Timothy C. Ryken

In Brief 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 is poorly defined especially in neoplastic disease. The SOSG has developed a comprehensive classification system to define neoplastic spinal instability (the Spine Instability Neoplastic Score). The Spine Instability Neoplastic Score will aid oncologists and primary care physicians in determining timing of referral to spine surgeons and will aid surgeons in assessing need for surgical stabilization.

In 2002, an author group selected and sponsored by the Joint Section on Spine and Peripheral Nerves of the American Association of Neurological Surgeons and Congress of Neurological Surgeons published the first evidence-based guidelines for the management of patients with acute cervical spinal cord injuries (SCIs).1-23 In the spirit of keeping up with changes in information available in the medical literature that might provide more contemporary and more robust medical evidence, another author group was recruited to revise and update the guidelines. The review process has been completed and is published and can be once again found as a supplement to Neurosurgery. The purpose of this article is to provide an overview of the changes in the recommendations as a result of new evidence or broadened scope. CHANGES IN METHODOLOGY In accordance with the established practice of guideline development within organized neurosurgery, a thorough review of the medical literature was undertaken for each subject chosen for evaluation. Although literature outside the English language was excluded, a sample of non-English abstracts that could be found in the database of the National Library of Medicine failed to reveal any data significantly different from what we found in the English literature. Each chapter of recommendations contained in the new guidelines uses standard search techniques fully described in each chapter. After articles appropriate to each review question were identified, a rigorous critical evaluation was undertaken to establish the strength (quality) of the evidence and the level (certainty) of the recommendations. As in previous guidelines, published evidence was divided into Class I (well-designed and -executed randomized controlled trials), Class II (comparative studies, including randomized controlled trials with significant flaws, nonrandomized cohort studies, or case-control studies), and Class III (case series and expert opinion). Different from previous recommendations, the levels that used to be called standards, guidelines, and options are now referred to as Level I, Level II, and Level III, bringing them more in line with other neurosurgical and medical specialty paradigms and allowing the use of the term guidelines to denote the broader scope of the overall recommendations.24 Our author group universally felt that further stratification of guidelines into additional subsets (1a, 1b, 1c, 2a, 2b, 2c, etc)25 would not denote improved certainty or strength but instead would undermine consensus building and promote confusion among the readership. NOTABLE EXCLUSIONS FROM THE GUIDELINES Topical areas not included in the current guidelines pertain to the timing of surgery and use of hypothermia. The published evidence for these clinical strategies is so sparse that recommendations cannot be made with any degree of confidence pending further study. A single prospective study on surgical timing has subsequently been published since completion of our SCI guidelines review. Although designed as a prospective, nonrandomized comparative study (Class II), methodological flaws downgrade it to Class III evidence, rendering it unhelpful for establishing quality and certainty in the case of acute surgical intervention in SCI.26 Systemic hypothermia has been studied in animal models of SCI but only anecdotally in humans by way of a single Class II study also published after the current guidelines went to press. Again, in this instance, the evidence is early and cannot support a practice recommendation.27 The use of intraoperative somatosensory evoked potentials in the setting of trauma as a warning of SCI has not been addressed in the current guidelines. Those studies that our author group was able to find were carried out in nonacute (elective) spinal surgical situations. Although we felt that inferences might be made to acute SCI surgery, our supervising Joint Guidelines Committee of the American Association of Neurological Surgeons and Congress of Neurological Surgeons preferred to minimize such extrapolations. Hence, recommendations with respect to intraoperative electrophysiological monitoring will be made under a different (nontraumatic) guidelines initiative. Functional magnetic resonance imaging may potentially contribute to SCI research, but to date, there are no clinical studies that establish its usefulness in human SCI. Thus, it has been excluded from the current guidelines.28 Similarly, there are no recommendations on the use of drugs,29 biologicals,30 or devices31 aimed at neural regeneration of the spinal cord because of the absence of clinical evidence. It is our hope that such evidence will be forthcoming in time for the next SCI guidelines review. SCOPE OF THE REVISED GUIDELINES In this 2013 iteration of the cervical SCIs guidelines, the scope has been broadened, as have the recommendations. In 2002, the guidelines featured 76 recommendations in contrast to 112 recommendations in the present version. Among the new guidelines are 19 Level I recommendations supported by Class I medical evidence. These include assessment of functional outcomes (1); assessment of pain after SCI (1); radiographic assessment (1); pharmacology (2); diagnosis of atlanto-occipital dislocation (1); cervical subaxial injury classification schemes (2); pediatric spinal injuries (1); vertebral artery injuries (1); and venous thromboembolism (1). In addition, there are 11 Level II recommendations, based on Class II evidence, with the remaining 77 recommendations qualifying as Level III recommendations from a variety of Class III medical evidence. The Table highlights these differences between the 2 SCI guidelines processes (used with permission from the published guidelines).32TABLE-a: Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32TABLE-b: Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32TABLE-c: Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32TABLE-d: Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32TABLE-e: Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32TABLE-f: Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32TABLE: g Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32TABLE: h Comparison of Cervical Spine and Spinal Cord Injury Guidelines Recommendations Between 2 Iterations Where Differences in Recommendations Have Occurred (All Other Recommendations Remain as Previously Stated) a 32The most contentious of the present recommendations likely pertains to the use of methylprednisolone in acute SCI and therefore deserves special comment. Methylprednisolone has been used for decades as a standard of care to improve neurological and functional outcome in SCI; however, careful examination, particularly of randomized clinical trials expected to produce Class I data,33-35 reveals many methodological flaws in study design and data analysis that refute the conclusions of the authors.36-38 As these limitations have come to light, there has also been a change in the perception of frontline surgeons treating SCI with respect to the necessity of steroids at all.39-43 In the case of the present guidelines, our author group downgraded them from Class I to Class III because the primary (a priori) outcome measures were all negative. Any positive results reported from either National Acute Spinal Cord Injury Study (NASCIS) II or NASCIS III came from post hoc analysis rather than being preplanned. In a randomized clinical trial, comparison of data defined by protocol (ie, before data are accrued) is considered Class I evidence, including both primary and secondary outcomes. All other queries within the data set are Class III, whether they are published at the time of initial analysis or 10 years later. Class II is reserved for a priori comparisons within a prospective study in which the study population is nonrandomized but still comparative (eg, cohort studies, case-control studies, or before-and-after studies). This is fundamentally important and explains why retrospective mining of a prospective database still yields Class III evidence (unless in the format of a case-control study). Class of evidence pertains to how the research question was asked (study design). It does not pertain to how the data were accrued. The underlying tenet is that retrospective examination of prospective data is still a “fishing expedition” or essentially a retrospective exercise unless clearly stated as part of the prospective research question(s). Outside of a priori analyses, any number of post hoc comparisons can be made within a data set (retrospective or prospective) until an interesting result is found. In a perfect world, authors should report how many post hoc comparisons they make and apply a correction to their statistical testing (eg, Bonferroni) before reporting claims of positive results. However, in reality, we know that this rarely happens, including in the case of the NASCIS studies. SUMMARY The 2013 update on the “Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries” is meant to help the practicing neurosurgeon in his or her efforts to provide up-to-date, evidence-based care to patients with acute SCIs. They are based on a formal critical evaluation of the evidence, with a well-developed relationship between the strength of the evidence and the level of recommendations. This time-consuming and extensive process produces the best estimate of scientific foundation for current SCI care. For related video content, please access the Supplemental Digital Content: http://www.youtube.com/watch?v=KB1NBEDkw9c Disclosures Funding was provided by the Joint Section on Spine and Peripheral Nerves of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons for author travel and accommodation. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

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.

QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities? Target population These recommendations apply to adults with newly diagnosed solid brain metastases amenable to SRS; lesions amenable to SRS are typically defined as measuring less than 3 cm in maximum diameter and producing minimal (less than 1 cm of midline shift) mass effect. Recommendations SRS plus WBRT vs. WBRT alone Level 1 Single-dose SRS along with WBRT leads to significantly longer patient survival compared with WBRT alone for patients with single metastatic brain tumors who have a KPS > or = 70.Level 1 Single-dose SRS along with WBRT is superior in terms of local tumor control and maintaining functional status when compared to WBRT alone for patients with 1-4 metastatic brain tumors who have a KPS > or =70.Level 2 Single-dose SRS along with WBRT may lead to significantly longer patient survival than WBRT alone for patients with 2-3 metastatic brain tumors.Level 3 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS<70 [corrected].Level 4 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS < 70. SRS plus WBRT vs. SRS alone Level 2 Single-dose SRS alone may provide an equivalent survival advantage for patients with brain metastases compared with WBRT + single-dose SRS. There is conflicting class I and II evidence regarding the risk of both local and distant recurrence when SRS is used in isolation, and class I evidence demonstrates a lower risk of distant recurrence with WBRT; thus, regular careful surveillance is warranted for patients treated with SRS alone in order to provide early identification of local and distant recurrences so that salvage therapy can be initiated at the soonest possible time. Surgical Resection plus WBRT vs. SRS +/- WBRT Level 2 Surgical resection plus WBRT, vs. SRS plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3: Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. SRS alone vs. WBRT alone Level 3 While both single-dose SRS and WBRT are effective for treating patients with brain metastases, single-dose SRS alone appears to be superior to WBRT alone for patients with up to three metastatic brain tumors in terms of patient survival advantage.