Zvi R. Cohen

Poor drug distribution as a possible explanation for the results of the PRECISE trial

OBJECT Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Transsphenoidal Surgery for Acromegaly: Endocrinological Follow-up of 98 Patients

OBJECTIVETranssphenoidal surgery is the preferred treatment modality for growth hormone (GH)-secreting pituitary adenomas. In many series, the reported postoperative remission is based mainly on achievement of GH levels less than 2 ng/ml. Strict criteria for insulin-like growth factor I normalization and even lower GH levels (<1 ng/ml) are now suggested to define cure of acromegaly, but the evidence does not yet support such low GH levels in epidemiological follow-up. We analyzed our postoperative results in a large cohort of patients with acromegaly. METHODSNinety-eight patients harboring GH-secreting adenomas (46 microadenomas and 52 macroadenomas) underwent transsphenoidal surgery between 1990 and 1999. Ninety-one patients were operated for the first time, and 12 patients underwent reoperations because of previous surgical failure (7 had undergone surgery elsewhere previously). Biochemical remission was defined as a repeated fasting or glucose-suppressed GH level of 2 ng/ml or less, and a normal insulin-like growth factor I level. RESULTSRemission was achieved in 74% of all patients after one operation, including 84% of patients with microadenomas and 64% of patients with macroadenomas. Seventy-three percent of patients with macroadenomas 11 to 20 mm in size achieved remission, as compared with a 20% remission rate for patients with adenomas larger than 20 mm. Patients with preoperative random GH levels lower than 50 ng/ml had a better outcome (85% remission), whereas GH greater than 50 ng/ml was associated with remission in 30% of the patients. Only one of the patients (8%) with postoperative active disease who underwent a second operation achieved remission. Recurrence was rare (one patient), and all failed surgical attempts could be detected during the immediate postoperative evaluation. CONCLUSIONOn the basis of strict postoperative GH and insulin-like growth factor I criteria to define remission, our series demonstrates the efficacy of transsphenoidal surgery for acromegalic patients with microadenomas and noninvasive macroadenomas. However, patients with large adenomas (>20 mm) and preoperative GH greater than 50 ng/ml have a poor prognosis and require adjunctive medical or radiation therapy to control GH hypersecretion.

Magnetic resonance imaging-guided, high-intensity focused ultrasound for brain tumor therapy

OBJECTIVEMagnetic resonance imaging-guided high-intensity focused ultrasound (MRIgFUS) is a novel technique that may have the potential for precise image-guided thermocoagulation of intracranial lesions. The system delivers small volumetric sonications from an ultrasound phased array transmitter that focuses energy selectively to destroy the target with verification by magnetic resonance imaging-generated thermal maps. A Phase I clinical study was initiated to treat patients with recurrent glioma with MRIgFUS. METHODSTo date, three patients with histologically verified recurrent glioblastoma multiforme have been treated with MRIgFUS. All patients underwent craniectomy 7 to 10 days before therapy to create a bony window for the ultrasound treatment. Sonications were applied to induce thermocoagulation of the enhancing tumor mass. Long-term radiological follow-up and post-treatment tissue specimens were available for all patients. RESULTSMRIgFUS treatment resulted in immediate changes in contrast-enhanced T1-, T2-, and diffusion-weighted magnetic resonance imaging scans in the treated regions with subsequent histological evidence of thermocoagulation. In one patient, heating of brain tissue in the sonication path resulted in a secondary focus outside the target causing neurological deficit. New software modifications were developed to address this problem. CONCLUSIONIn this first clinical report, MRIgFUS was demonstrated to be a potentially effective means of destroying tumor tissue by thermocoagulation, although with an associated morbidity and the inherent invasive nature of the procedure requiring creation of a bone window. A modified technology to allow MRIgFUS treatment through a closed cranium is being developed.

Transsphenoidal surgery for Cushing's disease: endocrinological follow-up monitoring of 82 patients.

OBJECTIVE Transsphenoidal surgery is the preferred treatment modality for adrenocorticotropic hormone-secreting pituitary adenomas. In the past 2 decades, several institutions in the United States and Europe have reported remission rates of 70 to 85% after transsphenoidal surgery for treatment of Cushing’s disease. We analyzed our postoperative results for a large cohort of patients with Cushing’s disease. METHODS Eighty-two patients with adrenocorticotropic hormone-secreting adenomas (79 microadenomas and 3 macroadenomas) underwent transsphenoidal surgery between 1990 and 2000. Seventy-seven patients were surgically treated for the first time, and 13 patients underwent reoperations (5 had undergone the first operation elsewhere) because of previous surgical failure (10 patients) or recurrence (3 patients). The mean postoperative follow-up period was 4.2 ± 2.8 years. Biochemical remission was defined as postoperative normalization of elevated 24-hour urinary free cortisol secretion and suppression of morning cortisol levels with 1 mg of dexamethasone. RESULTS Remission was achieved for 78% of all patients after one operation and for 62% of patients who underwent a second operation. The recurrence rate was 5%. Ten patients did not exhibit a visible tumor on magnetic resonance imaging scans, and the other patients were divided according to adenoma size (2–5 or 6–10 mm). Remission rates were similar for the three groups of patients (78–80%). Pituitary tumor stained for adrenocorticotropic hormone was detected in 78% of resected pituitary tissue specimens obtained from patients who achieved remission, compared with 53% from patients who experienced surgical failure (P = 0.06). CONCLUSION Our series demonstrates the efficacy of transsphenoidal surgery for Cushing’s disease resulting from pituitary microadenomas. Microadenoma size had no effect on the remission rate. Reoperations are indicated after initial surgical failures.

Localized RNAi Therapeutics of Chemoresistant Grade IV Glioma Using Hyaluronan-Grafted Lipid-Based Nanoparticles

Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood-brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNPs surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM.

Magnetic resonance imaging-guided focused ultrasound for thermal ablation in the brain: a feasibility study in a swine model.

INTRODUCTIONMagnetic resonance imaging (MRI)-guided focused ultrasound is a novel technique that was developed to enable precise, image-guided targeting and destruction of tumors by thermocoagulation. The system, ExAblate2000, is a focused ultrasound delivery system embedded within the MRI bed of a conventional diagnostic MRI scanner. The device delivers small volumetric sonications from an ultrasound phased array transmitter that converge energy to selectively destroy the target. Temperature maps generated by the MRI scanner verify the location and thermal rise as feedback, as well as thermal destruction. To assess the safety, feasibility, and precision of this technology in the brain, we have used the ExAblate system to create predefined thermal lesions in the brains of pigs. METHODSTen pigs underwent bilateral craniectomy to provide a bone window for the ultrasound beams. Seven to 10 days later, the animals were anesthetized and positioned in the ExAblate system. A predefined, 1-cm3 frontal para ventricular region was delineated as the target and treated with multiple sonications. MRI was performed immediately and 1 week after treatment. The animals were then sacrificed and the brains removed for pathological study. The size of individual sonication points and the location of the lesion were compared between the planned dose maps, posttreatment MRI scans, and pathological specimen. RESULTSHigh-energy sonications led to precise coagulation necrosis of the specified targets as shown by subsequent MRI, macroscopic, and histological analysis. The thermal lesions were sharply demarcated from the surrounding brain with no anatomic or histological abnormalities outside the target. CONCLUSIONMRI-guided focused ultrasound proved a precise and an effective means to destroy anatomically predefined brain targets by thermocoagulation with minimal associated edema or damage to adjacent structures. Contrast-enhanced T1-, T2-, and diffusion-weighted MRI scans may be used for real-time assessment of tissue destruction.

Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats

Our aim was to assess the ability of convection-enhanced drug delivery (CED), a novel approach of direct delivery of drugs into brain tissue and brain tumors, to treat brain tumors using salirasib (farsnesyl thiosalicylic acid). CED was achieved by continuous infusion of drugs via intracranial catheters, thus enabling convective distribution of high drug concentrations over large volumes while avoiding systemic toxicity. Several phase II/III CED-based trials are currently in progress but have yet to overcome two major pitfalls of this methodology (the difficulty in attaining efficient CED and the significant nonspecific neurotoxicity caused by high drug doses in the brain). In this study, we addressed both issues by employing our previously described novel CED imaging and increased efficiency methodologies to exclusively target the activated form of the Ras oncogene in a 9L gliosarcoma rat model. The drug we used was salirasib, a highly specific Ras inhibitor shown to exert its suppressive effects on growth and migration of proliferating tumor cells in in vitro and in vivo models, including human glioblastoma, without affecting normal tissues. The results show a significant decrease in tumor growth rate in salirasib-treated rats relative to vehicle-treated rats as well as a significant correlation between CED efficacy and tumor growth rate with no observed toxicity despite drug concentrations an order of magnitude higher than previously detected in the brain. The results show that CED of salirasib is efficient and nontoxic for the treatment of glioblastoma in a rat model, thus suggesting that it may be considered for clinical application. [Mol Cancer Ther 2008;7(11):3609–16]

Harnessing nanomedicine for therapeutic intervention in glioblastoma

ABSTRACT Introduction: Glioblastoma is a type of brain cancer arises from glial cells. Glioblastoma multiforme (GBM), a subtype of glioblastoma, is the most common and most aggressive primary brain tumor. Currently, GBM therapy includes surgery and post-operative high-doses of radiation and chemotherapy. This therapeutic strategy has a limited contribution in extending the survival rate of GBM patients. Areas covered: Herein, we focus on harnessing nanoscale drug delivery strategies to treat brain malignancies. Specifically, we briefly discuss the challenges facing GBM therapy such as restricted passage across the blood-brain barrier (BBB) and low enhanced permeability and retention effect. Next, we describe different pathways to address these challenges. Finally, we discuss the field of nanomedicine, which emerged as a promising platform for drug delivery to brain malignancies. Expert opinion: Countless strategies have been applied in preclinical and clinical settings to treat GBM. Among them is the use of different types of nanoparticles (NPs) and viruses with different approaches to cross or bypass the BBB. We suggest here a paradigm shift in thinking about crossing the BBB and tumor penetration as fundamental issues that need to be address in order to improve the therapeutic outcome in GBM

Prenatal sonographic diagnosis of lateral ventricle choroid plexus papilloma in an in vitro fertilization-induced pregnancy.

This is a report of a prenatal sonographic diagnosis of a lateral ventricle choroid plexus papilloma in an in vitro fertilization (IVF)-induced pregnancy of a 40-year-old woman. The baby was delivered at 35 weeks of gestation and surgery was performed 5 days later with a good outcome. Several cases of malignancies associated with IVF are reported in the literature. To the best of the authors’ knowledge, this is the first report of a prenatal diagnosis of choroid plexus papilloma in an IVF-induced pregnancy. The authors also review other cases of choroid plexus papilloma diagnosed prenatally by ultrasound. The theoretical association between IVF and neoplasia is also considered.

Intraoperative Magnetic Resonance Imaging for Resection of Intra-Axial Brain Lesions: A Decade of Experience Using Low-Field Magnetic Resonance Imaging, Polestar N-10, 20, 30 Systems

OBJECTIVE The aim of this study was to determine the utility of an intraoperative magnetic resonance imaging (i-MRI) system (Polestar N-10, 20, 30) in achieving maximal resection of intra-axial brain lesions. METHODS The subjects comprised 163 patients with intra-axial brain lesions who underwent resection at Sheba Medical Center using the Polestar from February 2000 through February 2012. Demographic and imaging data were obtained and analyzed retrospectively. The patients included 83 men (50.9%) and had a mean age of 43 years. High-grade gliomas were diagnosed in 72 patients, low-grade gliomas in 35, metastases in 22, and various pathologies (e.g., cavernous angiomas, juvenile pilocytic astrocytoma, pleomorphic xanthoastrocytoma, etc.) were diagnosed in 34. The majority of the lesions (84, 51.5%) were located in or near eloquent areas. Fifty-one patients had nonenhancing lesions. RESULTS We intended to achieve complete resection in 110 of 163 cases, based on preoperative imaging. Complete resection was achieved in 90 of these 110 (81.8%) cases. Intraoperative MRI led to additional resection in 42.3% of the total cases and to complete resection in 43.3% of all the cases in which a complete resection was achieved. In 76.8% of these cases, 2 intraoperative scans were sufficient to achieve complete resection. Sex, age, intent of resection, recurrence, affected side, and radiologic characteristics did not differ significantly between cases in which intraoperative MRI led to further resection and cases in which it did not. Nonenhancing lesions of all types were 3 times more likely to require additional resection after obtaining intraoperative MRIs (P = .02). CONCLUSIONS The Polestar (N-10, 20, 30) proved useful for evaluating residual intra-axial brain lesions and achieving the maximal extent of resection in 42.3% of the total cases and in 43.3% of cases in which complete resection was achieved. Intraoperative MRI led to extended resection in 46.9% of patients for whom the initial intent was to perform an incomplete resection. Nonenhancement was the only independent variable predicting the usefulness of intraoperative MRI for additional lesion resection.