Michelle J. Clarke

Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines

Resistance to temozolomide and radiotherapy is a major problem for patients with glioblastoma but may be overcome using the poly(ADP-ribose) polymerase inhibitor ABT-888. Using two primary glioblastoma xenografts, the efficacy of ABT-888 combined with radiotherapy and/or temozolomide was evaluated. Treatment with ABT-888 combined with temozolomide resulted in significant survival prolongation (GBM12: 55.1%, P = 0.005; GBM22: 54.4%, P = 0.043). ABT-888 had no effect with radiotherapy alone but significantly enhanced survival in GBM12 when combined with concurrent radiotherapy/temozolomide. With multicycle therapy, ABT-888 further extended the survival benefit of temozolomide in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for temozolomide resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with temozolomide, and a similar lack of efficacy was observed in two other temozolomide-resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that have not been previously exposed to temozolomide, and these results suggest that patients with newly diagnosed glioblastoma may be more likely to respond to combined temozolomide/poly(ADP-ribose) polymerase inhibitor therapy than patients with recurrent disease. [Mol Cancer Ther 2009;8(2):OF407–8]

The impact of provider volume on the outcomes after surgery for lumbar spinal stenosis.

BACKGROUND Investigation into the provider volume-outcomes association for patients undergoing spine surgery has been limited. OBJECTIVE To examine the impact of surgeon and hospital volume on the outcomes after decompression with or without fusion for lumbar spinal stenosis. METHODS Data from the Nationwide Inpatient Sample (2005-2008) were retrospectively extracted. Multivariate logistic regression analyses were performed to calculate the adjusted odds of in-hospital mortality and the development of a postoperative complication with increasing surgeon or hospital volume. Provider volume was evaluated continuously and categorically, divided by percentiles into quintiles. Very-low-volume surgeons performed < 15 procedures over 4 years. All analyses were adjusted for differences in patient age, sex, comorbidities, and primary payer, as well as hospital bed size, teaching status, and location (urban vs rural). RESULTS A total of 48,971 admissions were examined. In-hospital mortality did not differ significantly with increasing provider volume. When examined continuously, greater surgeon volume was associated with a significantly lower adjusted odds of developing a complication (odds ratio, 0.72; 95% confidence interval, 0.65-0.78; P < .001). Patients who underwent surgery by very-low-volume surgeons (odds ratio, 1.38; 95% confidence interval, 1.19-1.60; P = .001), but not those treated by low-, medium-, or high-volume surgeons, had a significantly higher complication rate compared with those who underwent surgery by very high-volume surgeons. After adjustment for surgeon volume, hospital volume was not significantly associated with in-hospital mortality or complications. CONCLUSION In this nationwide study, patients treated by very-low-volume surgeons had a significantly higher complication rate compared with those treated by very high-volume surgeons.

Rheumatoid arthritis of the craniovertebral junction.

BACKGROUNDRheumatoid arthritis (RA) is the most common inflammatory disease involving the spine. It has a predilection for involving the craniocervical spine. Despite widespread involvement of the cervical spine with RA, few patients need surgery. The 3 major spinal manifestations of RA in the cervical spine are basilar invagination, atlantoaxial instability, and subaxial subluxations. Surgical management of RA involving the craniovertebral junction remains a challenge despite a decline in severe cases and an improvement in surgical techniques. METHODSWe conducted an exhaustive review of English-language publications discussing RA involving the craniovertebral junction. We paid special attention to publications detailing modern surgical management of these conditions. In addition, we outline our own surgical experience with such patients. RESULTSWe discuss alternative surgical methods for treating basilar invagination, atlantoaxial instability, and concurrent subaxial subluxations. We detail our surgical technique for transoral odontoidectomy, occipital cervical fusion, and atlantoaxial fusion. We detail the use of spinal surgical navigation in both of these procedures. CONCLUSIONSurgical management of RA remains a challenging field. There clearly has been a decrease in cases of mutilating RA involving the craniovertebral junction. Surgical techniques for managing these conditions have steadily improved.BACKGROUND Rheumatoid arthritis (RA) is the most common inflammatory disease involving the spine. It has a predilection for involving the craniocervical spine. Despite widespread involvement of the cervical spine with RA, few patients need surgery. The 3 major spinal manifestations of RA in the cervical spine are basilar invagination, atlantoaxial instability, and subaxial subluxations. Surgical management of RA involving the craniovertebral junction remains a challenge despite a decline in severe cases and an improvement in surgical techniques. METHODS We conducted an exhaustive review of English-language publications discussing RA involving the craniovertebral junction. We paid special attention to publications detailing modern surgical management of these conditions. In addition, we outline our own surgical experience with such patients. RESULTS We discuss alternative surgical methods for treating basilar invagination, atlantoaxial instability, and concurrent subaxial subluxations. We detail our surgical technique for transoral odontoidectomy, occipital cervical fusion, and atlantoaxial fusion. We detail the use of spinal surgical navigation in both of these procedures. CONCLUSION Surgical management of RA remains a challenging field. There clearly has been a decrease in cases of mutilating RA involving the craniovertebral junction. Surgical techniques for managing these conditions have steadily improved.

Endoscopic image-guided transcervical odontoidectomy: Outcomes of 15 patients with basilar invagination

BACKGROUND: Ventral decompression with posterior stabilization is the preferred treatment for symptomatic irreducible basilar invagination. Endoscopic image-guided transcervical odontoidectomy (ETO) may allow for decompression with limited morbidity. OBJECTIVE: To describe the perioperative outcomes of patients undergoing anterior decompression of basilar invagination with the use of ETO. METHODS: Fifteen patients who had a follow-up of at least 16 months were retrospectively reviewed. Intraoperatively, the vertebral body of C2 was removed and the odontoid was resected in a “top-down” manner using endoscopic visualization and frameless stereotactic navigation. Posterior instrumented stabilization was subsequently performed. RESULTS: The average (± standard deviation) age of the patients was 42.6 ± 24.5 (range, 11-72) years. Postoperative complications occurred in 6 patients, including a urinary tract infection (n = 2), upper airway swelling (n = 2), dysphagia (n = 2), gastrostomy tube placement (n = 1), and an asymptomatic pseudomeningocele (n = 1). No patients required a tracheostomy, had bacterial meningitis, or developed a venous thromboembolic event; only 1 patient was intubated for more than 48 hours postoperatively. With a mean follow-up of 41.9 ± 14.4 (range, 16-59) months, myelopathy improved in all patients and no patient experienced late neurological deterioration. The mean modified Japanese Orthopedic Association (JOA) score increased from 11.2 ± 4.2 to 15.9 ± 1.4 (P = .002). Patients with a diagnosis other than rheumatoid arthritis or who had a higher preoperative JOA score had a significantly better postoperative neurological recovery (P = .005). CONCLUSION: ETO may be a valid treatment for patients with symptomatic irreducible basilar invagination that avoids some of the morbidity of transoral surgery and leads to long-term improvement in myelopathy.

Posterior-only approach for en bloc sacrectomy: Clinical outcomes in 36 consecutive patients

BACKGROUND En bloc resection of primary sacral tumors has a demonstrated survival benefit. Total and high sacral amputations are traditionally performed by using a staged anterior and subsequent posterior approach. However, we have found that en bloc resection and biomechanical reconstruction of the spinal column is possible from a posterior-only approach in many cases. OBJECTIVE To assess our series of posterior-only sacrectomies, emphasizing postoperative complications and overall surgical and oncologic outcome. METHODS Sixty-nine consecutive patients underwent sacral resections for tumor at our institution between 2004 and 2009. Medical records of all patients were reviewed, and patients were excluded if they had an intentional intralesional resection, hemipelvectomy, or a previous operation. The records of the resulting 36 consecutive patients who underwent primary posterior-only en bloc sacral resections were retrospectively reviewed. RESULTS Of the posterior-only patients, all underwent midline posterior approaches for en bloc sacral resection. Sacral amputation was defined by the by sacral root preservation: total (2 cases), high (8 cases), middle (9 cases), low (12 cases), and distal (5 cases). Chordoma was the most common tumor type (30 cases), and surgical margins were marginal in 34 cases and contaminated in 2. Overall, there were 13 complications, including 9 wound infections/revisions. The extent of sacrectomy, and thus the extent of roots sacrificed, correlated with functional outcome. CONCLUSION It may be possible to perform a posterior-only approach to en bloc sacral resections/reconstructions in patients with tumors that do not extend beyond the lumbosacral junction or invade the bowel requiring bowel resection and diversion.

USING FLUORODEOXYTHYMIDINE TO MONITOR ANTI-EGFR INHIBITOR THERAPY IN SQUAMOUS CELL CARCINOMA XENOGRAFTS

3′‐18F‐fluoro‐3′‐deoxy‐fluorothymidine (18F‐FLT), a nucleoside analog, could monitor effects of molecularly targeted therapeutics on tumor proliferation.

The clinical case for proton beam therapy

AbstractOver the past 20 years, several proton beam treatment programs have been implemented throughout the United States. Increasingly, the number of new programs under development is growing. Proton beam therapy has the potential for improving tumor control and survival through dose escalation. It also has potential for reducing harm to normal organs through dose reduction. However, proton beam therapy is more costly than conventional x-ray therapy. This increased cost may be offset by improved function, improved quality of life, and reduced costs related to treating the late effects of therapy. Clinical research opportunities are abundant to determine which patients will gain the most benefit from proton beam therapy. We review the clinical case for proton beam therapy.Summary sentenceProton beam therapy is a technically advanced and promising form of radiation therapy.

The impact of July hospital admission on outcome after surgery for spinal metastases at academic medical centers in the United States, 2005 to 2008

Despite widespread belief that patients admitted to teaching hospitals in July—the beginning of the academic year—have inferior outcomes, there has been little evidence to support the existence of the July phenomenon. Moreover, the impact of July admission on the outcomes after surgery for spinal metastases has not been investigated.

Reconstruction of extensive defects from posterior en bloc resection of sacral tumors with human acellular dermal matrix and gluteus maximus myocutaneous flaps

BACKGROUND Performing a sacrectomy from an exclusively posterior approach allows the en bloc resection of tumors without the morbidity of a laparotomy. However, reconstruction of the resultant extensive soft-tissue defects is challenging because a vertical rectus abdominis myocutaneous flap is not harvested. OBJECTIVE To report the largest series (with the longest follow-up) of sacral reconstructions using a combination of human acellular dermal matrix (HADM) and gluteus maximus myocutaneous flaps. METHODS Thirty-four patients with sacral tumors with a follow-up of at least 1 year were reviewed retrospectively. After the tumor was excised, HADM (AlloDerm, LifeCell Corp, Branchburg, New Jersey) was secured to create a pelvic diaphragm. Subsequently, the gluteus maximus muscles were freed from their origins and advanced to cover the HADM. RESULTS The mean age of patients was 50.1 years (SD, 16.0 years), and the histopathology was a chordoma in 82.4%. Seven patients (20.6%) developed a postoperative wound dehiscence, 5 of whom (14.7%) required operative debridement. An estimated blood loss of >1500 mL, an operative time of >9 hours during sacrectomy, and postoperative bowel incontinence were associated with a significantly higher likelihood of undergoing a subsequent debridement for dehiscence (P ⩽ .03). With a mean follow-up of 45.7 months, only 1 patient developed an asymptomatic parasacral hernia. CONCLUSION Reconstruction of posterior sacrectomy defects with HADM and gluteus maximus myocutaneous flaps may be valid. This approach may have rates of wound dehiscence comparable to other techniques and low rates of parasacral herniation.

Understanding the impact of obesity on short-term outcomes and in-hospital costs after instrumented spinal fusion

BACKGROUND Obesity rates continue to rise along with the number of obese patients undergoing elective spinal fusion. OBJECTIVE To evaluate the impact of obesity on resource utilization and early complications in patients undergoing surgery for degenerative spine disease. METHODS A single-institution retrospective analysis was conducted on patients with degenerative spine disease requiring instrumentation between 2008 and 2012. The 801 identified patients were grouped based on a body mass index (BMI) of <30 (nonobese, n = 478), ≥30 and <40 (obese, n = 283), and alternatively BMIs of ≥40 (morbidly obese, n = 40). Baseline characteristics, surgical outcomes and requirements, complications, and cost were compared. Logistic and linear regression analyses were used to determine the strength of association between obesity and outcomes for categorical and continuous data, respectively. RESULTS Significant differences were found in comorbidities between cohorts. Multivariate analysis revealed significant associations between obesity and longer anesthesia times (30 minutes, P = .008), and surgical times (24 minutes, P = .02). Additionally, there was a 2.8 times higher rate of wound complications in obese patients (4.2% vs 1.5, P = .03), and 2.5 times higher rate of major medical complications (7.8% vs 3.1, P = .01). Morbid obesity resulted in a 10 times higher rate of wound complications (P < .001). Morbid obesity resulted in a