Ehud Mendel

Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline

PURPOSE To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. METHODS AND MATERIALS A systematic search of the National Library of Medicines PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. RESULTS The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. CONCLUSIONS Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use and provide consensus views concerning contemporary controversies or unanswered questions that warrant prospective trial evaluation.

Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure

OBJECT The authors report data concerning the safety, effectiveness, and patterns of failure obtained in a Phase I/II study of stereotactic body radiotherapy (SBRT) for spinal metastatic tumors. METHODS Sixty-three cancer patients underwent near-simultaneous computed tomography-guided SBRT. Spinal magnetic resonance imaging was conducted at baseline and at each follow-up visit. The National Cancer Institute Common Toxicity Criteria 2.0 assessments were used to evaluate toxicity. RESULTS The median tumor volume of 74 spinal metastatic lesions was 37.4 cm3 (range 1.6-358 cm3). No neuropathy or myelopathy was observed during a median follow-up period of 21.3 months (range 0.9-49.6 months). The actuarial 1-year tumor progression-free incidence was 84% for all tumors. Pattern-of-failure analysis showed two primary mechanisms of failure: 1) recurrence in the bone adjacent to the site of previous treatment, and 2) recurrence in the epidural space adjacent to the spinal cord. Grade 3 or 4 toxicities were limited to acute Grade 3 nausea, vomiting, and diarrhea (one case); Grade 3 dysphagia and trismus (one case); and Grade 3 noncardiac chest pain (one case). There was no subacute or late Grade 3 or 4 toxicity. CONCLUSIONS Analysis of the data obtained in the present study supports the safety and effectiveness of SBRT in cases of spinal metastatic cancer. The authors consider it prudent to routinely treat the pedicles and posterior elements using a wide bone margin posterior to the diseased vertebrae because of the possible direct extension into these structures. For patients without a history of radiotherapy, more liberal spinal cord dose constraints than those used in this study could be applied to help reduce failures in the epidural space.

A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group.

Study Design. Systematic review and modified Delphi technique. Objective. To use an evidence-based medicine process using the best available literature and expert opinion consensus to develop a comprehensive classification system to diagnose neoplastic spinal instability. Summary of Background Data. Spinal instability is poorly defined in the literature and presently there is a lack of guidelines available to aid in defining the degree of spinal instability in the setting of neoplastic spinal disease. The concept of spinal instability remains important in the clinical decision-making process for patients with spine tumors. Methods. We have integrated the evidence provided by systematic reviews through a modified Delphi technique to generate a consensus of best evidence and expert opinion to develop a classification system to define neoplastic spinal instability. Results. A comprehensive classification system based on patient symptoms and radiographic criteria of the spine was developed to aid in predicting spine stability of neoplastic lesions. The classification system includes global spinal location of the tumor, type and presence of pain, bone lesion quality, spinal alignment, extent of vertebral body collapse, and posterolateral spinal element involvement. Qualitative scores were assigned based on relative importance of particular factors gleaned from the literature and refined by expert consensus. Conclusion. The Spine Instability Neoplastic Score is a comprehensive classification system with content validity that can guide clinicians in identifying when patients with neoplastic disease of the spine may benefit from surgical consultation. It can also aid surgeons in assessing the key components of spinal instability due to neoplasia and may become a prognostic tool for surgical decision-making when put in context with other key elements such as neurologic symptoms, extent of disease, prognosis, patient health factors, oncologic subtype, and radiosensitivity of the tumor.

Spinal Instability Neoplastic Score: An Analysis of Reliability and Validity From the Spine Oncology Study Group

PURPOSE Standardized indications for treatment of tumor-related spinal instability are hampered by the lack of a valid and reliable classification system. The objective of this study was to determine the interobserver reliability, intraobserver reliability, and predictive validity of the Spinal Instability Neoplastic Score (SINS). METHODS Clinical and radiographic data from 30 patients with spinal tumors were classified as stable, potentially unstable, and unstable by members of the Spine Oncology Study Group. The median category for each patient case (consensus opinion) was used as the gold standard for predictive validity testing. On two occasions at least 6 weeks apart, each rater also scored each patient using SINS. Each total score was converted into a three-category data field, with 0 to 6 as stable, 7 to 12 as potentially unstable, and 13 to 18 as unstable. RESULTS The κ statistics for interobserver reliability were 0.790, 0.841, 0.244, 0.456, 0.462, and 0.492 for the fields of location, pain, bone quality, alignment, vertebral body collapse, and posterolateral involvement, respectively. The κ statistics for intraobserver reliability were 0.806, 0.859, 0.528, 0.614, 0.590, and 0.662 for the same respective fields. Intraclass correlation coefficients for inter- and intraobserver reliability of total SINS score were 0.846 (95% CI, 0.773 to 0.911) and 0.886 (95% CI, 0.868 to 0.902), respectively. The κ statistic for predictive validity was 0.712 (95% CI, 0.676 to 0.766). CONCLUSION SINS demonstrated near-perfect inter- and intraobserver reliability in determining three clinically relevant categories of stability. The sensitivity and specificity of SINS for potentially unstable or unstable lesions were 95.7% and 79.5%, respectively.

Radiotherapy and Radiosurgery for Metastatic Spine Disease: What Are the Options, Indications, and Outcomes?

Study Design. Systematic literature review. Objective. To determine the options, indications, and outcomes for conventional radiotherapy and radiosurgery for metastatic spine disease. Methods. Three research questions were determined through a consensus among a multidisciplinary panel of spine oncology experts. A systematic review of the literature was conducted regarding radiotherapy and radiosurgery for metastatic spine disease using PubMed, Embase, the Cochrane Evidence Based Medicine Database, and a review of bibliographies of reviewed articles. Research questions:What are the clinical outcomes of the current indications for conventional radiotherapy alone and stereotactic radiosurgery for metastatic spine disease?What are the current dose recommendations and fractionation schedules for conventional spine radiotherapy and stereotactic radiosurgery for metastatic spine disease?What are the current known patterns of failure and complications after conventional spine radiation and stereotactic radiosurgery for metastatic spine disease? Results. For conventional radiotherapy, the initial literature search yielded a total of 531 potentially relevant abstracts. Each of these abstracts was reviewed for relevance, and 62 were selected for in-depth review. Forty-nine studies met all the inclusion criteria. References from the articles included in the analysis and review articles were also examined for potential inclusion in the study. For conventional radiotherapy, 3 randomized trials (high-quality evidence), 4 prospective studies (moderate-quality evidence), and over 40 nonprospective data sets (low- or very-low-quality evidence) that included over 5000 patients in the literature were included in this review. Drawing from the same databases, a systematic search for radiosurgery yielded 195 abstracts, of which 29 met all inclusion criteria. They all represented single-institution reports (low- or very-low-quality data). No randomized data are available for spine radiosurgery. Conclusion. A systematic review of the available evidence suggests that conventional radiotherapy is safe and effective with good symptomatic response and local control, particularly for radiosensitive histologies. A strong recommendation can be made with moderate quality evidence that conventional fractionated radiotherapy is an appropriate initial therapy option for patients with spine metastases in cases in which no relative contraindication exists. A systematic review of the available evidence suggests that radiosurgery is safe and provides an incremental benefit over conventional radiotherapy with more durable symptomatic response and local control independent of histology, even in the setting of prior fractionated radiotherapy. A strong recommendation can be made with low-quality evidence that radiosurgery should be considered over conventional fractionated radiotherapy for the treatment of solid tumor spine metastases in the setting of oligometastatic disease and/or radioresistant histology.

Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: An emerging paradigm for achieving true stereotaxy

PURPOSE To report treatment setup data from an emerging technique using near-simultaneous computed tomography (CT) image-guided stereotactic radiotherapy for the treatment of spinal and paraspinal tumors. METHODS AND MATERIALS A targeting system that integrates a CT-on-rails scanner with a linear accelerator (LINAC) was evaluated in the lead-in portion of a Phase I/II protocol for treating patients with paraspinal metastases. Patients were immobilized in supine position by a moldable body cushion vacuum wrapped with a plastic fixation sheet. Planning CT and immediately repeated CT were performed on the LINAC/CT-on-rails unit to assess respiratory-related vertebral body motion. Coplanar intensity-modulated radiotherapy (IMRT) using 7-9 beams was used to deliver 30 Gy in five fractions to the target volume, while limiting the spinal cord dose to <10 Gy. Pretreatment CT scans were fused with the planning CT scans to determine the correct target isocenter by accounting for any translational and roll (axial) rotational discrepancies from the planning CT. (Corrections caused by yaw and pitch rotations have not yet been implemented.) The reproducibility of the treatment isocenter as compared with the planned isocenter was measured with digitally reconstructed radiographs (DRRs), portal film imaging, and immediate post-treatment verification CT scans. Phantom measurements were taken for dose verification for each IMRT plan. RESULTS Based on a total of 36 CT scans (3 for planning, 3 for respiration study, 15 pretreatment, and 15 post-treatment) from 3 patients, no respiration-associated vertebral body motion was seen. A comparison of the corrected daily anterior-posterior (AP) and lateral (LAT) digital portal images with the planning AP and LAT DRRs confirmed that the isocenter setup accuracy for the 15 treatments was within 1 mm of the planning isocenter. The results from the immediate post-treatment CT scans reconfirmed the findings from the portal images and verified the absence of spinal movement during the treatment. The ion-chamber measurement for the high-dose region was within 2% of the planning dose for three patient treatment plans. Film dose measurement in an IMRT quality assurance phantom demonstrated good agreement from 90% to 30% isodose lines between the planned and measured results. CONCLUSION Preliminary experience suggests that the near-simultaneous CT image-guided verification technique can be used as a new platform technology for extracranial applications of stereotactic radiotherapy and radiosurgery to spinal and paraspinal tumors.

Percutaneous techniques in the treatment of spine tumors: what are the diagnostic and therapeutic indications and outcomes?

Study Design. Systematic review of the literature. Objective. Should cement augmentation procedures such as vertebroplasty and kyphoplasty be used in patients with painful compression fractures associated with metastatic spine disease? What is the role of embolization in the treatment of metastatic spine disease? Summary of Background Data. Vertebral augmentation is commonly employed in treating osteoporotic fractures and is now increasingly used in the management of pain in patients with spinal tumors. Intra-arterial and transcutaneous embolization techniques are also available in the management of spinal tumors. To date, the effectiveness and safety of these procedures have not been adequately demonstrated. Methods. A review of the English literature was performed in Pub-Med. One search was performed using the following keywords: cancer, tumor, vertebroplasty, kyphoplasty, vertebral augmentation, outcome, safety, pain, and quality of life. A Second search was performed using the keywords: embolization, spinal, and tumors. Original studies reporting on at least 10 patients were included and systematically reviewed. The results were reviewed and discussed through consensus among a multidisciplinary panel of expert members of the Spine Oncology Study Group. Recommendations were made according to the Guyatt Guidelines. Results. A total of 1665 abstracts were identified. Twenty-eight articles using vertebroplasty reported on 877 patients and 1599 treated levels. Medical and neurologic complications varied from 0% to 7.1% and 0% to 8.1%, respectively. Twelve articles using kyphoplasty reported on 333 patients and 481 treated levels. Medical complication rates varied from 0% to 0.5%, without any neurologic complications. Pain and functional outcomes were universally successful using either technique. Ten studies on embolization reported on 330 patients. There were 4 permanent complications (1.4%). Complete or partial embolization was possible in 97.5% with an estimated reduction of intraoperative blood loss of 2.3 L. Conclusion. There is strong recommendation and moderate evidence for vertebral augmentation as safe and effective in providing pain relief and improving functional outcome in patients with vertebral body fractures and axial pain due to metastatic disease. There is a strong recommendation and very low evidence for embolization techniques as safe and effective in decreasing intraoperative blood loss in hypervascular tumors.

Dislocations in gadolinium gallium garnet (Gd3Ga5O12)—I. Dislocations at inclusions

Abstract Dislocations near inclusions in gadolinium gallium garnet crystals have been examined by optical microscopy. The inclusions were 5–200 μm in diameter and were compressed by the matrix. Dislocations were detected by means of the optical birefringence they induced or from the etch pits formed where they met the sample surface. The dislocations were loops 0.01–0.5 mm in diameter which encircled the inclusions and lay on {111}, {110} and {100}. The Burgers vectors of the loops were perpendicular to their plane. Loops were formed by climb and were of the interstitial variety. Mechanisms for the formation of interstitial loops at inclusions compressed by the matrix are described.

IDENTIFICATION OF AN IgE-BINDING PROTEIN BY MOLECULAR CLONING

The synthesis and function of IgE are dependent on IgE-binding proteins, which include cell surface IgE receptors and IgE-binding lymphokines. To further our understanding of the IgE system, we have engaged in the molecular cloning of genes for some of these proteins. In studying the in vitro translation products of mRNA from rat basophilic leukemia (RBL) cells, we have identified a Mr 31,000 polypeptide that binds IgE and is also reactive with antibodies to proteins affinity-purified from RBL cells with IgE immunoadsorbent. For the molecular cloning, double-stranded cDNA was synthesized from sucrose gradient-fractionated RBL mRNA, inserted into plasmid pBR322, and used to transform Escherichia coli. By screening transformants with a hybridization-selection/in vitro translation procedure, we identified one clone containing cDNA that hybridized to mRNA coding for a Mr 31,000 IgE-binding protein. The DNA sequence of this cloned cDNA (571 base pairs) was determined and the amino acid sequence corresponding to part of the protein was deduced. In RNA blot analysis, the cDNA hybridized with a mRNA of 1100 nucleotides found in RBL cells but absent in cells not expressing IgE receptors. This cloned cDNA most likely codes for the Mr 31,000 IgE-binding protein identified in RBL cells, which appears to be related to the IgE-binding phenotype of the cells and which may have a significant role in the IgE-mediated activation of basophils and mast cells.

Outcome, Cost Analysis, and Long-term Follow-up in Preterm Infants with Massive Grade IV Germinal Matrix Hemorrhage and Progressive Hydrocephalus

OBJECTIVE The benefit of aggressive management and surgical intervention in preterm infants with massive Grade IV intracranial hemorrhage has been questioned based on the poor outcome of this group of patients despite such therapy. To further delineate this problem, we reviewed the records of premature neonates in this category as to outcome and initial hospital cost. METHODS We performed a retrospective review of the medical records at our institution from 1977 to 1987 to identify premature neonates who had sustained massive hemorrhagic infarction of one hemisphere in addition to having blood in both ventricles and progressive hydrocephalus. RESULTS During the study, a total of 52 such patients were identified, only 19 (6 female and 13 male patients) of whom survived. Intellectual function was observed to be greater than 2 standard deviations below the mean in 15 of the 19 patients, between 1 and 2 standard deviations below the mean in 1 of 19, and 1 standard deviation below the mean in 3 of 19. Motor function was as follows: 12 of 19 had marked spastic quadriparesis, 2 of 19 had moderate spastic quadriparesis, 3 of 19 had spastic hemiplegia, 1 of 19 had spastic diplegia, and 1 of 19 had mild spastic hemiparesis. Eleven of 19 had chronic seizure disorders. The first hospitalization cost for the group of patients exceeded, on the average,