Todd J. Albert

Surgical versus nonsurgical therapy for lumbar spinal stenosis.

BACKGROUND Surgery for spinal stenosis is widely performed, but its effectiveness as compared with nonsurgical treatment has not been shown in controlled trials. METHODS Surgical candidates with a history of at least 12 weeks of symptoms and spinal stenosis without spondylolisthesis (as confirmed on imaging) were enrolled in either a randomized cohort or an observational cohort at 13 U.S. spine clinics. Treatment was decompressive surgery or usual nonsurgical care. The primary outcomes were measures of bodily pain and physical function on the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36) and the modified Oswestry Disability Index at 6 weeks, 3 months, 6 months, and 1 and 2 years. RESULTS A total of 289 patients were enrolled in the randomized cohort, and 365 patients were enrolled in the observational cohort. At 2 years, 67% of patients who were randomly assigned to surgery had undergone surgery, whereas 43% of those who were randomly assigned to receive nonsurgical care had also undergone surgery. Despite the high level of nonadherence, the intention-to-treat analysis of the randomized cohort showed a significant treatment effect favoring surgery on the SF-36 scale for bodily pain, with a mean difference in change from baseline of 7.8 (95% confidence interval, 1.5 to 14.1); however, there was no significant difference in scores on physical function or on the Oswestry Disability Index. The as-treated analysis, which combined both cohorts and was adjusted for potential confounders, showed a significant advantage for surgery by 3 months for all primary outcomes; these changes remained significant at 2 years. CONCLUSIONS In the combined as-treated analysis, patients who underwent surgery showed significantly more improvement in all primary outcomes than did patients who were treated nonsurgically. (ClinicalTrials.gov number, NCT00000411 [ClinicalTrials.gov].).

Surgical Versus Nonoperative Treatment for Lumbar Disc Herniation Four-Year Results for the Spine Patient Outcomes Research Trial (SPORT)

Study Design. Concurrent, prospective, randomized, and observational cohort study. Objective. To assess the 4-year outcomes of surgery versus nonoperative care. Summary of Background Data. Although randomized trials have demonstrated small short-term differences in favor of surgery, long-term outcomes comparing surgical to nonoperative treatment remain controversial. Methods. Surgical candidates with imaging-confirmed lumbar intervertebral disc herniation meeting SPORT eligibility criteria enrolled into prospective, randomized (501 participants), and observational cohorts (743 participants) at 13 spine clinics in 11 US states. Interventions were standard open discectomy versus usual nonoperative care. Main outcome measures were changes from baseline in the SF-36 Bodily Pain (BP) and Physical Function (PF) scales and the modified Oswestry Disability Index (ODI - AAOS/Modems version) assessed at 6 weeks, 3 months, 6 months, and annually thereafter. Results. Nonadherence to treatment assignment caused the intent-to-treat analyses to underestimate the treatment effects. In the 4-year combined as-treated analysis, those receiving surgery demonstrated significantly greater improvement in all the primary outcome measures (mean change surgery vs. nonoperative; treatment effect; 95% CI): BP (45.6 vs. 30.7; 15.0; 11.8 to 18.1), PF (44.6 vs. 29.7; 14.9;12.0 to 17.8) and ODI (−38.1 vs. −24.9; −13.2; −15.6 to −10.9). The percent working was similar between the surgery and nonoperative groups, 84.4% versus 78.4% respectively. Conclusion. In a combined as-treated analysis at 4 years, patients who underwent surgery for a lumbar disc herniation achieved greater improvement than nonoperatively treated patients in all primary and secondary outcomes except work status.

Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy.

Objective. Because mesenchymal stem cells can differentiate into chondrocyte-like cells, we ask the question, can mesenchymal stem cells commit to the nucleus pulposus phenotype? Background. Back pain, a significant source of morbidity in our society, is linked to degenerative changes of the intervertebral disc. Absence of suitable graft tissue limits therapeutic approaches for repair of disc tissue. For this reason, there is considerable interest in developing “tissue engineering” strategies for the regeneration of the nucleus pulposus. Methods. Rat mesenchymal stem cells were immobilized in 3-dimensional alginate hydrogels and cultured in a medium containing transforming growth factor-&bgr;1 under hypoxia (2% O2) and normoxia (20% O2). Mesenchymal stem cells were examined by confocal microscopy to evaluate their viability and metabolic status after labeling with Celltracker green, a thiol sensitive dye, and Mitotracker red, a dye sensitive to the mitochondrial membrane potential. Flow cytometry, semiquantitative reverse transcription polymerase chain reaction and Western blot analysis were carried out to evaluate phenotypic and biosynthetic activities and the signaling pathways involved in the differentiation process. Results. Under hypoxic conditions, mesenchymal stem cells formed large aggregates and exhibited positive Celltracker and Mitotracker signals. Glucose transporter-3, matrix metalloproteinase-2, collagen type II and type XI, and aggrecan mRNA and protein expression was upregulated, whereas there was no change in the levels of decorin, biglycan, fibromodulin, and lumican. Hypoxia maintained the expression of CD44 (hyaluronan receptor), ALCAM (CD166), and endoglin (transforming growth factor-&bgr; receptor). Likewise, expression of &bgr;3 and &agr;2 integrin was upregulated. Transforming growth factor-&bgr; treatment increased MAPK activity and Sox-9, aggrecan, and collagen type II gene expression. Basal levels of the phosphorylated MAPK isoform ERK1/2, but not p38, were higher under hypoxic conditions than normoxia, and its activation was further augmented by treatment of cells with transforming growth factor-&bgr;. In hypoxia, transforming growth factor-&bgr; sustained phosphorylated p38 expression for an extended time period. Pharmacological inhibition of ERK1/2 and p38 enzymatic activity resulted in a decrease in Sox-9, aggrecan, and collagen type II mRNA levels. Conclusions. Our results indicate that hypoxia and transforming growth factor-&bgr; drive mesenchymal stem cell differentiation towards a phenotype consistent with that of the nucleus pulposus. Measurement of selected signaling molecules and response to specific inhibitors suggest involvement of MAPK signaling pathways. It is concluded that mesenchymal stem cells could be used to repopulate the damaged or degenerate intervertebral disc.

Surgical versus nonoperative treatment for lumbar spinal stenosis four-year results of the Spine Patient Outcomes Research Trial.

Study Design. Randomized trial and concurrent observational cohort study. Objective. To compare 4 year outcomes of surgery to nonoperative care for spinal stenosis. Summary of Background Data. Surgery for spinal stenosis has been shown to be more effective compared to nonoperative treatment over 2 years, but longer-term data have not been analyzed. Methods. Surgical candidates from 13 centers in 11 US states with at least 12 weeks of symptoms and confirmatory imaging were enrolled in a randomized cohort (RC) or observational cohort (OC). Treatment was standard decompressive laminectomy or standard nonoperative care. Primary outcomes were SF-36 bodily pain (BP) and physical function scales and the modified Oswestry Disability index assessed at 6 weeks, 3 months, 6 months, and yearly up to 4 years. Results. A total of 289 patients enrolled in the RC and 365 patients enrolled in the OC. An as-treated analysis combining the RC and OC and adjusting for potential confounders found that the clinically significant advantages for surgery previously reported were maintained through 4 years, with treatment effects (defined as mean change in surgery group minus mean change in nonoperative group) for bodily pain 12.6 (95% confidence interval [CI], 8.5–16.7); physical function 8.6 (95% CI, 4.6–12.6); and Oswestry Disability index −9.4 (95% CI, −12.6 to −6.2). Early advantages for surgical treatment for secondary measures such as bothersomeness, satisfaction with symptoms, and self-rated progress were also maintained. Conclusion. Patients with symptomatic spinal stenosis treated surgically compared to those treated nonoperatively maintain substantially greater improvement in pain and function through 4 years.

Evidence for skeletal progenitor cells in the degenerate human intervertebral disc.

Study Design. To identify and characterize endogenous progenitor cell population from intervertebral disc. Objective. To determine if progenitor cells exist in degenerate human discs. Summary of Background Data. Back pain, a significant source of morbidity in our society, is directly linked to the pathology of the intervertebral disc. Because disc disease is accompanied by a loss of cellularity, there is considerable interest in regeneration of cells of both the anulus fibrosus (AF) and nucleus pulposus (NP). Methods. To determine if skeletal progenitor cells are present in the disc, samples were obtained from the degenerate AF and NP of 5 patients (Thompson grade 2 and 3, mean age 34 ± 7.6 years) undergoing anterior cervical discectomy and fusion procedures as well as adult rat lumbar spine. Results. Cells isolated from degenerate human tissues expressed CD105, CD166, CD63, CD49a, CD90, CD73, p75 low affinity nerve growth factor receptor, and CD133/1, proteins that are characteristic of marrow mesenchymal stem cells. In osteogenic media, there was an induction of alkaline phosphatase activity and expression of alkaline phosphatase, osteocalcin, and Runx-2 mRNA. When maintained in adipogenic media, a small percentage of cells displayed evidence of adipogenic differentiation: accumulation of cytosolic lipid droplets and increased expression of peroxisome proliferator-activated receptor-&ggr;2 and lipoporotein lipase mRNA. AF- and NP-derived cells also evidenced chondrogenic differentiation. CD133 (+) cells in the AF were able to commit to either the chondrogenic or adipogenic lineages. The results of the human disc studies were confirmed using cell derived from the NP and AF tissue of the mature rat disc. Conclusion. The analytical data indicated that the pathologically degenerate human disc contained populations of skeletal progenitor cells. These findings suggest that these endogenous progenitors may be used to orchestrate the repair of the intervertebral disc.

Surgical Treatment of Spinal Stenosis with and without Degenerative Spondylolisthesis: Cost-Effectiveness after 2 Years

BACKGROUND The SPORT (Spine Patient Outcomes Research Trial) reported favorable surgery outcomes over 2 years among patients with stenosis with and without degenerative spondylolisthesis, but the economic value of these surgeries is uncertain. OBJECTIVE To assess the short-term cost-effectiveness of spine surgery relative to nonoperative care for stenosis alone and for stenosis with spondylolisthesis. DESIGN Prospective cohort study. DATA SOURCES Resource utilization, productivity, and EuroQol EQ-5D score measured at 6 weeks and at 3, 6, 12, and 24 months after treatment among SPORT participants. TARGET POPULATION Patients with image-confirmed spinal stenosis, with and without degenerative spondylolisthesis. TIME HORIZON 2 years. PERSPECTIVE Societal. INTERVENTION Nonoperative care or surgery (primarily decompressive laminectomy for stenosis and decompressive laminectomy with fusion for stenosis associated with degenerative spondylolisthesis). OUTCOME MEASURES Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS Among 634 patients with stenosis, 394 (62%) had surgery, most often decompressive laminectomy (320 of 394 [81%]). Stenosis surgeries improved health to a greater extent than nonoperative care (QALY gain, 0.17 [95% CI, 0.12 to 0.22]) at a cost of

Nucleus pulposus cells express HIF‐1α under normoxic culture conditions: A metabolic adaptation to the intervertebral disc microenvironment

77,600 (CI,

A Pilot Study Evaluating the Safety and Efficacy of OP-1 Putty (rhBMP-7) as a Replacement for Iliac Crest Autograft in Posterolateral Lumbar Arthrodesis for Degenerative Spondylolisthesis

49,600 to

Dysphagia after anterior cervical decompression and fusion: prevalence and risk factors from a longitudinal cohort study.

120,000) per QALY gained. Among 601 patients with degenerative spondylolisthesis, 368 (61%) had surgery, most including fusion (344 of 368 [93%]) and most with instrumentation (269 of 344 [78%]). Degenerative spondylolisthesis surgeries significantly improved health versus nonoperative care (QALY gain, 0.23 [CI, 0.19 to 0.27]), at a cost of

Impact of neck and arm pain on overall health status.

115,600 (CI,