Faculty Bibliography

BACKGROUND: Stereotactic radiosurgery, with or without whole-brain radiation therapy, has become a valued management choice for patients with brain metastases, although their median survival remains limited. In patients who receive successful extracranial cancer care, patients who have controlled intracranial disease are living longer. The authors evaluated all brain metastasis in patients who lived for > or = 4 years after radiosurgery to determine clinical and treatment patterns potentially responsible for their outcome. METHODS: Six hundred seventy-seven patients with brain metastases underwent 781 radiosurgery procedures between 1988 and 2000. Data from the entire series were reviewed; and, if patients had > or = 4 years of survival, then they were evaluated for information on brain and extracranial treatment, symptoms, imaging responses, need for further care, and management morbidity. These long-term survivors were compared with a cohort who lived for < 3 months after radiosurgery (n = 100 patients). RESULTS: Forty-four patients (6.5%) survived for > 4 years after radiosurgery (mean, 69 mos with 16 patients still alive). The mean age at radiosurgery was 53 years (maximum age, 72 yrs), and the median Karnofsky performance score (KPS) was 90. The lung (n = 15 patients), breast (n = 9 patients), kidney (n = 7 patients), and skin (melanoma; n = 6 patients) were the most frequent primary sites. Two or more organ sites outside the brain were involved in 18 patients (41%), the primary tumor plus lymph nodes were involved in 10 patients (23%), only the primary tumor was involved in 9 patients (20%), and only brain disease was involved in 7 patients (16%), indicating that extended survival was possible even in patients with multiorgan disease. Serial imaging of 133 tumors showed that 99 tumors were smaller (74%), 22 tumors were unchanged (17%), and 12 tumors were larger (9%). Four patients had a permanent neurologic deficit after brain tumor management, and six patients underwent a resection after radiosurgery. Compared with the patients who had limited survival (< 3 mos), long-term survivors had a higher initial KPS (P = 0.01), fewer brain metastases (P = 0.04), and less extracranial disease (P < 0.00005). CONCLUSIONS: Although the expected survival of patients with brain metastases may be limited, selected patients with effective intracranial and extracranial care for malignant disease can have prolonged, good-quality survival. The extent of extracranial disease at the time of radiosurgery was predictive of outcome, but this does not necessarily mean that patients cannot live for years if treatment is effective.

Therapeutic brain irradiation can cause progressive decline in cognitive function, particularly in children, but the reason for this effect is unclear. The study explored whether age-related differences in apoptotic sensitivity might contribute to the increased vulnerability of the young brain to radiation. Postnatal day 1 (P1) to P30 mice were treated with 0-16 Gy whole-body X-irradiation. Apoptotic cells were identified and quantified up to 48 h later using the TdT-UTP nick end-labelling method (TUNEL) and immunohistochemistry for activated caspase-3. The number of neuron-specific nuclear protein (NeuN)-positive and -negative cells were also counted to measure neuronal and non-neuronal cell loss. Significantly greater TUNEL labelling occurred in the cortex of irradiated P1 animals relative to the other age groups, but there was no difference among the P7, P14 and P30 groups. Irradiation decreased the %NeuN-positive cells in the mice irradiated on P1, whereas in P14 animals, irradiation led to an increase in the %NeuN-positive cells. These data demonstrate that neocortical neurons of very young mice are more susceptible to radiation-induced apoptosis. However, this sensitivity decreases rapidly after birth. By P14, acute cell loss due to radiation occurs primarily in non-neuronal populations.

OBJECTIVE: Dural arteriovenous fistulas (DAVFs) comprise 10% to 15% of all arteriovenous malformations. Recent studies have demonstrated promising results when radiosurgery is used for DAVFs. We retrospectively analyzed our patients with DAVFs who received stereotactic radiosurgery with or without embolization. METHODS: Between 1991 and 2002, 18 patients with 23 angiographically confirmed symptomatic DAVFs underwent gamma knife radiosurgery, either alone (n = 8) or in combination with embolization (n = 10). A retrospective chart review was performed to identify DAVF location, venous drainage pattern, radiosurgery dosimetry, clinical outcomes, and imaging results. The series included 9 men and 9 women with a mean age of 65 (range 50-89) years. Nine patients received particulate, coil, and/or absolute ethanol embolization before radiosurgery, and 1 patient received particulate embolization after radiosurgery. The mean duration of clinical follow-up was 43 (range 2-116) months. The mean margin radiosurgery dose was 20 (range 15-30) Gy. RESULTS: Nine patients had complete resolution of their presenting symptoms, and 9 patients had resolution of all but 1 of their presenting symptoms. Angiographic follow-up (mean 46 months) was performed on 8 patients demonstrating complete obliteration in all the cases. Seven patients evaluated by magnetic resonance angiography or computed tomography angiography showed no evidence of DAVF (4 patients) or decreased DAVF size (3 patients). After radiosurgery, 1 patient developed a temporary hemiparesis. Two permanent neurological deficits occurred after embolization before radiosurgery. No patient had an intracranial hemorrhage after treatment. CONCLUSION: Stereotactic radiosurgery provides effective long-term relief of symptoms in selected patients with DAVFs.

OBJECT: Deep brain stimulation (DBS) of the thalamus is used for the treatment of patients with medically refractory essential tremor (ET). The authors evaluated patient outcomes after DBS surgery. METHODS: Clinical outcomes were evaluated in 19 patients who had undergone DBS surgery by using the Fahn-Tolosa-Marin clinical tremor rating scale. All adverse outcomes were also systematically recorded during follow-up outpatient visits. Eighteen DBS systems were implanted. The median follow-up period after surgery was 27 months (range 10-75 months). The preoperative mean Fahn-Tolosa-Marin action tremor score was 3.3 +/- 0.5, and the postoperative mean score with the DBS system activated was 0.8 +/- 0.4. The mean preoperative writing score was 2.8 +/- 0.9, and the postoperative mean writing score with the DBS system activated was 1 +/- 0.6. (Wilcoxon rank-sum test, p < 0.005). Fourteen patients were treated with bipolar stimulation, and four eventually required monopolar stimulation. Complications included lead breakage (one patient); temporary erythema of the incision through which the pulse generator had been implanted, which required oral antibiotics (one patient); electrode migration, which required surgery (one patient); and mild hand tingling during stimulation (three patients). Twelve of 18 patients with implanted systems experienced no morbid condition. CONCLUSIONS: Thalamic DBS is safe and effective for medically refractory ET. Stimulator adjustments can frequently occur in some patients, and tremor may worsen despite a readjustment in the system.

PURPOSE OF REVIEW: This review is focused on indications for resection, stereotactic radiosurgery, and fractionated radiotherapy for patients with single or multiple brain metastases. Our purpose is to summarize the indications and effect of these management approaches. RECENT FINDINGS: Brain metastases are a frequent challenge in patients with extracranial solid cancers. More than 40% of patients with cancer will develop metastases to the brain. While some patients present with large lesions and symptoms related to mass effect, many are diagnosed when asymptomatic tumors are found on screening studies. The main options for patients with brain metastases are whole brain radiation therapy, surgical resection, and stereotactic radiosurgery. Much information regarding outcomes, survival, management morbidity, and quality of life is available. Randomized, class III clinical trials demonstrate that multimodal therapy is important for both life quality and extended survival. A better understanding of the current therapeutic options should result in improvements in patient care. SUMMARY: This is a review of the literature from May 2004 to June 2005 with special attention on publications related to effect on quality of life with different procedures and therapies.

OBJECT: No definitive treatment exists to restore lost brain function following a stroke. Transplantation of cultured neuronal cells has been shown to be safe and effective in animal models of stroke and safe in a Phase 1 human trial. In the present study the authors tested the usefulness of human neuron transplantation followed by participation in a 2-month stroke rehabilitation program compared with rehabilitation alone in patients with substantial fixed motor deficits associated with a basal ganglia stroke. METHODS: Human neuronal cells (LBS-Neurons; Layton BioScience, Inc.) were delivered frozen and then thawed and formulated on the morning of surgery. The entry criteria in this randomized, observer-blinded trial of 18 patients included age between 18 and 75 years, completed stroke duration of 1 to 6 years, presence of a fixed motor deficit that was stable for at least 2 months, and no contraindications to stereotactic surgery. Patients were randomized at two centers to receive either 5 or 10 million implanted cells in 25 sites (seven patients per group) followed by participation in a stroke rehabilitation program, or to serve as a nonsurgical control group (rehabilitation only; four patients). The surgical techniques used were the same at both centers. All patients underwent extensive pre- and postoperative motor testing and imaging. Patients received cyclosporine A for 1 week before and 6 months after surgery. The primary efficacy measure was a change in the European Stroke Scale (ESS) motor score at 6 months. Secondary outcomes included Fugl-Meyer, Action Research Arm Test, and Stroke Impact Scale scores, as well as the results of other motor tests. Nine strokes were ischemic in origin and nine were hemorrhagic. All 14 patients who underwent surgery (ages 40-70 years) underwent uncomplicated surgeries. Serial evaluations (maximum duration 24 months) demonstrated no cell-related adverse serological or imaging-defined effects. One patient suffered a single seizure, another had a syncopal event, and in another there was burr-hole drainage of an asymptomatic chronic subdural hematoma. Four of seven patients who received 5 million cells (mean improvement 6.9 points) and two of seven who received 10 million cells had improved ESS scores at 6 months; however, there was no significant change in the ESS motor score in patients who received cell implants (p = 0.756) compared with control or baseline values (p = 0.06). Compared with baseline, wrist movement and hand movement scores recorded on the Fugl-Meyer Stroke Assessment instrument were not improved (p = 0.06). The Action Research Arm Test gross hand-movement scores improved compared with control (p = 0.017) and baseline (p = 0.001) values. On the Stroke Impact Scale, the 6-month daily activities score changed compared with baseline (p = 0.045) but not control (p = 0.056) scores, and the Everyday Memory test score improved in comparison with baseline (p = 0.004) values. CONCLUSIONS: Human neuronal cells can be produced in culture and implanted stereotactically into the brains of patients with motor deficits due to stroke. Although a measurable improvement was noted in some patients and this translated into improved activities of daily living in some patients as well, this study did not find evidence of a significant benefit in motor function as determined by the primary outcome measure. This experimental trial indicates the safety and feasibility of neuron transplantation for patients with motor stroke.

PURPOSE: To better analyze how whole-brain radiotherapy (WBXRT) affects long-term tumor control and toxicity from the initial stereotactic radiosurgery (SRS) for brain metastases, we studied these outcomes in patients who had survived at least 1 year from SRS. METHODS AND MATERIALS: We evaluated the results of gamma knife radiosurgery for 160 brain metastases in 110 patients who were followed for a median of 18 months (range, 12-122 months) after SRS. Eighty-two patients had a solitary brain metastasis and 28 patients had multiple metastases. Seventy patients (116 tumors) were treated with initial radiosurgery and WBXRT, whereas 40 patients (44 lesions) initially received radiosurgery alone. Median treatment volume was 1.9 cc in the entire group, 2.3 cc in the WBXRT group, and 1.6 cc in the SRS alone group. Median tumor dose was 16 Gy (range, 12-21 Gy). RESULTS: At 1, 3, and 5 years, local tumor control was 84.1% +/- 5.5%, 68.6% +/- 8.7%, and 68.6% +/- 8.7% with SRS alone compared with 93.1% +/- 2.4%, 87.7% +/- 4.9%, and 65.7% +/- 10.2%. with concurrent WBXRT and SRS (p = 0.0228, univariate). We found that WBXRT improved local control in patient subsets tumor volume > or =2 cc, peripheral dose < or =16 Gy, single metastases, nonradioresistant tumors, and lung cancer metastases (p = 0.0069, 0.0080, 0.0083, 0.0184, and 0.0348). Distal intracranial failure developed at 1, 3, and 5 years in 26.0% +/- 7.1%, 74.5% +/- 9.4%, and 74.5% +/- 9.4% with SRS alone compared with 20.7% +/- 4.9%, 49.0% +/- 8.7%, and 61.8% +/- 12.8% with concurrent WBXRT and SRS (p = 0.0657). We found a trend for improved distal intracranial control with WBXRT for only nonradioresistant tumors (p = 0.054). Postradiosurgery complications developed in 2.8% +/- 1.2% and 10.7% +/- 3.5% at 1 and 3-5 years and was unaffected by WBXRT (p = 0.7721). WBXRT did not improve survival in the entire series (p = 0.5027) or in any subsets. CONCLUSIONS: In this retrospective study of 1-year survivors of SRS for brain metastases, the addition of concurrent WBXRT to SRS was associated with an improved local control rate in patient subsets with tumor volume > or =2 cc, peripheral dose < or =16 Gy, single metastases, nonradioresistant tumors, and specifically lung cancer metastases. A trend was noted for improved distal intracranial control for patients having nonradioresistant tumors. Distant intracranial relapse >1 year posttreatment is a significant problem with or without initial WBXRT.