Ilya Laufer

Risk of Fracture After Single Fraction Image-Guided Intensity-Modulated Radiation Therapy to Spinal Metastases

PURPOSE Single-fraction image-guided intensity-modulated radiation therapy (IG-IMRT) allows for tumoricidal treatment of traditionally radioresistant cancers while sparing critical adjacent structures. Risk of vertebral fracture after IG-IMRT for spinal metastases has not been defined. PATIENTS AND METHODS We evaluated 62 consecutive patients undergoing single fraction IG-IMRT at 71 sites for solid organ metastases. A neuroradiologist and three spine surgeons evaluated prospectively obtained magnetic resonance/computed tomography (CT) imaging studies for post-treatment fracture development and tumor recurrence. RESULTS Fracture progression was noted in 27 vertebrae (39%). Multivariate logistic regression analysis showed that CT appearance, lesion location, and percent vertebral body involvement independently predicted fracture progression. Lesions located between T10 and the sacrum were 4.6 times more likely to fracture than were lesions above T10 (95% CI, 1.1 to 19.7). Lytic lesions were 6.8 times more likely to fracture than were sclerotic and mixed lesions (95% CI, 1.4 to 33.3). As percent vertebral body involvement increased, odds of fracture also increased. Patients with fracture progression had significantly higher narcotic use, change in Karnofsky performance score, and a strong trend toward higher pain scores. Local tumor progression occurred in seven patients and contributed to one fracture. Obesity, posterior element involvement, bisphosphonate use, and local kyphosis did not confer increased risk. CONCLUSION Vertebral fracture is common after single fraction IG-IMRT for metastatic spine lesions. Lytic disease involving more than 40% of the vertebral body and location at or below T10 confer a high risk of fracture, the presence of which yields significantly poorer clinical outcomes. These results may help clinicians identify high-risk patients who would benefit from prophylactic vertebro- or kyphoplasty.

Local disease control for spinal metastases following "separation surgery" and adjuvant hypofractionated or high-dose single-fraction stereotactic radiosurgery: outcome analysis in 186 patients.

OBJECT Decompression surgery followed by adjuvant radiotherapy is an effective therapy for preservation or recovery of neurological function and achieving durable local disease control in patients suffering from metastatic epidural spinal cord compression (ESCC). The authors examine the outcomes of postoperative image-guided intensity-modulated radiation therapy delivered as single-fraction or hypofractionated stereotactic radiosurgery (SRS) for achieving long-term local tumor control. METHODS A retrospective chart review identified 186 patients with ESCC from spinal metastases who were treated with surgical decompression, instrumentation, and postoperative radiation delivered as either single-fraction SRS (24 Gy) in 40 patients (21.5%), high-dose hypofractionated SRS (24-30 Gy in 3 fractions) in 37 patients (19.9%), or low-dose hypofractionated SRS (18-36 Gy in 5 or 6 fractions) in 109 patients (58.6%). The relationships between postoperative adjuvant SRS dosing and fractionation, patient characteristics, tumor histology-specific radiosensitivity, grade of ESCC, extent of surgical decompression, response to preoperative radiotherapy, and local tumor control were evaluated by competing risks analysis. RESULTS The total cumulative incidence of local progression was 16.4% 1 year after SRS. Multivariate Gray competing risks analysis revealed a significant improvement in local control with high-dose hypofractionated SRS (4.1% cumulative incidence of local progression at 1 year, HR 0.12, p = 0.04) as compared with low-dose hypofractionated SRS (22.6% local progression at 1 year, HR 1). Although univariate analysis demonstrated a trend toward greater risk of local progression for patients in whom preoperative conventional external beam radiation therapy failed (22.2% local progression at 1 year, HR 1.96, p = 0.07) compared with patients who did not receive any preoperative radiotherapy (11.2% local progression at 1 year, HR 1), this association was not confirmed with multivariate analysis. No other variable significantly correlated with progression-free survival, including radiation sensitivity of tumor histology, grade of ESCC, extent of surgical decompression, or patient sex. CONCLUSIONS Postoperative adjuvant SRS following epidural spinal cord decompression and instrumentation is a safe and effective strategy for establishing durable local tumor control regardless of tumor histology-specific radiosensitivity. Patients who received high-dose hypofractionated SRS demonstrated 1-year local progression rates of less than 5% (95% CI 0%-12.2%), which were superior to the results of low-dose hypofractionated SRS. The local progression rate after single-fraction SRS was less than 10% (95% CI 0%-19.0%).

Complement component C3 mediates inflammatory injury following focal cerebral ischemia.

The complement cascade has been implicated in ischemia/reperfusion injury, and recent studies have shown that complement inhibition is a promising treatment option for acute stroke. The development of clinically useful therapies has been hindered, however, by insufficient understanding of which complement subcomponents contribute to post-ischemic injury. To address this issue, we subjected mice deficient in selected complement proteins (C1q, C3, C5) to transient focal cerebral ischemia. Of the strains investigated, only C3−/− mice were protected, as demonstrated by 34% reductions in both infarct volume (P<0.01) and neurological deficit score (P<0.05). C3-deficient mice also manifested decreased granulocyte infiltration (P<0.02) and reduced oxidative stress (P<0.05). Finally, administration of a C3a-receptor antagonist resulted in commensurate neurological improvement and stroke volume reduction (P<0.05). Together, these results establish C3 activation as the key constituent in complement-related inflammatory tissue injury following stroke and suggest a C3a anaphylatoxin-mediated mechanism.

Reliability analysis of the epidural spinal cord compression scale.

OBJECTIVE The evolution of imaging techniques, along with highly effective radiation options has changed the way metastatic epidural tumors are treated. While high-grade epidural spinal cord compression (ESCC) frequently serves as an indication for surgical decompression, no consensus exists in the literature about the precise definition of this term. The advancement of the treatment paradigms in patients with metastatic tumors for the spine requires a clear grading scheme of ESCC. The degree of ESCC often serves as a major determinant in the decision to operate or irradiate. The purpose of this study was to determine the reliability and validity of a 6-point, MR imaging-based grading system for ESCC. METHODS To determine the reliability of the grading scale, a survey was distributed to 7 spine surgeons who participate in the Spine Oncology Study Group. The MR images of 25 cervical or thoracic spinal tumors were distributed consisting of 1 sagittal image and 3 axial images at the identical level including T1-weighted, T2-weighted, and Gd-enhanced T1-weighted images. The survey was administered 3 times at 2-week intervals. The inter- and intrarater reliability was assessed. RESULTS The inter- and intrarater reliability ranged from good to excellent when surgeons were asked to rate the degree of spinal cord compression using T2-weighted axial images. The T2-weighted images were superior indicators of ESCC compared with T1-weighted images with and without Gd. CONCLUSIONS The ESCC scale provides a valid and reliable instrument that may be used to describe the degree of ESCC based on T2-weighted MR images. This scale accounts for recent advances in the treatment of spinal metastases and may be used to provide an ESCC classification scheme for multicenter clinical trial and outcome studies.

The NOMS Framework: Approach to the Treatment of Spinal Metastatic Tumors

BACKGROUND Spinal metastases frequently arise in patients with cancer. Modern oncology provides numerous treatment options that include effective systemic, radiation, and surgical options. We delineate and provide the evidence for the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which is used at Memorial Sloan-Kettering Cancer Center to determine the optimal therapy for patients with spine metastases. METHODS We provide a literature review of the integral publications that serve as the basis for the NOMS framework and report the results of systematic implementation of the NOMS-guided treatment. RESULTS The NOMS decision framework consists of the neurologic, oncologic, mechanical, and systemic considerations and incorporates the use of conventional external beam radiation, spinal stereotactic radiosurgery, and minimally invasive and open surgical interventions. Review of radiation oncology and surgical literature that examine the outcomes of treatment of spinal metastatic tumors provides support for the NOMS decision framework. Application of the NOMS paradigm integrates multimodality therapy to optimize local tumor control, pain relief, and restoration or preservation of neurologic function and minimizes morbidity in this often systemically ill patient population. CONCLUSION NOMS paradigm provides a decision framework that incorporates sentinel decision points in the treatment of spinal metastases. Consideration of the tumor sensitivity to radiation in conjunction with the extent of epidural extension allows determination of the optimal radiation treatment and the need for surgical decompression. Mechanical stability of the spine and the systemic disease considerations further help determine the need and the feasibility of surgical intervention.

Shifting Paradigms in the Treatment of Metastatic Spine Disease

Study Design. Systematic review and evidence appraisal. Objective. To evaluate the optimal treatment for patients with spinal cord compression secondary to solid metastases and in patients with solitary renal metastases, without spinal cord compression. Methods. Focused Medline and OVID database searches were conducted using relevant keywords. Only clinical articles that evaluated specific end points of interest were included in the literature review. The quality of evidence provided by each article was assessed using the ATS guidelines. The expert opinion was synthesized based on the evidence and rated as strong or weak, depending on the quality of the supporting literature. Results. Twelve surgical and 7 radiation clinical series were identified that evaluated post-treatment ambulation in patients with metastatic spinal cord compression. Only 1 surgical article met the criteria for moderate quality evidence while the remaining surgical and radiation articles presented very low quality of evidence. All articles that evaluated treatment of solitary renal metastases presented very low quality of evidence. Conclusion. A strong recommendation is made for patients with high-grade cord compression due to solid tumor metastases to undergo surgical decompression with stabilization followed by radiation therapy. A weak recommendation is made for patients with solitary renal metastases without spinal cord compression to undergo spinal stereotactic radiosurgery.

Endonasal endoscopic resection of the odontoid process in a nonachondroplastic dwarf with juvenile rheumatoid arthritis: feasibility of the approach and utility of the intraoperative Iso-C three-dimensional navigation : Case report

The authors report a case of a nonachondroplastic dwarf with severe basilar invagination and compression of the cervicomedullary junction (CMJ) due to juvenile rheumatoid arthritis. Initially excellent reduction of the invagination and decompression of the CMJ was achieved using posterior fixation. However, 1 month postoperatively symptoms recurred and the authors found imaging evidence of recurrence as well. The patient subsequently underwent an endoscopic transnasal resection of the dens with assistance of Iso-C navigation. He recovered well and tolerated regular diet on postoperative Day 2.

Outcomes and Toxicity for Hypofractionated and Single-Fraction Image-Guided Stereotactic Radiosurgery for Sarcomas Metastasizing to the Spine

PURPOSE Conventional radiation treatment (20-40 Gy in 5-20 fractions, 2-5 Gy per fraction) for sarcoma metastatic to the spine provides subtherapeutic doses, resulting in poor durable local control (LC) (50%-77% at 1 year). Hypofractionated (HF) and/or single-fraction (SF) image-guided stereotactic radiosurgery (IG-SRS) may provide a more effective means of managing these lesions. METHODS AND MATERIALS Patients with pathologically proven high-grade sarcoma metastatic to the spine treated with HF and SF IG-SRS were included. LC and overall survival (OS) were analyzed by the use of Kaplan-Meier statistics. Univariate and multivariate analyses were performed by the use of Cox regression with competing-risks analysis; all confidence intervals are 95%. Toxicities were assessed according to Common Terminology Criteria for Adverse Events, version 4.0. RESULTS From May 2005 to November 11, 2012, 88 patients with 120 discrete metastases received HF (3-6 fractions; median dose, 28.5 Gy; n=52, 43.3%) or SF IG-SRS (median dose, 24 Gy; n=68, 56.7%). The median follow-up time was 12.3 months. At 12 months, LC was 87.9% (confidence interval [CI], 81.3%-94.5%), OS was 60.6% (CI, 49.6%-71.6%), and median survival was 16.9 months. SF IG-SRS demonstrated superior LC to HF IG-SRS (12-month LC of 90.8% [CI, 83%-98.6%] vs 84.1% [CI, 72.9%-95.3%] P=.007) and retained significance on multivariate analysis (P=.030, hazard ratio 0.345; CI, 0.132-0.901]. Treatment was well tolerated, with 1% acute grade 3 toxicity, 4.5% chronic grade 3 toxicity, and no grade >3 toxicities. CONCLUSIONS In the largest series of metastatic sarcoma to the spine to date, IG-SRS provides excellent LC in the setting of an aggressive disease with low radiation sensitivity and poor prognosis. Single-fraction IG-SRS is associated with the highest rates of LC with minimal toxicity.

Elevation of Soluble Intercellular Adhesion Molecule-1 Levels in Symptomatic and Asymptomatic Carotid Atherosclerosis

OBJECTIVERecent data suggest that the increased expression of intercellular adhesion molecule-1 (ICAM-1) in atherosclerotic plaque taken from the carotid bifurcation correlates with the development of neurological symptoms. As a result, the authors sought to compare the serum levels of soluble forms of ICAM-1 (sICAM-1) in patients who were asymptomatic with those who were symptomatic for carotid artery stenosis as well as in patients who were matched in terms of sex, age, and risk factors who did not have carotid artery disease. METHODSUsing enzyme-linked immunosorbent assay, serum sICAM-1 levels were prospectively determined in 54 patients scheduled to undergo carotid endarterectomy for either symptomatic or asymptomatic high-grade stenosis (≥60%) and in 5 additional patient controls. Data are expressed as mean ± standard error of the mean, with significance defined as P < 0.05 using the Mann-Whitney two-tailed test for two-column comparison or analysis of variance and Fisher protected least significant difference test. RESULTSUsing a univariate model, serum sICAM-1 levels were significantly elevated in patients with carotid artery stenosis as compared with control patients without stenosis (347 ± 15 ng/ml versus 216 ± 8.2 ng/ml) (P < 0.01). When the asymptomatic and symptomatic patients with carotid artery stenosis were considered separately, these levels were still elevated relative to those of control patients (asymptomatic [312 ± 18 ng/ml] and symptomatic [376 ± 22 ng/ml] patients;P = 0.06 for asymptomatic versus control patients, P < 0.01 for symptomatic versus control patients). Symptomatic patients also had significantly elevated sICAM-1 levels as compared with asymptomatic patients (P < 0.05). Despite the fact that female patients demonstrated higher ICAM-1 levels than male patients (P < 0.05), sex, age, and risk factors such as the presence of hypercholesterolemia, diabetes, hypertension, or a history of smoking did not confound these findings. CONCLUSIONLevels of sICAM-1 are higher in patients with carotid stenosis than in control patients. Symptomatic patients demonstrate significantly elevated levels as compared with asymptomatic patients. These data support the contention that ICAM-1 is a reliable marker of carotid disease progression and suggest that serum levels may be useful in following certain asymptomatic patients.

Preliminary Results of High-Dose Single-Fraction Radiotherapy for the Management of Chordomas of the Spine and Sacrum

BACKGROUND En bloc wide-margin excision significantly decreases the risk of chordoma recurrence. However, a wide surgical margin cannot be obtained in many chordomas because they arise primarily in the sacrum, clivus, and mobile spine. Furthermore, these tumors have shown resistance to fractionated photon radiation at conventional doses and numerous chemotherapies. OBJECTIVE To analyze the outcomes of single-fraction stereotactic radiosurgery (SRS) in the treatment of chordomas of the mobile spine and sacrum. METHODS Twenty-four patients with chordoma of the sacrum and mobile spine were treated with high-dose single-fraction SRS (median dose, 2400 cGy). Twenty-one primary and 3 metastatic tumors were treated. Seven patients were treated for postoperative tumor recurrence. In 7 patients, SRS was administered as planned adjuvant therapy, and in 13 patients, SRS was administered as neoadjuvant therapy. All patients had serial magnetic resonance imaging follow-up. RESULTS The overall median follow-up was 24 months. Of the 24 patients, 23 (95%) demonstrated stable or reduced tumor burden based on serial magnetic resonance imaging. One patient had radiographic progression of tumor 11 months after SRS. Only 6 of 13 patients who underwent neoadjuvant SRS proceeded to surgery. This decision was based on the lack of radiographic progression and the patients preference. Complications were limited to 1 patient in whom sciatic neuropathy developed and 1 with vocal cord paralysis. CONCLUSION High-dose single-fraction SRS provides good tumor control with low treatment-related morbidity. Additional follow-up is required to determine the long-term recurrence risk.