 patients (96.8%), with two additional patients needing a further procedure for maintaining the mechanical stability of the spine. There was mild early surgery-related morbidity, and no mortality. The most frequent temporary surgery-related side effect was reversible vocal cord paresis in 5 cases (8.0%). There were 3 cases (4.8%) of early instrumentation failure. One of these was symptomatic and underwent second-look surgery. No late complications occurred due to instrumentation hardware failure. The 1-year survival rate of all patients after surgery was 58%, and the 2-year survival rate was 21%. Our results demonstrate that surgical removal of extradural metastases with subsequent instrumented fusion is a low-morbidity and low-complications procedure with high rates of permanent stabilisation of the compromised cervical spine. In addition, it improves the neurological deficits and relieves the local pain in a significant proportion of patients. Excellent local control of malignant disease can be achieved by the surgical procedure aided by subsequent local and systemic adjuvant therapy. Overall survival time and prognosis of the patients, however, are mainly depending on the type and the stage of the primary malignancy.

Local convection enhanced delivery of IL4-Pseudomonas exotoxin (NBI-3001) for treatment of patients with recurrent malignant glioma.

PURPOSE: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas Exotoxin (NBI-3001) in patients with recurrent malignant glioma. PATIENTS AND METHODS: A total of 31 patients with histologically verified supratentorial grade 3 and 4 astrocytoma were studied. Of these, twenty-five patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma (AA). Patients were over 18 years of age and had Karnofsky performance scores > or = 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6 microg/ml x 40 ml, 9 microg/ml x 40 ml, 15 microg/ml x 40 ml, or 9 microg/ml x 100 ml of NBI-3001 administered intratumorally via stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26. RESULTS: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related Grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6 microg/ml x 40 ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients. CONCLUSIONS: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma.

Oncolytic viruses for treatment of malignant brain tumours.

Wild type viruses have been known for decades for their capability to destroy malignant tumour cells upon infection and intracellular replication. Genetic engineering of such viruses was, however, only recently done in an attempt to improve their utility as biological anticancer agents. Wild type or recombinant viruses able to selectively destroy tumour cells while sparing normal tissue are known as oncolytic viruses. Most oncolytic viruses currently investigated in clinical trials are derived from adenovirus (AV) or herpes simplex virus type I (HSVI). More than 300 patients with solid tumours were now treated in clinical trials with oncolytic viruses, and in most cases virus was administered directly into the tumour mass. About 10% of the above patients had recurrent malignant glioma. Total intratumoral doses of up to 2 x 10(12) virus particles were well tolerated, and in general no severe side effects resulted from the clinical use of oncolytic AV and HSVI, either in the brain or in the rest of the body. Encouraging anti-tumoral activity was demonstrated in some types of tumours treated locally with oncolytic viruses, and systemic chemotherapy was found to potentiate the anti-tumour effect of virus mediated oncolysis. In malignant glioma, standard gene therapy approaches employing non-replicating virus vectors failed to demonstrate significant benefit in clinical studies. Therapy with oncolytic viruses seems to hold more promise in early clinical trials than gene therapy with non-replicating virus vectors. However, further major advancements in virus designs, application modalities, and understanding of the interactions of the host's immune system with the virus are clearly needed before oncolytic virus therapy of malignant brain tumours can be introduced to clinical practice.

Immunogene therapy of recurrent glioblastoma multiforme with a liposomally encapsulated replication-incompetent Semliki forest virus vector carrying the human interleukin-12 gene--a phase I/II clinical protocol.

Glioblastoma multiforme (GBM) is an incurable brain tumor resistant to standard treatment modalities such as surgery, radiation, and chemotherapy. Since recurrent GBM tends to develop predominantly within the infiltrative rim surrounding the primary tumor focus, novel therapy strategies need in addition to focal tumor destruction to target this somewhat diffuse area. This is a phase I/II clinical study in adult patients with recurrent GBM which is aimed at evaluating biological safety, maximum tolerated dose, and antitumor efficacy of a genetically modified replication-disabled Semliki forest virus vector (SFV) carrying the human interleukin 12 (IL-12) gene and encapsulated in cationic liposomes (LSFV-IL12). The vector will be administered in doses of 1 x 10(7)-1 x 10(9) infectious particles by continuous intratumoral infusion, thus exploiting the advantages of convection-enhanced drug delivery in the brain. The present protocol is also designed to investigate systemic and local immune response and to identify factors predicting tumor response to LSFV-IL12 therapy, such as volume of extracellular space of the tumor, volume of contrast enhancing lesion, and immune status of the patients. SFV, an insect alphavirus, infects mitotic and non-mitotic cells and triggers apoptosis in tumor cells within 48-72 h. Preclinical work with the LSFV-IL12 vector in breast and prostate cancer animal models demonstrated its biosafety and some antitumor efficacy. An ongoing phase I clinical study in patients with melanoma and renal cell carcinoma seems also to confirm the biosafety of intravenously administered vectors. This protocol will be the first study of SFV-IL12 therapy of human recurrent GBM.

Combined radiation and cytochrome CYP4B1/4-ipomeanol gene therapy using the EGR1 promoter.

BACKGROUND: Cytochrome p450 isozyme CYP4B1 converts the inert prodrug 4-ipomeanol (4-IM) into toxic alkylating metabolites. Induction of cytotoxicity by 4-IM combined with ionizing radiation (IR) in cells transfected with a fusion protein of rabbit cytochrome CYP4B1 under control of the radiation inducible EGR1 promoter was investigated. The capability of activated 4-IM to sensitize cells to IR was also assessed. MATERIALS AND METHODS: Survival fractions of cells, determined by MTT assays, stably transfected with EGR1-CYP4B1 were compared with that of cells transfected with a control plasmid after IR followed by 4-IM. Radiosensitization was tested by comparing clonogenic survival curves of cells transfected with the CYP4B1 cassette under a CMV promoter instead of EGR-1, irradiated with or without 4-IM. RESULTS: MTT assays for cytotoxicity indicated a decrease in relative survival fractions (survival with 4-IM/survival without 4-IM) of the EGR1-CYP4B1 transfected cells with increasing radiation dosage, but not of control cells. Clonogenic assays revealed decreased survival fractions with increasing radiation doses (CYP4B1 transfected and control cells) and 4-IM concentrations (CYP4B1 transfected cells), but showed no significant differences in slope of survival curves with 4-IM. CONCLUSION: The results indicate IR potentiates the cytotoxic activity of the EGR1-CYP4B1/4-IM transgene system, but activated 4-IM does not sensitize cells to IR. Thus, the EGR1-CYP4B1/4-IM system is a viable radiation-gene therapy system that may allow for improved spatial and temporal control of cytotoxicity by therapeutic radiation fields.