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Ryszard M. Pluta, Zvi Ram, Nicholas J. Patronas and Harry Keiser

✓ A 42-year-old woman presented with otorrhea 22 years after extracranial resection of a norepinephrinesecreting glomus jugulare tumor with intravascular embolization and radiation therapy to the intracranial portion of the tumor. Tumor growth was arrested and was associated with a decrease in blood and urine norepinephrine levels. Extensive evaluation of the otorrhea, including computerized tomography-cisternography, gadoliniumenhanced magnetic resonance imaging, and arteriography showed marked diffuse necrosis of the temporal bone and skull base with limited tumor vascularity. Cerebrospinal fluid (CSF) collected from the right ear showed norepinephrine levels of 2975 pg/ml; plasma norepinephrine levels were normal. The precise site of CSF leakage could not be delineated. Exploration of the posterior fossa revealed a large dural defect at the anteromedial aspect of the petrous bone through which CSF flowed over the surface of the residual extradural glomus tumor. The defect was successfully sealed with a fascial patch. Postoperatively, CSF norepinephrine levels were normal and no further leakage was observed.

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Zvi Ram, Roberto Spiegelman, Gideon Findler and Moshe Hadani

✓ Sodium nitroprusside is commonly used for the induction of hypotension during neurosurgical procedures. Its toxicity stems from hemodynamic compromise as well as from its metabolites, especially the formation of cyanide. A patient is described who underwent craniotomy for hypertensive intracerebral hemorrhage. He gradually recovered following the operation, but needed continued administration of sodium nitroprusside for control of hypertension. On the 7th postoperative day, he deteriorated into coma with evidence of severe edema and herniation on the computerized tomography scan. Cessation of sodium nitroprusside and treatment for cyanide poisoning resulted in resolution of his symptoms within hours. The potential toxicity of sodium nitroprusside, measures to prevent toxicity, and therapeutic steps are discussed.

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M. Beatriz S. Lopes

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Rachel Grossman, Erez Nossek, Nir Shimony, Michal Raz and Zvi Ram

The authors report a case of primary CNS lymphoma located in the floor of the fourth ventricle that showed intense fluorescence after preoperative administration of 5-aminolevulinic acid. The authors believe that this is the first demonstration of a 5-aminolevulinic acid–induced fluorescence pattern in primary CNS lymphoma.

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Zvi Ram, Moshe Hadani, Roberto Spiegelman, Rina Tadmor and Itzchack Shacked

✓ Delayed nonhemorrhagic encephalopathy following mild head trauma is a rare condition with an unknown etiology. The few cases reported in the literature are in young adults, all of them in the era before computerized tomography (CT) became available, and all had a devastating clinical course with multifocal ischemia or necrotic lesions found at autopsy. A case is presented of a young man with this syndrome who survived the acute encephalopathic phase with severe residual neurological deficits. Repeat CT scans during and following the acute phase as well as magnetic resonance imaging showed diffuse multifocal lesions compatible with ischemic changes and demyelination in the “watershed” areas of the brain.

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Zvi Lidar, Yael Mardor, Tali Jonas, Raphael Pfeffer, Meir Faibel, Dvora Nass, Moshe Hadani and Zvi Ram

Object. A minority of patients with recurrent glioblastomas multiforme (GBMs) responds to systemic chemotherapy. The authors investigated the safety and efficacy of intratumoral convection-enhanced delivery (CED) of paclitaxel in patients harboring histologically confirmed recurrent GBMs and anaplastic astrocytomas.

Methods. Fifteen patients received a total of 20 cycles of intratumoral CED of paclitaxel. The patients were observed daily by performing diffusion-weighted (DW) magnetic resonance (MR) imaging to assess the convective process and routine diagnostic MR imaging to identify the tumor response. Effective convection was determined by the progression of the hyperintense signal within the tumor on DW MR images, which corresponded to a subsequent lytic tumor response displayed on conventional MR images. Of the 15 patients, five complete responses and six partial responses were observed, giving a response rate of 73%. The antitumor effect was confirmed by one biopsy and three en bloc resections of tumors, which showed a complete response, and by one tumor resection, which demonstrated a partial response. Lack of convection and a poor tumor response was associated with leakage of the convected drug into the subarachnoid space, ventricles, and cavities formed by previous resections, and was seen in tumors containing widespread necrosis. Complications included transient chemical meningitis in six patients, infectious complications in three patients, and transient neurological deterioration in four patients (presumably due to increased peritumoral edema).

Conclusions. On the basis of our data we suggest that CED of paclitaxel in patients with recurrent malignant gliomas is associated with a high antitumor response rate, although it is associated with a significant incidence of treatment-associated complications. Diffusion-weighted MR images may be used to predict a response by demonstrating the extent of convection during treatment. Optimization of this therapeutic approach to enhance its efficacy and reduce its toxicity should be explored further.

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Zvi R. Cohen, Nachshon Knoller, Moshe Hadani, Ben Davidson, Dvora Nass and Zvi Ram

✓ Intratumoral hemorrhage as the presenting symptom of spinal tumors is rare. The authors describe a patient who presented with rapidly progressing paraplegia 24 hours after sustaining a minor traumatic injury of the thoracic spine. Radiological evaluation demonstrated a low-thoracic intradural tumor that was resected and found to be a neurinoma in which severe intra- and peritumoral hemorrhage was revealed. The radiological, surgical, and pathological findings are presented and discussed.

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Zvi Ram, Thomas H. Shawker, Mary H. Bradford, John L. Doppman and Edward H. Oldfield

✓ Microadenomas of the pituitary vary in size, particularly those related to Cushing's disease. They are often not visualized on preoperative magnetic resonance (MR) imaging and may be difficult to find during surgical exploration of the pituitary. To enhance intraoperative localization of pituitary adenomas, we assessed the feasibility of using ultrasound to detect and localize pituitary tumors. Intraoperative ultrasound (IS) in the axial and sagittal planes was performed with an Intrascan system using a 12-MHz mechanically oscillating, end-firing transducer. Interpretation of the scans was performed by two individuals, who were usually blinded to the results of preoperative MR imaging or petrosal sinus sampling.

Twenty-eight patients were examined. Eighteen of these patients had microadenomas (1.5–7 mm), all with Cushing's disease; nine had macroadenomas (10–20 mm), three of which were adrenocorticotropic hormone—secreting, three growth hormone—secreting, two thyroid-stimulating hormone—secreting, and one nonfunctioning; and one patient had an intrasellar craniopharyngioma. Normal sellar and parasellar structures, such as intrapituitary cysts, the intracavernous carotid arteries, and the diaphragma sella were easily visualized. Twenty-three of the 28 tumors, including 13 of the 18 microadenomas, were detected on IS (82% sensitivity). Tumors were seen as hyperechoic masses in 19 patients, mixed echogenicity in three, and isoechoic in one. In most macroadenomas IS allowed visualization of the interface between the tumor and the normal pituitary gland. These results indicate the potential of IS to aid the intraoperative localization and definition of pituitary tumors.

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Zvi Ram, Stuart Walbridge, John D. Heiss, Kenneth W. Culver, R. Michael Blaese and Edward H. Oldfield

✓ The authors have recently shown the feasibility of eradicating brain tumors using in vivo retroviral-mediated transduction of tumors with the herpes simplex thymidine kinase (HStk) gene and ganciclovir therapy. However, thymidine kinase-transduced subcutaneous tumors in immunocompromised (athymic) mice were less responsive to this therapy than in immunocompetent animals, suggesting a role of the immune system in the process of tumor eradication. Broad suppression of humoral and cell-mediated immunity is found in patients with malignant gliomas. Interleukin-2 (IL-2) production and IL-2 receptor expression are decreased in glioma patients. These findings and the proposed association between lymphocytic infiltration of brain tumors and survival suggest that immune response modifiers may be useful in treating glioma patients.

To evaluate the role of local cytokine expression by tumor cells, alone or combined with HStk gene transfer and ganciclovir therapy, the authors investigated the efficacy of tumor (9L gliosarcoma) eradication in Fischer rats by in vitro and in vivo tumor transduction with the IL-2 gene alone or with a combined vector carrying both the HStk and IL-2 genes. Tumors injected with HStk vector-producer cells alone, with or without ganciclovir, and rats inoculated in the brain and subcutaneously with 9L cells that had previously been transduced in vitro served as controls. Murine vector-producer cells (3 × 106/50 µl) were injected into the brain tumors 7 days after tumor inoculation. Ganciclovir (15 mg/kg) was administered intraperitoneally twice daily for 10 days to animals that received HStk with or without IL-2 vector-producer cells, starting 5 days after producer-cell injection. The experiment was repeated with continuous daily treatment of all rats with oral dexamethasone (0.5 mg/kg). Rats were sacrificed 21 days after tumor inoculation, and the brains were removed for histological and immunohistochemical analysis for IL-2. Within each experimental group, tumors were found in a similar proportion in the dexamethasone-treated and untreated rats. Large brain tumors developed in all 10 rats that had been inoculated with 9L cells which had been pretransduced in vitro with the IL-2 gene, whereas only three of eight rats receiving subcutaneous inoculation of similar cells developed palpable tumors. No enhancement of tumor eradication was observed by adding the IL-2 gene in the HStk vector construct compared to the use of the vector with HStk alone. Lymphocytic infiltration was absent in all dexamethasone-treated rats but was observed in all treatment groups not receiving steroids. The degree of lymphocytic infiltration was not enhanced by intratumoral injection of IL-2 or IL-2/HStk vector-producer cells.

The findings suggest a limited role, if any, for immune enhancement by transduction with IL-2 to eradicate brain tumors, either used alone or in combination with HStk.