Gordon T. Sakamoto

Staged stereotactic irradiation for acoustic neuroma.

OBJECTIVE: Stereotactic radiosurgery has proven effective in the treatment of acoustic neuromas. Prior reports using single-stage radiosurgery consistently have shown excellent tumor control, but only up to a 50 to 73% likelihood of maintaining hearing at pretreatment levels. Staged, frame-based radiosurgery using 12-hour interfraction intervals previously has been shown by our group to achieve excellent tumor control while increasing the rate of hearing preservation at 2 years to 77%. The arrival of CyberKnife (Accuray, Inc., Sunnyvale, CA) image-guided radiosurgery now makes it more practical to treat acoustic neuroma with a staged approach. We hypothesize that such factors may further minimize injury of adjacent cranial nerves. In this retrospective study, we report our experience with staged radiosurgery for managing acoustic neuromas. METHODS: Since 1999, the CyberKnife has been used to treat more than 270 patients with acoustic neuroma at Stanford University. Sixty-one of these patients have now been followed up for a minimum of 36 months and form the basis for the present clinical investigation. Among the treated patients, the mean transverse tumor diameter was 18.5 mm, whereas the total marginal dose was either 18 or 21 Gy using three 6- or 7-Gy fractions. Audiograms and magnetic resonance imaging were obtained at 6-months intervals after treatment for the first 2 years and then annually thereafter. RESULTS: Of the 61 patients with a minimum of 36 months of follow-up (mean, 48 mo), 74% of patients with serviceable hearing (Gardner-Robinson Class 1–2) maintained serviceable hearing at the last follow-up, and no patient with at least some hearing before treatment lost all hearing on the treated side. Only one treated tumor (2%) progressed after radiosurgery; 29 (48%) of 61 decreased in size and 31 (50%) of the 61 tumors were stable. In no patients did new trigeminal dysfunction develop, nor did any patient experience permanent injury to their facial nerve; two patients experienced transient facial twitching that resolved in 3 to 5 months. CONCLUSION: Although still preliminary, these results indicate that improved tumor dose homogeneity and a staged treatment regimen may improve hearing preservation in acoustic neuroma patients undergoing stereotactic radiosurgery.

Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1

The ECM protein Del-1 is one of several novel ECM proteins that accumulate around angiogenic blood vessels in embryonic and tumor tissue and promote angiogenesis in the absence of exogenous growth factors. Del-1 expressed in mouse or rabbit ischemic hind-limb muscle by gene transfer rapidly promotes new blood vessel formation and restores muscle function. This angiogenic ECM protein initiates angiogenesis by binding to integrin alphavbeta5 on resting endothelium, thereby resulting in expression of the transcription factor Hox D3 and integrin alphavbeta3. Hox D3 converts resting endothelium to angiogenic endothelium by inducing expression of proangiogenic molecules such as integrin alphavbeta3. These findings provide evidence for an angiogenic switch that can be initiated in the absence of exogenous growth factors and indicate that the angiogenic matrix protein Del-1 may be a useful tool for the therapy of ischemic disease.

Multisession stereotactic radiosurgery for vestibular schwannomas: single-institution experience with 383 cases.

BACKGROUND Single-session stereotactic radiosurgery (SRS) treatment of vestibular schwannomas results in excellent tumor control. It is not known whether functional outcomes can be improved by fractionating the treatment over multiple sessions. OBJECTIVE To examine tumor control and complication rates after multisession SRS. METHODS Three hundred eighty-three patients treated with SRS from 1999 to 2007 at Stanford University Medical Center were retrospectively reviewed. Ninety percent were treated with 18 Gy in 3 sessions, targeting a median tumor volume of 1.1 cm3 (range, 0.02-19.8 cm3). RESULTS During a median follow-up duration of 3.6 years (range, 1-10 years), 10 tumors required additional treatment, resulting in 3- and 5-year Kaplan-Meier tumor control rates of 99% and 96%, respectively. Five-year tumor control rate was 98% for tumors < 3.4 cm3. Neurofibromatosis type 2–associated tumors were associated with worse tumor control (P = .02). Of the 200 evaluable patients with pre-SRS serviceable hearing (Gardner-Robertson grade 1 and 2), the crude rate of serviceable hearing preservation was 76%. Smaller tumor volume was associated with hearing preservation (P = .001). There was no case of post-SRS facial weakness. Eight patients (2%) developed trigeminal dysfunction, half of which was transient. CONCLUSION Multisession SRS treatment of vestibular schwannomas results in an excellent rate of tumor control. The hearing, trigeminal nerve, and facial nerve function preservation rates reported here are promising.

Predictors of peritumoral edema after stereotactic radiosurgery of supratentorial meningiomas.

OBJECTIVEAnecdotal evidence suggests that radiosurgical ablation of parasagittal meningiomas may be associated with increased risk of subsequent edema. Potential predictors of postradiosurgical peritumoral edema, including parasagittal tumor location, tumor size, and treatment dose, were evaluated. METHODSWe retrospectively reviewed records of 102 patients with 111 supratentorial meningiomas treated with CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS). A median marginal dose of 18.0 Gy (range, 11.3–25.0 Gy) was delivered in 1 to 5 sessions (fractions). Potential predictors of posttreatment symptomatic edema were evaluated using Fishers exact test. RESULTSOf the 102 patients followed for a mean of 20.9 months (range, 6–77 mo), 15 (14.7%) developed symptomatic edema after SRS. Nine of 31 with parasagittal meningiomas (29.0%) and 6 of 80 with nonparasagittal supratentorial meningiomas (7.5%) developed symptomatic edema (P = 0.0053). Compared with patients with meningiomas in nonmidline supratentorial locations, patients with parasagittal meningiomas were more than 4 times as likely to develop symptomatic edema after SRS (odds ratio, 4.1; 95% confidence interval, 1.5–11.5). The 6-, 12-, and 18-month actuarial rates of symptomatic edema development were significantly greater for patients with parasagittal meningiomas than for patients with nonparasagittal meningiomas (17.8 versus 1.3%, 25.4 versus 5.8%, and 35.2 versus 7.8%, respectively). CONCLUSIONPatients with parasagittal meningiomas are at greater risk of developing peritumoral symptomatic edema after SRS. Close follow-up after SRS may be particularly important in such patients. These results highlight the need to pursue strategies that could decrease the incidence of postradiosurgical edema in patients with parasagittal meningioma.

Cyberknife stereotactic radiosurgical rhizotomy for trigeminal neuralgia: anatomic and morphological considerations.

OBJECTIVETo search for correlations between specific anatomic, geometric, and morphological properties of the trigeminal nerve and the success of radiosurgical treatment and elimination of facial hypesthesia as a complication. METHODSForty-six patients with at least 6 months of follow-up after CyberKnife (Accuray, Inc., Sunnyvale, CA) rhizotomy were retrospectively reviewed. Patients treated after 2004 were entered into the study after congruity in treatment parameters was established. Anatomic variations regarding the length of each nerve segment and angle of trigeminal nerve takeoff from brainstem to Meckels cave in the axial and sagittal planes were studied. Dose distribution to surrounding critical structures (brainstem and trigeminal ganglion) was measured. After spatial relationships of involved structures and dose distributions were recorded, their relationship to treatment success, failure, or complication (primarily facial numbness) was tabulated. RESULTSForty-five patients (97.2%) experienced pain relief immediately or within weeks. Thirty-four patients maintained excellent outcome. Some degree of facial numbness developed in 18 patients (39.1%) and was mild in 11 of them (Grade II on the Barrow Neurological Institute scale). Patients with a sagittal-angle trigeminal nerve takeoff from the brainstem in the range of 150 to 170 degrees measured from the horizontal plane had a more favorable outcome (P = 0.03) than patients with less obtuse relationships to the proximal nerve origin. Patients who received higher doses of radiation to the brainstem/dorsal root entry zone of the trigeminal nerve experienced a higher rate of posttreatment facial anesthesia. CONCLUSIONThere may be important anatomic and geometric relationships between the treated trigeminal nerve and surrounding critical structures that warrant pretreatment target volume placement and dose distribution considerations.OBJECTIVE To search for correlations between specific anatomic, geometric, and morphological properties of the trigeminal nerve and the success of radiosurgical treatment and elimination of facial hypesthesia as a complication. METHODS Forty-six patients with at least 6 months of follow-up after CyberKnife (Accuray, Inc., Sunnyvale, CA) rhizotomy were retrospectively reviewed. Patients treated after 2004 were entered into the study after congruity in treatment parameters was established. Anatomic variations regarding the length of each nerve segment and angle of trigeminal nerve takeoff from brainstem to Meckels cave in the axial and sagittal planes were studied. Dose distribution to surrounding critical structures (brainstem and trigeminal ganglion) was measured. After spatial relationships of involved structures and dose distributions were recorded, their relationship to treatment success, failure, or complication (primarily facial numbness) was tabulated. RESULTS Forty-five patients (97.2%) experienced pain relief immediately or within weeks. Thirty-four patients maintained excellent outcome. Some degree of facial numbness developed in 18 patients (39.1%) and was mild in 11 of them (Grade II on the Barrow Neurological Institute scale). Patients with a sagittal-angle trigeminal nerve takeoff from the brainstem in the range of 150 to 170 degrees measured from the horizontal plane had a more favorable outcome (P = 0.03) than patients with less obtuse relationships to the proximal nerve origin. Patients who received higher doses of radiation to the brainstem/dorsal root entry zone of the trigeminal nerve experienced a higher rate of posttreatment facial anesthesia. CONCLUSION There may be important anatomic and geometric relationships between the treated trigeminal nerve and surrounding critical structures that warrant pretreatment target volume placement and dose distribution considerations.

Cochlea Radiation Dose Correlates with Hearing Loss After Stereotactic Radiosurgery of Vestibular Schwannoma

OBJECTIVE For multisession radiosurgery, no published data relate the volume and dose of cochlear irradiation to quantified risk of hearing loss. We conducted a retrospective, dosimetric study to evaluate the relationship between hearing loss after stereotactic radiosurgery (SRS) and the dose-volume of irradiated cochlea. METHODS Cochlear dose data were retrospectively collected on consecutive patients who underwent SRS (18 Gy in 3 sessions) for vestibular schwannoma between 1999 and 2005 at Stanford University Hospital. Inclusion criteria included Gardner-Robertson (GR) grade I or II hearing prior to radiosurgical treatment, complete audiograms, and magnetic resonance imaging (MRI) follow-up. A cochlea dose-volume histogram was generated for each of the 94 patients who qualified for this study. RESULTS GR grade I-II hearing posttreatment was maintained in 74% of patients (70/94). Median time to last follow-up audiogram was 2.4 years (range 0.4-8.9) and to last MRI was 3.6 years (range 0.5-9.4). Each higher level of cochlear irradiation was associated with increased risk of hearing loss. Larger cochlear volume was associated with lower risk of hearing loss. Controlling for differences in cochlear volume among subjects, each additional mm(3) of cochlea receiving 10 to 16 Gy (single session equivalent doses of 6.6-10.1 Gy3) significantly increased the odds of hearing loss by approximately 5%. CONCLUSIONS Larger cochlear volume is associated with lower risk of hearing loss following trisession SRS for vestibular schwannoma. Controlling for this phenomenon, higher radiation dose and larger irradiated cochlear volume are significantly associated with higher risk of hearing loss. This study confirms and quantifies the risk of hearing loss following trisession SRS for vestibular schwannoma.

Stereotactic Radiosurgery of Cranial Nonvestibular Schwannomas: Results of Single- and Multisession Radiosurgery

BACKGROUND:Surgical resection of nonvestibular cranial schwannomas carries a considerable risk of postoperative complications. Stereotactic radiosurgery (SRS) offers a non-invasive treatment alternative. The efficacy and safety of multi-session SRS of nonvestibular cranial schwannomas has not been well studied. OBJECTIVE:To analyze the results of single- and multi-session SRS of nonvestibular cranial schwannomas. METHODS:From 2001 to 2007, 42 lesions in 40 patients were treated with SRS at Stanford University Medical Center, targeting schwannomas of cranial nerves IV (n = 1), V (n = 18), VII (n = 6), X (n = 5), XII (n = 2), jugular foramen (n = 8), and cavernous sinus (n = 2). SRS was delivered to a median marginal dose of 18 Gy (range, 15-33 Gy) in 1 to 3 sessions, targeting a median tumor volume of 3.2 cm3 (range, 0.1-23.7 cm3). The median doses for treatments in 1 (n = 18), 2 (n = 9), and 3 (n = 15) sessions were 17.5, 20, and 18 Gy, respectively. RESULTS:With a median follow-up of 29 months (range, 6-84 months), tumor control was achieved in 41 of the 42 lesions. Eighteen of 42 lesions (43%) decreased in size; 23 tumors (55%) remained stable. There were 2 cases of new or worsening cranial nerve deficits in patients treated in single session; no patient treated with multi-session SRS experienced any cranial nerve toxicity (P = 0.18). CONCLUSION:SRS of nonvestibular cranial schwannomas provides excellent tumor control with minimal risk of complications. There was a trend towards decreased complications with multi-session SRS.

Cyberknife radiosurgery for trigeminal schwannomas.

OBJECTIVE Trigeminal schwannomas (TS) are benign tumors that are managed by surgical resection and/or stereotactic radiosurgery. Most radiosurgical series report results using the gamma knife. The CyberKnife (Accuray, Inc., Sunnyvale, CA) is a frameless, robotic stereotactic radiosurgical system. In this series, we report our experience using the CyberKnife in the treatment of TS. METHODS We retrospectively reviewed the medical records and diagnostic imaging in 13 consecutive patients with TS who were treated with the CyberKnife from 2003 to 2007. Seven patients had a previous surgical resection. The mean tumor volume was 6.3 mL (range, 0.39-19.98 mL), and the mean marginal dose was 18.5 Gy. Six of the tumors were treated in a single session. The mean clinical follow-up period was 21.8 months (range, 7-53 months). RESULTS In this series, the tumor control rate was 100%. The average reduction in tumor volume was 45% (range, 14-98%). A modest improvement in facial pain was noted in 4 of the 6 patients who presented with this symptom. One patient had improvement in facial numbness, and another had improvement in pretreatment headaches. One patient developed jaw weakness and facial dysesthesia, and another patient developed asymptomatic radiation necrosis. CONCLUSION Although the length of follow-up is limited, we report our initial experience with CyberKnife treatment of TS. Our results demonstrate tumor control rates and clinical outcomes that parallel those of previous reports using gamma knife radiosurgery; however, long-term follow-up studies are needed.OBJECTIVETrigeminal schwannomas (TS) are benign tumors that are managed by surgical resection and/or stereotactic radiosurgery. Most radiosurgical series report results using the gamma knife. The CyberKnife (Accuray, Inc., Sunnyvale, CA) is a frameless, robotic stereotactic radiosurgical system. In this series, we report our experience using the CyberKnife in the treatment of TS. METHODSWe retrospectively reviewed the medical records and diagnostic imaging in 13 consecutive patients with TS who were treated with the CyberKnife from 2003 to 2007. Seven patients had a previous surgical resection. The mean tumor volume was 6.3 mL (range, 0.39–19.98 mL), and the mean marginal dose was 18.5 Gy. Six of the tumors were treated in a single session. The mean clinical follow-up period was 21.8 months (range, 7–53 months). RESULTSIn this series, the tumor control rate was 100%. The average reduction in tumor volume was 45% (range, 14–98%). A modest improvement in facial pain was noted in 4 of the 6 patients who presented with this symptom. One patient had improvement in facial numbness, and another had improvement in pretreatment headaches. One patient developed jaw weakness and facial dysesthesia, and another patient developed asymptomatic radiation necrosis. CONCLUSIONAlthough the length of follow-up is limited, we report our initial experience with CyberKnife treatment of TS. Our results demonstrate tumor control rates and clinical outcomes that parallel those of previous reports using gamma knife radiosurgery; however, long-term follow-up studies are needed.

Comparison of developmental endothelial locus-1 angiogenic factor with vascular endothelial growth factor in a porcine model of cardiac ischemia

BACKGROUND This study compared the angiogenic effects of developmental endothelial locus-1 (DEL-1), vascular endothelial growth factor (VEGF), as well as the negative control, beta-galactosidase (beta-gal), in a porcine model of cardiac ischemia. METHODS Twenty pigs underwent left circumflex artery occlusions. After 3 weeks, the animals received myocardial injections of adenovirus expressing beta-gal (n=6), DEL-1 (n=7), or VEGF (n=7). At 7 weeks, animals were assessed for both function and coronary flow and compared with baseline measurements. RESULTS Regional wall motion index and global ejection fraction showed deterioration in function in the beta-gal group and no change in the VEGF and DEL-1 groups between the treatment and harvest time points. Preload recruitable stroke work suggested functional improvement in the VEGF group (35.8 +/- 8.6 vs 56.4 +/- 17.8, p = 0.033). The increase in the DEL-1 group was not statistically significant (27.3 +/- 9.8 vs, 40.2 +/- 19.4, p = 0.067). The beta-gal group exhibited minimal change (30.7 +/- 14.8 vs 35.9 +/- 12.1, p = 0.96). Regional blood flow as assessed by fluorescent microspheres was improved under stress conditions in the VEGF group (1.00 +/- 0.15 vs 1.15 +/-0.22, p = 0.03). CONCLUSIONS Treatment with VEGF led to a modest improvement in regional blood flow and cardiac function in previously ischemic myocardial tissue.