Perspectives on postgenome medicine: Gene therapy for brain tumors

Recent development of therapeutic modalities in neurosurgery has brought about dramatic improvement for prognosis of brain tumors. Nevertheless, malignant glioma is one of the most formidable neoplasms in humans. According to a report by the Committee of Brain Tumor Registry of Japan, five-year relative survival rate of malignant gliomas is less than 10%. Malignant gliomas grow aggressively infiltrating into the surrounding normal brain tissue. So that total surgical resection is impossible. The tumors respond to radiation and chemotherapy, however, the efficiency has sustained transiently. The advert of new strategies for the treatment of malignant gliomas has long been awaited. We have developed a cytokine gene therapy for malignant glioma since about 10 years ago. Here, we introduce both suicide gene therapies and immune gene therapies including our case(IFN-beta gene therapy).     

Retrospective analysis of re-irradiation in malignant glioma: a single-center experience

INTRODUCTION: Malignant gliomas are brain tumors deriving from the brain's glia cells. Primary treatment comprises resection, irradiation and chemotherapy, but these tumors almost always recur. In this situation, palliative chemotherapy is relatively well established, but a second local treatment is sometimes possible. We evaluated the safety and efficacy of re-irradiation in patients with recurrent malignant glioma. PATIENTS AND METHODS: Twenty-two patients were treated with a second irradiation for recurrent or progressive glioma. Patients either received hypo-fractionated stereotactic treatment or conventionally fractionated conformal therapy, depending on tumor size. Wherever possible, a second resection was performed. Time to progression (TTP) and survival were estimated using the Kaplan-Meier product-limit method. RESULTS: Median age was 31 (8-77) years. Median TTP after onset of re-treatment was 4 (1-31) months. Median overall survival was 7 (1-46) months, and overall survival from primary diagnosis was 49 (7-136) months. Significantly longer TTP (P = 0.008) and overall survival (P = 0.005) were observed in re-resected patients than in those without a second surgical intervention. CONCLUSION: Re-irradiation in malignant glioma is a feasible and safe treatment option, and the benefit appears to be especially large in re-resected patients. To make a final conclusion possible, larger prospective trials are warranted.     

Convection-enhanced delivery of 131I-chTNT-1/B mAB for treatment of high-grade adult gliomas

Introduction: Despite treatment advances for malignant gliomas in adults, prognosis remains poor, largely due to the infiltrative and heterogeneous biology of these tumors. Response to adjuvant therapy is not always uniform and the blood–brain barrier prevents the majority of chemotherapeutics from adequately reaching primary tumor sites. These obstacles necessitate development of novel delivery methods and agents.

Areas covered: ¹³¹I-chTNT-1/B mAB (Cotara) is a genetically engineered chimeric monoclonal antibody that binds to the DNA–histone H1 complex. It carries ¹³¹I, which delivers sufficient energy to kill adjacent tumor cells. Through convection-enhanced delivery (CED) it provides radioimmunotherapy directly to the resection cavity. We review the pharmacology and clinical experience with ¹³¹I-chTNT-1/B mAB, detailing results of completed Phase I and II trials.

Expert opinion: Novel agents and therapeutic modalities, such as ¹³¹I-chTNT-1/B mAB, are of interest for treatment of malignant glioma, for which the prognosis continues to be dismal. ¹³¹I-chTNT-1/B mAB targets tumor cells and radioisotope labeling allows radiation delivery to the tumor with sharp fall-off. Data from Phase I and II trials of CED delivery of ¹³¹I-chTNT-1/B mAB shows it is well tolerated. Phase II trial data suggests it could be promising therapeutically, though conclusions about efficacy require further trials and clinical experience. The compound is currently in a Phase II trial for dose confirmation in patients with malignant gliomas.     

Convection-enhanced delivery of 131I-chTNT-1/B mAB for treatment of high-grade adult gliomas

INTRODUCTION: Despite treatment advances for malignant gliomas in adults, prognosis remains poor, largely due to the infiltrative and heterogeneous biology of these tumors. Response to adjuvant therapy is not always uniform and the blood-brain barrier prevents the majority of chemotherapeutics from adequately reaching primary tumor sites. These obstacles necessitate development of novel delivery methods and agents. AREAS COVERED: (131)I-chTNT-1/B mAB (Cotara) is a genetically engineered chimeric monoclonal antibody that binds to the DNA-histone H1 complex. It carries (131)I, which delivers sufficient energy to kill adjacent tumor cells. Through convection-enhanced delivery (CED) it provides radioimmunotherapy directly to the resection cavity. We review the pharmacology and clinical experience with (131)I-chTNT-1/B mAB, detailing results of completed Phase I and II trials. EXPERT OPINION: Novel agents and therapeutic modalities, such as (131)I-chTNT-1/B mAB, are of interest for treatment of malignant glioma, for which the prognosis continues to be dismal. (131)I-chTNT-1/B mAB targets tumor cells and radioisotope labeling allows radiation delivery to the tumor with sharp fall-off. Data from Phase I and II trials of CED delivery of (131)I-chTNT-1/B mAB shows it is well tolerated. Phase II trial data suggests it could be promising therapeutically, though conclusions about efficacy require further trials and clinical experience. The compound is currently in a Phase II trial for dose confirmation in patients with malignant gliomas.     

Cell-based Immunotherapy Against Gliomas: From Bench to Bedside

Glioblastoma (GBM) comprises 51% of all gliomas and is the most malignant form of brain tumors with a median survival of 18–21 months. Standard-of-care treatment includes maximal surgical resection of the tumor mass in combination with radiation and chemotherapy. However, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. Cellular immunotherapy is currently being explored as therapeutic approach to treat malignant brain tumors. In this review, we discuss advances in active, passive, and vaccine-based immunotherapeutic strategies for gliomas both at the bench and in the clinic.     

脑恶性胶质瘤术后放化疗肿瘤复发再手术治疗的临床研究

目的 探讨脑恶性胶质瘤术后放化疗复发肿瘤再手术治疗的临床意义.方法 选取有完整 临床资料的原发恶性胶质瘤术后及其复发再手术治疗患者48 例,术后同步放和(或)化疗.采用免疫荧光双 染色法检测并比较脑胶质瘤干细胞(GSCs)标记物CD133/Nestin 在原、复发胶质瘤中的表达,Kaplan-Meier 生 存分析和Cox 回归风险模型分析原发术后放化疗肿瘤复发患者再次手术术前KPS 评分、肿瘤体积、切除程 度、GSCs 数目、两次手术间隔等因素与预后的关系.结果 CD133/Nestin 在原、复发恶性胶质瘤组织中阳性 表达百分数分别为(3.06 ±0.38)%、(14.89 ±2.54)%,差异有统计学意义(P <0.001);单Kaplan-Meier 生存 分析示原发术后放和(或)疗肿瘤复发再手术术前KPS 评分≥70 分、肿瘤全切、肿瘤体积<50 cm3 等因素显 著延长患者二次术后生存时间(P <0.05);Cox 回归风险模型分析表明再手术术前KPS 评分、肿瘤体积、切除 程度等因素可作为独立的预后因素(P <0.05).结论 脑恶性胶质瘤术后放和(或)化疗复发肿瘤富集胶质 瘤干细胞,复发胶质瘤再手术治疗是靶向胶质瘤干细胞治疗的重要举措,早期积极再次手术有益于延长患者 生存时间和提高生存质量.     

Primary brain tumors in adults

Primary malignant brain tumors account for 2 percent of all cancers in U.S. adults. The most common malignant brain tumor is glioblastoma multiforme, and patients with this type of tumor have a poor prognosis. Previous exposure to high-dose ionizing radiation is the only proven environmental risk factor for a brain tumor. Primary brain tumors are classified based on their cellular origin and histologic appearance. Typical symptoms include persistent headache, seizures, nausea, vomiting, neurocognitive symptoms, and personality changes. A tumor can be identified using brain imaging, and the diagnosis is confirmed with histopathology. Any patient with chronic, persistent headache in association with protracted nausea, vomiting, seizures, change in headache pattern, neurologic symptoms, or positional worsening should be evaluated for a brain tumor. Magnetic resonance imaging is the preferred initial imaging study. A comprehensive neurosurgical evaluation is necessary to obtain tissue for diagnosis and for possible resection of the tumor. Primary brain tumors rarely metastasize outside the central nervous system, and there is no standard staging method. Surgical resection of the tumor is the mainstay of therapy. Postoperative radiation and chemotherapy have improved survival in patients with high-grade brain tumors. Recent developments in targeted chemotherapy provide novel treatment options for patients with tumor recurrence. Primary care physicians play an important role in the perioperative and supportive treatment of patients with primary brain tumors, including palliative care and symptom control.     

Combination of FOSCAN mediated fluorescence guided resection and photodynamic treatment as new therapeutic concept for malignant brain tumors

Photodynamic therapy (PDT), the combination of tumor-selective photosensitizers (PS) and light at the appropriate wavelength is under investigation for adjuvant therapy in brain tumors. Malignant brain tumors carry a lethal prognosis with a median survival of 15 months despite surgery, radiotherapy and chemotherapy.

Recently photodynamic diagnosis mediated by FOSCAN^® (meta-tetrahydroxyphenylchlorin – mTHPC) was introduced by our institution for intraoperative photo diagnosis (PDD) and fluorescence guided resection (FGR) for a more radical tumor removal. Twenty-six patients suffering from malignant brain tumors were sensitized with 0.15 mg/kg m-THPC body weight and underwent a combination of fluorescent guided resection followed by intraoperative PDT (20 J/cm² at 652 nm) after 4 days.

Intraoperative fluorescence was induced by a UV light source at 370–440 nm. A standard neurosurgical microscope was optimized for fluorescence detection. Intraoperative PDT was performed by lasers at 652 nm and 20 J/cm².

The fluorescence sensitivity and specificity in 172 tissue samples were 87.9% and 95.7%, respectively. Tumor could be predicted to an accuracy of 90.7%. Photodynamic diagnosis (PDD) proved to be useful in tumor resection accounting for a radical resection in 75% under fluorescenceguided resection as compared to 52% in the control group. The median survival time for the PDD/PDT group was 9 months as compared to the matched pair control group of 3.5 months, respectively.

The side effects consisted of two severe toxic reactions to sunlight due to unintentional exposure to direct sunlight and one patient experienced a transitional brain swelling.

Our results indicate that fluorescence guided surgery is feasible and proved to be of significant help in delineating tumor margins and in resection of residual tumor that could not be detected by the surgeon. The addition of intraoperative PDT significantly enhanced survival.     

Adipose-derived Stem Cells as Therapeutic Delivery Vehicles of an Oncolytic Virus for Glioblastoma

Glioblastoma multiforme (GBM) accounts for the majority of primary malignant brain tumors and remains virtually incurable despite extensive surgical resection, radiotherapy, and chemotherapy. Treatment difficulty is due to its exceptional infiltrative nature and proclivity to integrate into normal brain tissue. Long-term survivors are rare, and median survival for patients is about 1 year. Use of adult stem cells as cellular delivery vehicles for anticancer agents is a novel attractive therapeutic strategy. We hypothesized that adipose-derived stem cells (ADSCs) possess the ability to home and deliver myxoma virus to glioma cells and experimental gliomas. We infected ADSCs with vMyxgfp and found them to be permissive for myxoma virus replication. ADSCs supported single and multiple rounds of replication leading to productive infection. Further, we observed no significant impact on ADSC viability. We cocultured fluorescently labeled GBM cells with myxoma virus–infected ADSCs in three-dimensional assay and observed successful cross infection and concomitant cell death almost exclusively in GBM cells. In vivo orthotopic studies injected with vMyxgfp-ADSCs intracranially away from the tumor demonstrated that myxoma virus was delivered by ADSCs resulting in significant survival increase. Our data suggest that ADSCs are promising new carriers of oncolytic viruses, specifically myxoma virus, to brain tumors.     

Cytokine gene therapy for malignant glioma

Despite advances in surgical and adjuvant therapy, the prognosis for malignant gliomas remains dismal. Malignant gliomas, like other malignancies, are able to overcome host immune defences through a variety of mechanisms that have become increasingly well-characterised over the past decade. However, this ‘immunologically privileged’ status of the brain is not absolute. Systemic immunisation with brain-specific antigens can induce immune responses that are manifested in the CNS, such as experimental allergic encephalomyelitis. The efficacy of peripheral immunisation against brain tumours has also been demonstrated in preclinical models. Based on these observations, clinical trials of peripheral immunisations with brain tumour-derived antigens have been initiated. A limitation of this approach is that the immunological environment within brain tumours is suboptimal for functions of antitumour immune effector cells. As a means to overcome this issue, delivery of cytokine genes to the tumour site may reverse the inhibitory immunological environment of the brain tumours and enhance the efficacy of peripheral vaccine-induced immune effector cells. The brain tumour environment may also be rendered more immunologically favourable by the delivery of additional antigen-presenting cells that can provide infiltrating effector cells with secondary activation signals. Indeed, the authors’ recent data indicate that the injection of intracranial tumours with dendritic cells secreting interferon-α enhances the efficacy of peripheral vaccinations with tumour-specific antigens by cross-priming tumour antigen-specific T cells in the cervical lymph nodes. This review highlights the recent literature on cytokine gene therapy for brain tumours, and proposes the effective use of cytokine gene delivery both at the site of vaccines (i.e., the site of antigen presentation) and within the target brain tumours (i.e., the site where the effector cells exert their antitumour immunity). Successful immunogene therapy for brain tumours requires detailed understanding of cytokine functions and the use of them at the appropriate stages/sites of the immunological milieu.     

Gene therapy of intracranial glioma using interleukin 12-secreting human umbilical cord blood-derived mesenchymal stem cells

Clinical trials of gene therapy using a viral delivery system for glioma have been limited. Recently, gene therapy using stem cells as the vehicles for delivery of therapeutic agents has emerged as a new treatment strategy for malignant brain tumors. In this study, we used human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) as delivery vehicles with glioma-targeting capabilities, and modified interleukin-12 (IL-12p40N220Q; IL-12M) as a novel therapeutic gene. We also engineered UCB-MSCs to secret IL-12M (UCB-MSC-IL12M) via tetrameric cell-permeable peptide (4HP4)-mediated adenoviral transduction. We confirmed the migratory capacity of UCB-MSC-IL12M toward GL26 mouse glioma cells by an in vitro migration assay and in vivo injection of UCB-MSC-IL12M into the ipsilateral hemisphere of implanted gliomas in C57BL/6 mice. In vivo efficacy experiments showed that intratumoral injection of UCB-MSC-IL12M significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with control mice. Antitumor effects were associated with increased local IL-12M levels, followed by interferon-γ secretion and T-cell infiltration in intracranial gliomas, as well as antiangiogenesis. Interestingly, tumor-free mice after UCB-MSC-IL12M treatment were resistant to ipsilateral and contralateral tumor rechallenge, which was closely associated with tumor-specific long-term T-cell immunity. Thus, our results provide the rationale for designing novel experimental protocols to induce long-term antitumor immunity against intracranial gliomas using UCB-MSCs as an effective delivery vehicle for therapeutic cytokines including IL-12M.     

Brain tumor treatment: chemotherapy and other new developments

OBJECTIVES: To provide a summary of chemotherapy used in the management of malignant brain tumors, including a historical perspective, current standard therapies, and promising new therapies. DATA SOURCES: Published articles, research data, and reference books. CONCLUSION: Chemotherapy is used to treat several types of brain tumors, including primary central nervous system lymphomas, medulloblastomas, brain metastases, and malignant gliomas. New therapies, including cytostatic agents and molecular therapies, are being evaluated and used in the management of brain tumors. IMPLICATIONS FOR NURSING PRACTICE: It is essential for the oncology nurse to possess knowledge of the different types of brain tumors treated with chemotherapy, current chemotherapy regimens, new innovative therapies, and nursing management issues specific to this population.     

(131)I-chTNT-1/B mAb: tumour necrosis therapy for malignant astrocytic glioma

Treatment of malignant glioma is therapeutically challenging. Despite improvements in neurosurgery, radiotherapy and chemotherapy, few patients diagnosed with anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) (WHO grades 3 and 4, respectively) will live beyond 2 years. Poor survival is due to the highly invasive nature and protected location of these tumours. Most malignant gliomas cannot be completely resected or irradiated due to their ability to infiltrate diffusely into normal brain tissue. Brain tissue is protected from the systemic circulation via the blood-brain barrier (BBB), which impedes entry of water-soluble chemotherapeutic agents into the tumour at therapeutic concentrations. (131)I-chTNT-1/B mAb (Cotara) employs an innovative strategy to treat the invasive portion of the tumour and the core lesion. (131)I-chTNT-1/B mAb is a genetically engineered, radiolabelled, chimeric monoclonal antibody specific for a universal intracellular antigen (i.e., DNA/histone H1 complex) exposed in the necrotic core of malignant gliomas. This antigen provides an abundant, insoluble, non-diffusible anchor for the mAb. Once localised to necrotic regions of the tumour, (131)I-chTNT-1/B mAb delivers a cytotoxic dose of (131)I radiation to the core lesion. (131)I-chTNT-1/B mAb is delivered via convection-enhanced delivery in order to maximise coverage to the tumour and the invasive front of the glial tumour. The clinical experience to date with (131)I-chTNT-1/B mAb is presented.     

Gene therapy for high grade gliomas

High grade gliomas in adults are devastating diseases, with very poor survival despite their lack of distant metastases. Local treatments, such as surgical resection and stereotactic radiosurgery, have been most successful, whereas systemic therapy (for example, chemotherapy and immunotherapy) have been rather disappointing. Several gene therapy systems have been successful in controlling or eradicating these tumours in animal models and are now being tested as a logical addition to current clinical management. This review describes the gene therapy clinical protocols that have been completed or that are ongoing for human gliomas. These include the prodrug activating system, herpes simplex thymidine kinase (HSVtk)/ganciclovir (GCV), utilising either retrovirus vector producer cells or adenovirus vectors; adenovirus mediated p53 gene transfer; adenovirus mediated IFN-β gene transfer and oncolytic herpes virus and adenovirus vectors. To date, all of the clinical studies have used direct injection of the vector into the glioma. The Phase I clinical studies have demonstrated low to moderate toxicity and variable levels of gene transfer and in some cases anti-tumour effect. Future directions will rely upon improvements in gene delivery as well as gene therapies and combinations of gene therapy with other treatment modalities.     

Oncolytic viral therapy and immunotherapy of malignant brain tumors: two potential new approaches of translational research

Brain tumors arise at a rate of nearly 5/100,000 in the general population, with over 17,000 U.S. residents being diagnosed each year. Approximately 60% of all brain tumors are gliomas, which are derived from interstitial tissue of the brain, such as astrocytic or ependymal tissue, or oligodendrocytes. The traditional protocols for treatment of malignant gliomas include diagnostic surgery, followed by regimens of radio- and chemotherapies. In the case of chemotherapy, the treatment protocols have remained nearly unchanged for over 30 years despite high mortality rates, and with little to no improvement in outcome. New advances in the fields of molecular biology and immunology have resulted in new possibilities for treating malignant gliomas by targeting cellular and molecular mechanisms of tumor cells, and stand in contrast to traditional forms of treatment. In the field of gene therapy, the possibility of using oncolytic viruses, such as HSV-1, for glioma therapy--specifically, of high grade astrocytomas--is being explored, and trials have begun using a replication-selective mutant strain known as G207. An increased understanding of the role of the cytokine TGF-beta2 has led to developments of anti-sense immunotherapy targeting this factor. The two examples mentioned here are discussed in this review and cited as possible improvements in the treatment of high grade astrocytomas.     

Biodegradable polymer implants to treat brain tumors.

We have developed a systematic approach for the discovery and evaluation of local treatment strategies for brain tumors using polymers. We demonstrated the feasibility of polymer-mediated drug delivery by using the standard chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and showed that local treatment of gliomas by this method is effective in animal models of intracranial tumors. This led to clinical trials for glioma patients, and subsequent approval of Gliadel [(3.8% BCNU): p(CPP:SA)] by the FDA and other worldwide regulatory agencies. Twenty-two additional clinical trials are currently underway evaluating other issues related to the BCNU polymer, such as dosage, combination with systemic treatments, and combination with various forms of radiation and resistance modifiers. These trials are a result of laboratory investigations using brain tumor models; based on these models, other research groups have initiated clinical trials with novel combinations of different drugs and new polymers for both intracranial tumors (5-fluorouracil delivered via poly(D-L lactide-co-glycolide) polymer) and for tumors outside the brain (paclitaxel in PPE microspheres for ovarian cancer). Since only 1/3 of patients with glioblastoma multiforme (GBM) are sensitive to BCNU, the need to search for additional drugs continues. Although we are attacking major resistance mechanisms, there still will be tumors that do not respond to BCNU therapy but are sensitive to agents with different mechanisms of action, such as taxanes, camptothecin, platinum drugs, and antiangiogenic agents. Thus, it is necessary to explore multiple single agents and ultimately to combine the most effective agents for the clinical treatment of GBM. Furthermore, multimodal approaches combining radiotherapy with microsphere delivery of cytokines and antiangiogenic agents have demonstrated encouraging results.     

Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma.

Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.     

显微手术后间质化疗联合增敏放疗治疗恶性脑胶质瘤

目的：探讨显微外科手术后间质化疗联合增敏放疗治疗脑胶质瘤的临床疗效。方法：对45例恶性脑胶质瘤患者行开颅显微手术全切除，术中于瘤腔内安置化疗囊，并行化疗药物体外敏感性及放疗增敏作用检测，术后第2，4，8，12周和6个月分别行经皮穿刺注入敏感化疗药物联合增敏放疗。随访6～36个月，并与以前随访的40例接受肉眼下全切后常规放化疗的脑胶质瘤结果相比较。结果：45例患者均获随访，生存期明显延长，6个月内复发4例(8．8％)，死亡3例(6．6％)；1年内复发9例(20．0％)，死亡7例(15．6％)；2年内复发19例(42．2％)，死亡15例(33．3％)；3年内复发25例(55．6％)，死亡22例(48．9％)。未发现明显的不良反应，生存质量得到明显改善。结论：显微外科手术力争全切除，术后敏感药物间质化疗联合增敏放疗，是一种可供选择的治疗人脑恶性胶质瘤安全有效的方法。     

Convection-enhanced delivery to achieve widespread distribution of viral vectors: Predicting clinical implementation

Convection-enhanced delivery (CED) has been introduced to overcome the inability of many pharmacological agents to cross the blood-brain barrier, making these agents potentially effective in situ and suitable for the treatment of brain disorders. To achieve CED, drugs are pumped continuously through stereotactically placed catheters directly into the brain, or into or within the vicinity of a tumor mass. This medical technology has been applied to the local delivery of small-molecule drugs, including standard chemotherapeutics, and novel experimental targeted drugs, including targeted cytotoxins. When administered by an experienced clinician, the CED of a molecularly targeted cytotoxin has resulted in a significantly better outcome in patients with recurrent glioblastoma multiforme (GBM). More recent gene therapy clinical trials have also demonstrated that such treatments impact on the course of the disease when administered using CED. The use of CED to administer gene therapy for brain neoplasms may improve the efficacy of this treatment. However, CED is under development, and issues such as the type of catheters to use and their placement, as well as the pharmacological formulation and stability of drugs or vectors, are being studied to achieve efficacious delivery into the desired regions of the diseased brain. This review discusses the use of CED to deliver gene therapy for brain tumors, particularly gliomas, such as GBM.     

Photodynamic treatment of malignant brain tumors

30 patients with primary or recurrent malignant brain tumors (9 primary, 18 recurrent malignant gliomas, 1 malignant meningioma, 2 melanomas) were treated altogether 37 times by photodynamic therapy (PDT) whether after intravenous, intraarterial or direct intratumoral sensitisation by hematoporphyrin (HPD) after conventional surgical removal of the tumor mass. The light was produced by an Argon pumped dye laser at doses varying from 40-220 J/cm2. A single dose of radiation of 4 Gy was administered to 18 patients immediately after PDT. The 9 patients with primary glioblastomas received in addition a full course of radiation therapy. The histological specimens taken during PDT demonstrated tumor necrosis, with oedema of normal brain tissue adjacent to the tumorbed. The median survival of patients with multiple recurrences and various radio- and chemotherapeutic modalities was 6 months (range 4-13 months). 9 patients with primary manifestation of a glioblastoma had a median survival of 19 months (0.5-29 months). Increased phototoxicity of the skin was the only side effect of PDT and did not reduce the quality of life of the patients.