Postoperative lead migration in deep brain stimulation surgery: Incidence, risk factors, and clinical impact.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for multiple movement disorders and shows substantial promise for the treatment of some neuropsychiatric and other disorders of brain neurocircuitry. Optimal neuroanatomical lead position is a critical determinant of clinical outcomes in DBS surgery. Lead migration, defined as an unintended post-operative displacement of the DBS lead, has been previously reported. Despite several reports, however, there have been no systematic investigations of this issue. This study aimed to: 1) quantify the incidence of lead migration in a large series of DBS patients, 2) identify potential risk factors contributing to DBS lead migration, and 3) investigate the practical importance of this complication by correlating its occurrence with clinical outcomes. METHODS: A database of all DBS procedures performed at UF was queried for patients who had undergone multiple post-operative DBS lead localization imaging studies separated by at least two months. Bilateral DBS implantation has commonly been performed as a staged procedure at UF, with an interval of six or more months between sides. To localize the position of each DBS lead, a head CT is acquired ~4 weeks after lead implantation and fused to the pre-operative targeting MRI. The fused targeting images (MR + stereotactic CT) acquired in preparation for the delayed second side lead implantation provide an opportunity to repeat the localization of the first implanted lead. This paradigm offers an ideal patient population for the study of delayed DBS lead migration because it provides a large cohort of patients with localization of the same implanted DBS lead at two time points. The position of the tip of each implanted DBS lead was measured on both the initial post-operative lead localization CT and the delayed CT. Lead tip displacement, intracranial lead length, and ventricular indices were collected and analyzed. Clinical outcomes were characterized with validated rating scales for all cases, and a comparison was made between outcomes of cases with lead migration versus those where migration of the lead did not occur. RESULTS: Data from 138 leads in 132 patients with initial and delayed lead localization CT scans were analyzed. The mean distance between initial and delayed DBS lead tip position was 2.2 mm and the mean change in intracranial lead length was 0.45 mm. Significant delayed migration (>3 mm) was observed in 17 leads in 16 patients (12.3% of leads, 12.1% of patients). Factors associated with lead migration were: technical error, repetitive dystonic head movement, and twiddler's syndrome. Outcomes were worse in dystonia patients with lead migration (p = 0.035). In the PD group, worse clinical outcomes trended in cases with lead migration. CONCLUSIONS: Over 10% of DBS leads in this large single center cohort were displaced by greater than 3 mm on delayed measurement, adversely affecting outcomes. Multiple risk factors emerged, including technical error during implantation of the DBS pulse generator and failure of lead fixation at the burr hole site. We hypothesize that a change in surgical technique and a more effective lead fixation device might mitigate this problem.

ASSOCIATION BETWEEN COMPUTED TOMOGRAPHIC CHARACTERISTICS AND FRACTURES FOLLOWING STEREOTACTIC RADIOSURGERY IN DOGS WITH APPENDICULAR OSTEOSARCOMA.

The objective of this observational, descriptive, retrospective study was to report CT characteristics associated with fractures following stereotactic radiosurgery in canine patients with appendicular osteosarcoma. Medical records (1999 and 2012) of dogs that had a diagnosis of appendicular osteosarcoma and undergone stereotactic radiosurgery were reviewed. Dogs were included in the study if they had undergone stereotactic radiosurgery for an aggressive bone lesion with follow-up information regarding fracture status, toxicity, and date and cause of death. Computed tomography details, staging, chemotherapy, toxicity, fracture status and survival data were recorded. Overall median survival time (MST) and fracture rates of treated dogs were calculated. CT characteristics were evaluated for association with time to fracture. Forty-six dogs met inclusion criteria. The median overall survival time was 9.7 months (95% CI: 6.9-14.3 months). The fracture-free rates at 3, 6, and 9 months were 73%, 44%, and 38% (95% CI: 60-86%, 29-60%, and 22-54%), respectively. The region of bone affected was significantly associated with time to fracture. The median time to fracture was 4.2 months in dogs with subchondral bone involvement and 16.3 months in dogs without subchondral bone involvement (P-value = 0.027, log-rank test). Acute and late skin effects were present in 58% and 16% of patients, respectively. Findings demonstrated a need for improved patient selection for this procedure, which can be aided by CT-based prognostic factors to predict the likelihood of fracture.

Radiosurgery technology development and use.

Radiosurgery first became a clinical option in the 1960's because of the Gamma Knife, and the technology proliferated in the 1980's due to the availability of linear accelerator radiosurgery. The technology has continued to develop with both Gamma Knife and linac radiosurgery due primarily to advances in computer technology and robotic automation. Many of these advances include planning systems that enhance the conformity of the dose distribution, and delivery systems that can more safely and efficiently delivery these more complex treatment plans. This manuscript details the evolution of technologies in stereotactic localization and delivery for intracranial radiosurgery.

Development of an intramuscular xenograft model of canine osteosarcoma in mice for evaluation of the effects of radiation therapy.

OBJECTIVE: To develop an IM xenograft model of canine osteosarcoma in mice for the purpose of evaluating effects of radiation therapy on tumors. ANIMALS: 27 athymic nude mice. PROCEDURES: Mice were randomly assigned to 1 of 3 groups of 9 mice each: no treatment (control group), radiation at 10 Gy, or radiation at 15 Gy. Each mouse received 5 x 10(5) highly metastasizing parent osteosarcoma cells injected into the left gastrocnemius muscle. Maximum tumor diameter was determined with a metric circles template to generate a tumor growth curve. Conscious mice were restrained in customized plastic jigs allowing local tumor irradiation. The behavior and development of the tumor xenograft were assessed via evaluations of the interval required for tumor-bearing limbs to reach diameters of 8 and 13 mm, extent of tumor vasculature, histomorphology of tumors, degree of tumor necrosis, and existence of pulmonary metastasis and clinical disease in affected mice. RESULTS: Tumor-bearing limbs grew to a diameter of 8 mm (0.2-g tumor mass) in a mean +/- SEM interval of 7.0 +/- 0.2 days in all mice. Interval to grow from 8 to 13 mm was significantly prolonged for both radiation therapy groups, compared with that of the control group. Histologic evaluation revealed the induced tumors were highly vascular and had characteristics consistent with those of osteosarcoma. Pulmonary metastasis was not detected, and there was no significant difference in percentage of tumor necrosis between groups. CONCLUSIONS AND CLINICAL RELEVANCE: A reliable, repeatable, and easily produced IM xenograft model was developed for in vivo assessment of canine osteosarcoma.

Intrinsic radiosensitivity and repair of sublethal radiation-induced damage in canine osteosarcoma cell lines.

OBJECTIVE: To characterize the radiosensitivity and capacity for sublethal damage repair (SLDR) of radiation-induced injury in 4 canine osteosarcoma cell lines. SAMPLE POPULATION: 4 canine osteosarcoma cell lines (HMPOS, POS, COS 31, and D17). PROCEDURES: A clonogenic colony-forming assay was used to evaluate the cell lines' intrinsic radiosensitivities and SLDR capacities. Dose-response curves for the cell lines were generated by fitting the surviving fractions after radiation doses of 0 (control cells), 1, 2, 3, 6, and 9 Gy to a linear quadratic model. To evaluate SLDR, cell lines were exposed to 2 doses of 3 Gy (split-dose experiments) at an interval of 0 (single 6-Gy dose), 2, 4, 6, or 24 hours, after which the surviving fractions were assessed. RESULTS: Mean surviving fraction did not differ significantly among the 4 cell lines at the radiation doses tested. Mean surviving fraction at 2 Gy was high (0.62), and the alpha/beta ratios (predictor of tissue sensitivity to radiation therapy) for the cell lines were low (mean ratio, 3.47). The split-dose experiments revealed a 2.8- to 3.9-fold increase in cell survival when the radiation doses were applied at an interval of 24 hours, compared with cell survival after radiation doses were applied consecutively (0-hour interval). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that these canine osteosarcoma cell lines are fairly radioresistant; alpha/beta ratios were similar to those of nonneoplastic, late-responding tissues. Future clinical investigations should involve increasing the fraction size in a manner that maximizes tumor killing without adverse effects on the nonneoplastic surrounding tissues.

Nonspecific immunotherapy with intratumoral lipopolysaccharide and zymosan A but not GM-CSF leads to an effective anti-tumor response in subcutaneous RG-2 gliomas.

PURPOSE: Nonspecific stimulation of cells of the immune system may be useful in generating an anti-tumor response for a variety of cancers and may work synergistically with currently available cytotoxic therapies. In this study we examined the response of syngeneic rat gliomas to treatment with several nonspecific stimulators of dendritic cells and macrophages alone or in combination with radiation therapy. EXPERIMENTAL DESIGN: RG-2 gliomas were implanted subcutaneously and treated with intratumoral (IT) injections of the toll-like receptor (TLR) ligands lipopolysaccharide (LPS) and zymosan A (ZymA) and the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). Combination treatment with IT LPS and single-fraction external beam radiotherapy (EBRT) was also evaluated. RESULTS: Treatment with IT LPS and ZymA delayed tumor growth compared to saline controls. Multiple doses of both substances were superior to single doses, and led to complete tumor regression in 71% (LPS) and 50% (ZymA) of animals. GM-CSF showed no anti-tumor effects in this study. Combinations of IT LPS and EBRT appeared to have a synergistic effect in delaying tumor growth. Rechallenge studies and IT LPS treatment of RG-2 tumors in nude rats suggested the importance of T cells in this treatment paradigm. CONCLUSIONS: Direct IT treatment with the TLR ligands LPS and ZymA are effective in generating an anti-tumor response. These treatments may synergize with cytotoxic therapies such as EBRT, and appear to require T cells for a successful outcome.

A geometrically based method of step and shoot stereotactic radiosurgery with a miniature multileaf collimator.

Conventional methods of inverse planning for intensity-modulated radiotherapy (IMRT) and intensity-modulated radiosurgery (IMRS) are generally based upon optimizing a set of beam fluence profiles according to a set of dose-volume constraints specified by a human planner. This optimization is generally carried out through an iterative approach that relies upon the optimization of a score, driving the plan's ability to satisfy the user-provided constraints. Following optimization of the fluence distribution, the non-trivial problem of converting the fluence distribution into a set of deliverable, intensity-modulated beams must be solved. A novel approach to solving this IMRS total inverse problem is presented in this paper. The proposed method uses a class solution that provides an optimized dose gradient and a method of designing a conformal plan based on an existing geometrically based optimization algorithm. After developing an optimal fluence distribution, the process then arranges the fluence into a set of simple and efficient MLC beam delivery sequences. The algorithm presented here offers several potential advantages for the application of intensity modulation to radiosurgery treatment planning. The geometrically based optimization process' simplicity requires far less human user input and decision making in the specification of dose and dose-volume constraints than do conventional inverse planning algorithms. This simplicity allows the optimization process to be completed much faster than conventional inverse-planning algorithms, literally seconds compared with at least several minutes. Likewise, the fluence conversion step is a simplified process (compared to conventional IMRT planning), which takes advantage of some simplifications uniquely appropriate to the problem at hand (IMRS). The converted, deliverable IMRS beams allow superior conformity and dose gradient relative to conventional IMRS planning or 3DCRT radiosurgery planning. Another benefit is that the number of beam intensity levels is greatly reduced, from hundreds to as few as a half-dozen intensity levels. Finally, since the treatment plan optimization process is based upon proven principles applicable to optimizing radiosurgery (rather than the general problem of optimizing fractionated radiotherapy plans), the plans generated and deliverable with this method of IMRS are potentially superior to those produced by conventional inverse-planning methods of IMRT/IMRS.

Optically guided patient positioning techniques.

Optical tracking determines an object's position by measuring light either emitted or reflected from the object. The hallmark of optical tracking systems is their high spatial resolution and measurement in real time; such systems can resolve the position of a point source within a fraction of a millimeter and report at a rate of 10 Hz or faster. Several systems have been developed for radiation therapy, all of which track infrared markers attached to the patient's external surface. The positions of the optical markers relative to the target volume, together with the desired marker positions relative to treatment isocenter, are determined during computed tomography simulation. In the treatment room, the real marker positions are measured relative to isocenter; rigid-body mathematics then determine marker displacements from their desired positions and hence target displacement from isocenter. Real-time feedback allows one to correct the patient's position. The first systems were used for intracranial stereotaxis radiotherapy; rigid arrays of optical markers were attached to the patient via a biteplate linkage. Subsequent systems for extracranial radiotherapy tracked external markers to determine patient position and/or gate the radiation beam based on patient motion. Lastly, optical tracking has been integrated with ultrasound or stereoscopic x-ray imaging to determine the position of internal anatomy targets relative to isocenter.

Stereotactic radiosurgery for treatment of osteosarcomas involving the distal portions of the limbs in dogs.

Stereotactic radiosurgery (SRS) involves precise delivery of a single large dose of radiation to a designated tumor target. This report describes use of SRS in combination with a frameless stereotactic localization system to treat 11 dogs with appendicular osteosarcomas. Five dogs were treated with SRS alone; 6 were treated with a combination of SRS and chemotherapy. Overall median survival time was 363 days (range, 145 to 763 days), with 6 dogs still alive 90, 142, 234, 367, 633, and 763 days after SRS. Limb function was good or excellent in all 6 dogs that were still alive. Results in these dogs suggest that SRS may be a viable option for dogs with appendicular osteosarcoma, with the potential to provide long-term local tumor control and improvement in limb function, especially when combined with chemotherapy. Because of the destructive nature of osteosarcoma and limitations of SRS, dogs with tumors that are small and have caused minimal bone destruction would likely be the best candidates for this procedure.

A simple and reliable index for scoring rival stereotactic radiosurgery plans.

PURPOSE: A simple and robust index for ranking rival stereotactic radiosurgery plans is presented. METHODS: The radiosurgery plan score index, CGI (Conformity/Gradient Index), is an average of a conformity score and a gradient score. Computation of the CGI score is simple, requiring only three pieces of data: (1) the total volume irradiated to the prescription isodose level, (2) the volume of the target, and (3) the total volume irradiated at half of the prescription isodose level. The overall CGI Index is a simple function of these three pieces of data. RESULTS: When multiple sets of rival stereotactic radiosurgery plans were ranked with respect to this single score index, the resulting plan rankings closely matched the plan rankings according to biologic indices (calculated nontarget brain normal tissue complication probabilities). CONCLUSIONS: The CGI is a simple and fast plan evaluation tool that can assist the radiosurgery planner in evaluating and optimizing multiple candidate radiosurgery plans.

Ultrasound-guided extracranial radiosurgery: technique and application.

PURPOSE: Stereotactic radiosurgery is an effective treatment modality for many intracranial lesions, but target mobility limits its utility for extracranial applications. We have developed a new technique for extracranial radiosurgery based on optically guided three-dimensional ultrasound (3DUS). The 3DUS system provides the ability to image the target volume and critical structures in real time and determine any misregistration of the target volume with the linear accelerator. In this paper, we describe the system and its initial clinical application in the treatment of localized metastatic disease. METHODS AND MATERIALS: The extracranial stereotactic system consists of an ultrasound unit that is optically tracked and registered with the linear accelerator coordinate system. After an initial patient positioning based on computed tomographic (CT) simulation, stereotactic ultrasound images are acquired and correlated with the CT-based treatment plan to determine any soft-tissue shifts between the time of the planning CT and the actual treatment. Optical tracking is used to correct any patient offsets that are revealed by the real-time imaging. RESULTS: Preclinical testing revealed that the ultrasound-based stereotactic navigation system is accurate to within 1.5 mm in comparison with an absolute coordinate phantom. Between March 2001 and March 2002, the system was used to deliver extracranial radiosurgery to 17 metastatic lesions in 16 patients. Treatments were delivered in 1 or 2 fractions, with an average fractional dose of 16 Gy (range 12.5-24 Gy) delivered to the 80% isodose surface. Before each fraction, the target misalignment from isocenter was determined using the 3DUS system and the misalignments averaged over all patients were anteroposterior = 4.8 mm, lateral = 3.6 mm, axial = 2.1 mm, and average total 3D displacement = 7.4 mm (range = 0-21.0 mm). After correcting patient misalignment, each plan was delivered as planned using 6-11 noncoplanar fields. No acute complications were reported. CONCLUSIONS: A system for high-precision radiosurgical treatment of metastatic tumors has been developed, tested, and applied clinically. Optical tracking of the ultrasound probe provides real-time tracking of the patient anatomy and allows computation of the target displacement before treatment delivery. The patient treatments reported here suggest the feasibility and safety of the technique.

Commissioning and quality assurance of an optically guided three-dimensional ultrasound target localization system for radiotherapy.

Recently, there has been proliferation of image-guided positioning systems for high-precision radiation therapy, with little attention given to quality assurance procedures for such systems. To ensure accurate treatment delivery, errors in the imaging, localization, and treatment delivery processes must be systematically analyzed. This paper details acceptance tests for an optically guided three-dimensional (3D) ultrasound system used for patient localization. While all tests were performed using the same commercial system, the general philosophy and procedures are applicable to all systems utilizing image guidance. Determination of absolute localization accuracy requires a consistent stereotactic, or three-dimensional, coordinate system in the treatment planning system and the treatment vault. We established such a coordinate system using optical guidance. The accuracy of this system for localization of spherical targets imbedded in a phantom at depths ranging from 3 to 13 cm was determined to be (average +/- standard deviation) AP = 0.2 +/- 0.7 mm, Lat = 0.9 +/- 0.6 mm, Ax = 0.6 +/- 1.0 mm. In order to test the ability of the optically guided 3D ultrasound localization system to determine the magnitude of an internal organ shift with respect to the treatment isocenter, a phantom that closely mimics the typical human male pelvic anatomy was used. A CT scan of the phantom was acquired, and the regions of interest were contoured. With the phantom on the treatment couch, optical guidance was used to determine the positions of each organ to within imaging uncertainty, and to align the phantom so the plan and treatment machine coordinates coincided. To simulate a clinical misalignment of the treatment target, the phantom was then shifted by different precise offsets, and an experimenter blind to the offsets used ultrasound guidance to determine the magnitude of the shifts. On average, the magnitude of the shifts could be determined to within 1.0 mm along each axis.