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Jonathan Cohen, Nima Alan, James Zhou and D. Kojo Hamilton

OBJECTIVE

Despite the growing neurosurgical literature, a subset of pioneering studies have significantly impacted the field of metastatic spine disease. The purpose of this study was to identify and analyze the 100 most frequently cited articles in the field.

METHODS

A keyword search using the Thomson Reuters Web of Science was conducted to identify articles relevant to the field of metastatic spine disease. The results were filtered based on title and abstract analysis to identify the 100 most cited articles. Statistical analysis was used to characterize journal frequency, past and current citations, citation distribution over time, and author frequency.

RESULTS

The total number of citations for the final 100 articles ranged from 74 to 1169. Articles selected for the final list were published between 1940 and 2009. The years in which the greatest numbers of top-100 studies were published were 1990 and 2005, and the greatest number of citations occurred in 2012. The majority of articles were published in the journals Spine (15), Cancer (11), and the Journal of Neurosurgery (9). Forty-four individuals were listed as authors on 2 articles, 9 were listed as authors on 3 articles, and 2 were listed as authors on 4 articles in the top 100 list. The most cited article was the work by Batson (1169 citations) that was published in 1940 and described the role of the vertebral veins in the spread of metastases. The second most cited article was Patchell's 2005 study (594 citations) discussing decompressive resection of spinal cord metastases. The third most cited article was the 1978 study by Gilbert that evaluated treatment of epidural spinal cord compression due to metastatic tumor (560 citations).

CONCLUSIONS

The field of metastatic spine disease has witnessed numerous milestones and so it is increasingly important to recognize studies that have influenced the field. In this bibliographic study the authors identified and analyzed the most influential articles in the field of metastatic spine disease.

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James J. Zhou, Tsinsue Chen, S. Harrison Farber, Andrew G. Shetter and Francisco A. Ponce

OBJECTIVE

The field of deep brain stimulation (DBS) for epilepsy has grown tremendously since its inception in the 1970s and 1980s. The goal of this review is to identify and evaluate all studies published on the topic of open-loop DBS for epilepsy over the past decade (2008 to present).

METHODS

A PubMed search was conducted to identify all articles reporting clinical outcomes of open-loop DBS for the treatment of epilepsy published since January 1, 2008. The following composite search terms were used: (“epilepsy” [MeSH] OR “seizures” [MeSH] OR “kindling, neurologic” [MeSH] OR epilep* OR seizure* OR convuls*) AND (“deep brain stimulation” [MeSH] OR “deep brain stimulation” OR “DBS”) OR (“electric stimulation therapy” [MeSH] OR “electric stimulation therapy” OR “implantable neurostimulators” [MeSH]).

RESULTS

The authors identified 41 studies that met the criteria for inclusion. The anterior nucleus of the thalamus, centromedian nucleus of the thalamus, and hippocampus were the most frequently evaluated targets. Among the 41 articles, 19 reported on stimulation of the anterior nucleus of the thalamus, 6 evaluated stimulation of the centromedian nucleus of the thalamus, and 9 evaluated stimulation of the hippocampus. The remaining 7 articles reported on the evaluation of alternative DBS targets, including the posterior hypothalamus, subthalamic nucleus, ventral intermediate nucleus of the thalamus, nucleus accumbens, caudal zone incerta, mammillothalamic tract, and fornix. The authors evaluated each study for overall epilepsy response rates as well as adverse events and other significant, nonepilepsy outcomes.

CONCLUSIONS

Level I evidence supports the safety and efficacy of stimulating the anterior nucleus of the thalamus and the hippocampus for the treatment of medically refractory epilepsy. Level III and IV evidence supports stimulation of other targets for epilepsy. Ongoing research into the efficacy, adverse effects, and mechanisms of open-loop DBS continues to expand the knowledge supporting the use of these treatment modalities in patients with refractory epilepsy.

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Linda S. Aglio, Muhammad M. Abd-El-Barr, Vwaire Orhurhu, Grace Y. Kim, Jie Zhou, Laverne D. Gugino, Lisa J. Crossley, James L. Gosnell, John H. Chi and Michael W. Groff

OBJECTIVE

Preemptive administration of analgesic medication is more effective than medication given after the onset of the painful stimulus. The efficacy of preoperative or preemptive pain relief after thoracolumbosacral spine surgery has not been well studied. The present study was a double-blind, placebo-controlled randomized trial of preemptive analgesia with a single-shot epidural injection in adult patients undergoing spine surgery.

METHODS

Ninety-nine adult patients undergoing thoracolumbosacral operations via a posterior approach were randomized to receive a single shot of either epidural placebo (group 1), hydromorphone alone (group 2), or bupivacaine with hydromorphone (group 3) before surgery at the preoperative holding area. The primary outcome was the presence of opioid sparing and rescue time—defined as the time interval from when a patient was extubated to the time pain medication was first demanded during the postoperative period. Secondary outcomes include length of stay at the postanesthesia care unit (PACU), pain score at the PACU, opioid dose, and hospital length of stay.

RESULTS

Of the 99 patients, 32 were randomized to the epidural placebo group, 33 to the hydromorphone-alone group, and 34 to the bupivacaine with hydromorphone group. No significant difference was seen across the demographics and surgical complexities for all 3 groups. Compared to the control group, opioid sparing was significantly higher in group 2 (57.6% vs 15.6%, p = 0.0007) and group 3 (52.9% vs 15.6%, p = 0.0045) in the first demand of intravenous hydromorphone as a supplemental analgesic medication. Compared to placebo, the rescue time was significantly higher in group 2 (187 minutes vs 51.5 minutes, p = 0.0014) and group 3 (204.5 minutes vs 51. minutes, p = 0.0045). There were no significant differences in secondary outcomes.

CONCLUSIONS

The authors’ study demonstrated that preemptive analgesia in thoracolumbosacral surgeries can significantly reduce analgesia requirements in the immediate postoperative period as evidenced by reduced request for opioid medication in both analgesia study groups who received a preoperative analgesic epidural. Nonetheless, the lack of differences in pain score and opioid dose at the PACU brings into question the role of preemptive epidural opioids in spine surgery patients. Further work is necessary to investigate the long-term effectiveness of preemptive epidural opioids and their role in pain reduction and patient satisfaction.

Clinical trial registration no.: NCT02968862 (clinicaltrials.gov)

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Christopher D. Duntsch, Qihong Zhou, Himangi R. Jayakar, James D. Weimar, Jon H. Robertson, Lawrence M. Pfeffer, Lie Wang, Zixiu Xiang and Michael A. Whitt

Object. The purpose of this study was to evaluate both replication-competent and replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as therapeutic agents for high-grade gliomas by using an organotypic brain tissue slice—glioma coculture system.

Methods. The coculture system involved growing different brain structures together to allow neurons from these tissues to develop synaptic connections similar to those found in vivo. Rat C6 or human U87 glioma cells were then introduced into the culture to evaluate VSV as an oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt) rapidly eliminated C6 glioma cells from the coculture, but also caused significant damage to neurons, as measured by a loss of microtubule-associated protein 2 immunoreactivity and a failure in electrophysiological responses from neurons in the tissue slice. Nonetheless, pretreatment with interferon beta (IFNβ) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNβ pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pretreatment with IFNβ and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-ΔG) effectively destroyed rat C6 and human U87 glioma cells in the coculture, without causing detectable damage to the neuronal integrity and electrophysiological properties of the healthy tissue in the culture.

Conclusions. Data in this study provide in vitro proof-of-principle that rVSV-ΔG is an effective oncolytic agent that has minimal toxic side effects to neurons compared with rVSV-wt and therefore should be considered for development as an adjuvant to surgery in the treatment of glioma.

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Ian F. Pollack, Ronald L. Hamilton, C. David James, Sydney D. Finkelstein, Judith Burnham, Allan J. Yates, Emiko J. Holmes, Tianni Zhou, Jonathan L. Finlay and Group for the Children’s Oncology

Object

In reporting on molecular studies involving malignant gliomas in adults, authors have noted that deletions of PTEN and amplification of EGFR are common and may contribute to tumor development, providing a rationale for a number of therapies aimed at these molecular targets. The frequency of comparable abnormalities has not been defined in a sizable pediatric cohort. To address this issue, we examined tumor samples from the Children’s Cancer Group 945 study, a large randomized trial of treatment for childhood malignant gliomas.

Methods

Tissue sections in 62 evaluable cases were examined, and the tumors were isolated by microdissection. Polymerase chain reaction amplification was used to detect PTEN mutations. Deletions of PTEN were also assessed by fluorescence in situ hybridization (FISH) in 27 cases and loss of heterozygosity analysis in 54; EGFR was assessed using immunohistochemistry to identify areas with maximal EGFR expression, followed by FISH to determine EGFR amplification.

Alteration of the PTEN sequence was detected in just one of 62 tumors, in conjunction with loss of chromosome 10; PTEN deletions without mutation were evident in seven additional tumors. The PTEN alterations were more common in glioblastoma multiforme (seven of 25 tumors) than other tumor subgroups (one of 37 tumors) (p = 0.0056). Although 14 of 38 evaluable tumors had increased EGFR expression compared to normal tissue, only one tumor exhibited amplification of EGFR.

Conclusions

Alterations in PTEN and amplification of EGFR are uncommon in pediatric malignant gliomas, in contrast to adult malignant gliomas. From this one can infer that the pediatric and adult tumors involve distinct molecular causes. The results of this study have important implications for the adaptation of glioma therapies aimed at molecular targets in adults to the treatment of childhood gliomas, and highlight the need for investigations of therapies specifically directed toward childhood tumors.

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Nitin Agarwal, Federico Angriman, Ezequiel Goldschmidt, James Zhou, Adam S. Kanter, David O. Okonkwo, Peter G. Passias, Themistocles Protopsaltis, Virginie Lafage, Renaud Lafage, Frank Schwab, Shay Bess, Christopher Ames, Justin S. Smith, Christopher I. Shaffrey, Douglas Burton, D. Kojo Hamilton and the International Spine Study Group

OBJECTIVE

Obesity, a condition that is increasing in prevalence in the United States, has previously been associated with poorer outcomes following deformity surgery, including higher rates of perioperative complications such as deep and superficial infections. To date, however, no study has examined the relationship between preoperative BMI and outcomes of deformity surgery as measured by spine parameters such as the sagittal vertical axis (SVA), as well as health-related quality of life (HRQoL) measures such as the Oswestry Disability Index (ODI) and Scoliosis Research Society–22 patient questionnaire (SRS-22). To this end, the authors sought to clarify the relationship between BMI and postoperative change in SVA as well as HRQoL outcomes.

METHODS

The authors performed a retrospective review of a prospectively managed multicenter adult spinal deformity database collected and maintained by the International Spine Study Group (ISSG) between 2009 and 2014. The primary independent variable considered was preoperative BMI. The primary outcome was the change in SVA at 1 year after deformity surgery. Postoperative ODI and SRS-22 outcome measures were evaluated as secondary outcomes. Generalized linear models were used to model the primary and secondary outcomes at 1 year as a function of BMI at baseline, while adjusting for potential measured confounders.

RESULTS

Increasing BMI (compared to BMI < 18) was not associated with change of SVA at 1 year postsurgery. However, BMIs in the obese range of 30 to 34.9 kg/m2, compared to BMI < 18 at baseline, were associated with poorer outcomes as measured by the SRS-22 score (estimated change −0.47, 95% CI −0.93 to −0.01, p = 0.04). While BMIs > 30 appeared to be associated with poorer outcomes as determined by the ODI, this correlation did not reach statistical significance.

CONCLUSIONS

Baseline BMI did not affect the achievable SVA at 1 year postsurgery. Further studies should evaluate whether even in the absence of a change in SVA, baseline BMIs in the obese range are associated with worsened HRQoL outcomes after spinal surgery.