In vivo animal models of spinal metastasis.

The vertebral column is the commonest site for skeletal metastases, with breast, prostate and lung cancers being the most common primary sources. The spine has structural and neural-protective properties thus involvement by metastatic cancer often causes bony instability and fracture, intractable pain and neurological deficit. In vivo animal models which resemble the human condition are essential in order to improve understanding of the pathophysiology behind the spread of metastatic cancer to the spine and its subsequent local growth and invasion, to enable in-depth analysis of the interaction between host and tumour cells and the molecular processes behind local cancer invasion and barriers to invasion as well as to allow assessment of novel treatment modalities for spinal metastases. This review summarizes the current status of the animal models specifically used for the study of spinal metastasis, their relevance, advantages and limitations, and important considerations for the development of future in vivo animal models.

An in vivo mouse model of intraosseous spinal cancer causing evolving paraplegia.

The spine is the commonest site of skeletal metastatic disease and uncontrolled growth of cancer in the spine will inevitably cause pain and neurologic compromise. Improved understanding of the pathobiology behind this devastating condition is urgently needed. For this reason, the aim of this study was to establish a clinically relevant, animal model of spinal cancer. A percutaneous orthotopic injection of human breast (MDA-MB-231) or human prostate (PC-3) cancer cells was administered into the upper lumbar spine of nude mice (n = 6). Animals were monitored twice daily for general welfare, gait asymmetry or disturbance, and hindlimb weakness. After sacrifice, plain radiographs, micro-CT imaging and histological analysis of the spines were performed on each mouse. All mice recovered fully from the inoculation procedure and displayed normal gait and behaviour patterns for at least 3 weeks post-inoculation. Subsequently, between 3 and 5 weeks post-inoculation, each mouse developed evolving paralysis in their hindlimbs over 48-72 h. All followed the same pattern of decline following onset of neurological dysfunction; from gait asymmetry and unilateral hindlimb weakness, to complete unilateral hindlimb paralysis and finally to complete bilateral hindlimb paralysis. Plain radiographs, micro-CT scanning and histological analysis confirmed local tumour growth and destruction of the spine in all six mice. An in vivo mouse model of human intraosseous spinal cancer has been established forming cancers that grow within the spine and cause epidural spinal cord compression, resulting in a reproducible, evolving neurological deficit and paralysis that closely resembles the human condition.

Surgery improves pain, function and quality of life in patients with spinal metastases: a prospective study on 118 patients.

PURPOSE: There are few prospective studies on surgical outcomes and survival in patients with metastatic disease to the spine. The magnitude and duration of effect of surgery on pain relief and quality of life remains uncertain. Therefore, the aim of this clinical study was to prospectively evaluate clinical, functional, quality of life and survival outcomes after palliative surgery for vertebral metastases. METHODS: 118 consecutive patients who underwent spinal surgery for symptomatic vertebral metastases were prospectively followed up for 12 months or until death. Clinical data and data from the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire were obtained pre- and post-operatively and at regular follow-up intervals. RESULTS: Surgery was effective in achieving rapid improvement in axial and radicular pain, neurological deficit, sphincteric dysfunction and ambulatory status, with a complication rate of 26% and a 12 month mortality rate of 48%. Almost 50% of patients had complete resolution of back pain, radiculopathy and neurological deficit. Of the patients who were non-ambulant and incontinent, over 50% regained ambulatory ability and recovered urinary continence. The overall incidence of wound infection or breakdown was 6.8% and the local recurrence rate was 8.5%. There was a highly significant improvement in physical, role, cognitive and emotional functioning and global health status post-operatively. Greatest improvement in pain, function and overall quality of life occurred in the early post-operative period and was maintained until death or during the 12 month prospective follow-up period. CONCLUSION: The potential for immediate and prolonged improvement in pain, function and quality of life in patients with symptomatic vertebral metastases should be considered during the decision-making process when selecting and counselling patients for surgery.

Risk Factors for Pathological Fracture and Metastatic Epidural Spinal Cord Compression in Patients With Spinal Metastases.

Vertebral pathological fracture and metastatic epidural spinal cord compression (MESCC) due to metastatic cancer inevitably cause pain, neurological deficit, impaired function, and decreased quality of life and are indications for surgery. In such cases, earlier surgical intervention has the potential to prevent permanent neurological deficit and disability and to maintain function and quality of life. Therefore, the aim of this study was to identify and evaluate risk factors for pathological fracture and MESCC in patients with spinal metastases. Retrospective assessment of clinical and radiological parameters was undertaken in patients with spinal metastases. Seventy-two patients with spinal metastases underwent decompressive and/or stabilization surgery for pathological fracture and/or MESCC or nerve root compression. The following items were assessed for association with pathological fracture or MESCC: tumor size, location, type, and morphology; disease burden; pain; and function. Pain, tumor size within the vertebral body, vertebral endplate and 3-column involvement, primary tumor growth rate, and multiple vertebral metastases were associated with increased risk for pathological fracture. Vertebral posterior element and costovertebral joint involvement by tumor, primary tumor growth rate, and the presence of visceral metastases were associated with MESCC or nerve root compression. These factors should be considered in the decision-making process for surgery for spinal metastases. Patients with osteolytic spinal metastatic lesions causing pain, greater than 25% occupancy of the vertebral body, and involvement of the vertebral endplate or all 3 columns should be considered for prophylactic or therapeutic decompressive and stabilization surgery. [Orthopedics. 2018; 41(1):e38-e45.].

Accuracy of Preoperative Scoring Systems for the Prognostication and Treatment of Patients with Spinal Metastases.

BACKGROUND: In patients with spinal metastatic disease, survival prognosis is a key consideration in selection for surgery and determining the extent of treatment. Individual survival prediction however remains difficult. We sought to validate the prognostic accuracy of seven preoperative scoring systems. METHODS: 61 patients surgically treated for spinal metastases were retrospectively reviewed. Preoperative scores were calculated for Tokuhashi, Revised Tokuhashi, Bauer, Modified Bauer, Sioutos, Tomita, and van der Linden scoring systems. Prognostic value was determined by comparison of predicted and actual survival. RESULTS: The Revised Tokuhashi and Modified Bauer scoring systems had the best survival predictive accuracy. Rate of agreement for survival prognosis was the greatest for the Modified Bauer score. There was a significant difference in survival of the prognostic groups for all but the van der Linden score, being most significant for the Revised Tokuhashi, Bauer, Modified Bauer, and Tomita scoring systems (p ≤ 0.001). CONCLUSION: Overall, the scoring systems are accurate at differentiating patients into short-, intermediate-, and long-term survivors. More precise prediction of actual survival is limited and the decision for or against surgery should never be based on survival prognostication alone but should take into account symptoms such as neurological deficit or pain from pathological fracture and instability.

Is spinal surgery safe in octogenarians?

BACKGROUND: An ageing population and advances in medical management often requires spinal surgeons to increasingly operate on patients older than 80 years. The ability to predict complications and mortality rates would allow discrimination of which octogenarians are able to safely undergo spinal surgery. Therefore, the aims of this study were to determine whether comorbidities and extent of surgery were associated with complications in this age group, in addition to which comorbidity and physical status assessment scales were best associated with the development of complications following spinal surgery. METHODS: A retrospective cohort study was performed. Comorbidities and physical health status were analysed using the American Society of Anesthesiologists (ASA) physical illness rating, Charlson Comorbidity Index (CCI) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score. Complications and extent of operation were sourced from patient records. The association between comorbidities/extent of operation and complications was analysed using negative binomial regression analysis. RESULTS: A total of 54 patients were included in our study (22 elective and 32 emergency); 38 patients suffered at least one complication (14 elective and 24 emergency, including six deaths). Increased CIRS-G and CCI scores were associated with increased incidence of total complications in the elective cohort. Increased number of operated spinal levels was also associated with complications. CONCLUSION: Elective spinal surgery can be safely performed in well selected patients over 80 years of age. However, extent of surgery, CIRS-G and CCI scores were associated with increased complications from spinal surgery in octogenarians.

The role of vascular endothelial growth factor in metastatic prostate cancer to the skeleton.

Despite the clinical implication and high incidence of bone and spinal metastases, the molecular mechanisms behind prostate cancer metastasis to bone and spine are not well understood. In this review the molecular mechanisms that may contribute to the highly metastatic phenotype of prostate cancer are discussed. Proangiogenic factors such as vascular endothelial growth factor (VEGF) have been shown to not only aid in the metastatic capabilities of prostate cancer but also encourage the colonization and growth of prostate tumour cells in the skeleton. The importance of VEGF in the complex process of prostate cancer dissemination to the skeleton is discussed, including its role in the development of the bone premetastatic niche, metastatic tumour cell recognition of bone, and bone remodeling. The expression of VEGF has also been shown to be upregulated in prostate cancer and is associated with clinical stage, Gleason score, tumour stage, progression, metastasis, and survival. Due to the multifaceted effect VEGF has on tumour angiogenesis, tumour cell proliferation, and bone destruction, therapies targeting the VEGF pathways have shown promising clinical application and are being investigated in clinical trials.

Animal cancer models of skeletal metastasis.

The bony skeleton is one of the most common sites of metastatic spread of cancer and is a significant source of morbidity in cancer patients, causing pain and pathologic fracture, impaired ambulatory ability, and poorer quality of life. Animal cancer models of skeletal metastases are essential for better understanding of the molecular pathways behind metastatic spread and local growth and invasion of bone, to enable analysis of host-tumor cell interactions, identify barriers to the metastatic process, and to provide platforms to develop and test novel therapies prior to clinical application in human patients. Thus, the ideal model should be clinically relevant, reproducible and representative of the human condition. This review summarizes the current in vivo animal models used in the study of cancer metastases of the skeleton.

The osteoblastic and osteoclastic interactions in spinal metastases secondary to prostate cancer.

Prostate cancer (PC) is one of the most common cancers arising in men and has a high propensity for bone metastasis, particularly to the spine. At this stage, it often causes severe morbidity due to pathological fracture and/or metastatic epidural spinal cord compression which, if untreated, inevitably leads to intractable pain, neurological deficit, and paralysis. Unfortunately, the underlying molecular mechanisms driving growth of secondary PC in the bony vertebral column remain largely unknown. Further investigation is warranted in order to identify therapeutic targets in the future. This review summarizes the current understanding of PC bone metastasis in the spine, highlighting interactions between key tumor and bone-derived factors which influence tumor progression, especially the functional roles of osteoblasts and osteoclasts in the bone microenvironment through their interactions with metastatic PC cells and the critical pathway RANK/RANKL/OPG in bone destruction.

Multidisciplinary treatment and survival of patients with vertebral metastases from thyroid carcinoma.

BACKGROUND: Distant metastases from differentiated thyroid carcinoma occur in up to 20% of cases and represent the most frequent cause of thyroid cancer-related death. Metastatic disease to the spine has the potential to cause severe morbidity, including pain, neurological deficit, and paraplegia. SUMMARY: We present a case series of eight consecutive patients with symptomatic spinal metastases due to thyroid carcinoma treated by our multidisciplinary team consisting of spinal surgeons, oncologists, and radiologists, with management of each case determined by our surgical algorithm. Four patients underwent surgical decompression and stabilization for spinal metastases causing instability, spinal cord compression, neurological deficit, or intractable pain. Three patients underwent vertebroplasty for focal mechanical pain due to osteolytic metastases in the absence of significant spinal cord compression or spinal instability; one of these patients required subsequent surgical decompression for spinal cord compression. One patient was nonoperatively treated. All patients underwent total thyroidectomy for the primary cancer and adjuvant radioiodine-131 treatment. The only patient with poorly differentiated thyroid cancer, which was refractory to radioiodine-131 died at 6 months after vertebroplasty procedures for symptomatic spinal metastases. One patient with medullary thyroid carcinoma died at 18 months after vertebroplasty. All remaining six patients who had well-differentiated papillary or follicular thyroid carcinoma were alive at an average of 50 months (range: 17-96 months) after diagnosis and treatment of symptomatic spinal metastases and were ambulant, independent, and able to perform activities of daily living and had no significant pain or neurologic symptoms. CONCLUSION: The potential for long-term survival of several years following development of spinal metastases should be considered during the counseling and decision-making process for patients with thyroid cancer.

Eight-year clinical and radiological follow-up of the Bryan cervical disc arthroplasty.

STUDY DESIGN: Single institution, prospective cohort study of 21 patients who underwent single- or bilevel cervical disc arthroplasty for radiculopathy. OBJECTIVE: To evaluate the long-term outcome of cervical disc arthroplasty. SUMMARY OF BACKGROUND DATA: There is an increasing trend in the use of cervical arthroplasty; however, no long-term outcome studies exist to verify their safety, functionality, and durability. METHODS: A total of 21 patients underwent 27 total disc arthroplasties using the Bryan cervical disc (Medtronic Sofamor Danek Inc, Memphis, TN) after anterior cervical discectomy. Clinical and radiological data were obtained from the 8-year postoperative review. RESULTS: Nineteen of twenty-one patients were able to perform daily activities without limitation. Twenty of twenty-one patients reported fair to excellent outcome according to Odom criteria and 21 of 27 (78%) operated segments were mobile. Functional prostheses moved an average of 10.6°, which was similar to the range of movement of the adjacent nonoperated segments of the cervical spine. Heterotopic ossification was evident in 13 of the 27 (48%) operated segments and restricted movement of the prosthesis in nine cases. Five of the six patients who received bilevel arthroplasties developed heterotopic ossification. There was one case of posterior migration of the prosthesis, which did not have any clinical repercussion. No other case showed evidence of migration, subsidence, loosening, or wear. Radiological evidence of adjacent segment degeneration was observed in four patients (19%); however, each of these patients had pre-existing degenerative disc disease at these levels on preoperative imaging. CONCLUSION: At 8-year follow-up, the Bryan cervical disc arthroplasty maintains favorable clinical and radiological results, with preservation of movement and satisfactory clinical outcome in the majority of cases. However, the incidence of heterotopic ossification causing restricted range of movement of the prosthesis appears to increase with time, especially in bilevel procedures.

Correction of main thoracic adolescent idiopathic scoliosis using pedicle screw instrumentation: does higher implant density improve correction?

STUDY DESIGN: Single institution, retrospective cohort study of 49 consecutive patients with Lenke I adolescent idiopathic scoliosis, all operated by a single surgeon using identical surgical technique and type of instrumentation. OBJECTIVE: To evaluate the early coronal and sagittal correction of main thoracic adolescent idiopathic scoliosis using all-pedicle screw instrumentation and to determine whether implant density influences correction. SUMMARY OF BACKGROUND DATA: There is an increasing trend in the use of pedicle screws in scoliosis correction surgery, particularly in using segmental all-pedicle screw constructs. No previous studies have investigated whether higher pedicle screw implant density improves correction of scoliosis in vivo. METHODS: Forty-nine consecutive patients with Lenke I main thoracic adolescent idiopathic scoliosis underwent single stage posterior correction and instrumented spinal fusion with pedicle screw fixation between 2006 and 2008. Pre- and postoperative radiographs were analyzed. Mean patient age at the time of operation was 14.4 years (range: 11-19.7 years). RESULTS: The preoperative main thoracic curve of 60.0 degrees +/- 13.4 degrees was corrected to 17.4 degrees +/- 6.9 degrees (69.9% correction) on the postoperative radiographs. The preoperative thoracic kyphosis of 20.0 degrees +/- 10.2 degrees decreased to 11.6 degrees +/- 4.9 degrees after surgery. There was a significant correlation between decrease in sagittal kyphosis and magnitude of coronal Cobb angle correction (P = 0.002). There was no correlation between implant density and magnitude of coronal or sagittal curve correction, with and without curve flexibility taken into consideration. CONCLUSION: Pedicle screw constructs provided excellent coronal correction of thoracic idiopathic scoliosis, however, this was at the expense of sagittal contour. Bilateral segmental pedicle screw fixation did not improve curve correction compared with unilateral or alternate segmental fixation.

Anti-angiogenic therapy for osteosarcoma.

Even in tumor centers using established protocols, the survival rate of patients with osteosarcoma has not improved significantly in recent years. Novel therapies are urgently needed as an adjunct to conventional treatment modalities, to reduce the dose and subsequent toxicity associated with current chemotherapy, improve local disease control, prevent development of metastases, and offer an alternative treatment for those tumors that are poorly responsive to chemotherapy. Anti-angiogenic therapy currently holds great potential in conjunction with conventional treatment modalities for osteosarcoma. Specifically, anti-angiogenic factors derived from cartilage, a natural barrier to osteosarcoma invasion, may have important therapeutic applications in osteosarcoma.

Localization of pigment epithelium-derived factor in growing mouse bone.

Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor found in a wide range of fetal and adult tissues, where it is thought to play a role in the regulation of angiogenesis during development. The temporal expression of PEDF during endochondral bone formation has not previously been reported. In this study, we analysed the expression pattern of PEDF in growing mouse hindlimbs from newborn day one through to maturation at week 9, using immunohistochemistry and in situ hybridization. PEDF expression was demonstrated in chondrocytes within the resting, proliferative and upper hypertrophic zones of the epiphyseal growth plate. The pattern of expression was consistent throughout the developmental stages of the mouse. In addition, PEDF was expressed by osteoblasts lining the bone spicules in the ossification zone of metaphyseal bone, as well as by osteoblasts lining cortical periosteum. These novel results demonstrate that PEDF is developmentally expressed in both cartilage and bone cells during endochondral bone formation, and strongly suggest that it may play a regulatory role in the processes of chondrocyte and osteoblast differentiation, endochondral ossification, and bone remodelling during growth and development of long bones.

Osteosarcoma near joints: assessment and implications.

BACKGROUND: The choice of performing surgery when tumors encroach onto joints remains a challenging and controversial issue. Pre-operative assessment by magnetic resonance imaging (MRI) is of critical importance in dictating surgical management and subsequent functional outcome. METHODS: We examined archival samples from 27 patients with osteosarcoma, adjacent to synovial joints for the incidence and mechanism of osteosarcoma extension into the joint space. Histopathologic findings were correlated with pre-operative MRI findings and choice of operation. RESULTS: There was no evidence of penetration across the entire thickness of articular cartilage into the joint cavity in all of the 27 cases. When pre-operative MRI confidently excluded joint involvement by tumor, enabling an intra-articular surgical approach, histopathologic correlation confirmed the absence of joint involvement in all cases. The low incidence of joint involvement was despite the presence of extensive bone and soft tissue involvement in most cases, a tendency for peripheral extension of tumor around the articular margin of the bone, and evidence of joint effusions pre-operatively in more than one-third of cases. CONCLUSIONS: Joint involvement by osteosarcoma is uncommon, with articular cartilage being a relative barrier to tumor invasion. If pre-operative MRI does not show definite evidence of intra-articular tumor involvement, it is likely to be safe to proceed with intra-articular resection.

Resistance of epiphyseal cartilage to invasion by osteosarcoma is likely to be due to expression of antiangiogenic factors.

OBJECTIVES: Epiphyseal cartilage is a barrier to osteosarcoma invasion, however the mechanisms behind this resistance remain unclear. The aim of this study was to examine the chronological and spatial patterns of osteosarcoma growth and invasion of local tissue structures including epiphyseal cartilage. METHODS: We used an in vivomouse model of osteosarcoma to histologically examine tumors at different stages of disease progression. We compared the pattern of osteosarcoma penetration of epiphyseal cartilage with the expression pattern of two potent mediators of angiogenesis; proangiogenic vascular endothelial growth factor (VEGF) and antiangiogenic pigment epithelium-derived factor (PEDF). RESULTS: Epiphyseal cartilage remained intact across its entire length in all sections examined, despite increasing tumor size as well as intra- and extraosseous destruction. In the most advanced cases, only the proangiogenic lowermost layers of the hypertrophic zone of the growth plate were eroded. This corresponded with the growth plate layers which highly expressed the angiogenic factor VEGF. In contrast, the resting, proliferative and upper hypertrophic layers were resistant to osteosarcoma invasion in all cases. This corresponded to the layers with the highest expression of the potent antiangiogenic factor PEDF. CONCLUSION: Epiphyseal cartilage is resistant to local invasion by osteosarcoma. The balance of angiogenesis, influenced by pro- and antiangiogenic factors, is likely to play an important role in this resistance.