Effect of recombinant human bone morphogenetic protein-2 in an experimental model of spinal fusion in a radiated area.

STUDY DESIGN: An animal model of posterolateral intertransverse process spine fusion was used. OBJECTIVES: To investigate whether recombinant human bone morphogenetic protein-2 (rhBMP-2) can overcome the adverse effects of radiation treatment (RT) on spine fusion. SUMMARY OF BACKGROUND DATA: Spinal metastases are common. Some of these patients are candidates for spinal cord decompression and vertebral reconstruction; however, radiation has significant adverse effects on bone healing. METHODS: A posterolateral fusion model was used with rhBMP-2 or iliac crest bone graft (ICBG). Eighty one-year-old rabbits were divided into eight groups: 1) RT 14 days before surgery, rhBMP-2; 2) RT 14 days before surgery, ICBG; 3) RT 2 days after surgery, rhBMP-2; 4) RT 2 days after surgery, ICBG; 5) RT 14 days after surgery, rhBMP-2; 6) RT 14 days after surgery, ICBG; 7) no RT, rhBMP-2; 8) no RT, ICBG. Animals were killed approximately 35 days after surgery. Manual palpation was the definitive test of fusion. Biomechanical and histologic assessments were also performed. RESULTS: All rhBMP-2 groups had significantly greater fusion rates versus respective ICBG control groups: 1 (86%) versus 2 (0%) (P = 0.005), 3 (100%) versus 4 (0%) (P < 0.0001), 5 (100%) versus 6 (0%) (P < 0.0001), and 7 (100%) versus 8 (60%) (P = 0.003). Stiffness and ultimate strength did not differ significantly between the experimental and control groups. Histologic assessment confirmed new bone formation in the fusion masses from rhBMP-2 groups. CONCLUSIONS: Use of rhBMP-2 produced a significantly greater rate of fusion compared with ICBG in a previously radiated area in an animal model, without the morbidity of ICBG harvesting and without the risk of inadvertently using autograft contaminated by micrometastases.

Two-year clinical follow-up of 90Sr/90 Y beta-radiation versus placebo control for the treatment of in-stent restenosis.

BACKGROUND: It is an ongoing concern that intracoronary brachytherapy may possibly just delay the problem of in-stent restenosis ("late catch up"). For gamma-radiation, 3 placebo-controlled studies have shown the maintenance of the initially positive effect after 2 years, but similar data do not exist for beta-radiation. STents And Restenosis Trial (START) was the first placebo-controlled randomized trial for in-stent restenosis with beta-radiation; herein, we report the 2-year clinical follow-up. METHODS AND RESULTS: Two hundred and forty-four patients were randomized to active treatment, 232 patients to placebo (nonactive source train) treatment. The primary end point of efficacy was target vessel revascularization (TVR); primary safety end point was any major adverse cardiac event (MACE) at 8 months and 2 years. Two-year clinical outcome in patients receiving brachytherapy was based on 195 of 244 original patients (79.9%) and in the placebo arm on 183 of 232 original patients (78.9%). TVR was significantly reduced by 25%; from 36.6% (placebo) to 27.5% (brachytherapy) remained significant after 2 years (RR .7 [.57-.98], 95% CI -9.2 [-17.5-0.8]). The Kaplan-Meier analysis for TVR and MACE showed improvement beginning approximately 90 days after radiation and remained almost constant for the 2 following years. Freedom from TVR was significantly increased from 62.4% +/- 3.8% to 71.6% +/- 3.3% (P = .027) and freedom from MACE from 58.9% +/- 3.7% to 68.0% +/- 3.4% (P = .035). CONCLUSIONS: The START trial shows for the first time that the initial beneficial effects of intracoronary brachytherapy with beta-radiation using 90 Sr/ 90 Y are maintained at 2-year clinical follow-up period.

Is gross-total resection sufficient treatment for posterior fossa ependymomas?

OBJECT: The goals of this study were to analyze outcomes in patients with posterior fossa ependymomas, determine whether gross-total resection (GTR) alone is appropriate treatment, and evaluate the role of radiation therapy. METHODS: All patients with newly diagnosed intracranial ependymomas treated at Barrow Neurological Institute between 1983 and 2002 were identified. Those with supratentorial primary lesions, subependymomas, or neuraxis dissemination were excluded. Forty-five patients met the criteria for the study. Gross-total resection was accomplished in 32 patients (71%) and subtotal resection (STR) in 13 (29%). Radiation therapy was given to 25 patients: 13 following GTR and 12 after STR. The radiation fields were craniospinal followed by a posterior fossa boost in six patients and posterior fossa or local only in the remaining patients. With a median follow-up period of 66 months, the median duration of local control was 73.5 months with GTR alone, but has not yet been reached for patients with both GTR and radiotherapy (p = 0.020). The median duration of local control following STR and radiotherapy was 79.6 months. The 10-year actuarial local control rate was 100% for patients who underwent GTR and radiotherapy, 50% for those who underwent GTR alone, and 36% for those who underwent both STR and radiotherapy, representing significant differences between the GTR-plus-radiotherapy and GTR-alone cohorts (p = 0.018), and between the GTR-plus-radiotherapy and the STR-plus-radiotherapy group (p = 0.003). There was no significant difference in the 10-year actuarial local control rate between the GTR-alone and STR-plus-radiotherapy cohorts (p = 0.370). The 10-year overall survival was numerically superior in patients who underwent both GTR and radiotherapy: 83% compared with 67% in those who underwent GTR alone and 43% in those who underwent both STR and radiotherapy. These differences did not achieve statistical significance. Univariate analyses revealed that radiotherapy, tumor grade, and extent of resection were significant predictors of local control. CONCLUSIONS: Gross-total resection should be the intent of surgery when it can be accomplished with an acceptable degree of morbidity. Even after GTR has been confirmed with postoperative imaging, however, adjuvant radiotherapy significantly improves local control. The authors currently recommend the use of postoperative radiotherapy, regardless of whether the resection is gross total or subtotal.

Microvascular decompression after gamma knife surgery for trigeminal neuralgia: intraoperative findings and treatment outcomes.

OBJECT: The authors sought to determine whether the results of trigeminal microvascular decompression (MVD) are influenced by prior gamma knife surgery (GKS). METHODS: Gamma knife surgery is an established procedure for treating medically intractable trigeminal neuralgia but failures do occur. The authors assessed six patients (two men and four women; mean age 52 years) who experienced pain recurrence after GKS and elected to undergo trigeminal MVD via retrosigmoid craniotomy. Three patients underwent a single GKS to a maximal dose of 80 Gy, whereas three others underwent a second GKS to total of 120 to 135 Gy. At surgery, none of the six patients demonstrated excess arachnoid thickening, grossly apparent changes in the nerve itself, or any other tissue alterations that made successful mobilization of a blood vessel from the trigeminal root entry zone technically more difficult. A single individual had a small atherosclerotic plaque in the superior cerebellar artery near its contact point with the trigeminal nerve. Follow up at a mean of 25.4 months (range 7.5-42 months) indicated that five patients were pain free. One patient had improved but still relied on medications for pain control. CONCLUSIONS: In the authors' experience, trigeminal MVD can be performed without added difficulty in patients who have previously undergone GKS. The success rates seem similar to those normally associated with MVD. Patients who elect the less invasive option of GKS can be assured that trigeminal MVD remains a viable alternative at a later date if further surgery is required.

Surgery and permanent 125I seed paraspinal brachytherapy for malignant tumors with spinal cord compression.

PURPOSE: To evaluate the functional outcome, predictors of response, and toxicity from spinal surgery and 125I brachytherapy in patients with malignant tumors resulting in spinal cord compression. METHODS AND MATERIALS: Between July 1985 and September 2001, after surgical resection, 30 patients underwent 31 intraoperative paraspinal brachytherapy procedures at Barrow Neurological Institute. Twenty-four (with 25 procedures) had follow-up at our clinic and form the basis for this report. Surgical procedures were based on the location of the impinging lesion: corpectomy or spondylectomy in 13 cases and laminectomy in 12. Permanent 125I seeds in absorbable suture were placed with open exposure after resection. RESULTS: Spinal cord compression was cervical in 4 (16%), thoracic in 14 (56%), and lumbar in 7 (28%) of the 25 cases. One patient underwent two separate procedures at different spinal sites. Of the 25 brachytherapy sites, 22 also received external beam radiotherapy (EBRT): 5, EBRT with a planned brachytherapy boost; 4, brachytherapy and prompt EBRT after recovery; and 13, brachytherapy as salvage for local failure after prior EBRT. Three had no EBRT: 1 had lymphoma treated with chemotherapy, 1 had remote previous EBRT for a childhood tumor, and 1 refused EBRT. The mean follow-up was 19.8 months. The 2- and 3-year actuarial local control rate was 87.4% and 72.9%, respectively. Four sites (16.0%) experienced local failure. The mean time to recurrence for these 4 patients was 20.3 months. Three of the four had failed prior EBRT, with surgery and brachytherapy used for salvage. The 2- and 3-year actuarial overall survival rates were 24.0% and 16.0%, mean 19.2 months. An ambulatory function score was assigned pre- and postoperatively: I, normal ambulation; II, abnormal not requiring assistance; III, abnormal requiring assistance; and IV, unable to ambulate. All patients with score I, 91% of those with score II, 67% of those with score III, and 67% of those with score IV were ambulatory after the procedure; 84% had either normal or improved ambulation postoperatively. Morbidity was restricted to four postoperative events: one cerebrospinal fluid leak, two wound infections treated in situ without removal of seeds or instrumentation, and one pulmonary embolus. No myelopathies or other neurologic sequelae were encountered. CONCLUSION: This is the largest series in the literature exploring surgery and 125I brachytherapy in the treatment of malignant spinal cord compression. We found this to be well tolerated and to result in durable local control and ambulatory function. Our results suggest a benefit to aggressive local therapy in selected patients with spinal cord compression.

Randomized trial of 90Sr/90Y beta-radiation versus placebo control for treatment of in-stent restenosis.

BACKGROUND: After conventional treatment of in-stent restenosis, the incidence of recurrent clinical restenosis may approach 40%. We report the first multicenter, blinded, and randomized trial of intracoronary radiation with the use of a 90Sr/90Y beta-source for the treatment of in-stent restenosis. METHODS AND RESULTS: After successful catheter-based treatment of in-stent restenosis, 476 patients were randomly assigned to receive an intracoronary catheter containing either 90Sr/90Y (n=244) or placebo (n=232) sources. The prescribed dose 2 mm from the center of the source was 18.4 Gy for vessels between 2.70 and 3.35 mm in diameter and 23.0 Gy for vessels between 3.36 and 4.0 mm. The primary end point, ie, clinically driven target-vessel revascularization by 8 months, was observed in 56 (26.8%) of the patients assigned to placebo and 39 (17.0%) of the patients assigned to radiation (P=0.015). The incidence of the composite including death, myocardial infarction, and target-vessel revascularization was observed in 60 (28.7%) of the patients assigned to placebo and 44 (19.1%) of the patients assigned to radiation (P=0.024). Binary 8-month angiographic restenosis (> or =50% diameter stenosis) within the entire segment treated with radiation was reduced from 45.2% in the placebo-treated patients to 28.8% in the 90Sr/90Y-treated patients (P=0.001). Stent thromboses occurred in 1 patient assigned to placebo <24 hours after the procedure and in 1 patient assigned to 90Sr/90Y at day 244. CONCLUSIONS: The results of this study demonstrated that beta-radiation using 90Sr/90Y is both safe and effective for preventing recurrence in patients with in-stent restenosis.

Gamma knife radiosurgery for trigeminal neuralgia associated with multiple sclerosis.

OBJECT: The authors assessed the efficacy and complications from gamma knife radiosurgery (GKS) for multiple sclerosis (MS)-associated trigeminal neuralgia (TN). METHODS: There were 15 patients with MS-associated TN (MS-TN). Treatment involved three sequential protocols, 70 to 90-Gy maximum dose, using a single 4-mm isocenter targeting the ipsilateral trigeminal nerve at its junction with the pons with the 50% isodose. Pain was appraised by each patient by using Barrow Neurological Institute (BNI) Scores I through IV: I, no pain; II, occasional pain not requiring medication; IIIa, no pain but continued medication; IIIb, some pain, controlled with medication; IV, some pain, not controlled with medication; and V, severe pain/no pain relief. With a mean follow up of 17 months (range 6-38 months), 12 (80%) of 15 patients experienced pain relief. Three patients (20%) reported no relief (BNI Score V). For responders, the mean latency from treatment to the onset of pain relief was 13 days (range 1-61 days). Maximal relief was achieved after a mean latency of 56 days (range 1-157 days). Five patients underwent a second GKS after a mean interval of 534 days (range 231-946 days). The mean maximum dose at this second treatment was 48 Gy. The target was unchanged from the first treatment. All five patients who underwent repeated GKS improved. Complications were limited to delayed facial hypesthesias. Two (13%) of 15 patients experienced onset of numbness after the first GKS, as well as two of five patients following a second GKS. The patients found this mild and not bothersome. Each patient who developed hypesthesias also experienced complete pain relief. CONCLUSIONS: Gamma knife radiosurgery is an effective treatment for MS-TN. Radiosurgery carries an acceptable small risk of mild facial hypesthesias, and hypesthesia appears predictive of a favorable outcome.

Gamma knife radiosurgery for recurrent trigeminal neuralgia.

OBJECT: Pain may fail to respond or may recur after initial gamma knife radiosurgery (GKS) for trigeminal neuralgia (TN). The authors examined their experience with performing a second GKS procedure in these patients. METHODS: Twenty-nine patients underwent repeated GKS for TN at our institution between March 1997 and March 2002. Questionnaires were mailed to patients to assess the degree of their pain relief and the extent of facial numbness. Nineteen patients responded. All patients underwent repeated GKS involving a single 4-mm isocenter directed at the trigeminal nerve as it exited the brainstem (mean maximum dose 23.2 Gy). At a mean follow up of 13.5 months after the second procedure, 10 patients (53%) were pain free and medication free. Four patients (21%) were pain free but elected to continue medication in reduced dose, and two patients (11%) had incomplete but satisfactory pain control and were still taking medication. There was new-onset facial numbness in eight patients (42%), rated as tolerable in all instances. CONCLUSIONS: Patients with facial numbness had a greater likelihood of being pain free than those with no sensory loss. The authors observed no cases of corneal anesthesia, keratitis, or deafferentation pain.