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Robert L. Martuza

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Daniel T. Ginat and Robert L. Martuza

Symptomatic vestibular schwannomas can be treated with resection (translabyrinthine, retrosigmoid [suboccipital], or middle cranial fossa approaches) or stereotactic radiosurgery. When appropriate, auditory brainstem stimulators can also be implanted in patients with current or impending hearing loss due to bilateral vestibular schwannomas. Imaging plays a prominent role in determining management following these procedures. In this article, the expected postoperative imaging appearances are depicted. The radiological features of complications are also reviewed, including recurrent tumor, fat graft necrosis, CSF leakage, infection, hydrocephalus, cerebral infarction, venous sinus thrombosis, hemorrhage, and temporal lobe and cerebellar contusions.

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John D. Steichen, Kathleen Dashner and Robert L. Martuza

✓ Hematoporphyrin derivative (HPD) is a photosensitizing agent that has been used to locate and kill tumors. The distribution of tritiated (3H)-HPD was studied in a transplantable canine glioma model following intraperitoneal or direct intraneoplastic injection. Compared to intraperitoneal adminstration of 3H-HPD, direct injection resulted in levels that were more than 2.5 times higher in tumor tissue and approximately 10 times lower in skin. Dose-corrected analysis of the data indicated that outside the central nervous system (CNS) the distribution of 3H-HPD is dose-related, regardless of route of injection. Within the CNS, direct injection leads to more efficient uptake of 3H-HPD, especially at the tumor periphery. Fluorescence microscopy confirmed the selective biodistribution of HPD fluorescence within the cytoplasm of tumor cells.

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Andrea L. Halliday, Raymond A. Sobel and Robert L. Martuza

✓ Benign spinal nerve sheath tumors (neurofibromas and schwannomas) often occur on dorsal nerve roots sporadically or in neurofibromatosis types 1 and 2. These are histologically benign tumors, and distinction between them is frequently not made by clinicians. To determine if there is a correlation between the histological pattern of benign spinal nerve sheath tumors and the type of neurofibromatosis, the clinical and pathological features of these tumors (86 surgical specimens and five autopsies) in 68 patients were reviewed. The patients were classified into one of four categories: neurofibromatosis type 1, neurofibromatosis type 2, uncertain, or sporadic.

The diagnostic criteria used for neurofibromatosis types 1 and 2 were established by the National Institutes of Health. Patients who did not fulfill criteria for either neurofibromatosis type 1 or 2 but who had multiple nervous system tumors or other stigmata of neurofibromatosis were designated “uncertain.” Spinal nerve sheath tumors were considered sporadic in 42 cases (40 schwannomas and two neurofibromas). In the 14 patients with neurofibromatosis type 1, all spinal nerve sheath tumors were neurofibromas. In six of the seven patients with neurofibromatosis type 2, all spinal nerve sheath tumors were schwannomas. One patient with neurofibromatosis type 2 had a spinal nerve sheath schwannoma and a tumor with features of both tumor types.

The authors conclude that spinal nerve sheath tumors in patients with neurofibromatosis type 1 are neurofibromas. In contrast, spinal nerve sheath tumors occurring in neurofibromatosis type 2 or sporadically are most frequently schwannomas. The distinct histological features of these tumors may reflect different pathogenetic mechanisms even though they arise at identical sites in neurofibromatosis types 1 and 2.

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Robert L. Martuza, Paul L. Kornblith and Theodore M. Liszczak

✓ Nine human optic gliomas were examined in tissue culture. Typically, growth from the explants revealed well differentiated bipolar cells with abundant 9 to 10 nm fibers similar to those observed in the surgical specimens. Multinucleation was rare except for one culture, which had as many as 20 nuclei arranged in a palisading fashion along the periphery of some of the cells. Degenerative changes of the 9 to 10 nm fiber bundles with the production of amorphous electron-dense deposits were observed both in vivo and in vitro, and were thought to represent the formation of Rosenthal fibers. A distinctive feature of some of the optic gliomas was the ability of their long, thin cellular processes to form fibrous tangles in tissue culture. The correlation of these fibrous tangles in culture with Rosenthal fibers in vivo is still uncertain.

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John D. Steichen, Michael J. Weiss, David R. Elmaleh and Robert L. Martuza

✓ Photodynamic therapy is a promising treatment for human brain tumors because of the selective retention of certain compounds by tumor cells. Certain lipophilic cationic compounds, such as tetraphenylphosphonium (TPP), are selectively taken up by a variety of carcinomas. Although preferential retention of TPP has been demonstrated for the breast carcinoma cell line MCF-7, this compound had not been tested previously on cells derived from nervous system tumors. In the present study, tritiated-TPP (3H-TPP) uptake and retention for eight different cell cultures of three histologically different types of nervous system tumors was measured and the data were compared to a positive control (MCF-7) and negative controls (normal African Green monkey kidney epithelium (CV-1) and the normal human fibroblast (WI-38) cell lines). Uptake and retention characteristics could be grouped by specific pathological tumor types, but individual tumor variability was notable. Malignant astrocytoma (grade III/III glioblastoma) and malignant neurofibrosarcoma cells showed preferential uptake and retention of 3H-TPP relative to meningioma cells and normal controls. A clonogenic assay utilizing the cytotoxic lipophilic cationic compound dequalinium showed strong retainers of 3H-TPP to be more susceptible to the effects of dequalinium than weak retainers. These data demonstrate that certain human and experimental animal nervous system tumor cell lines retain lipophilic compounds possessing a delocalized positive charge. Lipophilic cationic compounds may be useful in the intraoperative delineation of tumor margins and in the photodynamic therapy of certain nervous system tumors.

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Sameer A. Sheth, Jennifer L. Tirino and Robert L. Martuza

Microsurgery via the suboccipital approach is a common treatment option for vestibular schwannomas (VS). The procedure is performed under general anesthesia with cranial nerve monitoring in the supine position. Following suboccipital craniectomy, durotomy, CSF release from the foramen magnum, and identification of cranial nerve position, the tumor is debulked internally. The internal auditory canal is drilled and dissection of the tumor progresses. Following resection, the IAC is waxed and a fat graft placed. A watertight pericranial graft is sewn in and a titanium mesh cranioplasty placed. The muscle and skin are closed in layers.

The video can be found here: http://youtu.be/ialtKy3cuPU.

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Robert L. Martuza, Douglas C. Miller and David T. MacLaughlin

✓ Frozen tissue samples were obtained from meningiomas in 42 patients. Both cytosolic and nuclear fractions were tested for estradiol and progestin binding using equilibrium binding assays. The results were correlated with the age of the patient and the histological type and cellular density of the tumor.

Cytosolic estradiol binding was noted in 25 (60%) of 42 tumors, with eight (19%) of the 42 having levels over 10 femtomoles (fM)/mg protein. Nuclear estradiol binding was detected in 16 (57%) of 28 tumors, with six (21%) of the 28 having levels over 10 fM/mg protein. Cytosolic progestin binding was noted in 16 (73%) of 22 samples, with levels in nine (41%) of 22 being greater than 10 fM/mg protein. There was no correlation between the level of cytoplasmic progestin binding and either the level of cytoplasmic estradiol binding or the level of nuclear estradiol binding. In several specimens, levels of cytoplasmic progestin binding in excess of 100 fM/mg protein were found in tissues demonstrating little or no estradiol binding by either the nucleus or the cytosol. This discrepancy differs from the situation found in other hormonally responsive tissues such as breast or uterus, and suggests either a possible derangement of the normal cellular hormonal control mechanism or that the measured hormone binder is a molecule other than a classical hormone receptor.

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Deva S. Jeyaretna, Samuel D. Rabkin and Robert L. Martuza

✓Oncolytic viruses are one of many emerging cancer therapies. The surgical management of peripheral nerve tumors carries an inherent risk of damaging the nerves involved and so the search for novel therapies with reduced risk of morbidity continues. In this review the authors discuss the use of oncolytic herpes simplex virus (HSV) in the treatment of peripheral nerve tumors. Herpes simplex virus has a number of characteristics that make it a useful oncolytic vector, including its large, sequenced genome that can accommodate multiple transgenes, its lack of insertional mutagenesis, its ability to infect a wide array of cell types in various species, and the availability of well-established antiviral therapies to treat it. The efficacy of oncolytic HSV therapy against schwannomas and malignant peripheral nerve sheath tumors has been studied in multiple experimental models both in vitro and in vivo. The virus utilizes cell pathways unique to tumors to enhance its oncolytic efficacy, preferentially and effectively targeting and destroying peripheral nerve tumor cells without harming normal cells. This effect is augmented by trans-genes expressing antiangiogenic factors, such as dominant-negative fibroblast growth factor receptor and platelet factor 4, and displays synergy with chemotherapy. Different oncolytic HSV vectors have been tested, including hrR3, G207, and G47Δ. In addition, new animal models have been developed to test the efficacy of oncolytic HSV therapy in peripheral nerve tumors. The safety of oncolytic HSV is well-established and has been tested in nonhuman primates and in human clinical trials.

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Jeffrey R. Jay, David T. MacLaughlin, Kathleen R. Riley and Robert L. Martuza

✓ Meningiomas were removed from four patients and estradiol binding was measured in the tumor tissue. Cell cultures were established and an in vitro system was developed to test the biological activity of physiologically relevant concentrations (10−7 M and 10−9 M) of estradiol-17pβ, progesterone, and the antiestrogen, tamoxifen, on the growth of meningioma cells in early culture (passages 3 to 5). Assays of the frozen surgical specimens demonstrated cytosolic estradiol binding, with levels of 0.3 to 26.7 femtomoles (fM)/mg protein, in all four tumors. Nuclear estradiol binding was detected in three tumors, with levels of 16.8 to 39.5 fM/mg protein. In cell culture, estradiol at either 10−7 M or 10−9 M consistently stimulated cell growth in all four cultures. When tested alone, progesterone stimulated the growth of all four tumors and tamoxifen stimulated the growth of three of the four tumors, but the levels of stimulation produced by either of these compounds were less pronounced than the level produced by estradiol. When tested in combination with estradiol, progesterone significantly inhibited the growth stimulation produced by estradiol in all four meningioma cultures and tamoxifen significantly inhibited estradiol-induced growth stimulation in three of four cultures. It is not known if these effects are mediated by a hormone receptor or by a hormone binder different from a true receptor, or if they are caused by alterations in cellular metabolism that are independent of specific hormone binding. However, the authors conclude that this in vitro technique can be used to further study the biological activity of hormones on human meningiomas in order to answer these questions.