Bakhtiar Yamini

Lumboperitoneal Shunting as a Treatment for Slit Ventricle Syndrome

Objective: Slit ventricle syndrome (SVS) has been described in hydrocephalus patients who continue to have shunt malfunction-like symptoms in the presence of a functioning shunt system and small ventricles on imaging studies. These symptoms usually present years after shunt placement or revision and can consist of headache, nausea and vomiting, lethargy and decreased cognitive skills. Treatments offered range from observation, medical therapy (migraine treatment) and shunt revision to subtemporal decompression or cranial vault expansion. We describe a subset of patients with SVS who were symptomatic with high intracranial pressure (ICP) as measured by sedated lumbar puncture and whose symptoms completely resolved after lumboperitoneal shunt (LPS) placement. Methods: Seven patients with a diagnosis of SVS underwent lumboperitoneal shunting. The age at shunting ranged from 3 to 18 years. Most had undergone recent ventriculoperitoneal shunt (VPS) revisions for presentation of shunt malfunction-like symptoms. Despite this, all remained symptomatic and underwent a sedated lumbar puncture to measure opening pressure (OP). All had high OP in spite of a functional VPS and underwent LPS placement. Results: All 7 patients had a prolonged period of overdrainage symptoms after lumboperitoneal shunting that resolved completely over several weeks. The initial etiology of hydrocephalus was reported to include trauma, aqueductal stenosis and intraventricular hemorrhage of prematurity. Two patients required revision of their LPS, after which their symptoms again resolved. Conclusion: In a certain subset of patients with SVS who are symptomatic from increased ICP, placement of an LPS is an effective treatment option. It appears that this subgroup of patients previously treated with ventriculoperitoneal shunting behave in a fashion similar to pseudotumor cerebri patients and respond well to lumboperitoneal shunting.

Transcriptional Targeting of Adenovirally Delivered Tumor Necrosis Factor α by Temozolomide in Experimental Glioblastoma

Temozolomide is an oral alkylating agent shown to have modest efficacy in the treatment of glioblastoma multiforme. Tumor necrosis factor α (TNF-α) is a polypeptide cytokine with synergistic antitumor activity in combination therapy with alkylating agents. We investigated the combined use of Ad.Egr-TNF, a replication-defective adenoviral vector encoding the cDNA for TNF-α under the control of chemo-inducible elements of the egr1 gene promoter, and intraperitoneal temozolomide in an intracranial human malignant glioma model. In hind limb U87MG xenografts, temozolomide produced a 6.4-fold greater induction of TNF-α after infection with Ad.Egr-TNF compared with Ad.Egr-TNF alone at 96 hours (P < 0.02). TNF-α and temozolomide combination leads to a synergistic decrease in U87 cell viability at 72 hours compared with either treatment alone (P < 0.001). Median survival for animals treated with Ad.Egr-TNF alone, temozolomide alone, and Ad.Egr-TNF/temozolomide was 21, 28, and 74 days, respectively (P < 0.001 by log-rank). Flow cytometric assessment of apoptosis revealed a synergistic increase in U87 cell apoptosis in vitro at 72 hours (P < 0.05), and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) evaluation of tumor sections revealed significantly increased TUNEL-positive cells after combination treatment compared with either treatment alone (P < 0.05). In conclusion, combination treatment with transcriptionally activated intratumoral TNF-α and systemic temozolomide significantly prolongs survival in an experimental glioblastoma multiforme model.

Convection-enhanced delivery and in vivo imaging of polymeric nanoparticles for the treatment of malignant glioma.

UNLABELLED A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells was demonstrated. Convection-enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ-bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma. FROM THE CLINICAL EDITOR GBM remains one of the most notoriously treatment-unresponsive cancer types. In this study, a multifunctional nanoparticle-based temozolomide delivery system was demonstrated to possess enhanced treatment efficacy in a rodent xenograft GBM model, with the added benefit of MRI-based tracking via the incorporation of iron oxide as a T2* contrast material in the nanoparticles.

Ionizing radiation: a genetic switch for cancer therapy

Gene therapy of cancer represents a promising but challenging area of therapeutic research. The discovery of radiation-inducible genes led to the concept and development of radiation-targeted gene therapy. In this approach, promoters of radiation-inducible genes are used to drive transcription of transgenes in the response to radiation. Constructs in which the radiation-inducible promoter elements activate a transgene encoding a cytotoxic protein are delivered to tumors by adenoviral vectors. The tumoricidal effects are then localized temporally and spatially by X-rays. We review the conceptual development of TNFerade™, an adenoviral vector containing radiation-inducible elements of the early growth response-1 promoter upstream of a cDNA encoding human tumor necrosis factor-α. We also summarize the preclinical work and clinical trials utilizing this vector as a treatment for diverse solid tumors.

Treatment of deep cerebral venous thrombosis by local infusion of tissue plasminogen activator.

BACKGROUND Treatment of extensive intracranial venous sinus thrombosis with thrombolytic drugs is described, although the indications for and most efficacious technique for achieving thrombolysis remain uncertain. We report the successful lysis of superficial and deep venous system thrombosis by infusion of recombinant human tissue-type plasminogen activator (rt-PA) into the anterior superior sagittal sinus. CASE DESCRIPTION A 34-year-old man presented with headaches followed by decreased level of consciousness and left hemiplegia. Angiography showed thrombosis of the superior sagittal and both transverse and straight sinuses with extension into the internal cerebral veins. The superior sagittal sinus was catheterized via a transfemoral route and rt-PA, 25 mg, was infused. There was no significant change in the thrombosis. The catheter was left in place and rt-PA was infused at 1 mg/minute for 19 hours. Repeat angiography showed resolution of the thrombosis. The patient was placed on heparin and then coumadin. He recovered completely. CONCLUSIONS This report suggests that superselective infusion of thrombolytics into thrombosed intracranial venous sinuses can lyse intracranial venous sinus thrombosis. The thrombolytic agent must be infused for hours. The apparent successful lysis of clot in the deep venous system when infusion was into the superior sagittal sinus might be related to diffusion of rt-PA throughout the intracranial venous system or to improved venous outflow caused by lysis of clot in superficial dural sinuses.

Inhibition of Nuclear Factor-κB Activity by Temozolomide Involves O6-Methylguanine–Induced Inhibition of p65 DNA Binding

The alkylating agent temozolomide, commonly used in the treatment of malignant glioma, causes cellular cytotoxicity by forming O(6)-methylguanine adducts. In this report, we investigated whether temozolomide alters the activity of the transcription factor nuclear factor-kappaB (NF-kappaB). Temozolomide inhibits basal and tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB transcriptional activity without altering phosphorylation or degradation of inhibitor of kappaB-alpha. Inhibition of NF-kappaB is secondary to attenuation of p65 DNA binding, not nuclear translocation. Inhibition of DNA binding is shown both in vitro, with gel shift studies and DNA binding assays, and in vivo at kappaB sites. Consistent with inhibition of NF-kappaB activity, temozolomide reduces basal and TNFalpha-induced kappaB-dependent gene expression. Temozolomide also inhibits NF-kappaB activated by inducers other than TNFalpha, including lipopolysaccharide, doxorubicin, and phorbol 12-myristate 13-acetate. The inhibitory action of temozolomide on NF-kappaB is observed to be maximal following pretreatment of cells with temozolomide for 16 h and is also seen with the S(N)1-type methylating agent methylnitrosourea. The ability of temozolomide to form O(6)-methylguanine adducts is important for inhibition of NF-kappaB as is the presence of a functioning mismatch repair system. Activation of NF-kappaB with TNFalpha before administration of temozolomide reduces the cytotoxicity of temozolomide, whereas 16-h pretreatment with temozolomide resensitizes cells to killing. This work shows a mechanism whereby O(6)-methylguanine adducts formed by temozolomide lead to inhibition of NF-kappaB activity and illustrates a link between mismatch repair processing of alkylator-induced DNA damage and cell death.

Nuclear factor-κB in glioblastoma: insights into regulators and targeted therapy

Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that regulates multiple aspects of cancer formation, growth, and treatment response. Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system, is characterized by molecular heterogeneity, resistance to therapy, and high NF-κB activity. In this review, we examine the mechanisms by which oncogenic pathways active in GBM impinge on the NF-κB system, discuss the role of NF-κB signaling in regulating the phenotypic properties that promote GBM and, finally, review the components of the NF-κB pathway that have been targeted for treatment in both preclinical studies and clinical trials. While a direct role for NF-κB in gliomagenesis has not been reported, the importance of this transcription factor in the overall malignant phenotype suggests that more rational and specific targeting of NF-κB-dependent pathways can make a significant contribution to the management of GBM.

Adenovirally Delivered Tumor Necrosis Factor-A Improves the Antiglioma Efficacy of Concomitant Radiation and Temozolomide Therapy

Purpose: Treatment of malignant glioma involves concomitant temozolomide and ionizing radiation (IR). Nevertheless, overall patient survival remains poor. This study was designed to evaluate if addition of Ad.Egr–tumor necrosis factor (TNF), a replication defective adenovector encoding a cDNA for TNF-α, to temozolomide and IR can improve overall antiglioma effect. Experimental Design: The efficacy of combination treatment with Ad.Egr-TNF, IR, and temozolomide was assessed in two glioma xenograft models. Animal toxicity and brain histopathology after treatment were also examined. In addition, in an attempt to explain the antitumor interaction between these treatments, the activation status of the transcription factor nuclear factor-κB was examined. Results: Triple therapy (Ad.Egr-TNF, IR, and temozolomide) leads to significantly increased survival in mice bearing glioma xenografts compared with dual treatment. Fifty percent of animals treated with the triple regimen survive for >130 days. Pathologic examination shows that triple therapy leads to a complete response with formation of a collagenous scar. No significant change in myelination pattern is noted after triple therapy, compared with any double treatment. Treatment of intracranial glioma bearing mice with Ad.Egr-TNF and IR leads to cachexia and poor feeding that does not improve, whereas triple therapy results in less toxicity, which improves over 21 days. Both Ad.Egr-TNF and IR activate nuclear factor-κB, and temozolomide inhibits this activity in an inhibitor of κBα (IκBα)–independent manner. Conclusion: This work shows that the addition of adenoviral TNF-α gene delivery to temozolomide and IR significantly improves antiglioma efficacy and illustrates a potential new treatment regimen for use in patients with malignant glioma.

p50 (NF-κB1) Is an Effector Protein in the Cytotoxic Response to DNA Methylation Damage

The functional significance of the signaling pathway induced by O(6)-methylguanine (O(6)-MeG) lesions is poorly understood. Here, we identify the p50 subunit of NF-κB as a central target in the response to O(6)-MeG and demonstrate that p50 is required for S(N)1-methylator-induced cytotoxicity. In response to S(N)1-methylation, p50 facilitates the inhibition of NF-κB-regulated antiapoptotic gene expression. Inhibition of NF-κB activity is noted to be an S phase-specific phenomenon that requires the formation of O(6)-MeG:T mismatches. Chk1 associates with p50 following S(N)1-methylation, and phosphorylation of p50 by Chk1 results in the inhibition of NF-κB DNA binding. Expression of an unphosphorylatable p50 mutant blocks inhibition of NF-κB-regulated antiapoptotic gene expression and attenuates S(N)1-methylator-induced cytotoxicity. While O(6)-MeG:T-induced, p50-dependent signaling is not sufficient to induce cell death, this pathway sensitizes cells to the cytotoxic effects of DNA breaks.

Convection-enhanced delivery for treatment of brain tumors

Recently, innovative therapies have been developed for the treatment of malignant gliomas. Unfortunately, adequate delivery of these therapies has been a major obstacle to clinical success. Intravenous administration is restricted by the presence of the blood–brain barrier while local delivery, such as with drug-impregnated wafers, results in limited parenchyma penetration. Convection-enhanced delivery is a promising method for the delivery of macromolecules to the CNS. Convection-enhanced delivery involves the infusion of therapeutic agents via surgically implanted catheters and uses a pressure gradient to achieve a greater volume of distribution compared with that seen with diffusion alone. This article will review the development of convection-enhanced delivery and its use in the treatment of malignant gliomas.