Tunable Lipidoid-Telodendrimer Hybrid Nanoparticles for Intracellular Protein Delivery in Brain Tumor Treatment.

A strategy to precisely engineer lipidoid-telodendrimer binary hybrid nanoparticles that offer enhanced cell membrane permeability for therapeutic proteins to reach the intracellular targets is established. The highly controllable biochemical and physical properties of the nanoparticles make them promising for protein-based brain cancer treatment with the assistance of convection-enhanced delivery.

Diphtheria toxin-based targeted toxin therapy for brain tumors.

Targeted toxins (TT) are molecules that bind cell surface antigens or receptors such as the transferrin or interleukin-13 receptor that are overexpressed in cancer. After internalization, the toxin component kills the cell. These recombinant proteins consist of an antibody or carrier ligand coupled to a modified plant or bacterial toxin such as diphtheria toxin (DT). These fusion proteins are very effective against brain cancer cells that are resistant to radiation therapy and chemotherapy. TT have shown an acceptable profile for toxicity and safety in animal studies and early clinical trials have demonstrated a therapeutic response. This review summarizes the characteristics of DT-based TT, the animal studies in malignant brain tumors and early clinical trial results. Obstacles to the successful treatment of brain tumors include poor penetration into tumor, the immune response to DT and cancer heterogeneity.

[Efficacy of bispecific targeted immunotoxin DTATEGF against NSCLC brain metastatic tumor PC9-BrM3 cells].

OBJECTIVE: To investigate the in vitro and in vivo anticancer efficacy of the immunotoxin DTATEGF against human NSCLC brain metastatic tumor PC9-BrM3 cell line. METHODS: The effect of the immunotoxin DTATEGF was tested for its ability to inhibit the proliferation of PC9-BrM3 cells in vitro by MTT assay. The cell cycle and the apoptosis of cells with 1 pmol/L DTATEGF were examined by flow cytometry. In vivo, 2 µg of DTATEGF or control Bickel3 was given intratumor to nude mice with established PC9-BrM3 xenografts on their hips, and tumor volumes were measured and tumor samples were investigated by immunchistochemistry SABC method. The microvessel density (MVD) was measured in each group. RESULTS: In vitro, DTATEGF killed PC9-BrM3 cells and showed an IC50 of 1 pmol/L. The apoptotic rate in the 1 pmol/L DTATEGF group was (64.0±0.5)% , significantly higher than that in the control group (1.5±0.4)% (P<0.01). The cell cycle was obviously inhibited by DTATEGF in a dose-dependent manner. The percentage of cells treated with 1 pmol/L DTATEGF in SubG0/G1 phase was (32.0±1.5)%, significantly higher than that in the control group (2.0±0.4)% (P<0.01). In vivo, DTATEGF significantly inhibited the growth of PC9-BrM3 hip tumors (P<0.05). The MVD of the DTATEGF group was (15.6±4.6)/mm2, significantly lower than that of the control group (31.2±5.4)/mm2 (P<0.01). CONCLUSION: DTATEGF inhibits the growth of the PC9-BrM3 cell line and induces its apoptosis. It is highly efficacious against human metastatic NSCLC brain tumor and against neovascularization.

Surgery for pediatric drug resistant epilepsy: a narrative review of its history, surgical implications, and treatment strategies.

Background and Objective: Drug-resistant epilepsy (DRE), also known as medically refractory epilepsy, is a disorder of high prevalence and negatively impacts a patients quality of life, neurodevelopment, and life expectancy. Pediatric epilepsy surgery has been conducted since the late 1800s, and randomized controlled trials have demonstrated the marked effectiveness of surgery on seizure reduction and the potential for cure. Despite the strong evidence for pediatric epilepsy surgery, there is also strong evidence describing its underutilization. The objective of this narrative review is to describe the history, strength, and limitations in the evidence of surgery for pediatric drug resistant epilepsy. Methods: This narrative review was conducted utilizing standard search engines to include the relevant articles on the topic of surgery for drug resistant epilepsy in children, with main keywords including surgery in pediatric epilepsy and drug-refractory epilepsy. Key Content and Findings: The first components describe the historical perspective of pediatric epilepsy surgery and the evidence that highlight the strengths and limitations of epilepsy surgery. We then highlight the importance of presurgical referral and evaluation, followed by a section detailing the surgical options for children with DRE. Lastly, we provide a perspective on the future of pediatric epilepsy surgery. Conclusions: Evidence supports the role for surgery in pediatric medically refractory epilepsy in seizure frequency reduction, improved curative rates, and improvements in neurodevelopment and quality of life.

Bilateral fronto-orbital advancement combined with cranial vault release using a free-floating bone flap technique for nonsyndromic unilateral coronal synostosis.

Background: The goals of operative treatment for unilateral coronal synostosis (UCS) are to improve appearance and allow unrestricted brain growth. However, for severe unilateral premature closure of the coronal suture, existing methods do not address the compression of the brain or expand the volume of the skull cavity. We report our retrospective experience with bilateral fronto-orbital advancement combined with cranial vault release using a free-floating bone flap (CVR + FFBF) technique and the resulting changes in the anterior cranial vault asymmetry index (ACVAI) and intracranial volume. Methods: Twenty patients with UCS who underwent bilateral fronto-orbital advancement combined with CVR + FFBF technique from April 2014 to May 2019 were included. Surgical efficacy was evaluated by the ACVAI and intracranial volume before the operation, 1 week after the operation, and at the last follow-up (average 19.8 months; range, 12 to 40 months). The measurement data are presented as the mean ± standard deviation and were statistically analyzed by t-test. Results: The ACVAI was 9.07%±3.55% before the operation, 3.56%±3.42% 1 week after the operation, and 3.13%±2.41% at the last follow-up. The ACVAI 1 week after the operation was significantly lower than that before the operation (t=4.827, P<0.001). There was no significant difference between the ACVAI 1 week after the operation and at the last follow-up (t=0.660, P=0.517). The intracranial volume was 1,027.85±112.25 mL in patients before the operation and 1,131.92±161.71 mL in the normal control group, which was a statistically significant difference (t=2.364, P=0.023). The intracranial volume significantly increased 1 week after surgery: 1,081.62±111.10 mL (t=8.703, P<0.001), and this trend continued at the last follow-up (1,386.90±119.30 mL) similarly to the normal control group (1,438.22±89.28 mL). At the last follow-up, there was no significant difference between the two groups (t=1.540, P=0.132). Conclusions: For the treatment of UCS, bilateral fronto-orbital advancement combined with CVR + FFBF technique offers functional and cosmetic outcomes in terms of intracranial volume expansion and fronto-orbital symmetry.

Intracerebral infusion of the bispecific targeted toxin DTATEGF in a mouse xenograft model of a human metastatic non-small cell lung cancer.

The aim of this study is to investigate the anti-cancer effect of the bispecific diphtheria toxin (DT) based immunotoxin DTATEGF, which targets both the epidermal growth factor (EGF) receptor (EGFR) and the urokinase-type plasminogen activator (uPA) receptor (uPAR) in vitro and in vivo when delivered by convection-enhanced delivery (CED) via an osmotic minipump in a human metastatic non-small cell lung cancer (NSCLC) brain tumor mouse xenograft model. The effects of the bispecific immunotoxin DTATEGF, and monospecific DTAT, DTEGF and control DT at various concentrations were tested for their ability to inhibit the proliferation of human metastatic NSCLC PC9-BrM3 cells in vitro by MTT assay. A xenograft model of human metastatic NSCLC intracranial model was established in nude mice using the human NSCLC PC9-BrM3 cell line genetically marked with a firefly luciferase reporter gene. One microgram of DTATEGF in the treatment group or control DT in the control group was delivered intracranially by CED via an osmotic minipump. The bioluminescent imaging (BLI) was performed at day 7, 14, 1 month, 2 months, and 3 months. Kaplan-Meier survival curves for the two groups were generated. The brain tissue samples were stained by hematoxylin and eosin for histopathological assessment. In vitro, DTATEGF could selectively kill PC9-BrM3 cells and showed an IC(50) less than 0.001 nM, representing a more than 100- to 1000-fold increase in activity as compared to monospecific DTAT and DTEGF. In vivo, mice with tumors were treated intracranially with drug via CED where the results showed the treatment was successful in providing a survival benefit with the median survival of mice treated with DTATEGF being significantly prolonged relative to controls (87 vs. 63 days, P = 0.006). The results of these experiments indicate that DTATEGF kills the NSCLC PC9-BrM3 cell line in vitro, and when it is delivered via CED intracranially, it is highly efficacious against metastatic NSCLC brain tumors. DTATEGF is a safe and effective drug where further preclinical and clinical development is warranted for the management of metastatic brain tumors.

Iatrogenic Vascular Injury Associated with Cervical Spine Surgery: A Systematic Literature Review.

BACKGROUND: Iatrogenic vascular injury is an uncommon complication of anterior and/or posterior surgical approaches to the cervical spine. Although the results of this injury may be life-threatening, mortality/morbidity can be reduced by an understanding of its mechanism and proper management. METHODS: We conducted a literature review to provide an update of this devastating complication in spine surgery. A total of 72 articles including 194 cases of vascular lesions following cervical spine surgery between 1962 and 2021 were analyzed. RESULTS: There were 53 female and 41 male cases (in addition to 100 cases with unreported sex) with ages ranging from 3 to 86 years. The vascular injuries were classified according to the spinal procedures, such as anterior or posterior cervical spine surgery. The interval between the symptom of the vascular injury and the surgical procedure ranged from 0 to 10 years. Only two-thirds of patients underwent intra- or postoperative imaging and the most frequently injured vessel was the vertebral artery (86.60%). Laceration was the most common lesion (41.24%), followed by pseudoaneurysm (16.49%) and dissection (5.67%). Vascular repair was performed in 114 patients. The mortality rate was 7.22%, and 18.04% of patients had 1 or more other complications. Most presumed causes of vascular lesions were by instrumentation/screw placement (31.44%) or drilling (20.61%). Sixteen patients had an anomalous artery. Direct microsurgical repair was achieved in only 15 cases. CONCLUSIONS: Despite increased anatomical knowledge and advanced imaging techniques, we need to consider the risk of vascular injury as a surgical complication in patients with cervical spine pathologies.

Spontaneous acute subdural hematoma as the initial manifestation of chronic myeloid leukemia.

Spontaneous acute subdural hematoma is rare and limited to sporadic case reports, associated with neoplasm, aneurysm, arteriovenous malformation and cocaine use. Subdural hematoma has also been reported in association with leukemic malignancies, either during therapy or after diagnosis. However, there are no reports of spontaneous acute subdural hematoma as the primary initial presenting manifestation of a chronic myeloid leukemia. Here we describe one case of a 53-year-old male that presented with severe right-sided headache and intermittent left-sided paresthesias. CT scan showed non-traumatic right-sided acute subdural hematoma. Further evaluation revealed that the patient had chronic myeloid leukemia. His peripheral white blood count normalized after Gleevec and hydroxyurea chemotherapy. Furthermore, he had no neurological deficits after his subdural collection was adequately evacuated.

Intraoperative magnetic resonance imaging.

Neurosurgeons have become reliant on image-guidance to perform safe and successful surgery both time-efficiently and cost-effectively. Neuronavigation typically involves either rigid (frame-based) or skull-mounted (frameless) stereotactic guidance derived from computed tomography (CT) or magnetic resonance imaging (MRI) that is obtained days or immediately before the planned surgical procedure. These systems do not accommodate for brain shift that is unavoidable once the cranium is opened and cerebrospinal fluid is lost. Intraoperative MRI (ioMRI) systems ranging in strength from 0.12 to 3 Tesla (T) have been developed in part because they afford neurosurgeons the opportunity to accommodate for brain shift during surgery. Other distinct advantages of ioMRI include the excellent soft tissue discrimination, the ability to view the surgical site in three dimensions, and the ability to "see" tumor beyond the surface visualization of the surgeon's eye, either with or without a surgical microscope. The enhanced ability to view the tumor being biopsied or resected allows the surgeon to choose a safe surgical corridor that avoids critical structures, maximizes the extent of the tumor resection, and confirms that an intraoperative hemorrhage has not resulted from surgery. Although all ioMRI systems allow for basic T1- and T2-weighted imaging, only high-field (>1.5 T) MRI systems are capable of MR spectroscopy (MRS), MR angiography (MRA), MR venography (MRV), diffusion-weighted imaging (DWI), and brain activation studies. By identifying vascular structures with MRA and MRV, it may be possible to prevent their inadvertent injury during surgery. Biopsying those areas of elevated phosphocholine on MRS may improve the diagnostic yield for brain biopsy. Mapping out eloquent brain function may influence the surgical path to a tumor being resected or biopsied. The optimal field strength for an ioMRI-guided surgical system and the best configuration for that system are as yet undecided.

Intracranial elimination of human glioblastoma brain tumors in nude rats using the bispecific ligand-directed toxin, DTEGF13 and convection enhanced delivery.

A bispecific ligand-directed toxin (BLT) consisting of human interleukin-13, epithelial growth factor, and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma. In vitro, DTEGF13 selectively killed the human glioblastoma cell line U87-luc as well as other human glioblastomas. DTEGF13 fulfilled the requirement of a successful BLT by having greater activity than either of its monospecific counterparts or their mixture proving it necessary to have both ligands on the same single chain molecule. Aggressive brain tumors established intracranially (IC) in nude rats with U87 glioma genetically marked with a firefly luciferase reporter gene were treated with two injections of DTEGF13 using convection enhanced delivery resulting in tumor eradication in 50% of the rats which survived with tumor free status at least 110 days post tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The bispecific DTEGF13 MTD dose was measured at 2 microg/injection or 0.5 microg/kg and toxicity studies indicated safety in this dose. Combination of monospecific DTEGF and DTIL13 did not inhibit tumor growth. ELISA assay indicated that anti-DT antibodies were not generated in normal immunocompetent rats given identical intracranial DTEGF13 therapy. Thus, DTEGF13 is safe and efficacious as an alternative drug for glioblastoma therapy and warrants further study.

Persistence of CD133+ cells in human and mouse glioma cell lines: detailed characterization of GL261 glioma cells with cancer stem cell-like properties.

The concept of cancer stem cells suggests that there are malignant stem-like cells within a tumor that are responsible for tumor renewal and resistance to cytotoxic therapies. Studies have identified glioma stem-like cells that extrude Hoechst 33342 dye, representing a double-negative "side population" (SP) thought to be selectively resistant to drug therapy. A CD133+ stem cell-like subpopulation has been isolated from a human glioma that was enriched for tumor-initiating cells. It is unknown whether CD133+ cells with similar phenotype persist in established glioma cell lines, or if CD133 is a marker of glioma stem-like cells in rodents. We investigated whether CD133+ and SP cells existed in the GL261 cell line, a syngeneic mouse glioma model that is widely used for preclinical and translational research. Intracerebral injection of less than 100 CD133+ GL261 cells formed tumors, whereas it required 10,000 CD133(-) cells to initiate a tumor. CD133+ GL261 cells expressed nestin, formed tumor spheres with high frequency, and differentiated into glial and neuronal-like cells. Similar to GL261, seven human glioma cell lines analyzed also contained a rare CD133+ population. Surprisingly, we found that CD133+ GL261 cells did not reside in the SP, nor did the majority ( approximately 94%) of CD133+ human glioma cells. These results demonstrate that the expression of CD133 in murine glioma cells is associated with enhanced tumorigenicity and a stem-like phenotype. This study also reveals a previously unrecognized level of heterogeneity in glioma cell lines, exposing several populations of cells that have characteristics of cancer stem cells.

Brain Abscess of Basal Ganglia Presenting with Persistent Hiccups.

BACKGROUND: Brain abscesses are well-known to neurologic surgeons with well-recognized presentations, which include seizures, neurologic deficit, and headache. Rare symptoms may lead to a delay in diagnosis, which can be life threatening in the setting of a brain abscess. CASE DESCRIPTION: We present the case of a 46-year-old male with intractable hiccups found to have an abscess of the right basal ganglia. The brain abscess was treated by frameless stereotactic-guided aspiration. The patient's hiccups improved after surgical aspiration and medical management. CONCLUSIONS: A comprehensive literature review confirmed brain abscess as a rare cause of intractable hiccups. In addition, there are few reports of lesions of the basal ganglia causing intractable hiccups. Aspiration and medical therapy resulted in resolution of the hiccups. Knowledge of the hiccup reflex arc and unusual presentation of basal ganglia lesions may shorten time to diagnosis.

Postoperative central nervous system infection: incidence and associated factors in 2111 neurosurgical procedures.

BACKGROUND: Postoperative central nervous system infection (PCNSI) in patients undergoing neurosurgical procedures represents a serious problem that requires immediate attention. PCNSI most commonly manifests as meningitis, subdural empyema, and/or brain abscess. Recent studies (which have included a minimum of 1000 operations) have reported that the incidence of PCNSI after neurosurgical procedures is 5%-7%, and many physicians believe that the true incidence is even higher. To address this issue, we examined the incidence of PCNSI in a sizeable patient population. METHODS: The medical records and postoperative courses for patients involved in 2111 neurosurgical procedures at our institution during 1991-2005 were reviewed retrospectively to determine the incidence of PCNSI, the identity of offending organisms, and the factors associated with infection. RESULTS: The median age of patients at the time of surgery was 45 years. Of the 1587 cranial operations, 14 (0.8%) were complicated by PCNSI, whereas none of the 32 peripheral nerve operations resulted in PCNSI. The remaining 492 operative cases involved spinal surgery, of which 2 (0.4%) were complicated by PCNSI. The overall incidence of PCNSI was 0.8% (occurring after 16 of 2111 operations); the incidence of bacterial meningitis was 0.3% (occurring after 4 of 1587 operations), and the incidence of brain abscess was 0.2% (occurring after 3 of 1587 operations). The most common offending organism was Staphylococcus aureus (8 cases; 50% of infections), followed by Propionibacterium acnes (4 cases; 25% of infections). Cerebrospinal fluid leakage, diabetes mellitus, and male sex were not associated with PCNSI (P>.05). CONCLUSIONS: In one of the largest neurosurgical studies to have investigated PCNSI, the incidence of infection after neurosurgical procedures was <1%--more than 6 times lower than that reported in recent series of comparable numerical size. Cerebrospinal fluid leak, diabetes mellitus, and male sex were not associated with an increased incidence of PCNSI. The results from this study indicate that the true incidence of PCNSI after neurosurgical procedures may be greatly overestimated in the literature and that, in surgical procedures associated with a high risk of infection, prophylaxis for S. aureus and/or P. acnes infection should be of primary concern.

Fractionated stereotactic radiotherapy for pituitary adenomas following microsurgical resection: safety and efficacy.

The treatment of pituitary adenomas following medical management has historically involved surgical excision or stereotactic radiosurgery, with the two modalities often utilized collectively. However, there have been only a limited number of reports on the use of fractionated stereotactic radiotherapy (FSRT) for the treatment of pituitary adenomas. To enhance the existing knowledge regarding the safety and efficacy of this treatment modality, we describe our initial experience with FSRT for residual pituitary adenomas following microsurgical resection. From 1999 to 2005, 14 patients (7F, 7M) with residual pituitary adenomas (7 nonsecretory, 2 growth hormone secreting, 2 prolactin secreting, 2 thyrotropin secreting, 1 adrenocorticotropic hormone secreting) underwent FSRT. All patients were planned using the Radionics X-Knife 3D planning system, and received a median dose of 50.4 Gy in daily 1.8 Gy fractions administered to the 90% prescription isodose line. Treatments were delivered stereotactically using a dedicated Varian 6/100 linear accelerator, with immobilization achieved with the Gill-Thomas-Cosman relocatable head frame. Mean tumor size was 3.6 cm (median, 3.2 cm), and mean patient age was 44.6 years (median, 47 years). The mean dosages to the optic chiasm and brainstem were 0.159 and 0.040 Gy (median, 0.163 and 0.031 Gy) per fraction. All patients were evaluated with visual field testing and pre- and postgadolinium-enhanced magnetic resonance imaging at a minimum of one year follow-up (median, 22.5 months; mean, 27.8 months). Following FSRT, local control (defined as absence of tumor progression) was achieved in all fourteen patients. Three patients developed hypopituitarism (average, 30 months after treatment), with no patient experiencing visual changes or acute complications following FSRT. These results demonstrate the efficacy and safety of FSRT for achieving long-term local tumor control for pituitary adenomas, further validating this technique as an appropriate treatment modality for residual adenomas following microsurgery.

Improved distribution of small molecules and viral vectors in the murine brain using a hollow fiber catheter.

OBJECT: A hollow fiber catheter was developed to improve the distribution of drugs administered via direct infusion into the central nervous system (CNS). It is a porous catheter that significantly increases the surface area of brain tissue into which a drug is infused. METHODS: Dye was infused into the mouse brain through convection-enhanced delivery (CED) using a 28-gauge needle compared with a 3-mm-long hollow fiber catheter. To determine whether a hollow fiber catheter could increase the distribution of gene therapy vectors, a recombinant adenovirus expressing the firefly luciferase reporter was injected into the mouse striatum. Gene expression was monitored using in vivo bioluminescent imaging. To assess the distribution of gene transfer, an adenovirus expressing green fluorescent protein was injected into the striatum using a hollow fiber catheter or a needle. RESULTS: Hollow fiber catheter-mediated infusion increased the volume of brain tissue labeled with dye by 2.7 times relative to needle-mediated infusion. In vivo imaging revealed that catheter-mediated infusion of adenovirus resulted in gene expression that was 10-times greater than that mediated by a needle. The catheter appreciably increased the area of brain transduced with adenovirus relative to a needle, affecting a significant portion of the injected hemisphere. CONCLUSIONS: The miniature hollow fiber catheter used in this study significantly increased the distribution of dye and adenoviral-mediated gene transfer in the mouse brain compared with the levels reached using a 28-gauge needle. Compared with standard single-port clinical catheters, the hollow fiber catheter has the advantage of millions of nanoscale pores to increase surface area and bulk flow in the CNS. Extending the scale of the hollow fiber catheter for the large mammalian brain shows promise in increasing the distribution and efficacy of gene therapy and drug therapy using CED.

Treatment of a facial nerve neuroma with fractionated stereotactic radiotherapy.

BACKGROUND: Facial nerve neuromas are extremely rare and are often mistaken for acoustic neuromas when located near the vestibular nerve. Usually presenting with facial weakness and hearing loss, facial nerve neuromas of the cerebellopontine angle have commonly been managed by surgery. We present the first reported case of a facial nerve neuroma treated with fractionated stereotactic radiotherapy (FSRT). METHODS: The patient was a 40-year-old woman who presented with tinnitus, dizziness and decreased hearing that was associated with a right intracanalicular mass on magnetic resonance imaging (MRI). She underwent a middle fossa craniotomy only to reveal a facial nerve tumor rather than an acoustic neuroma that was not resected due to the high risk of facial paralysis. Following surgery, her facial function worsened and was associated with tumor enlargement on MRI. She was referred for FSRT and received 54 Gy in daily 1.8-Gy fractions with a prescription isodose line of 90%. RESULTS: Three months after treatment she had no worsening of her pretreatment symptoms, and at the 1-year follow-up, she experienced facial weakness improvement accompanied by an absence of tumor growth on MRI. These clinical and imaging findings persisted at 48 months of follow-up. CONCLUSION: In the first report of a facial nerve neuroma treated with FSRT, this treatment resulted in excellent long-term (4-year) tumor control with improvement of pretreatment symptomatology and absence of morbidity. This report demonstrates the potential for using FSRT to treat facial nerve neuromas of the cerebellopontine angle that could otherwise be associated with significant operative morbidity.

Convection-enhanced delivery of targeted toxins for malignant glioma.

Malignant gliomas represent a difficult treatment challenge for the neuro-oncologist and the neurosurgeon. These tumours continue to be refractory to standard therapies, such as surgery, radiotherapy and conventional chemotherapy, and new therapeutic options are clearly needed. Therefore, investigators have recently taken a new direction and started to engineer compounds such as recombinant cytotoxins, antiangiogenesis factors and genetic delivery vectors. However, these promising new agents are all dependent on an effective distribution method in order to bypass the blood-brain barrier. Convection-enhanced delivery (CED) allows for the administration of targeted toxins and other agents directly into the brain at the site of a tumour via catheters placed with the aid of stereotactic or image-guided surgery. The use of this technique is gaining momentum as a newly accepted treatment modality where little else has produced durable results in the fight against gliomas. Direct intratumoural infusion was first performed in nude mouse flank tumour models of human malignant glioma. After significant testing in preclinical animal studies, this method of delivery was followed by the successful demonstration of in vivo efficacy in Phase I and II clinical trials. Currently, this technique is being used in the investigational setting at academic medical centres where investigators are starting to define the best practice for CED. Fundamental issues in this method of delivery such as rate of infusion, cannula size, infusate concentration and tissue-cannula sealing time shape the current discussion in the literature. Targeted toxin therapy represents one of the newest and most promising treatments for this unfortunate patient population, with proven clinical efficacy administered through CED, which is a novel approach to drug delivery.