Four-Level Cervical Disc Arthroplasty.

BACKGROUND: Multilevel anterior cervical discectomy and fusion inevitably yields a higher chance of pseudarthrosis or require more reoperations than single-level procedures. Therefore, multilevel cervical disc arthroplasty (CDA) could be an alternative surgery for cervical spondylosis, as it (particularly 3- and 4-level CDA) could preserve more functional motility than single-level disc diseases. This study aimed to investigate the clinical and radiological outcomes of 4-level CDA, a relatively infrequently indicated surgery. METHODS: The medical records of consecutive patients who underwent 4-level CDA were retrospectively reviewed. These highly selected patients typically had multilevel disc herniations with mild spondylosis. The inclusion criteria were symptomatic cervical spondylotic myelopathy, radiculopathy, or both, that were medically refractory. The clinical outcomes were assessed. The radiographic outcomes, including global and individual segmental range of motion (ROM) at C3-7, and any complications were also analyzed. RESULTS: Data from a total of 20 patients (mean age: 56 ± 8 years) with an average follow-up of 34 ± 20 months were analyzed. All patients reported improved clinical outcomes compared with that of preoperation, and the ROMs at C3-7 were not only preserved but also trended toward an increase (35 ± 8 vs 37 ± 10 degrees, pre- vs postoperation, P = 0.271) after the 4-level CDA. However, global cervical alignment remained unchanged. There was one permanent C5 radiculopathy, but no other neurological deteriorations or any reoperations occurred. CONCLUSION: For these rare but unique indications, 4-level CDA yielded clinical improvement and preserved segmental motility with low rates of complications. Four-level CDA is a safe and effective surgery, maintaining the ROM in patients with primarily disc herniations and mild spondylosis. CLINICAL RELEVANCE: For patients with mild spondylosis, whose degeneration at the cervical spine is not so severe, CDA is more suitable.

Assessing Range of Motion Gap in Circumferential Surgery for Cervical Myelopathy due to Ossification of the Posterior Longitudinal Ligament.

OBJECTIVE: Only a few studies have investigated the gap range of motion (gROM) in cervical myelopathy or deformity caused by ossification of the posterior longitudinal ligament (OPLL). The aim of this study is to investigate the correlation between the individual gROM and the postoperative clinical outcomes of patients with OPLL. METHODS: Consecutive patients of cervical myelopathy caused by OPLL were analyzed retrospectively. The clinical outcomes were evaluated using Visual Analogue Scale scores of the neck and arm pain and the Japanese Orthopaedic Association scores. Radiologic measurements included flexion ROM (fROM), which was defined as the difference of cervical lordosis in flexion and neutral positions, extension ROM (eROM), defined as the difference between neutral and extension positions, and gROM, defined as the difference between fROM and eROM. Patients were grouped by the values of gROM, and comparisons of all outcomes were made between the groups. RESULTS: A total of 42 patients underwent surgery. The patients with greater gROM did not differ from those with smaller gROM by demographic characteristics. During follow-up (mean 45.8 months), both groups had similar improvements, but the C5 palsy rates were higher in the greater gROM group than in the smaller gROM group (71% and 22%, P < 0.05). CONCLUSIONS: Simultaneous circumferential decompression and fixation is an effective surgical option for patients with cervical myelopathy caused by OPLL. A higher rate of postoperative C5 palsy was observed in the patients with greater gROMs after surgery, although all patients presented with similar clinical improvements.

Comparison of intraoperative cone-beam CT versus preoperative fan-beam CT for navigated spine surgery: a prospective randomized study.

OBJECTIVE: This prospective randomized study aimed to investigate the accuracy, radiation exposure, and surgical workflow optimization of a novel intraoperative spinal navigation system using preoperative fan-beam (FB) CT versus the classic intraoperative cone-beam (CB) CT in patients undergoing minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). METHODS: In this two-arm, single-center, randomized study, the authors evaluated the safety and clinical outcomes of a novel navigation system for pedicle screw placement in spine surgery. RESULTS: The accuracy of pedicle screw placement in the experimental group (FB group) was 94.38%, while it was 94.55% in the control group (CB group). Notably, the intraoperative radiation exposure to patients in the FB CT group (mean 0.361 ± 0.261 mSv) was significantly lower than that in the CB CT group (mean 6.526 ± 13.591 mSv) (p < 0.0001). Furthermore, the intraoperative preparation time for screw placement in the FB group (mean 10.6 ± 5.62 minutes) was significantly lower than that in the CB group (mean 17.6 ± 5.59 minutes) (p = 0.0004). No significant differences were observed for blood loss during surgery, total radiation exposure to surgeons, mean time for inserting a single pedicle screw, revision surgery rate, patients' reported outcomes, and length of postoperative hospital stay between the two groups. Significant differences were observed for intraoperative radiation exposure to patients and the preparation time for pedicle screw placement. CONCLUSIONS: The preoperative FB CT-based intraoperative spinal navigation system demonstrated comparable accuracy and safety when compared with the intraoperative CB CT-based system. Moreover, the FB CT-based system had a shorter time for screw placement and reduced intraoperative radiation exposure to patients. These findings support the potential benefits of adopting this novel navigation system to enhance surgical precision and reduce radiation-related risks in MIS-TLIF procedures.

Ganoderma microsporum immunomodulatory protein as an extracellular epidermal growth factor receptor (EGFR) degrader for suppressing EGFR-positive lung cancer cells.

Epidermal growth factor receptor (EGFR) abnormalities relevant to tumor progression. A newly developed strategy for cancer therapy is induction of EGFR degradation. GMI, an immunomodulatory protein from the medicinal mushroom Ganoderma microsporum, exhibits anticancer activity. However, its role in the intracellular trafficking and degradation of EGFR remains unclear. In this study, we discovered that GMI inhibits the phosphorylation of multiple tyrosine kinases. Specifically, GMI was discovered to suppress lung cancer cells harboring both wild-type and mutant EGFR by inhibiting EGFR dimerization and eliminating EGFR-mediated signaling. Functional studies revealed that GMI binds to the extracellular segment of EGFR. GMI interacts with EGFR to induce phosphorylation of EGFR at tyrosine1045, which triggers clathrin-dependent endocytosis and degradation of EGFR. Furthermore, in the mouse models, GMI was discovered to suppress tumor growth. Knockdown of EGFR in lung cancer cells abolishes GMI's anticancer activity in vivo and in vitro. Our results reveal the interaction mechanisms through which GMI induces EGFR degradation and abolishes EGFR-mediated intracellular pathway. Our study indicates that GMI is an EGFR degrader for inhibiting EGFR-expressing tumor growth.

Cervical disc arthroplasty for magnetic resonance-evident cervical spondylotic myelopathy: comparison with anterior cervical discectomy and fusion.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is a standard surgical approach for cervical spondylotic myelopathy (CSM) caused by disc herniations. Although cervical disc arthroplasty (CDA) has become, in the past decade, a viable alternative to ACDF in selected patients, the differences among patients with CSM treated with CDA and ACDF remain elusive. The effectiveness of motion preservation devices in CSM is also unclear. METHODS: Adult patients who underwent 1- or 2-level CDA or ACDF between 2007 and 2021 were retrospectively reviewed. Patients whose preoperative T2-weighted MRI demonstrated increased intramedullary signal intensity (IISI) were included and analyzed for the following: comparison of the length of IISI on pre- and postoperative MR images as well as range of motion (ROM) at the indexed levels between the CDA and ACDF groups. Measurement for clinical outcomes included the visual analog scale (VAS) of the arm and neck, the Neck Disability Index, and modified Japanese Orthopaedic Association scores. Perioperative clinical data were also compared between the two groups. RESULTS: A total of 122 patients were allocated to the CDA group and 108 to the ACDF group, with mean follow-ups of 46.6 and 39.0 months, respectively. Patients in the CDA group were younger than those in the ACDF group (47.64 ± 12.40 vs 61.73 ± 12.25 years, p < 0.001) (mean ± SD). The ACDF group had more 2-level surgery compared to the CDA group (p = 0.002). Both groups had significant regression of IISI on postoperative MRI compared to that of preoperative imaging (CDA: 1.23 ± 0.84 to 0.28 ± 0.39 cm; ACDF: 1.07 ± 0.60 to 0.37 ± 0.42 cm; both p < 0.001). The decrease in the length of IISI was similar between the two groups (p = 0.058). The postoperative ROM was well preserved in the CDA group (superior to ACDF, which yielded minimal ROM postoperatively). Both the CDA and ACDF groups demonstrated improvement in Neck Disability Index and modified Japanese Orthopaedic Association scores at 24 months postoperatively. The CDA group had significant improvements on VAS scores, whereas the improvement did not reach significance for the ACDF group at 24 months postoperatively. CONCLUSIONS: Significant shortening of IISI on T2-weighted MRI was demonstrated after both CDA and ACDF. At 24 months postoperatively, all clinical outcomes demonstrated improvement after both strategies, except that the VAS score was not significantly improved for ACDF. Therefore, CDA is a safe and effective option for patients with MR-evident CSM.

Comparative Study of the Cytokine Profiles of Serum and Tissues from Patients with the Ossification of the Posterior Longitudinal Ligament.

BACKGROUND: The ossification of the posterior longitudinal ligament (OPLL) is one of the contributing factors leading to severe cervical spondylotic myelopathy (CSM). The mechanism causing ossification is still unclear. The current study was designed to analyze the specimens of patients with or without OPLL. METHODS: The study collected 51 patients with cervical spondylosis. There were six serum samples in both the non-OPLL (NOPLL) and OPLL groups. For tissue analysis, there were seven samples in the NOPLL group and five samples in the OPLL group. The specimens of serum and tissue were analyzed by using Human Cytokine Antibody Arrays to differentiate biomarkers between the OPLL and NOPLL groups, as well as between serum and OPLL tissue. Immunohistochemical staining of the ligament tissue was undertaken for both groups. RESULTS: For OPLL vs. NOPLL, the serum leptin levels are higher in the OPLL group, corroborating others' observations that it may serve as a disease marker. In the tissue, angiogenin (ANG), osteopontin (OPN), and osteopro-tegerin (OPG) are higher than they are in the OPLL group (p < 0.05). For serum vs. OPLL tissue, many chemotactic cytokines demonstrated elevated levels of MIP1 delta, MCP-1, and RANTES in the serum, while many cytokines promoting or regulating bone genesis were up-regulated in tissue (oncostatin M, FGF-9, LIF, osteopontin, osteoprotegerin, TGF-beta2), as well as the factor that inhibits osteoclastogenesis (IL-10), with very few cytokines responsible for osteoclastogenesis. Molecules promoting angiogenesis, including angiotensin, vEGF, and osteoprotegerin, are abundant in the OPLL tissue, which paves the way for robust bone growth.

Comparison of Cortical Bone Trajectory to Pedicle-Based Dynamic Stabilization: An Analysis of 291 Patients.

OBJECTIVE: Pedicle-based dynamic stabilization (DS) has gained popularity outside of America. Although pedicle screw (PS) loosening has always been a concern, it is reportedly innocuous. Cortical bone trajectory (CBT) screw is an emerging option with less invasiveness and similar effectiveness to PS in short-segment lumbar fusion. This study aimed to verify the use of CBT for DS by comparing the outcomes between pedicle- and CBT-based DS. METHODS: Consecutive patients with lumbar spondylosis or low-grade spondylolisthesis who underwent 1- or 2-level DS between L3-5 with a minimum follow-up of 24 months were reviewed. Screw loosening was determined by computed tomography and the incidences were compared. RESULTS: A total of 291 patients who underwent Dynesys DS (235 pedicle- and 56 CBT-based, respectively) were compared. The demographics and preoperative conditions were similar. All the clinical outcomes improved at 24-month postoperation, while the CBT-based group had less operation time and blood loss than the pedicle-based group. The rates of screw loosening were lower in the CBT-based (5.4% per screw and 12.5% per patient) than the pedicle-based group (9% per screw and 26.4% per patient). Furthermore, there were no differences in the clinical outcomes and complication profiles. CONCLUSION: The CBT-based DS for 1- or 2-level lumbar degeneration demonstrated equivalent clinical improvement as the pedicle-based DS. The adaption of CBT-based screws for DS could be a less invasive approach (shorter operation time and less blood loss), with lower chances of screw loosening than the conventional PS-based DS.

Incidence and Risk Factor of Implant Dislocation After Cervical Disk Arthroplasty: A Retrospective Cohort Analysis of 756 Patients.

BACKGROUND: Implant dislocation after cervical disk arthroplasty (CDA) is obviously a critical complication, but no information about the incidence and associated risk factor has been reported. OBJECTIVE: To investigate the incidence and risk factor of implant dislocation after CDA by a retrospective cohort analysis. METHODS: A retrospective review of a consecutive series of CDA performed between January 2009 and March 2021 at a single institution was conducted. Analyses of chart records and radiological data established the incidence and associated risk factor of implant dislocation after CDA. A Kaplan-Meier survival estimation of implant survival was performed. RESULTS: A total of 756 consecutive patients were included in this analysis. Five patients (0.7%) had a migration and even dropout of the artificial disk. The overall cumulative survival rate of the implant reached approximately 99.3% of the 756 patients. Preoperative kyphosis was significantly related to implant dislocation ( P = .016), with an odds ratio of 15.013. CONCLUSION: The incidence of implant dislocation after CDA is as low as 0.7% or 5/756 patients. Preoperative kyphosis significantly increases the risk of postoperative implant dislocation by a factor of 15. The migrating implants could be revealed on radiographs as early as 0.9 to 1.4 months postoperatively and were revised to anterior cervical diskectomy and fusion within half a year. No new event of implant dislocation occurred half a year postoperatively. The overall cumulative survival rate of the implant reached 99.3% of the 756 patients. In conclusion, CDA remains a safe and reliable procedure.

Multilevel cervical disc arthroplasty: a review of optimal surgical management and future directions.

OBJECTIVE: Cervical disc arthroplasty (CDA) has been recognized as a popular option for cervical radiculopathy or myelopathy caused by disc problems that require surgery. There have been prospective randomized controlled trials comparing CDA to anterior cervical discectomy and fusion (ACDF) for 1- and 2-level disc herniations. However, the indications for CDA have been extended beyond the strict criteria of these clinical trials after widespread real-world experiences in the past decade. This article provides a bibliometric analysis with a review of the literature to understand the current trends of clinical practice and research on CDA. METHODS: The PubMed database was searched using the keywords pertaining to CDA in human studies that were published before August 2022. Analyses of the bibliometrics, including the types of papers, levels of evidence, countries, and the number of disc levels involved were conducted. Moreover, a systematic review of the contents with the emphasis on the current practice of multilevel CDA and complex cervical disc problems was performed. RESULTS: A total of 957 articles published during the span of 22 years were analyzed. Nearly one-quarter of the articles (232, 24.2%) were categorized as level I evidence, and 33.0% were categorized as levels I or II. These studies clearly demonstrated the viability and effectiveness of CDA regarding clinical and radiological outcomes, including neurological improvement, maintenance, and preservation of segmental mobility with relatively low risks for several years postoperation. Also, there have been more papers published during the last decade focusing on multilevel CDA and fewer involving the comparison of ACDF. Overall, there was a clustering of CDA papers published from the US and East Asian countries. Based on substantial clinical data of CDA for 1- and 2-level disc diseases, the practice and research of CDA show a trend toward multilevel and complex disease conditions. CONCLUSIONS: CDA is an established surgical management procedure for 1- and 2-level cervical disc herniation and spondylosis. The success of motion preservation by CDA-with low rates of complications-has outscored ACDF in patients without deformity. For more than 2-level disc diseases, the surgery shows a trend toward multiple CDA or hybrid ACDF-CDA according to individual evaluation for each level of degeneration.

Exogenous FGF-1 Differently Regulates Oligodendrocyte Replenishment in an SCI Repair Model and Cultured Cells.

We studied the phenotypes in an oligodendrocyte genesis site at the acute stage of spinal cord injury, when we observed regenerated ascending neurites. Pan-oligodendrocyte marker OLIG2+ cells were more in fibroblast growth factor (FGF)-1-treated rats (F group) than in non-treated (T group) in this site, while the number of NG2+OX42- oligodendrocyte progenitor cell (OPC), CNPase+ OPC, Nkx2.2+ OPC, and APC+ remyelinating oligodendrocytes was less in the F group. Paradoxically, when we label the rats with pulsed bromodeoxyuridine (BrdU), we found that the mitotic NKX2.2+ OPC cells are more in the F group than in the T group. We tested the embryonic spinal cord mixed culture. FGF treatment resulted in more NG2(+) CNPase (+) than non-FGF-1-treated culture, while the more mature NG2(-) CNPase(+) cell numbers were reduced. When we block the FGF receptor in the injured rat model, the NG2+OX42- cell numbers were increased to be comparable to non-FGF-1 rats, while this failed to bring back the APC+ mature oligodendrocyte cell numbers. As migration of OPC toward injury is a major factor that was absent from the cell culture, we tested 8 mm away from the injury center, and found there were more NG2+ cells with FGF-1 treatment. We proposed that it was possibly a combination of migration and proliferation that resulted in a reduction in the NG2+ OPC population at the oligodendrocyte genesis site when FGF-1 was added to the spinal cord injury in vivo.

Nature or nurture: a latent ossification of the posterior longitudinal ligament after atlantoaxial fusion. Illustrative case.

BACKGROUND: The natural history of ossification of the posterior longitudinal ligament (OPLL) remains poorly understood and multiple etiologies have been reported. However, most have focused on the characteristics of the patient rather than alternation of mechanical stress after spinal fusion. OBSERVATIONS: This report describes, for the first time, a de novo OPLL found at the subaxial cervical spine 7 years after an atlantoaxial fusion surgery. A 57-year-old female initially required atlantoaxial arthrodesis for os odontoideum and stenosis that caused myelopathy. The posterior fusion surgery went smoothly without complications and the patient had good recovery of neurological functions. There was no associated instability, trauma, or reoperations during the follow-up. Seven years later, the patient presented with slight neck pain and a newly developed OPLL at C3-4 caudal to the C1-2 fusion construct. LESSONS: Conflicting with the conventional concept that OPLL is common in elderly men with genetic or hormonal factors, or associated spondyloarthropathies, OPLL could develop in women even after solid C1-2 fusion. The adjacent subaxial cervical spine is not free of risks for subsequent development of OPLL and cervical spondylotic myelopathy. This case illustration extends the scope of etiologies of OPLL within the present literature.

GMI, Ganoderma microsporum protein, suppresses cell mobility and increases temozolomide sensitivity through induction of Slug degradation in glioblastoma multiforme cells.

Glioblastoma multiforme (GBM), which is a malignant primary brain tumor, is the cancer that spreads most aggressively into the adjacent brain tissue. Patients with metastatic GBM have a poor chance of survival. In this study, we examined the anti-GBM mobility effect of small protein, called GMI, which is cloned and purified from Ganoderma microsporum. Proteomic profiles showed that GMI-mediated proteins were involved in cell motility and cell growth functions. Specifically, we demonstrated that GMI significantly suppressed cell migration and invasion of GBM cells. GMI combined with temozolomide (TMZ), which is a traditional chemotherapeutic agent for GBM treatment, synergistically inhibited motility in GBM cells. Mechanistically, we demonstrated that GMI induced proteasome-dependent degradation of Slug, which is a critical transcription factor, is frequently linked to metastasis and drug resistance in GBM. Knockdown of Slug reduced cell viability and colony formation of GBM cells but enhanced TMZ-suppressed cell migration and viability. The results of this study show that targeting Slug degradation is involved in GMI-suppressed mobility of GBM cells. Moreover, GMI may be a potential supplementary agent for the suppression of GBM.

Anterior Bone Loss in Cervical Disc Arthroplasty Correlates with Increased Cervical Lordosis.

OBJECTIVE: Although cervical disc arthroplasty (CDA) has reportedly been associated with similarly low incidences of complications to anterior cervical discectomy and fusion, the phenomenon of anterior bone loss (ABL) is unique to CDA and has only recently gained notice. This study thus aimed to investigate the incidence of ABL and its correlation with cervical alignment post-operation. METHODS: Consecutive patients who received CDA for herniated disc or spondylosis were retrospectively reviewed. The development and extent of ABL was detected by comparison of preoperative and postoperative serial images for the relative position of the anterior vertebral body with the CDA devices and graded into 3 levels: grade 1 (minor bone loss), grade 2 (anterior portion of the vertebral body without exposure of the artificial disc), and grade 3 (anterior portion of the vertebral body with exposure of the device). RESULTS: A total of 41 patients were analyzed with a mean follow-up of 24.1 months. Under serial radiologic examinations during follow-up, all patients (41 of 41 = 100%) had bone loss of various degrees, with grade 3 ABL the most common (30 of 41 = 73.1%). There were 8 and 3 patients who had grades 2 and 1 ABL, respectively. The changes of the Cobb angle (ΔCobb) trended towards higher grades of ABL. CONCLUSIONS: During the mean follow-up of 2 years, ABL was a common radiologic finding. More than half of the patients (26 of 41, 63.4%) in the series gained cervical lordosis (ΔCobb >0) after CDA. These patients with increased cervical lordosis (ΔCobb >0) after CDA had higher grades of ABL.

Multifaceted Benefits of GDF11 Treatment in Spinal Cord Injury: In Vitro and In Vivo Studies.

Traumatic spinal cord injury (SCI) initiates a series of cellular and molecular events that include both primary and secondary injury cascades. This secondary cascade provides opportunities for the delivery of therapeutic intervention. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-ß (TGF-ß) superfamily, regulates various biological processes in mammals. The effects of GDF11 in the nervous system were not fully elucidated. Here, we perform extensive in vitro and in vivo studies to unravel the effects of GDF11 on spinal cord after injury. In vitro culture studies showed that GDF11 increased the survival of both neuronal and oligodendroglial cells but decreased microglial cells. In stressed cultures, GDF11 effectively inhibited LPS stimulation and also protected neurons from ischemic damage. Intravenous GDF11 administration to rat after eliciting SCI significantly improved hindlimb functional restoration of SCI rats. Reduced neuronal connectivity was evident at 6 weeks post-injury and these deficits were markedly attenuated by GDF11 treatment. Furthermore, SCI-associated oligodendroglial alteration were more preserved by GDF11 treatment. Taken together, GDF11 infusion via intravenous route to SCI rats is beneficial, facilitating its therapeutic application in the future.