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Mark E. Linskey, A. Julio Martinez, Douglas Kondziolka, John C. Flickinger, Ann H. Maitz, Theresa Whiteside, and L. Dade Lunsford

✓ An experimental model with xenograft transplantation into the subrenal capsule of athymic (nude) mice was used to evaluate the early response of human acoustic schwannomas to stereotactic radiosurgery. After xenograft placement, 45 mice underwent radiosurgery with single doses of 10, 20, or 40 Gy using a 201-source 60Co gamma unit (4-mm collimator, single isocenter, 80% isodose line). The 45 radiosurgery-treated xenografts were compared with 15 untreated xenografts and 15 xenografts in mice that underwent “sham radiosurgery.” All five study groups were matched for the following pretreatment variables: patient of origin, animal weight, average xenograft diameter, and percentage of xenograft surface vascularity. Immediately prior to sacrifice of the mice all xenografts were evaluated in situ to determine the average tumor diameter, tumor volume, and percentage of surface vascularity. Mice were sacrificed 2 weeks, 1 month, or 3 months after radiosurgery. Blinded histological review was performed by an independent neuropathologist.

Tumor volume was reduced 33.6% after 2 weeks (p = 0.023) and 45% after 3 months (p = 0.018) in the 40-Gy radiosurgery group. Tumor volume was reduced by 46.2% after 1 month (p = 0.0002) and 35.2% after 3 months (p = 0.032) in the 20-Gy radiosurgery group. An average volume reduction of 16.4% was observed after 3 months (p = 0.17) in the 10-Gy radiosurgery group. At 3 months after surgery, tumor surface vascularity was reduced by an average of 19.7% (p = 0.043) in the 40-Gy radiosurgery group and 5.8% (p = 0.12) in the 20-Gy radiosurgery group and was unchanged in the 10-Gy radiosurgery group and both control groups. Histological examination demonstrated a higher incidence of hemosiderin deposits (p = 0.026) and vascular mural hyalinization (p = 0.032) in radiosurgery xenografts versus control.

The subrenal capsule xenograft in nude mice was an excellent model for studying the in vivo radiobiology of acoustic schwannomas after radiosurgery. Both cellular and vascular effects could be assessed serially in situ and the model was stable even 4 months after transplantation. Additional studies investigating radiobiology over periods better approximating the time course of clinical neuroimaging changes (6 to 12 months) are warranted.

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Douglas Kondziolka, L. Dade Lunsford, and A. Julio Martinez

✓ Many physicians rely upon neuroimaging studies alone to select therapy for adult patients suspected of having a glial neoplasm, in the belief that certain imaging features accurately characterize the histological diagnosis of low-grade astrocytoma. During a 4-year interval when both computerized tomography and magnetic resonance imaging was available, the authors performed stereotactic biopsies on 20 consecutive adult patients who were suspected of having an astrocytoma. The patients were generally young (mean age 37 years), had seizures (17 cases), and had lobar lesions. An accurate histological diagnosis was obtained, without morbidity, in all 20 patients. Only 10 (50%) in fact had low-grade astrocytomas, whereas nine (45%) had anaplastic astrocytomas and one (5%) had encephalitis. The results of this study indicate that modern high-resolution neuroimaging alone cannot be used as a reliable tool to predict the histological diagnosis of astrocytoma (50% false-positive rate). All patients with supratentorial mass lesions that exhibit the “typical” imaging features of astrocytoma should undergo stereotactic biopsy for confirmation in order that appropriate management may be planned.

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Salvador Somaza, Douglas Kondziolka, L. Dade Lunsford, John M. Kirkwood, and John C. Flickinger

✓ To determine local tumor control rates and survival of patients with melanoma metastases to the brain, the authors reviewed the results of 23 consecutive patients with a total of 32 tumors (19 patients had a solitary tumor and four had multiple tumors) who underwent adjuvant stereotactic radiosurgery. Tumor locations included the cerebral hemisphere (24 cases), brain stem (four cases), basal ganglia (two cases), and cerebellum (two cases). Fifteen patients had associated cranial symptomatology and eight had incidental metastases. All patients had tumors of 3 cm or less in diameter (mean tumor volume 2.5 cu cm), and all received fractionated whole-brain radiation therapy (30 Gy) in addition to radiosurgery (mean tumor margin dose 16 Gy). Nineteen patients were managed with both modalities at the time of diagnosis; four underwent radiosurgery 3 to 12 months after fractionated whole-brain radiotherapy. The mean patient follow-up period was 12 months (range 3 to 38 months).

After radiosurgery, eight patients improved, 13 remained stable, and two deteriorated. One patient subsequently required craniotomy because of intratumoral hemorrhage; this patient and three others are living 13 to 38 months after radiosurgery. Nineteen patients died, 18 from progression of their systemic disease and one from another hemorrhage into a new brain metastasis. The local tumor control rate was 97%. Only two patients subsequently developed new intracranial metastases. The median survival period after diagnosis was 9 months (range 3 to 38 months). The authors believe that stereotactic radiosurgery coupled with fractionated whole-brain irradiation is an effective management strategy for cerebral metastases from a melanoma. Multi-institutional trials are warranted to confirm that stereotactic radiosurgery results equal or surpass the outcome achieved with craniotomy and tumor resection.

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Douglas Kondziolka, Thomas Lemley, John R. W. Kestle, L. Dade Lunsford, Gerhard H. Fromm, and Peter J. Jannetta

✓ To evaluate the reported benefit of ipsilateral single-application ophthalmic anesthetic eyedrops in patients with typical trigeminal neuralgia, a randomized double-blind placebo-controlled trial was performed. Forty-seven patients were randomly assigned to receive two drops of either proparacaine (25 cases) or saline placebo (22 cases). The experimental and placebo groups were equivalent in regard to patient age, distribution of trigeminal neuralgia pain, duration of pain, current medication regimens, and number of prior procedures performed. Pain response was assessed at 3, 10, and 30 days after instillation using two pain rating scales and a measure of pain frequency. Treatment failure was defined in advance as any of the following: a lack of clinical response, the need for an increase in medication, or the need for surgery. No significant difference in outcomes was found between the two groups either when using a verbal pain rating scale (p = 0.24) or when comparing overall pain status (unchanged, improved throughout the study period, or temporarily improved) (p = 0.98). No difference in the frequency of trigeminal neuralgia attacks between the two treatment groups (scaled within five levels of pain frequency) was detected (p = 0.09). During follow-up monitoring, 11 patients in the test drug group and 14 in the placebo group required surgery because of persistent pain (p = 0.24). The results of this study indicate that single-application topical ophthalmic anesthesia reduces neither the severity nor the frequency of pain in comparison to placebo administration. Although a simple and safe treatment, the single application of topical ophthalmic eyedrops provides no short- or long-term benefit to patients with trigeminal neuralgia.

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Olusola K. Ogunrinde, L. Dade Lunsford, John C. Flickinger, and Douglas Kondziolka

✓ Twenty patients with acoustic nerve tumors (mean diameter ≤ 30 mm) and useful preoperative hearing were examined 2 years after stereotactic radiosurgery to determine the effectiveness of the surgery in the control of tumor growth and the preservation of cranial nerve function. Results showed tumor volume stabilization (12 cases) or reduction (seven cases) was achieved in a total of 19 patients (95%). Useful hearing (defined as Gardner and Robertson Class I or II) preservation was obtained in 100% of cases immediately postoperatively, 50% at 6 months, and 45% at both 1 and 2 years. Two years after stereotactic radiosurgery, facial nerve function was preserved in 90% of patients and 75% continued to have normal trigeminal nerve function. All patients returned to and maintained their preoperative functional status within 3 to 5 days after radiosurgery.

These findings indicate that stereotactic radiosurgery with multiple isocenters and narrow radiation beams is a safe and effective management strategy for progressive acoustic nerve tumors. Auditory, facial, and trigeminal nerve function can be preserved in most patients. Prevention of further growth and preservation of cranial nerve function appear to be satisfactory goals in the current management of patients with acoustic neuromas.

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L. Dade Lunsford, Salvador Somaza, Douglas Kondziolka, and John C. Flickinger

✓ The authors investigated the outcome of stereotactic biopsy and radiotherapy in 35 consecutive adult patients with nonanaplastic, nonpilocytic astrocytomas who were diagnosed between 1982 and 1992. The median patient age at presentation was 32 years. All received fractionated external-beam radiation therapy (median dose 56 Gy) as the initial management strategy. Additional treatment in two patients included intracavitary irradiation with colloidal phosphorus-32.

Six patients (17%) had documented tumor progression during the follow-up interval and died. Three others died of causes unrelated to their tumor. Median survival after stereotactic biopsy and irradiation was 118 months (9.8 years). Median survival from the time of onset of neurological symptoms was 148 months (12.3 years). Only three patients required delayed cytoreductive surgery.

The outcome of brain astrocytomas, although improved because of earlier diagnosis and therapy, does not substantiate this tumor as having benign behavior; early recognition with neuroimaging, immediate histological diagnosis via stereotactic biopsy, and initial fractionated radiation therapy may provide the potential for longer survival for patients with low-grade astrocytomas. The majority of such surviving patients have a satisfactory quality of life, which is manifested by prolonged normal functional and employment status. The survival data reported in this prospective Phase I–II clinical trial suggest that stereotactic biopsy and radiation therapy are appropriate initial management strategies for astrocytomas.