Zvi H. Rappaport

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.

Endoscopic Transnasal Transsphenoidal Microsurgery Versus the Sublabial Approach for the Treatment of Pituitary Tumors: Endonasal Complications

Objective: To evaluate the nasal complications after transnasal transsphenoidal operations for pituitary tumors, comparing two surgical techniques: traditional sublabial transseptal and endoscopic transseptal techniques.

Ammonium Trichloro(dioxoethylene-o,o′)tellurate (AS101) Sensitizes Tumors to Chemotherapy by Inhibiting the Tumor Interleukin 10 Autocrine Loop

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o′)tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.

Non-resectable slow-growing meningiomas treated by hydroxyurea.

AbstractPurpose: To test the benefit of hydroxyurea in the treatment of recurrent and non-resectable slow-growing meningiomas. Methods: Twelve patients with regrowing non-malignant meningiomas, were enrolled for a protocol of 2 years with continuous chemotherapy with hydroxyurea, 20 mg/kg/day. Response to treatment was evaluated both clinically and by diagnostic imaging using computed tomography (CT) and 201-Thallium single photon emission CT. One minimal response was documented by CT, accompanied by clinical stabilization. Nine patients showed progressive disease, at least by one imaging procedure, with a median time to progression of 13 months (range 4–24). Two other patients were not available for response due to early removal from the study, following abrupt manifestation of grades 3–4 hematological toxicity. Conclusion: In this series hydroxyurea has not shown effectiveness in the treatment of non-resectable slow-growing meningiomas: neither for achieving response, nor for arresting disease progression.

Pediatric brain stem gliomas: an update

Abstract It has become evident that pediatric brain stem gliomas are a heterogeneous pathology and should be classified according to clinical and radiological criteria. This classification has contributed to better treatment and greatly improved prognosis. Based on a review of the literature, we describe the different types of brain stem astrocytomas reported, which are: cervicomedullary, exophytic, cystic, focal and diffuse. Particular attention is paid to therapeutic modalities. For the first three lesions named the treatment is surgical and oncological therapy should be evaluated only for regrowth of the mass. Focal tumors of the medulla and pons are still treated empirically (surgically and/or with radiotherapy), because a definitive therapeutic protocol has not yet been elaborated; on the other hand it is well estabilished that if the focal mass is in the midbrain this should merely be monitored by means of serial MRI, while radiotherapy should be applied in the event of the tumors growth. Diffuse gliomas are treated with oncological therapy, and surgery (for biopsy or tumor excision) is not indicated. Five illustrative cases from our department are presented.

Hearing preservation using combined monitoring of extra-tympanic electrocochleography and auditory brainstem responses during acoustic neuroma surgery

The aim of this study was to evaluate the efficacy of an intraoperative monitoring hearing preservation strategy that includes simultaneous recordings of an auditory brainstem response (ABR) and non-invasive electrocochleography (ECochG). The combined ABR and tympanic membrane (TM) ECochG testing was performed in 74 patients undergoing acoustic neuroma (AN) surgery. In addition, EMG recordings were conducted to monitor the facial nerve function. Hearing was preserved in 19 of the 30 patients with residual hearing prior to surgery (63%), and facial nerve function was maintained in 89% of the patients. In most cases, the presence of both auditory brainstem and TM-ECochG responses at the end of surgery was associated with preservation of postoperative functional hearing; however, eight patients had a TM-ECochG response with a complete loss of the ABR, pointing to deafferentation of the auditory nerve. Tumour size and preoperative hearing thresholds significantly affected the postoperative hearing. The TM-ECochG response yielded large reproducible responses, which, in some patients, was the only way to monitor the auditory function. This auditory monitoring approach offers a valuable auditory tool that helps to improve the hearing preservation during AN surgery.

Risk factors for development of significant chronic subdural hematoma following conservative treatment of acute subdural hemorrhage

Abstract Objective. One of the complications of untreated acute subdural hemorrhage (aSDH) is the late development of chronic subdural hematomas (cSDH). cSDH may cause major neurologic deficits, requiring their surgical evacuation. The aim of our work was to find risk factors for the development of significant cSDH requiring surgery following conservative treatment of trauma-related aSDH. Methods. In a retrospective manner, we analyzed the data of 95 adult patients admitted with a non-surgical, traumatic aSDH. The patients were divided into two groups. The first group contained 52 patients who did not, on follow-up, develop cSDH requiring surgery. The second group contained 43 patients who ended up with a significant cSDH, based on clinical and radiological criteria, requiring surgical evacuation. Data acquisition and comparison between the two groups was performed by analyzing the patients’ charts for diverse medical conditions and other trauma-related parameters. Results. The operation rate was significantly higher in patients with medical history of ischemic heart disease (IHD) or hypertension (66.7% vs. 38%, p = 0.019 and 56.9% vs. 20%, p < 0.01, respectively), with a 4-fold increase in the risk for developing surgical cSDH in patients with IHD and a 6-fold increase in the risk in patients with hypertension (odds ratio 4.2 [95% CI for odds, 1.3–13.1] and 5.9 [95% C.I for odds, 1.6–21.5], respectively). Among 21 patients, 20 (95%) patients, who were either on more than 1 anti-aggregant agents (AAA), used Clopidrogrel, or took anti-coagulant drug were in the operative group (OG). A larger initial thickness of the aSDH was statistically significant in the OG as compared to the non-OG (8.9 mm ± 4.6 vs. 5.5 mm ± 2.1, p < 0.001). Conclusion. Head-trauma patients with a medical history of IHD or hypertension, patients on more than one AAA or anti-coagulant agents and patients with worse initial CT scan parameters are at risk of developing significant cSDH requiring surgery after conservative treatment of aSDH and consequently should have closer follow-up.

Principles and Concepts of Brain Death and Organ Donation: The Jewish Perspective

Abstract The harvesting of organs for transplantation is dependent on a stringent definition of brain death. Different societies have had to struggle with their cultural heritage, adapting their traditional attitudes to conform to the advances in medical science and the needs of the sick. In this article, the development of the concept of brain death as it applies to organ transplantation in Judaism is outlined. The ability of traditional Jewish values to address themselves to the challenges of modern medicine can serve as a basis for cultural cross-fertilization and comparison in modern societies.

Intracranial Abscess: Current Concepts in Management

The outcome of patients harboring intracranial abscesses has improved in the last decade as a result of improvement in imaging technologies, the introduction of potent antibiotics that penetrate the blood–brain barrier more readily, and minimally invasive surgical techniques with the possibility of image and real-time guidance. These therapeutic advances have, however, been counterbalanced by the increase in immunocompromised patients with pathogens that are more aggressive and difficult to eradicate. This review highlights the current approach to the diagnosis and treatment of intracranial abscesses, emphasizes pitfalls in management, and discusses dilemmas in treatment strategies.

Orbital porencephalic cyst following penetrating orbitocranial trauma.

In a 10-year-old boy an orbitocranial penetrating wound produced by an umbrella tip caused an orbital roof bone fragment to penetrate up to the anterior part of the third ventricle behind the left foramen of Monro. Hemorrhages and encephalomalacia developed along the trajectory of the fragment and subsequently a porencephalic cyst was formed at this site. Six months after the trauma, increased pressure developed in the left ventricular system due to obstructive hydrocephalus and consequently the porencephalic cyst herniated into the orbit through the orbital roof fracture, producing intermittent diplopia, left exophthalmos, and palpebral swelling. A ventriculo-peritoneal shunt led to shrinkage of the orbital cyst content and resolution of the symptoms.