Daniel Lubelski

Brain tumor stem cells: Molecular characteristics and their impact on therapy

Glioblastoma (GBM) is the most prevalent primary brain tumor and ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding brain cancer genetics and modeling these tumors with new targeted therapies being tested, but these advances have not translated into substantially improved patient outcomes. Multiple chemotherapeutic agents, including temozolomide, the first-line treatment for glioblastoma, have been developed to kill cancer cells. However, the response to temozolomide in GBM is modest. Radiation is also moderately effective but this approach is plagued by limitations due to collateral radiation damage to healthy brain tissue and development of radioresistance. Therapeutic resistance is attributed at least in part to a cell population within the tumor that possesses stem-like characteristics and tumor propagating capabilities, referred to as cancer stem cells. Within GBM, the intratumoral heterogeneity is derived from a combination of regional genetic variance and a cellular hierarchy often regulated by distinct cancer stem cell niches, most notably perivascular and hypoxic regions. With the recent emergence as a key player in tumor biology, cancer stem cells have symbiotic relationships with the tumor microenvironment, oncogenic signaling pathways, and epigenetic modifications. The origins of cancer stem cells and their contributions to brain tumor growth and therapeutic resistance are under active investigation with novel anti-cancer stem cell therapies offering potential new hope for this lethal disease.

Radiation exposure to the spine surgeon in lumbar and thoracolumbar fusions with the use of an intraoperative computed tomographic 3-dimensional imaging system.

Study Design. A prospective clinical research article. Objective. The primary goals were to determine (1) radiation exposure to the spine surgeon with the use of an intraoperative 3-dimensional imaging system and (2) to define the safe distance from the computed tomographic scanner. Summary of Background. Intraoperative radiation exposure to the spinal surgeon has been assessed during 2-dimensional fluoroscopy but has not been investigated during intraoperative 3-dimensional imaging. Methods. Ten patients undergoing lumbar or thoracolumbar fusion were enrolled in a prospective trial to determine the radiation exposure to a spine surgeon standing in the substerile room, with the use of the O-ARM Imaging System (Medtronic, Memphis, TN). A thermolucent digital dosimeter was worn at chest level without a lead apron. Dosimeter readings and distance from the spine surgeon were recorded. Results. Average surgeon exposure was 44.22 ± 17.4 &mgr;rem (range: 17.71–70.76 &mgr;rem). The mean distance from the O-ARM was 4.56 ± .32 m, and the surgeon was exposed for an average of 19.6 ± 5.7 seconds (range: 8.05–28.7 s). The annual number of necessary procedures required to surpass the exposure limit, according to the data presented here, would be 113,071 operations using O-ARM. Hence, the number of necessary procedures for O-ARM use is predicted to be 1,130,710 annual procedures to reach the occupational exposure limits for extremity, skin, and all other organs and 339,213 procedures to reach the limits for the lens of eye. Conclusion. Radiation exposure is minimal to the surgical team during routine use of the O-ARM imaging system. The number of procedures required to surpass occupational exposure limits is high if using appropriate distance from the O-ARM.

Use of diffusion tensor imaging in glioma resection

Diffusion tensor imaging (DTI) is increasingly used in the resection of both high- and low-grade gliomas. Whereas conventional MRI techniques provide only anatomical information, DTI offers data on CNS connectivity by enabling visualization of important white matter tracts in the brain. Importantly, DTI allows neurosurgeons to better guide their surgical approach and resection. Here, the authors review basic scientific principles of DTI, include a primer on the technology and image acquisition, and outline the modalitys evolution as a frequently used tool for glioma resection. Current literature supporting its use is summarized, highlighting important clinical studies on the application of DTI in preoperative planning for glioma resection, preoperative diagnosis, and postoperative outcomes. The authors conclude with a review of future directions for this technology.

Differences in the surgical treatment of recurrent lumbar disc herniation among spine surgeons in the United States

BACKGROUND CONTEXT There are often multiple surgical treatment options for a spinal pathology. In addition, there is a lack of data that define differences in surgical treatment among surgeons in the United States. PURPOSE To assess the surgical treatment patterns among neurologic and orthopedic spine surgeons in the United States for the treatment of one- and two-time recurrent lumbar disc herniation. STUDY DESIGN Electronic survey. PATIENT SAMPLE An electronic survey was delivered to 2,560 orthopedic and neurologic surgeons in the United States. OUTCOME MEASURES The response data were analyzed to assess the differences among respondents over various demographic variables. The probability of disagreement is reported for various surgeon subgroups. METHODS A survey of clinical and radiographic case scenarios that included a one- and two-time lumbar disc herniation was electronically delivered to 2,560 orthopedic and neurologic surgeons in the United States. The surgical treatment options were revision microdiscectomy, revision microdiscectomy with in situ fusion, revision microdiscectomy with posterolateral fusion using pedicle screws, revision microdiscectomy with posterior lumbar interbody fusion/transforaminal lumbar interbody fusion (PLIF/TLIF), anterior lumbar interbody fusion (ALIF) with percutaneous screws, ALIF with open posterior instrumentation, or none of these. Significance of p=.01 was used to account for multiple comparisons. RESULTS Four hundred forty-five surgeons (18%) completed the survey. Surgeons in practice for 15+ years were more likely to select revision microdiscectomy compared with surgeons with fewer years in practice who were more likely to select revision microdiscectomy with PLIF/TLIF (p<.001). Similarly, those surgeons performing 200+ surgeries per year were more likely to select revision microdiscectomy with PLIF/TLIF than those performing fewer surgeries (p=.003). No significant differences were identified for region, specialty, fellowship training, or practice type. Overall, there was a 69% and 22% probability that two randomly selected spine surgeons would disagree on the surgical treatment of two- and one-time recurrent disc herniations, respectively. This probability of disagreement was consistent over multiple variables including geographic, practice type, fellowship training, and annual case volume. CONCLUSIONS Significant differences exist among US spine surgeons in the surgical treatment of recurrent lumbar disc herniations. It will become increasingly important to understand the underlying reasons for these differences and to define the most cost-effective surgical strategies for these common lumbar pathologies as the United States moves closer to a value-based health-care system.

The impact of preoperative depression on quality of life outcomes after lumbar surgery

BACKGROUND CONTEXT Some, smaller studies have investigated the effect of preoperative depression on postoperative improvement in quality of life (QOL). However, they have not used the Patient Health Questionnaire 9 (PHQ-9) in self-reported depression. PURPOSE To assess the effect of preoperative depression as measured by the PHQ-9 on postoperative improvement in QOL. STUDY DESIGN A retrospective review at a single tertiary-care referral center. PATIENT SAMPLE Patients who underwent lumbar decompression or fusion between 2008 and 2012. OUTCOMES MEASURES A self-reported EuroQol five-dimensions (EQ-5D) quality-adjusted life-years Index. METHODS Quality of life data were collected using the institutional prospectively collected database of patient-reported health status measures. The EQ-5D questionnare, PDQ, and PHQ-9 were used. Linear and logistic regression analyses were performed to assess the impact of preoperative depression on QOL improvement. RESULTS Elevated preoperative pain (PDQ, β=-0.0017, p=.0009) and worsened depression (PHQ-9, β=-0.0044, p=.0359) were significantly associated with diminished postoperative improvement in QOL, as measured by the EQ-5D. Furthermore, greater depression (PHQ-9, odds ratio [OR] 0.93, p<.0001) and pain (PDQ, OR 0.99, p=.02) were associated with significantly diminished postoperative improvement exceeding the minimum clinically important difference. CONCLUSIONS Increased preoperative pain and depression were shown to be associated with significantly reduced improvement in postoperative QOL, as measured by the EQ-5D.

Predicting C5 palsy via the use of preoperative anatomic measurements

BACKGROUND CONTEXT C5 nerve root palsy (C5P) is a relatively rare complication after anterior and posterior cervical decompression surgery that leads to a variety of debilitating symptoms. The precise etiology remains obscure, and a clear understanding of preoperative risk factors for C5P development does not exist. PURPOSE To determine whether postoperative C5P can be predicted from preoperative anteroposterior diameter (APD), foraminal diameter (FD), and/or cord-lamina angle (CLA). STUDY DESIGN Retrospective review. PATIENT SAMPLE Consecutive patients who underwent either anterior or posterior decompression surgery at C4-C5 for cervical spondylotic myelopathy. OUTCOME MEASURES Development of C5P. METHODS Blinded reviewers retrospectively assessed magnetic resonance images for each included patients C4-C5 interspace, including the midline APD, the left and right FDs, and the left and right CLA. Multivariable logistic regression was used to model the probability of palsy on the basis of one or more predictors. A jackknife validation was performed to internally validate the model and assess its generalizability. RESULTS A total of 98 patients fit the inclusion criteria; 12% had developed symptoms of C5 palsy postoperatively. Using the three variables in a predictor-model, we found that the odds ratio of having palsy for APD, FD, and CLA was 0.3, 0.02, and 1.4, respectively. For every 1-mm increase in APD and FD, the odds of developing palsy decrease 69% (p<.0001) and decrease 98% (p<.0003), respectively. In contrast, for every 1-degree increase in CLA, the odds of developing palsy increase by 43% (p<.0001). The receiver-operating characteristic curve for this three-variable model predicting development of palsy has an area under the curve (concordance index) of 0.97. After implementing a jackknife validation, the area under the curve was 95%. CONCLUSIONS This study is the first to use the combination of APD, FD, and CLA to predict development of postoperative C5 palsy after decompression surgery for patients with spondylotic myelopathy. This prediction formula may allow for better patient selection and to prepare patients that have an increased probability of developing this complication.

Reoperation rates after anterior cervical discectomy and fusion versus posterior cervical foraminotomy: a propensity-matched analysis.

BACKGROUND CONTEXT Anterior cervical discectomy and fusion (ACDF) and posterior cervical foraminotomy (PCF) are both used to surgically treat patients with cervical radiculopathy and have been shown to have similar outcomes. Nonetheless, ACDF has become increasingly more commonplace compared with PCF, in part because of a pervasive belief that PCF has a higher incidence of required reoperations. PURPOSE To determine the reoperation rate at the index level of ACDF versus PCF 2 years postoperatively. STUDY DESIGN A retrospective case-control. PATIENT SAMPLE All patients that underwent ACDF and PCF for radiculopathy (excluding myelopathy indications) between January 2005 and December 2011. OUTCOME MEASURES Revision surgery within 2 years, at the index level, was recorded. METHODS Propensity score analysis between the ACDF and PCF groups was done, matching for age, gender, race, body mass index, tobacco use, median income and insurance status, primary surgeon, level of surgery, surgery duration, and length of hospital stay. RESULTS Seven hundred ninety patients met the inclusion/exclusion criteria, including 627 ACDF and 163 PCF. Before propensity matching, the PCF group was found to be significantly older and more likely to be male. After matching, there were no significant differences between groups for any baseline characteristics. Reoperation rate at the index level was 4.8% for the ACDF group and 6.4% for the PCF group (p=.7) within 2 years of the initial surgery. Using equivalence testing, based on an a priori null hypothesis that a clinically meaningful difference between the two groups would be ≥5%, we found that the absolute difference of 1.6% was significantly (p=.01) less than our hypothesized difference. CONCLUSIONS This study demonstrates that even after accounting for patient demographics, operative characteristics, and primary surgeon, there are no significant differences in 2-year reoperation rates at the index level between ACDF and PCF. The reoperation rates are statistically equivalent. Thus, spine surgeons can operate via the posterior approach without putting patients at increased risk for revision surgery at the index level.

Cervical arthroplasty: a critical review of the literature

BACKGROUND CONTEXT Cervical disc arthroplasty (CDA) is a motion-preserving procedure that is an alternative to fusion. Proponents of arthroplasty assert that it will maintain cervical motion and prevent or reduce adjacent segment degeneration. Accordingly, CDA, compared with fusion, would have the potential to improve clinical outcomes. Published studies have varying conclusions on whether CDA reduces complications and/or improves outcomes. As many of these previous studies have been funded by CDA manufacturers, we wanted to ascertain whether there was a greater likelihood for these studies to report positive results. PURPOSE To critically assess the available literature on cervical arthroplasty with a focus on the time of publication and conflict of interest (COI). STUDY DESIGN/SETTING Review of the literature. METHODS All clinical articles about CDA published in English through August 1, 2013 were identified on Medline. Any article that presented CDA clinical results was included. Study design, sample size, type of disc, length of follow-up, use of statistical analysis, quality-of-life (QOL) outcome scores, COI, and complications were recorded. A meta-analysis was conducted stratifying studies by COI and publication date to identify differences in complication rates reported. RESULTS Seventy-four studies were included that investigated 8 types of disc prosthesis and 22 met the criteria for a randomized controlled trial (RCT). All Level Ib RCTs reported superior quality-of-life outcomes for CDA versus anterior cervical discectomy and fusion (ACDF) at 24 months. Fifty of the 74 articles (68%) had a disclosure section, including all Level Ib RCTs, which had significant COIs related to the respective studies. Those studies without a COI reported mean weighted average adjacent segment disease rates of 6.3% with CDA and 6.2% with ACDF. In contrast, the reverse was reported by studies with a COI, for which the averages were 2.5% with CDA and 6.3% with ACDF. Those studies with a COI (n=31) had an overall weighted average heterotopic ossification rate of 22%, whereas those studies with no COI (n=43) had a rate of 46%. CONCLUSIONS Associated COIs did not influence QOL outcomes. Conflicts of interest were more likely to be present in studies published after 2008, and those with a COI reported greater adjacent segment disease rates for ACDF than CDA. In addition, heterotopic ossification rates were much lower in studies with COI versus those without COI. Thus, COIs did not affect QOL outcomes but were associated with lower complication rates.

The impact of preoperative depression on quality of life outcomes after posterior cervical fusion.

BACKGROUND CONTEXT Posterior cervical fusion (PCF) has been shown to be an effective treatment for cervical spondylosis, but is associated with a 9% complication rate and high costs. To limit such complications and costs, it is imperative that proper selection of surgical candidates occur for those most likely to do well with the surgery. Affective disorders, such as depression, are associated with worsened outcomes after lumbar surgery; however, this effect has not been evaluated in patients undergoing cervical spine surgery. PURPOSE To assess the predictive value of preoperative depression and the health state on 1-year quality of life (QOL) outcomes after PCF. STUDY DESIGN A retrospective cohort analysis. PATIENT SAMPLE Eighty-eight patients who underwent PCF for cervical spondylosis were reviewed. OUTCOME MEASURES Preoperative and 1-year postoperative health outcomes were assessed based on the Pain Disability Questionnaire (PDQ), the Patient Health Questionnaire-9 (PHQ-9), and the EuroQol five-dimensions (EQ-5D) questionnaire. METHODS Univariable and multivariable regression analyses were performed to assess for preoperative predictors of 1-year change in health status. RESULTS Compared with preoperative health states, the PCF cohort showed statistically significant improved PDQ (87.8 vs. 73.6), PHQ-9 (7.7 vs. 6.6), and EQ-5D (0.50 vs. 0.60) scores at 1 year postoperatively. Only 10/88 (11%) patients achieved or surpassed the minimum clinically important difference for the PHQ-9 (5). Multiple linear and logistic regression analyses showed that increasing PHQ-9 and EQ-5D preoperative scores were associated with reduced 1-year postoperative improvement in health status (EQ-5D index). CONCLUSIONS Of patients who undergo PCF, those with a greater degree of preoperative depression have lower improvements in postoperative QOL compared with those with less depression. Additionally, patients with better preoperative health states also attain lower 1-year QOL improvements.

Rates of anterior cervical discectomy and fusion after initial posterior cervical foraminotomy

BACKGROUND CONTEXT In select patients, posterior cervical foraminotomy (PCF) and anterior cervical discectomy and fusion (ACDF) result in similar clinical outcomes when used to treat cervical radiculopathy. Nonetheless, ACDF is performed more frequently, in part because of surgeon perception that PCF requires operative revisions more frequently. The present study investigates the rate of ACDF reoperation at the index level after initial PCF. PURPOSE To determine the rate of ACDF after initial PCF and to further describe any patient characteristics or preoperative or operative data that increase the rate of reoperation after PCF. STUDY DESIGN Retrospective chart review. METHODS Demographic, operative, and reoperation information was collected from the electronic medical records for all patients who underwent PCF at one institution between 2004 and 2011. All patients were subsequently contacted by telephone to identify postoperative complications and more conclusively determine whether any revision operation was performed at the index level. RESULTS One hundred seventy-eight patients who underwent a PCF were reviewed, with an average follow-up of 31.7 months. Nine (5%) patients underwent an ACDF revision operation at the index level. The reason for reoperation in these patients included cervical radiculopathy, foraminal stenosis, disc herniation, and cervical spondylosis. Patients who subsequently underwent ACDF at the index level were significantly younger (25 vs. 35 years, p=.03), had lower body mass index (25 vs. 29, p=.01), and more likely to take anxiolytic (56% vs. 22%, p=.04) or antidepressant medication (67% vs. 27%, p=.02), compared with those that did not have a revision operation. CONCLUSIONS This is the first study to determine conversion to ACDF after PCF. The present study demonstrates that PCF is associated with a low reoperation rate, similar to the historical reoperation for ACDF. Accordingly, spine surgeons can operate via a PCF approach without a significant increased risk for ACDF revision surgery at the index level.