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Richard G. Fessler, Reza Ehsanian, Charles Y. Liu, Gary K. Steinberg, Linda Jones, Jane S. Lebkowski, Edward D. Wirth III, and Stephen L. McKenna

OBJECTIVE

The primary objective of this study was to evaluate the safety of 3 escalating doses of oligodendrocyte progenitor cells (LCTOPC1; previously known as GRNOPC1 and AST-OPC1) administered at a single time point between 21 and 42 days postinjury to participants with subacute cervical spinal cord injuries (SCIs). The secondary objective was to evaluate changes in neurological function following administration of LCTOPC1.

METHODS

This study was designed as an open-label, dose-escalation, multicenter clinical trial. Twenty-five participants with C4–7 American Spinal Injury Association Impairment Scale grade A or B injuries received a single dose of either 2 × 106, 1 × 107, or 2 × 107 LCTOPC1 delivered via intraparenchymal injection into the spinal cord at the site of injury using a custom-designed syringe positioning device. Low-dose tacrolimus was administered until day 60. Outcome measures included adverse event (AE) monitoring and neurological function as measured by the International Standards for Neurological Classification of Spinal Cord Injury.

RESULTS

All 25 participants experienced at least one AE, with a total of 534 AEs (32 study-related vs 502 study-unrelated anticipated complications of SCI) reported at the completion of 1-year follow-up. There were 29 serious AEs reported. Two grade 3 serious AEs (CSF leak in one participant and a bacterial infection in another) were considered related to the injection procedure and to immunosuppression with tacrolimus, respectively. The CSF leakage resolved with sequelae, including self-limited altered mental status, and the infection resolved with antibiotic therapy. For all participants, MRI scans demonstrated no evidence of an enlarging mass, spinal cord damage related to the injection procedure, inflammatory lesions in the spinal cord, or masses in the ventricular system. At 1-year follow-up, 21/22 (96%) of the intention-to-treat group recovered one or more levels of neurological function on at least one side of their body, and 7/22 (32%) recovered two or more levels of neurological function on at least one side of their body.

CONCLUSIONS

LCTOPC1 can be safely administered to participants in the subacute period after cervical SCI. The injection procedure, low-dose temporary immunosuppression regimen, and LCTOPC1 were well tolerated. The safety and neurological function data support further investigation to determine the efficacy of LCTOPC1 in the treatment of SCI.

Clinical trial registration no.: NCT02302157 (ClinicalTrials.gov)

Free access

Tobias Prasse and Christoph P. Hofstetter

Open access

Stephen L. McKenna, Reza Ehsanian, Charles Y. Liu, Gary K. Steinberg, Linda Jones, Jane S. Lebkowski, Edward Wirth III, and Richard G. Fessler

OBJECTIVE

The purpose of this study was to evaluate the safety of oligodendrocyte progenitor cells (LCTOPC1) derived from human pluripotent stem cells administered between 7 and 14 days postinjury to patients with T3 to T11 neurologically complete spinal cord injury (SCI). The rationale for this first-in-human trial was based on evidence that administration of LCTOPC1 supports survival and potential repair of key cellular components and architecture at the SCI site.

METHODS

This study was a multisite, open-label, single-arm interventional clinical trial. Participants (n = 5) received a single intraparenchymal injection of 2 × 106 LCTOPC1 caudal to the epicenter of injury using a syringe positioning device. Immunosuppression with tacrolimus was administered for a total of 60 days. Participants were followed with annual in-person examinations and MRI for 5 years at the time of this report and will be followed with annual telephone questionnaires for 6 to 15 years postinjection. The primary endpoint was safety, as measured by the frequency and severity of adverse events related to the LCTOPC1 injection, the injection procedure, and/or the concomitant immunosuppression administered. The secondary endpoint was neurological function as measured by sensory scores and lower-extremity motor scores as measured by the International Standards for Neurological Classification of Spinal Cord Injury examinations.

RESULTS

No unanticipated serious adverse events related to LCTOPC1 have been reported with 98% follow-up of participants (49 of 50 annual visits) through the first 10 years of the clinical trial. There was no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation. MRI results during the long-term follow-up period in patients administered LCTOPC1 cells showed that 80% of patients demonstrated T2 signal changes consistent with the formation of a tissue matrix at the injury site.

CONCLUSIONS

This study provides crucial first-in-human safety data supporting the pursuit of future human embryonic stem cell–derived therapies. While we cannot exclude the possibility of future adverse events, the experience in this trial provides evidence that this cell type can be well tolerated by patients, with an event-free period of up to 10 years. Based on the safety profile of LCTOPC1 obtained in this study, a cervical dose escalation trial was initiated (NCT02302157).

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Khoi D. Than, Vikram A. Mehta, Vivian Le, Jonah R. Moss, Paul Park, Juan S. Uribe, Robert K. Eastlack, Dean Chou, Kai-Ming Fu, Michael Y. Wang, Neel Anand, Peter G. Passias, Christopher I. Shaffrey, David O. Okonkwo, Adam S. Kanter, Pierce Nunley, Gregory M. Mundis Jr., Richard G. Fessler, and Praveen V. Mummaneni

OBJECTIVE

Minimally invasive surgery (MIS) for adult spinal deformity (ASD) can offer deformity correction with less tissue manipulation and damage. However, the impact of obesity on clinical outcomes and radiographic correction following MIS for ASD is poorly understood. The goal of this study was to determine the role, if any, that obesity has on radiographic correction and health-related quality-of-life measures in MIS for ASD.

METHODS

Data were collected from a multicenter database of MIS for ASD. This was a retrospective review of a prospectively collected database. Patient inclusion criteria were age ≥ 18 years and coronal Cobb angle ≥ 20°, pelvic incidence–lumbar lordosis mismatch ≥ 10°, or sagittal vertical axis (SVA) > 5 cm. A group of patients with body mass index (BMI) < 30 kg/m2 was the control cohort; BMI ≥ 30 kg/m2 was used to define obesity. Obesity cohorts were categorized into BMI 30–34.99 and BMI ≥ 35. All patients had at least 1 year of follow-up. Preoperative and postoperative health-related quality-of-life measures and radiographic parameters, as well as complications, were compared via statistical analysis.

RESULTS

A total of 106 patients were available for analysis (69 control, 17 in the BMI 30–34.99 group, and 20 in the BMI ≥ 35 group). The average BMI was 25.24 kg/m2 for the control group versus 32.46 kg/m2 (p < 0.001) and 39.5 kg/m2 (p < 0.001) for the obese groups. Preoperatively, the BMI 30–34.99 group had significantly more prior spine surgery (70.6% vs 42%, p = 0.04) and worse preoperative numeric rating scale leg scores (7.71 vs 5.08, p = 0.001). Postoperatively, the BMI 30–34.99 cohort had worse Oswestry Disability Index scores (33.86 vs 23.55, p = 0.028), greater improvement in numeric rating scale leg scores (−4.88 vs −2.71, p = 0.012), and worse SVA (51.34 vs 26.98, p = 0.042) at 1 year postoperatively. Preoperatively, the BMI ≥ 35 cohort had significantly worse frailty (4.5 vs 3.27, p = 0.001), Oswestry Disability Index scores (52.9 vs 44.83, p = 0.017), and T1 pelvic angle (26.82 vs 20.71, p = 0.038). Postoperatively, after controlling for differences in frailty, the BMI ≥ 35 cohort had significantly less improvement in their Scoliosis Research Society–22 outcomes questionnaire scores (0.603 vs 1.05, p = 0.025), higher SVA (64.71 vs 25.33, p = 0.015) and T1 pelvic angle (22.76 vs 15.48, p = 0.029), and less change in maximum Cobb angle (−3.93 vs −10.71, p = 0.034) at 1 year. The BMI 30–34.99 cohort had significantly more infections (11.8% vs 0%, p = 0.004). The BMI ≥ 35 cohort had significantly more implant complications (30% vs 11.8%, p = 0.014) and revision surgery within 90 days (5% vs 1.4%, p = 0.034).

CONCLUSIONS

Obese patients who undergo MIS for ASD have less correction of their deformity, worse quality-of-life outcomes, more implant complications and infections, and an increased rate of revision surgery compared with their nonobese counterparts, although both groups benefit from surgery. Appropriate counseling should be provided to obese patients.

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Gregory M. Mundis Jr., Jakub Godzik, Paul Park, Kai-Ming Fu, Stacie Tran, Juan S. Uribe, Michael Y. Wang, Khoi D. Than, David O. Okonkwo, Adam S. Kanter, Pierce D. Nunley, Neel Anand, Richard G. Fessler, Dean Chou, Renaud Lafage, Robert K. Eastlack, and

OBJECTIVE

Traditional surgery for adult spinal deformity (ASD) is effective but may result in exposure-related morbidity. Minimally invasive surgery (MIS) can potentially minimize this morbidity; however, high-level evidence is lacking. This study presents the first prospective multicenter investigation of MIS approaches for ASD.

METHODS

A prospective multicenter study was conducted. Inclusion criteria were age ≥ 18 years, with at least one of the following radiographic criteria: coronal Cobb (CC) angle ≥ 20°, sagittal vertical axis (SVA) > 5 cm, pelvic tilt (PT) > 25°, and thoracic kyphosis > 60°. Additional inclusion criteria were circumferential MIS, including interbody fusion (transforaminal lumbar interbody fusion [TLIF], lateral lumbar interbody fusion [LLIF], or anterior lumbar interbody fusion [ALIF]) with percutaneous posterior fixation on a minimum of 4 intervertebral levels. Radiographic and clinical outcomes (visual analog scale [VAS], Oswestry Disability Index [ODI], and Scoliosis Research Society–22 [SRS-22]) were collected preoperatively and at 12 months postoperatively; preoperative and postoperative values were compared using paired Student t-tests.

RESULTS

Seventy-five patients with a minimum 1-year follow-up were identified (75 of 111; 67.6%). The mean ± SD age was 68.8 ± 9.0 years, and 48 patients (64%) were female. Patients underwent a mean of 6.7 ± 2.9 levels of fusion with LLIF (85%), ALIF (55%), and TLIF (9%); the mean estimated blood loss was 547.6 ± 567.2 mL, and the mean length of stay was 7.0 ± 3.7 days. Significant improvements were observed in ODI (−19 ± 12.9, p < 0.001), SRS-22 (0.8 ± 0.66, p < 0.001), VAS back (−4.3 ± 2.8, p < 0.001), and VAS leg (−3.0 ± 3.2, p < 0.001) scores. Significant decreases in SVA (−26.4 ± 53.6 mm; p < 0.001), pelvic incidence–lumbar lordosis (−11.3° ± 14.9°, p < 0.001), and CC angle (−12.1° ± 11.8°, p < 0.001) were also observed. Complications occurred in 39 patients (52%); 11 patients (15%) experienced major complications, and 16 patients (21%) required reoperation.

CONCLUSIONS

MIS approaches for ASD resulted in meaningful symptomatic improvement. The complication rates were similar to historic norms, with a fairly high reoperation rate at 1 year. Longer follow-up will be necessary to evaluate the durability of this approach in the treatment of ASD.

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Andrew K. Chan, Robert K. Eastlack, Richard G. Fessler, Khoi D. Than, Dean Chou, Kai-Ming Fu, Paul Park, Michael Y. Wang, Adam S. Kanter, David O. Okonkwo, Pierce D. Nunley, Neel Anand, Juan S. Uribe, Gregory M. Mundis Jr., Shay Bess, Christopher I. Shaffrey, Vivian P. Le, Praveen V. Mummaneni, and

OBJECTIVE

Previous studies have demonstrated the short-term radiographic and clinical benefits of circumferential minimally invasive surgery (cMIS) and hybrid (i.e., minimally invasive anterior or lateral interbody fusion with an open posterior approach) techniques to correct adult spinal deformity (ASD). However, it is not known if these benefits are maintained over longer periods of time. This study evaluated the 2- and 3-year outcomes of cMIS and hybrid correction of ASD.

METHODS

A multicenter database was retrospectively reviewed for patients undergoing cMIS or hybrid surgery for ASD. Patients were ≥ 18 years of age and had one of the following: maximum coronal Cobb angle (CC) ≥ 20°, sagittal vertical axis (SVA) > 5 cm, pelvic incidence–lumbar lordosis mismatch (PI-LL) ≥ 10°, or pelvic tilt (PT) > 20°. Radiographic parameters were evaluated at the latest follow-up. Clinical outcomes were compared at 2- and 3-year time points and adjusted for age, preoperative CC, levels operated, levels with interbody fusion, presence of L5–S1 anterior lumbar interbody fusion, and upper and lower instrumented vertebral level.

RESULTS

Overall, 197 (108 cMIS, 89 hybrid) patients were included with 187 (99 cMIS, 88 hybrid) and 111 (60 cMIS, 51 hybrid) patients evaluated at 2 and 3 years, respectively. The mean (± SD) follow-up duration for cMIS (39.0 ± 13.3 months, range 22–74 months) and hybrid correction (39.9 ± 16.8 months, range 22–94 months) were similar for both cohorts. Hybrid procedures corrected the CC greater than the cMIS technique (adjusted p = 0.022). There were no significant differences in postoperative SVA, PI-LL, PT, and sacral slope (SS). At 2 years, cMIS had lower Oswestry Disability Index (ODI) scores (adjusted p < 0.001), greater ODI change as a percentage of baseline (adjusted p = 0.006), less visual analog scale (VAS) back pain (adjusted p = 0.006), and greater VAS back pain change as a percentage of baseline (adjusted p = 0.001) compared to hybrid techniques. These differences were no longer significant at 3 years. At 3 years, but not 2 years, VAS leg pain was lower for cMIS compared to hybrid techniques (adjusted p = 0.032). Those undergoing cMIS had fewer overall complications compared to hybrid techniques (adjusted p = 0.006), but a higher odds of pseudarthrosis (adjusted p = 0.039).

CONCLUSIONS

In this review of a multicenter database for patients undergoing cMIS and hybrid surgery for ASD, hybrid procedures were associated with a greater CC improvement compared to cMIS techniques. cMIS was associated with superior ODI and back pain at 2 years, but this difference was no longer evident at 3 years. However, cMIS was associated with superior leg pain at 3 years. There were fewer complications following cMIS, with the exception of pseudarthrosis.

Free access

Dean Chou, Virginie Lafage, Alvin Y. Chan, Peter Passias, Gregory M. Mundis Jr., Robert K. Eastlack, Kai-Ming Fu, Richard G. Fessler, Munish C. Gupta, Khoi D. Than, Neel Anand, Juan S. Uribe, Adam S. Kanter, David O. Okonkwo, Shay Bess, Christopher I. Shaffrey, Han Jo Kim, Justin S. Smith, Daniel M. Sciubba, Paul Park, Praveen V. Mummaneni, and

OBJECTIVE

Circumferential minimally invasive spine surgery (cMIS) for adult scoliosis has become more advanced and powerful, but direct comparison with traditional open correction using prospectively collected data is limited. The authors performed a retrospective review of prospectively collected, multicenter adult spinal deformity data. The authors directly compared cMIS for adult scoliosis with open correction in propensity-matched cohorts using health-related quality-of-life (HRQOL) measures and surgical parameters.

METHODS

Data from a prospective, multicenter adult spinal deformity database were retrospectively reviewed. Inclusion criteria were age > 18 years, minimum 1-year follow-up, and one of the following characteristics: pelvic tilt (PT) > 25°, pelvic incidence minus lumbar lordosis (PI-LL) > 10°, Cobb angle > 20°, or sagittal vertical axis (SVA) > 5 cm. Patients were categorized as undergoing cMIS (percutaneous screws with minimally invasive anterior interbody fusion) or open correction (traditional open deformity correction). Propensity matching was used to create two equal groups and to control for age, BMI, preoperative PI-LL, pelvic incidence (PI), T1 pelvic angle (T1PA), SVA, PT, and number of posterior levels fused.

RESULTS

A total of 154 patients (77 underwent open procedures and 77 underwent cMIS) were included after matching for age, BMI, PI-LL (mean 15° vs 17°, respectively), PI (54° vs 54°), T1PA (21° vs 22°), and mean number of levels fused (6.3 vs 6). Patients who underwent three-column osteotomy were excluded. Follow-up was 1 year for all patients. Postoperative Oswestry Disability Index (ODI) (p = 0.50), Scoliosis Research Society–total (p = 0.45), and EQ-5D (p = 0.33) scores were not different between cMIS and open patients. Maximum Cobb angles were similar for open and cMIS patients at baseline (25.9° vs 26.3°, p = 0.85) and at 1 year postoperation (15.0° vs 17.5°, p = 0.17). In total, 58.3% of open patients and 64.4% of cMIS patients (p = 0.31) reached the minimal clinically important difference (MCID) in ODI at 1 year. At 1 year, no differences were observed in terms of PI-LL (p = 0.71), SVA (p = 0.46), PT (p = 0.9), or Cobb angle (p = 0.20). Open patients had greater estimated blood loss compared with cMIS patients (1.36 L vs 0.524 L, p < 0.05) and fewer levels of interbody fusion (1.87 vs 3.46, p < 0.05), but shorter operative times (356 minutes vs 452 minutes, p = 0.003). Revision surgery rates between the two cohorts were similar (p = 0.97).

CONCLUSIONS

When cMIS was compared with open adult scoliosis correction with propensity matching, HRQOL improvement, spinopelvic parameters, revision surgery rates, and proportions of patients who reached MCID were similar between cohorts. However, well-selected cMIS patients had less blood loss, comparable results, and longer operative times in comparison with open patients.

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Dean Chou, Virginie Lafage, Alvin Y. Chan, Peter Passias, Gregory M. Mundis Jr., Robert K. Eastlack, Kai-Ming Fu, Richard G. Fessler, Munish C. Gupta, Khoi D. Than, Neel Anand, Juan S. Uribe, Adam S. Kanter, David O. Okonkwo, Shay Bess, Christopher I. Shaffrey, Han Jo Kim, Justin S. Smith, Daniel M. Sciubba, Paul Park, Praveen V. Mummaneni, and the International Spine Study Group (ISSG)

OBJECTIVE

Circumferential minimally invasive spine surgery (cMIS) for adult scoliosis has become more advanced and powerful, but direct comparison with traditional open correction using prospectively collected data is limited. The authors performed a retrospective review of prospectively collected, multicenter adult spinal deformity data. The authors directly compared cMIS for adult scoliosis with open correction in propensity-matched cohorts using health-related quality-of-life (HRQOL) measures and surgical parameters.

METHODS

Data from a prospective, multicenter adult spinal deformity database were retrospectively reviewed. Inclusion criteria were age > 18 years, minimum 1-year follow-up, and one of the following characteristics: pelvic tilt (PT) > 25°, pelvic incidence minus lumbar lordosis (PI-LL) > 10°, Cobb angle > 20°, or sagittal vertical axis (SVA) > 5 cm. Patients were categorized as undergoing cMIS (percutaneous screws with minimally invasive anterior interbody fusion) or open correction (traditional open deformity correction). Propensity matching was used to create two equal groups and to control for age, BMI, preoperative PI-LL, pelvic incidence (PI), T1 pelvic angle (T1PA), SVA, PT, and number of posterior levels fused.

RESULTS

A total of 154 patients (77 underwent open procedures and 77 underwent cMIS) were included after matching for age, BMI, PI-LL (mean 15° vs 17°, respectively), PI (54° vs 54°), T1PA (21° vs 22°), and mean number of levels fused (6.3 vs 6). Patients who underwent three-column osteotomy were excluded. Follow-up was 1 year for all patients. Postoperative Oswestry Disability Index (ODI) (p = 0.50), Scoliosis Research Society–total (p = 0.45), and EQ-5D (p = 0.33) scores were not different between cMIS and open patients. Maximum Cobb angles were similar for open and cMIS patients at baseline (25.9° vs 26.3°, p = 0.85) and at 1 year postoperation (15.0° vs 17.5°, p = 0.17). In total, 58.3% of open patients and 64.4% of cMIS patients (p = 0.31) reached the minimal clinically important difference (MCID) in ODI at 1 year. At 1 year, no differences were observed in terms of PI-LL (p = 0.71), SVA (p = 0.46), PT (p = 0.9), or Cobb angle (p = 0.20). Open patients had greater estimated blood loss compared with cMIS patients (1.36 L vs 0.524 L, p < 0.05) and fewer levels of interbody fusion (1.87 vs 3.46, p < 0.05), but shorter operative times (356 minutes vs 452 minutes, p = 0.003). Revision surgery rates between the two cohorts were similar (p = 0.97).

CONCLUSIONS

When cMIS was compared with open adult scoliosis correction with propensity matching, HRQOL improvement, spinopelvic parameters, revision surgery rates, and proportions of patients who reached MCID were similar between cohorts. However, well-selected cMIS patients had less blood loss, comparable results, and longer operative times in comparison with open patients.

Free access

Richard G. Fessler

Lumbar spinal stenosis is a common degenerative condition among the elderly population and a leading cause of morbidity in this age group. A recent Cochrane analysis reviewed the evidence for surgical versus nonsurgical treatment from 5 prospective, randomized controlled studies and concluded that “No clear benefits were observed with surgery versus non-surgical treatment.” This is despite the fact that all 5 of the reports analyzed concluded that surgery provided superior outcome compared to nonsurgical therapy. This report analyzes, in detail, the Cochrane analysis of Zaina et al., each of the 5 studies included in the Zaina analysis, and the Cochrane methodology itself. Unlike the ultimate in objectivity sought after by the creators of the Cochrane tool, what is revealed is a remarkably subjective methodology fraught with the potential for bias.

Free access

Richard G. Fessler, Charles Y. Liu, Stephen McKenna, R. David Fessler, Jane S. Lebkowski, Catherine A. Priest, and Edward D. Wirth III

OBJECTIVE

This study was conducted as a final proof-of-safety direct injection of oligodendrocyte progenitor cells into the uninjured spinal cord prior to translation to the human clinical trials.

METHODS

In this study, 107 oligodendrocyte progenitor cells (LCTOPC1, also known as AST-OPC1 and GRNOPC1) in 50-μL suspension were injected directly into the uninjured spinal cords of 8 immunosuppressed Göttingen minipigs using a specially designed stereotactic delivery device. Four additional Göttingen minipigs were given Hanks’ Balanced Salt Solution and acted as the control group.

RESULTS

Cell survival and no evidence of histological damage, abnormal inflammation, microbiological or immunological abnormalities, tumor formation, or unexpected morbidity or mortality were demonstrated.

CONCLUSIONS

These data strongly support the safety of intraparenchymal injection of LCTOPC1 into the spinal cord using a model anatomically similar to that of the human spinal cord. Furthermore, this research provides guidance for future clinical interventions, including mechanisms for precise positioning and anticipated volumes of biological payloads that can be safely delivered directly into uninjured portions of the spinal cord.