Occurrence and clinical implications of heterotopic ossification after cervical disc arthroplasty with the Prestige LP Cervical Disc at 2 contiguous levels

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  • 1 The Orthopedic Center of St. Louis, Missouri;
  • | 2 Institute for Spinal Disorders, Cedars-Sinai Medical Center, Los Angeles, California;
  • | 3 Wilderness Spine Services, Columbus, Georgia;
  • | 4 Central Texas Spine Institute, Austin, Texas;
  • | 5 Orthopedic Specialists, Allentown, Pennsylvania;
  • | 6 Center for Sports Medicine & Orthopaedics, Chattanooga, Tennessee;
  • | 7 SPIRITT Research, St. Louis, Missouri; and
  • | 8 Medtronic, Memphis, Tennessee
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OBJECTIVE

The authors sought to assess the impact of heterotopic ossification (HO) on clinical outcomes and angular range of motion (ROM) after cervical disc arthroplasty (CDA) performed with the Prestige LP Cervical Disc (Prestige LP disc) at 2 levels.

METHODS

HO was assessed and graded from 0 to IV for increasing severity on lateral neutral radiographs at each visit in 209 patients who underwent implantation of Prestige LP discs at 2 cervical levels in a clinical trial with extended 10-year follow-up. ROM was compared by using HO grade, and clinical outcomes were compared between HO subgroups (grade 0–II vs III/IV) based on HO severity at 2 and 10 years after surgery.

RESULTS

The grade III/IV HO incidence at either or both index levels was 24.2% (48/198) at 2 years and 39.0% (57/146) at 10 years. No statistical difference was found in overall success; neurological success; or Neck Disability Index (NDI), neck pain, arm pain, or SF-36 Physical Component Summary (PCS) scores between the HO subgroups (grade 0–II vs III/IV) at either 2 or 10 years. The cumulative rate of possible implant-related adverse events (AEs) was higher in patients having grade III/IV HO at 2 years (56.3%) and 10 years (47.8%) compared with those having grade 0–II HO at 2 years (24.4%) and 10 years (17.9%), specifically in 2 subcategories: spinal events and HOs reported by the investigators. No statistical difference was found between the HO subgroups in possible implant-related serious AEs or secondary surgeries at the index or adjacent levels. The average angular ROMs at index levels were lower in subjects with higher-grade HO at 2 and 10 years. The average ROMs at the superior level were 8.8°, 6.6°, 3.2°, and 0.3°, respectively, for the HO grade 0/I, II, III, and IV groups at 10 years, and 7.9°, 6.2°, 3.7°, and 0.6°, respectively, at the inferior level.

CONCLUSIONS

Radiographically severe (grade III or IV) HO after CDA with the Prestige LP disc at 2 levels did not significantly affect efficacy or safety outcomes (severe AEs or secondary surgeries). However, severe HO, particularly grade IV HO, significantly limited ROM, as expected.

ABBREVIATIONS

ACDF = anterior cervical discectomy and fusion; AE = adverse event; CDA = cervical disc arthroplasty; HO = heterotopic ossification; NDI = Neck Disability Index; PAS = postapproval study; Prestige LP disc = Prestige LP Cervical Disc; ROM = range of motion; SAE = serious AE; VAS = visual analog scale.

OBJECTIVE

The authors sought to assess the impact of heterotopic ossification (HO) on clinical outcomes and angular range of motion (ROM) after cervical disc arthroplasty (CDA) performed with the Prestige LP Cervical Disc (Prestige LP disc) at 2 levels.

METHODS

HO was assessed and graded from 0 to IV for increasing severity on lateral neutral radiographs at each visit in 209 patients who underwent implantation of Prestige LP discs at 2 cervical levels in a clinical trial with extended 10-year follow-up. ROM was compared by using HO grade, and clinical outcomes were compared between HO subgroups (grade 0–II vs III/IV) based on HO severity at 2 and 10 years after surgery.

RESULTS

The grade III/IV HO incidence at either or both index levels was 24.2% (48/198) at 2 years and 39.0% (57/146) at 10 years. No statistical difference was found in overall success; neurological success; or Neck Disability Index (NDI), neck pain, arm pain, or SF-36 Physical Component Summary (PCS) scores between the HO subgroups (grade 0–II vs III/IV) at either 2 or 10 years. The cumulative rate of possible implant-related adverse events (AEs) was higher in patients having grade III/IV HO at 2 years (56.3%) and 10 years (47.8%) compared with those having grade 0–II HO at 2 years (24.4%) and 10 years (17.9%), specifically in 2 subcategories: spinal events and HOs reported by the investigators. No statistical difference was found between the HO subgroups in possible implant-related serious AEs or secondary surgeries at the index or adjacent levels. The average angular ROMs at index levels were lower in subjects with higher-grade HO at 2 and 10 years. The average ROMs at the superior level were 8.8°, 6.6°, 3.2°, and 0.3°, respectively, for the HO grade 0/I, II, III, and IV groups at 10 years, and 7.9°, 6.2°, 3.7°, and 0.6°, respectively, at the inferior level.

CONCLUSIONS

Radiographically severe (grade III or IV) HO after CDA with the Prestige LP disc at 2 levels did not significantly affect efficacy or safety outcomes (severe AEs or secondary surgeries). However, severe HO, particularly grade IV HO, significantly limited ROM, as expected.

In Brief

The authors assessed the impact of bone growth (heterotopic ossification [HO]) surrounding the Prestige LP Cervical Disc prosthesis over time during long-term patient follow-up at 2 and 10 years after 2-level cervical disc arthroplasty (CDA) to determine whether HO significantly affects the outcome, including range of motion, or the safety of the procedure and device. It is important for clinicians and patients to know that even severe HO may not significantly reduce the effectiveness or safety (occurrence of severe adverse events or need for secondary surgeries) of CDA performed with the Prestige LP Cervical Disc.

Cervical disc arthroplasty (CDA) is an alternative to anterior cervical discectomy and fusion (ACDF) for the treatment of patients with degenerative disc disease.3,4,7,10,19 The artificial disc acts as an intervertebral body spacer while providing for a patient’s normal movement, thereby reducing the likelihood of accelerated degeneration in adjacent discs.11,18 However, the occurrence of heterotopic ossification (HO) surrounding the prosthesis following CDA has been reported.1,2 In some studies, HO was found to limit the range of motion (ROM) and to negatively impact function of the prosthesis.15,16 Based on the HO classification proposed by Mehren et al.,14 low-grade HO (grade 0–II) at an early stage had no or slight impact on prosthesis function, while grade III HO potentially limited movement of the prosthesis due to the formation of bridging ossifications. The most severe HO (grade IV) could cause the treated segment to become fused completely, with no movement.

Different types of prostheses have been reported to incur different HO incidences.2,9,15 A study by Zeng et al. found that the incidence of HO after CDA was higher for fixed-core prostheses (ProDisc-C and Discover discs) than mobile-core prostheses (Bryan and Prestige LP discs).21 In a long-term study of single-level use of the Prestige LP Cervical Disc (Prestige LP disc; Medtronic) in the treatment of intractable radiculopathy or myelopathy of the cervical spine, the grade IV HO prevalence was 1.2% at 2 years, 4.6% at 7 years, and 9.0% at 10 years.5 Two-level uses of CDA have been approved for certain artificial discs by the US FDA and other regulatory agencies worldwide. Although the occurrence of HO by each treated level in 2-level uses may be similar to that in single-level uses,6,15 the rate of HO on a patient basis (for either the superior or inferior level or both levels) can be expected to be higher in 2-level use. Recently published data for the Prestige LP disc used at 2 levels in a clinical trial showed severe HO (grade III or IV) at 10 years’ follow-up, with an incidence at either the superior or inferior level or both levels of 39.0% compared with an additional recently published result of a 28.5% incidence of HO in a single-level-use clinical trial of the Prestige LP disc.5,6 This slightly greater incidence in 2-level CDA provides an opportunity for unique insights regarding the clinical implications of HO, with a chance to examine the relationships between HO severity and clinical outcomes.

While the formation of HO restricts the motion of the prosthesis, most studies report good clinical outcomes after CDA. A meta-analysis showed no significant differences in scores for the visual analog scale (VAS) for pain and the Neck Disability Index (NDI) between patients with and those without HO after CDA, but did show a significant difference in the VAS pain score between patients with “high-grade HO” (McAfee grade 3 or 4 HO) and those with “low-grade HO” (McAfee grade 0, 1, or 2 HO).23 A prospective study conducted by Guérin et al. found that HO did not appear to affect clinical outcomes for patients with an average 21-month follow-up after CDA.8 Zeng et al. retrospectively investigated 61 patients who underwent 1- or 2-level CDA with the Prestige LP disc and were followed for a minimum of 6 years.22 These authors reported an incidence of any HO (grades I–IV) of 42.9% at final follow-up, but found that HO did not influence the clinical outcomes. Nevertheless, further investigation of the relationship between HO formation and clinical outcomes in the long term is still needed.

The primary objective of this study was to assess the relationship of HO occurrence and severity to efficacy and safety outcomes as well as ROM after 2-level use of the Prestige LP disc with 10-year follow-up.

Methods

An investigational device exemption randomized study (registered at clinicaltrials.gov as NCT00637156; Western Investigational Review Board, protocol 20060636, study 078218) was previously conducted to evaluate the safety and efficacy of the Prestige LP Cervical Disc compared with ACDF in patients with intractable radiculopathy or myelopathy at 2 contiguous levels of the cervical spine. Informed consent was obtained for all patients. Results of the clinical trial led to FDA approval of the Prestige LP disc for use in 2-level CDA in 2016. The study patients continued to be followed for 10 years in a postapproval study (PAS) to evaluate long-term performance of the device. Results of the clinical trial at 2, 7, and 10 years of follow-up have been published.6,7,10 The current study was performed as a subgroup analysis using the data accrued from the 209 patients who were implanted with the Prestige LP discs in that clinical trial and followed in the PAS. The specific study design, methods, and procedures for the clinical study have been described in the previous publications, including inclusion and exclusion criteria and definitions of all outcome measures, but the methods relevant to the current study are briefly summarized below.

Demographic information was collected preoperatively, and outcome data were collected postoperatively at 1.5, 3, and 6 months and 1, 2, 3, 5, 7, and 10 years. Treatment levels were C5–6 and C6–7 in 78% of the CDA patients. HO data were available for 198 patients at 2 years and 146 patients at 10 years postoperatively. The 10-year follow-up rate was 86% after exclusion of patients at sites not participating in the PAS study and patients who died or withdrew from the study.

Radiographic Evaluation

Radiographic evaluations were performed by independent radiologists from a core imaging laboratory (Biomedical Systems). Two independent radiologists served as the primary reviewers and a third independent radiologist served as the adjudicator. HO was assessed at both treated levels on all lateral neutral radiographs of the spine at each follow-up. The classification proposed by Mehren et al.14 was used for grading HO as grade 0, no HO present; grade I, HO detectable in front of the vertebral body but not in the anatomical interdiscal space; grade II, HO growing into the disc space with possible effect on the function of the prosthesis; grade III, bridging ossifications which still allow movement of the prosthesis; and grade IV, complete fusion of the treated segment without movement in flexion/extension. Figure 1 shows radiographic examples of the range of HO from grade 0 (Fig. 1A) to grade IV (Fig. 1B).

FIG. 1.
FIG. 1.

Examples of HO shown on radiographs. No HO (A) and severe HO (B) at both treated levels (grade III at inferior level, grade IV at superior level). Both images were taken 7 years after CDA surgery using the Prestige LP disc.

Angular ROM at each of the target levels was measured on lateral flexion and extension radiographs.

Clinical Outcome Measures

This subgroup analysis examined the primary endpoint of the study, overall success, and important secondary endpoints, including neurological success and the following patient-reported outcomes: NDI score (0–100), neck pain and arm pain scores (intensity + frequency numerical rating scales, 0–20), and SF-36 Physical Component Summary (PCS) score (0–100), as previously described.6,7,10

Safety Outcome Measures

Severity (grades 1–4) of adverse events (AEs) and possible association with the implant and/or surgical procedure were assessed by an independent Clinical Adjudication Committee. Grade 3 or 4 AEs were considered serious AEs (SAEs). This study examined possible implant-related AEs and SAEs in relation to HO. Rates of secondary surgical procedures (classified as revision, removal, supplemental fixation, and reoperation) at index levels as well as secondary surgical procedures involved with adjacent levels were also assessed. Some of the secondary surgeries may have involved both index and adjacent levels.6

Statistical Analysis

To evaluate the clinical implications of HO formation, statistical analyses were performed to compare clinical and safety outcomes between patients having grade 0–II HO and those having grade III or IV HO at either the superior or inferior level or both levels (HO subgroups) at 2 years and 10 years.

For continuous variables, ANCOVA with adjustment for preoperative scores was performed to compare the HO subgroups. For categorical outcomes, Fisher’s exact test was used. Time-to-event analyses were performed for comparing AEs and secondary surgeries between the HO subgroups. Presented are p values from the log-rank test, along with cumulative rates of AEs and secondary surgeries calculated by using the life-table method.

Comparisons were also made for patient demographics between HO subgroups at 2 and 10 years, and p values from Fisher’s exact test (categorical data) or ANOVA (continuous data) are presented.

To examine the impact of HO severity on angular ROM, mean ROMs were compared by HO grade 0/I, II, III, and IV for the corresponding superior and inferior levels; differences among the HO severity groups were assessed using ANCOVA, with adjustment for preoperative ROM values.

For all analyses, the criterion for statistical significance was set at p ≤ 0.05, 2-tailed. All analyses were performed by the clinical trial sponsor, with 2 different statisticians working independently of each other to validate the results.

Results

Prevalence of HO Over Time

Rates of HO at the superior and inferior levels over time up to 10 years postsurgery are presented in Table 1. The occurrence of HO and its severity progressed over the course of the study, but appeared fairly stable after 5 years. The proportion of patients with either grade III or IV HO at either the superior or inferior level or both levels was 24.2% at 2 years, 38.8% at 5 years, and 39.0% at 10 years.

TABLE 1.

Summary of HO at superior and inferior spinal levels at follow-up

No. of Patients (%)
HO Grade at Follow-UpSuperior LevelInferior LevelEither or Both Levels
1 yr (n = 202)
 0164 (81.2)151 (74.8)
 I9 (4.5)11 (5.4)
 II15 (7.4)18 (8.9)
 III14 (6.9)21 (10.4)
 IV0 (0.0)1 (0.5)1 (0.5)
 III/IV14 (6.9)22 (10.9)27 (13.4)
2 yrs (n = 198)
 0143 (72.2)126 (63.6)
 I10 (5.1)11 (5.6)
 II13 (6.6)22 (11.1)
 III28 (14.1)33 (16.7)
 IV4 (2.0)6 (3.0)7 (3.5)
 III/IV32 (16.2)39 (19.7)48 (24.2)
3 yrs (n = 184)
 0119 (64.7)111 (60.3)
 I11 (6.0)7 (3.8)
 II19 (10.3)18 (9.8)
 III26 (14.1)39 (21.2)
 IV9 (4.9)9 (4.9)14 (7.6)
 III/IV35 (19.0)48 (26.1)59 (32.1)
5 yrs (n = 165)
 083 (50.3)75 (45.5)
 I10 (6.1)15 (9.1)
 II26 (15.8)28 (17.0)
 III32 (19.4)33 (20.0)
 IV14 (8.5)14 (8.5)19 (11.5)
 III/IV46 (27.9)47 (28.5)64 (38.8)
7 yrs (n = 151)
 074 (49.0)64 (42.4)
 I7 (4.6)12 (7.9)
 II18 (11.9)26 (17.2)
 III39 (25.8)38 (25.2)
 IV13 (8.6)11 (7.3)18 (11.9)
 III/IV52 (34.4)49 (32.5)64 (42.4)
10 yrs (n = 146)
 073 (50.0)56 (38.4)
 I7 (4.8)7 (4.8)
 II24 (16.4)39 (26.7)
 III30 (20.5)29 (19.9)
 IV12 (8.2)15 (10.3)19 (13.0)
 III/IV42 (28.8)44 (30.1)57 (39.0)

Demographics by HO Subgroups

Patient demographics by HO subgroup (0–II, III/IV) at 2 and 10 years are presented in Table 2. There were few significant demographic differences between the HO subgroups at either time point. The more severe HO group included significantly more male patients at 2 years than the less severe group (p < 0.001) and showed a similar trend at 10 years, although the difference at 10 years was not as great and did not achieve statistical significance. Although the average age at surgery of patients having grade III/IV HO at 10 years was significantly older than that of patients with grade 0–II HO (p ≤ 0.036), the difference (3 years) was not large.

TABLE 2.

Patient demographics by HO subgroup at 2 and 10 years

HO at 2 YrsHO at 10 Yrs
VariableGrade 0–II (n = 150)Grade III/IV (n = 48)p Value*Grade 0–II (n = 89)Grade III/IV (n = 57)p Value*
Age at op, yrs47.2 ± 7.948.6 ± 9.00.28846.0 ± 8.649.0 ± 7.60.036
BMI, kg/m228.2 ± 5.828.7 ± 5.20.55727.5 ± 6.028.6 ± 5.60.261
Male, n (%)54 (36.0)32 (66.7)<0.00129 (32.6)27 (47.4)0.083
White, n (%)138 (92.0)46 (95.8)0.92286 (96.6)51 (89.5)0.125
Workers’ compensation, n (%)20 (13.3)3 (6.3)0.29913 (14.6)5 (8.8)0.440
Alcohol used, n (%)86 (57.3)26 (54.2)0.74049 (55.1)32 (56.1)>0.999
Preop work, n (%)106 (70.7)33 (68.8)0.85764 (71.9)39 (68.4)0.711

Mean values are presented ± SD.

Fisher’s exact test (categorical data) or ANOVA (continuous data).

Clinical Implications of HO

Figure 2 shows comparisons of the rates of overall success and neurological success from 2 to 10 years between the HO subgroups based on HO severity at 2 and 10 years. There were no consistent trends observed and no statistical differences between the HO subgroups at any postoperative follow-up time point.

FIG. 2.
FIG. 2.

Overall success (A and B) and neurological success (C and D) from 2 to 10 years by HO subgroup based on HO severity at 2 and 10 years. None of the comparisons between the HO subgroups are statistically significant. Y = years.

The comparisons for patient-reported outcomes from before surgery to the 10-year follow-up, including NDI, neck and arm pain, and SF-36 PCS scores between the HO subgroups based on HO at 2 years and 10 years, are shown in Figs. 3 and 4, respectively. Mean scores at all time points are similar, and there were no significant differences between the HO subgroups in any of those outcomes at preoperative or any postoperative follow-up, with just one exception: the mean NDI score at 1.5 months was lower in patients having grade III/IV HO at 2 years than that in patients having grade 0–II HO at 2 years (p = 0.007), a result that is most likely a chance finding.

FIG. 3.
FIG. 3.

Patient-reported outcomes by HO subgroup at 2 years according to scores for NDI (A), neck pain (B), arm pain (C), and SF-36 PCS (D). None of the comparisons between the HO subgroups are statistically significant, with the exception of NDI scores at 1.5 months (p = 0.007).

FIG. 4.
FIG. 4.

Patient-reported outcomes by HO subgroup at 10 years: NDI (A), neck pain (B), arm pain (C), and SF-36 PCS (D). None of the comparisons between the HO subgroups are statistically significant.

Table 3 presents the cumulative rates of AEs and SAEs (grades 3 or 4) that were possibly related to the implant by HO subgroups at 2 years and 10 years. The cumulative rate of patients with any AEs or SAEs that was possibly related to the implant was 56.3% in patients having grade III/IV HO at 2 years compared to 24.4% in patients having grade 0–II HO at 2 years (p < 0.001). The higher rate in the grade III/IV subgroup appears to be primarily related to the differences in 2 AE subcategories: investigator-reported HO (25.1% vs 9.0%, p < 0.001), which is to be expected, and spinal events (32.1% vs 7.4%, p < 0.001). Examples of AEs categorized as spinal events include intervertebral disc annular tear, cervical spine degeneration, vertebral foraminal stenosis, cervical disc herniation, lumbar disc herniation, vertebral lesion, facet joint syndrome, and kyphosis (acquired). Similarly, patients with grade III/IV HO at 10 years reported more AEs and SAEs that were possibly related to the implant than were reported by patients with grade 0–II HO at 10 years (47.8% vs 17.9%, p = 0.002). Likewise, the cumulative rates were higher for the same 2 AE subcategories of HO (22.7% vs 4.5%, p < 0.001) and spinal event (22.7% vs 5.6%, p = 0.018) in patients with grade III/IV HO. Overall, the cumulative rates of SAEs that were possibly related to the implant were low and not significantly different between the HO subgroups at either 2 years or 10 years (Table 3).

TABLE 3.

AEs and SAEs possibly related to the implant and secondary surgeries at index levels and involved with adjacent levels, by HO subgroup

HO at 2 YrsHO at 10 Yrs
CategoryGrade 0–II (n = 150)Grade III/IV (n = 48)p Value*Grade 0–II (n = 89)Grade III/IV (n = 57)p Value*
Possibly implant-related AEs24.4 (32)56.3 (22)0.00117.9 (15)47.8 (24)0.002
 Dysphagia/dysphonia0.0 (0)2.7 (1)0.0790.0 (0)0.0 (0)NA
 Heterotopic ossification9.0 (9)25.1 (10)0.0014.5 (3)22.7 (11)0.001
 Implant event6.2 (9)14.1 (5)0.2964.5 (4)12.2 (6)0.163
 Neck and/or arm pain9.2 (13)10.4 (5)0.71610.1 (9)10.5 (6)0.950
 Neurological8.3 (12)6.3 (3)0.6966.8 (6)7.0 (4)0.938
 Other1.3 (2)0.0 (0)0.4232.2 (2)0.0 (0)0.256
 Other pain2.7 (4)4.2 (2)0.6073.4 (3)3.5 (2)0.970
 Spinal event7.4 (9)32.1 (13)<0.0015.6 (5)22.7 (11)0.018
 Vascular0.7 (1)0.0 (0)0.5721.1 (1)0.0 (0)0.424
Possibly implant-related SAEs3.0 (4)4.8 (2)0.6104.5 (4)1.8 (1)0.379
 Dysphagia/dysphonia0.0 (0)2.7 (1)0.0790.0 (0)0.0 (0)NA
 Implant event0.7 (1)2.1 (1)0.4001.1 (1)1.8 (1)0.746
 Neck and/or arm pain1.6 (2)2.1 (1)0.7092.3 (2)1.8 (1)0.840
 Neurological0.9 (1)0.0 (0)0.5791.1 (1)0.0 (0)0.422
 Other0.7 (1)0.0 (0)0.5721.1 (1)0.0 (0)0.424
 Other pain0.7 (1)0.0 (0)0.5691.1 (1)0.0 (0)0.424
 Spinal event2.0 (3)0.0 (0)0.3223.4 (3)0.0 (0)0.163
 Vascular0.7 (1)0.0 (0)0.5721.1 (1)0.0 (0)0.424
Secondary ops at index levels5.1 (7)2.4 (1)0.4227.9 (7)1.8 (1)0.113
 Removal2.8 (4)2.4 (1)0.8044.5 (4)1.8 (1)0.370
 Supplemental fixation1.6 (2)0.0 (0)0.4282.3 (2)0.0 (0)0.257
 Reoperation1.5 (2)0.0 (0)0.4252.3 (2)0.0 (0)0.254
Secondary ops involved w/ adjacent levels10.9 (14)2.2 (1)0.10111.2 (10)7.0 (4)0.418

NA = not available.

Values are presented as percentage (number) of patients unless otherwise indicated.

Cumulative rates estimated by the life-table method; p values are from the log-rank test of the time-to-event analysis.

The cumulative rates of secondary surgeries at the index levels and those involved with adjacent levels were not significantly different between patients having grade 0–II HO and patients having grade III/IV HO at 2 or 10 years (Table 3). In fact, cumulative rates were numerically higher in patients with grade 0–II HO, though the rates in general were low and differences did not achieve statistical significance. Given the very small number of patients overall having secondary surgeries and the small number, in particular, having grade IV HO, these results should be interpreted with caution.

ROM and HO

Figure 5 provides the mean ROMs by HO grades at 2 and 10 years for both superior and inferior levels. At 2 years, the mean ROM at the superior level decreased as the severity of HO increased, from 7.5° in patients with grade 0/I HO down to 2.0° for grade IV HO (overall, p < 0.001). Although the trend was similar at the inferior level, the differences did not achieve statistical significance. At 10 years, the relationship between mean ROM and HO severity had become stronger. The mean ROM at the superior level decreased from 8.8° for the grade 0/I HO severity group to 0.3° for grade IV HO (overall, p < 0.001). Similarly, mean ROMs at the inferior level decreased from 7.9° to 0.6° (overall, p < 0.001) for the grade 0/I and IV HO severity groups, respectively. The prostheses with grade IV HO had almost no motion at 10 years.

FIG. 5.
FIG. 5.

Mean ROM (± SE) by HO grade at 2 years (upper panels) and 10 years (lower panels): superior level at 2 years (A), inferior level at 2 years (B), superior level at 10 years (C), and inferior level at 10 years (D). deg = degrees.

Discussion

The Prestige LP Cervical Disc, designed as a dynamic device made of a titanium ceramic composite, was approved by the US FDA and other regulatory agencies worldwide for treating degenerative disc disease and intractable radiculopathy or myelopathy at 1 or 2 levels. One of the intended treatment goals of CDA is to preserve disc joint motion, which potentially reduces disc degeneration at adjacent levels. The Prestige LP disc comprises 2 low-profile plates that interface through a ball-in-trough mechanism. The device permits segmental spinal motion and serves to maintain disc space height. The Prestige LP disc has been reported to show a lower incidence of HO compared with other discs.21 It has been suggested that differences in disc design, biomechanical properties, and prosthesis-specific endplate articulation components could contribute to HO formation.20

The occurrence of HO after CDA may decrease the ROM of the index level, which is contrary to one of the treatment goals. A meta-analysis of pooled data from 38 studies showed that the prevalence of HO increased gradually in short-term (1–2 years) and midterm (2–5 years) follow-up, but this prevalence did not increase significantly in the longer term (5–10 years).9 Although new occurrences of HO did not develop (no increase in prevalence at later follow-ups), HO, when present, still progressed gradually in severity in the long term for some patients, limiting movement of the index level and potentially influencing the clinical outcomes of CDA. In our study, the rates of grade III and IV HO were observed to be 14.1% and 2.0%, respectively, at the superior level and 16.7% and 3.0%, respectively, at the inferior level at 2 years. Seven (3.5%) of 198 patients had grade IV HO at either the superior or inferior level or at both levels, while 24.2% of the patients had either grade III or IV HO at either or both levels. The rates of severe HO increased over time, with rates of grade III and IV HO at 10 years of 20.5% and 8.2%, respectively, at the superior level and 19.9% and 10.3%, respectively, at the inferior level. Nineteen (13.0%) of 146 patients had grade IV HO at either the superior or inferior level or at both levels, while 39.0% of the patients had either grade III or IV HO at either or both levels at 10 years. Our study results also suggested that both the prevalence of HO and the progression of severity stabilized after 5 years. Mean angular ROM at the treated levels was reduced with severe HO, particularly grade IV HO, which yielded almost no motion at 10 years, as expected. As recently reported,6 overall mean angular ROM for the whole Prestige LP group was not found to be significantly reduced at either the superior or inferior level. This finding may be due to the fact that rates of severe HO were relatively low, particularly grade IV HO, and thus did not substantially influence the sample population averages of ROM.

The effects of HO on clinical outcomes have not been fully examined, particularly for 2-level uses of CDA. Most studies have reported that HO did not appear to affect clinical outcomes.8,12,17 Tu et al. found that clinical success rates, defined by “excellent” or “good” according to the Odom criteria, were the same for patients with HO (grades I to IV) and those without, and VAS scores for neck and arm pain were significantly improved in both groups.17 Lee et al. reported that grade III or IV HO could restrict the cervical ROM and may lead to spontaneous fusion; however, the occurrence of HO did not affect clinical outcome in a retrospective study of 28 consecutive patients at the 24-month follow-up.12 In the present study, no statistically significant differences in clinical outcomes were found between the patients with grade III/IV HO and those with grade 0–II HO, including overall success, NDI, neck pain, arm pain, SF-36 PCS, neurological success, possibly implant-related SAEs, and secondary surgeries at the index and adjacent levels. The patients having grade III/IV HO, however, experienced more mild or moderate AEs in the category of spinal events and, of course, HOs as an AE reported by the investigator. AEs were reported by investigators based on their observations of patients or patient complaints (or their own assessment of radiological studies), while the radiographic HO grading was assessed by independent radiologists at the imaging vendor. We have included the investigator-reported HO as an AE here because it is a category reported to the FDA. However, the presence of HOs noted by the radiologists and HOs as AEs noted by the investigator are obviously not independent. Thus, it is a given that in patients who had grade III/IV HO, the rate of HO as an AE was also reported to be higher.

The higher rate of “spinal events” in patients with more severe HO is also not unexpected as these “events” may have a clinical relationship to HO.

The potential factors that contribute to HO development are not well established. Male sex and older age have been previously reported to have associations with a higher incidence of HO.13 The current study had some similar findings when comparing the demographic characteristics of the 2 HO severity groups, but these findings were related to severity rather than incidence. However, other patient characteristics such as BMI and alcohol use showed no relationship to HO severity. For the purposes of this study, statistical analyses were used that controlled for many of the potential preoperative differences between groups, so that confounding due to such differences was minimized. A more comprehensive analysis for assessing risk and surgical factors for HO formation is warranted.

Study Limitations

A strength of this study is that the data were obtained during an FDA-approved clinical trial with prospective definition of all efficacy and safety variables. The study does, however, have some limitations, including the post hoc nature of this particular set of analyses, which does not allow for trying to obtain equal or near-equal numbers of patients in the HO severity groups. Like most subgroup analyses, the numbers of patients in some subgroups were relatively small and may not have provided sufficient statistical power for assessing long-term impacts—particularly, for example, the impact of grade IV HO on secondary surgery at adjacent levels. Because this study used data from long-term follow-up (10 years), there was the typical issue of patients lost to follow-up, although the follow-up rate was high (86%) and there is no evidence that such losses were related to the variables under consideration here. We also note that radiographs may not be the most sensitive radiological method for detecting HO and may lead to underestimation of its presence or severity. However, radiography is currently the standard in clinical practice and in reporting HO incidence in the literature. This study grouped the usual 4-grade classifications into 2 broader groups so that for analysis purposes of comparing lesser to greater HO, some lack of sensitivity to detection is not likely to have had a major impact on findings.

Conclusions

Radiographically severe (grade III or IV) HO after CDA with the Prestige LP disc in 2-level use did not significantly affect efficacy or most safety outcomes. Severe HO, particularly grade IV HO, significantly limited ROM, as expected. More research is needed to determine risk factors for HO and to develop means for reducing its prevalence and/or severity.

Acknowledgments

Medtronic statisticians, Jay Dong, PhD, and Ni Li, PhD, performed the statistical analyses and independently validated the results, respectively. Zhimin Liu, MD, PhD, Senior Medical Writer with Medtronic, provided medical writing assistance for the manuscript.

Disclosures

The investigational device exemption and postapproval study were sponsored by Medtronic.

The authors report the following: M. F. Gornet: consulting: Aesculap and Medtronic; stock ownership: Bonovo, International Spine & Orthopedic Institute, Nocimed, OuroBoros, and Paradigm Spine; royalties: Medtronic and RTI. T. H. Lanman: consulting: Medtronic, NuVasive, and Stryker; royalties: Stryker and Medtronic. J. K. Burkus: consulting: Medtronic and Zimmer-Biomet; royalties: Zimmer-Biomet; research support: Medtronic and NuVasive. R. G. Dryer: royalties: NuVasive and Globus Medical. J. R. McConnell: consulting: Globus Medical, DePuy Synthes, and IMSE; royalties: Globus Medical; stock ownership: Globus Medical; speakers bureau: Globus Medical and Zimmer-Biomet. S. D. Hodges: consulting: Medtronic. F. W. Schranck: stock ownership: Nocimed. G. Ma: employee: Medtronic.

Author Contributions

Conception and design: Gornet, Schranck, Ma. Acquisition of data: Gornet, Lanman, Burkus, Dryer, McConnell, Hodges. Analysis and interpretation of data: Ma. Drafting the article: Gornet, Ma. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Gornet. Administrative/technical/material support: Schranck. Study supervision: Schranck.

References

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    Arnold PM, Anderson KK, Selim A, Dryer RF, Burkus JK: Heterotopic ossification following single-level anterior cervical discectomy and fusion: results from the prospective, multicenter, historically controlled trial comparing allograft to an optimized dose of rhBMP-2. J Neurosurg Spine 25:292302, 2016

    • Crossref
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  • 2

    Brenke C, Scharf J, Schmieder K, Barth M: High prevalence of heterotopic ossification after cervical disc arthroplasty: outcome and intraoperative findings following explantation of 22 cervical disc prostheses. J Neurosurg Spine 17:141146, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Gao F, Mao T, Sun W, Guo W, Wang Y, Li Z, et al.: An updated meta-analysis comparing artificial cervical disc arthroplasty (CDA) versus anterior cervical discectomy and fusion (ACDF) for the treatment of cervical degenerative disc disease (CDDD). Spine (Phila Pa 1976) 40:18161823, 2015

    • Crossref
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  • 4

    Gornet MF, Burkus JK, Shaffrey ME, Argires PJ, Nian H, Harrell FE Jr: Cervical disc arthroplasty with PRESTIGE LP disc versus anterior cervical discectomy and fusion: a prospective, multicenter investigational device exemption study. J Neurosurg Spine 23:558573, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Gornet MF, Burkus JK, Shaffrey ME, Schranck FW, Copay AG: Cervical disc arthroplasty: 10-year outcomes of the Prestige LP cervical disc at a single level. J Neurosurg Spine 31:317325, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Gornet MF, Lanman TH, Burkus JK, Dryer RF, McConnell JR, Hodges SD, et al.: Two-level cervical disc arthroplasty versus anterior cervical discectomy and fusion: 10-year outcomes of a prospective, randomized investigational device exemption clinical trial. J Neurosurg Spine 31:508518, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Gornet MF, Lanman TH, Burkus JK, Hodges SD, McConnell JR, Dryer RF, et al.: Cervical disc arthroplasty with the Prestige LP disc versus anterior cervical discectomy and fusion, at 2 levels: results of a prospective, multicenter randomized controlled clinical trial at 24 months. J Neurosurg Spine 26:653667, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Guérin P, Obeid I, Bourghli A, Meyrat R, Luc S, Gille O, et al.: Heterotopic ossification after cervical disc replacement: clinical significance and radiographic analysis. A prospective study. Acta Orthop Belg 78:8086, 2012

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kong L, Ma Q, Meng F, Cao J, Yu K, Shen Y: The prevalence of heterotopic ossification among patients after cervical artificial disc replacement: a systematic review and meta-analysis. Medicine (Baltimore) 96:e7163, 2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Lanman TH, Burkus JK, Dryer RG, Gornet MF, McConnell J, Hodges SD: Long-term clinical and radiographic outcomes of the Prestige LP artificial cervical disc replacement at 2 levels: results from a prospective randomized controlled clinical trial. J Neurosurg Spine 27:719, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lavelle WF, Riew KD, Levi AD, Florman JE: Ten-year outcomes of cervical disc replacement with the BRYAN cervical disc: results from a prospective, randomized, controlled clinical trial. Spine (Phila Pa 1976) 44:601608, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Lee SE, Chung CK, Jahng TA: Early development and progression of heterotopic ossification in cervical total disc replacement. J Neurosurg Spine 16:3136, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Leung C, Casey AT, Goffin J, Kehr P, Liebig K, Lind B, et al.: Clinical significance of heterotopic ossification in cervical disc replacement: a prospective multicenter clinical trial. Neurosurgery 57:759763, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Mehren C, Suchomel P, Grochulla F, Barsa P, Sourkova P, Hradil J, et al.: Heterotopic ossification in total cervical artificial disc replacement. Spine (Phila Pa 1976) 31:28022806, 2006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Nunley PD, Cavanaugh DA, Kerr EJ III, Utter PA, Campbell PG, Frank KA, et al.: Heterotopic ossification after cervical total disc replacement at 7 years—prevalence, progression, clinical implications, and risk factors. Int J Spine Surg 12:352361, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Suchomel P, Jurák L, Benes V III, Brabec R, Bradác O, Elgawhary S: Clinical results and development of heterotopic ossification in total cervical disc replacement during a 4-year follow-up. Eur Spine J 19:307315, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Tu TH, Wu JC, Huang WC, Guo WY, Wu CL, Shih YH, et al.: Heterotopic ossification after cervical total disc replacement: determination by CT and effects on clinical outcomes. J Neurosurg Spine 14:457465, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Xu S, Liang Y, Zhu Z, Qian Y, Liu H: Adjacent segment degeneration or disease after cervical total disc replacement: a meta-analysis of randomized controlled trials. J Orthop Surg Res 13:244, 2018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Yang W, Si M, Hou Y, Nie L: Superiority of 2-level total disk replacement using a cervical disk prosthesis versus anterior cervical diskectomy and fusion. Orthopedics 41:344350, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Yi S, Kim KN, Yang MS, Yang JW, Kim H, Ha Y, et al.: Difference in occurrence of heterotopic ossification according to prosthesis type in the cervical artificial disc replacement. Spine (Phila Pa 1976) 35:15561561, 2010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Zeng J, Liu H, Chen H, Rong X, Meng Y, Yang Y, et al.: Effect of prosthesis width and depth on heterotopic ossification after cervical disc arthroplasty. Spine (Phila Pa 1976) 44:624628, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Zeng J, Liu H, Rong X, Wang B, Yang Y, Gao X, et al.: Clinical and radiographic outcomes of cervical disc arthroplasty with Prestige-LP Disc: a minimum 6-year follow-up study. BMC Musculoskelet Disord 19:285, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Zhou HH, Qu Y, Dong RP, Kang MY, Zhao JW: Does heterotopic ossification affect the outcomes of cervical total disc replacement? A meta-analysis. Spine (Phila Pa 1976) 40:E332E340, 2015

    • Crossref
    • Search Google Scholar
    • Export Citation

Image from van Bilsen et al. (pp 51–57).

  • View in gallery

    Examples of HO shown on radiographs. No HO (A) and severe HO (B) at both treated levels (grade III at inferior level, grade IV at superior level). Both images were taken 7 years after CDA surgery using the Prestige LP disc.

  • View in gallery

    Overall success (A and B) and neurological success (C and D) from 2 to 10 years by HO subgroup based on HO severity at 2 and 10 years. None of the comparisons between the HO subgroups are statistically significant. Y = years.

  • View in gallery

    Patient-reported outcomes by HO subgroup at 2 years according to scores for NDI (A), neck pain (B), arm pain (C), and SF-36 PCS (D). None of the comparisons between the HO subgroups are statistically significant, with the exception of NDI scores at 1.5 months (p = 0.007).

  • View in gallery

    Patient-reported outcomes by HO subgroup at 10 years: NDI (A), neck pain (B), arm pain (C), and SF-36 PCS (D). None of the comparisons between the HO subgroups are statistically significant.

  • View in gallery

    Mean ROM (± SE) by HO grade at 2 years (upper panels) and 10 years (lower panels): superior level at 2 years (A), inferior level at 2 years (B), superior level at 10 years (C), and inferior level at 10 years (D). deg = degrees.

  • 1

    Arnold PM, Anderson KK, Selim A, Dryer RF, Burkus JK: Heterotopic ossification following single-level anterior cervical discectomy and fusion: results from the prospective, multicenter, historically controlled trial comparing allograft to an optimized dose of rhBMP-2. J Neurosurg Spine 25:292302, 2016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Brenke C, Scharf J, Schmieder K, Barth M: High prevalence of heterotopic ossification after cervical disc arthroplasty: outcome and intraoperative findings following explantation of 22 cervical disc prostheses. J Neurosurg Spine 17:141146, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Gao F, Mao T, Sun W, Guo W, Wang Y, Li Z, et al.: An updated meta-analysis comparing artificial cervical disc arthroplasty (CDA) versus anterior cervical discectomy and fusion (ACDF) for the treatment of cervical degenerative disc disease (CDDD). Spine (Phila Pa 1976) 40:18161823, 2015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Gornet MF, Burkus JK, Shaffrey ME, Argires PJ, Nian H, Harrell FE Jr: Cervical disc arthroplasty with PRESTIGE LP disc versus anterior cervical discectomy and fusion: a prospective, multicenter investigational device exemption study. J Neurosurg Spine 23:558573, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Gornet MF, Burkus JK, Shaffrey ME, Schranck FW, Copay AG: Cervical disc arthroplasty: 10-year outcomes of the Prestige LP cervical disc at a single level. J Neurosurg Spine 31:317325, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Gornet MF, Lanman TH, Burkus JK, Dryer RF, McConnell JR, Hodges SD, et al.: Two-level cervical disc arthroplasty versus anterior cervical discectomy and fusion: 10-year outcomes of a prospective, randomized investigational device exemption clinical trial. J Neurosurg Spine 31:508518, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Gornet MF, Lanman TH, Burkus JK, Hodges SD, McConnell JR, Dryer RF, et al.: Cervical disc arthroplasty with the Prestige LP disc versus anterior cervical discectomy and fusion, at 2 levels: results of a prospective, multicenter randomized controlled clinical trial at 24 months. J Neurosurg Spine 26:653667, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Guérin P, Obeid I, Bourghli A, Meyrat R, Luc S, Gille O, et al.: Heterotopic ossification after cervical disc replacement: clinical significance and radiographic analysis. A prospective study. Acta Orthop Belg 78:8086, 2012

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Kong L, Ma Q, Meng F, Cao J, Yu K, Shen Y: The prevalence of heterotopic ossification among patients after cervical artificial disc replacement: a systematic review and meta-analysis. Medicine (Baltimore) 96:e7163, 2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Lanman TH, Burkus JK, Dryer RG, Gornet MF, McConnell J, Hodges SD: Long-term clinical and radiographic outcomes of the Prestige LP artificial cervical disc replacement at 2 levels: results from a prospective randomized controlled clinical trial. J Neurosurg Spine 27:719, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lavelle WF, Riew KD, Levi AD, Florman JE: Ten-year outcomes of cervical disc replacement with the BRYAN cervical disc: results from a prospective, randomized, controlled clinical trial. Spine (Phila Pa 1976) 44:601608, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Lee SE, Chung CK, Jahng TA: Early development and progression of heterotopic ossification in cervical total disc replacement. J Neurosurg Spine 16:3136, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Leung C, Casey AT, Goffin J, Kehr P, Liebig K, Lind B, et al.: Clinical significance of heterotopic ossification in cervical disc replacement: a prospective multicenter clinical trial. Neurosurgery 57:759763, 2005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Mehren C, Suchomel P, Grochulla F, Barsa P, Sourkova P, Hradil J, et al.: Heterotopic ossification in total cervical artificial disc replacement. Spine (Phila Pa 1976) 31:28022806, 2006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Nunley PD, Cavanaugh DA, Kerr EJ III, Utter PA, Campbell PG, Frank KA, et al.: Heterotopic ossification after cervical total disc replacement at 7 years—prevalence, progression, clinical implications, and risk factors. Int J Spine Surg 12:352361, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Suchomel P, Jurák L, Benes V III, Brabec R, Bradác O, Elgawhary S: Clinical results and development of heterotopic ossification in total cervical disc replacement during a 4-year follow-up. Eur Spine J 19:307315, 2010

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Tu TH, Wu JC, Huang WC, Guo WY, Wu CL, Shih YH, et al.: Heterotopic ossification after cervical total disc replacement: determination by CT and effects on clinical outcomes. J Neurosurg Spine 14:457465, 2011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Xu S, Liang Y, Zhu Z, Qian Y, Liu H: Adjacent segment degeneration or disease after cervical total disc replacement: a meta-analysis of randomized controlled trials. J Orthop Surg Res 13:244, 2018

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Yang W, Si M, Hou Y, Nie L: Superiority of 2-level total disk replacement using a cervical disk prosthesis versus anterior cervical diskectomy and fusion. Orthopedics 41:344350, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Yi S, Kim KN, Yang MS, Yang JW, Kim H, Ha Y, et al.: Difference in occurrence of heterotopic ossification according to prosthesis type in the cervical artificial disc replacement. Spine (Phila Pa 1976) 35:15561561, 2010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Zeng J, Liu H, Chen H, Rong X, Meng Y, Yang Y, et al.: Effect of prosthesis width and depth on heterotopic ossification after cervical disc arthroplasty. Spine (Phila Pa 1976) 44:624628, 2019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Zeng J, Liu H, Rong X, Wang B, Yang Y, Gao X, et al.: Clinical and radiographic outcomes of cervical disc arthroplasty with Prestige-LP Disc: a minimum 6-year follow-up study. BMC Musculoskelet Disord 19:285, 2018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Zhou HH, Qu Y, Dong RP, Kang MY, Zhao JW: Does heterotopic ossification affect the outcomes of cervical total disc replacement? A meta-analysis. Spine (Phila Pa 1976) 40:E332E340, 2015

    • Crossref
    • Search Google Scholar
    • Export Citation

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