Evaluation of Real and Perceived Risk to Health Care Workers Caring for Patients With the Omicron Variant of the SARS-CoV-2 Virus in Surgery and Obstetrics.

OBJECTIVES: The Omicron variant of the SARS-CoV-2 virus is described as more contagious than previous variants. We sought to assess risk to health care workers (HCWs) caring for patients with COVID-19 in surgical/obstetrical settings, and the perception of risk among this group. METHODS: From January to April 2022, reverse transcription polymerase chain reaction was used to detect the presence of SARS-CoV-2 viral ribonucleic acid in patient, environmental (floor, equipment, passive air) samples, and HCWs' masks (inside surface) during urgent surgery or obstetrical delivery for patients with SARS-CoV-2 infection. The primary outcome was the proportion of HCWs' masks testing positive. Results were compared with our previous cross-sectional study involving obstetrical/surgical patients with earlier variants (2020-2021). HCWs completed a risk perception electronic questionnaire. RESULTS: Eleven patients were included: 3 vaginal births and 8 surgeries. In total, 5/108 samples (5%) tested positive (SARS-CoV-2 Omicron) viral ribonucleic acid: 2/5 endotracheal tubes, 1/22 floor samples, 1/4 patient masks, and 1 nasal probe. No samples from the HCWs' masks (0/35), surgical equipment (0/10), and air (0/11) tested positive. No significant differences were found between the Omicron and 2020/21 patient groups' positivity rates (Mann-Whitney U test, P = 0.838) or the level of viral load from the nasopharyngeal swabs (P = 0.405). Nurses had a higher risk perception than physicians (P = 0.038). CONCLUSION: No significant difference in contamination rates was found between SARS-CoV-2 Omicron BA.1 and previous variants in surgical/obstetrical settings. This is reassuring as no HCW mask was positive and no HCW tested positive for COVID-19 post-exposure.

Quality of life issues in patients with bone metastases: A systematic review.

INTRODUCTION: Bones are frequent sites of metastatic disease, observed in 30-75% of advanced cancer patients. Quality of life (QoL) is an important endpoint in studies evaluating the treatments of bone metastases (BM), and many patient-reported outcome tools are available. The primary objective of this systematic review was to compile a list of QoL issues relevant to BM and its interventions. The secondary objective was to identify common tools used to assess QoL in patients with BM, and the QoL issues they fail to address. METHODS: A search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases between 1946 and 27 January 2023 with the keywords "bone metastases", "quality of life", and "patient reported outcomes". Specific QoL issues in original research studies and the QoL tools used were extracted. RESULTS: The review identified the QoL issues most prevalent to BM in the literature. Physical and functional issues observed in patients included pain, interference with ambulation and daily activities, and fatigue. Psychological symptoms, such as helplessness, depression, and anxiety were also common. These issues interfered with patients' relationships and social activities. Items not mentioned in existing QoL tools were related to newer treatments of BM, such as pain flare, flu-like symptoms, and jaw pain due to osteonecrosis. CONCLUSIONS: This systematic review highlights that QoL issues for patients with BM have expanded over time due to advances in BM-directed treatments. If they are relevant, additional treatment-related QoL issues identified need to be validated prospectively by patients and added to current assessment tools.

Advancing spinal fellowship training: an international multi-centre educational perspective.

PURPOSE: The purpose of this article is to review the importance of contemporary spine surgery fellowships and educational strategies to assist with fellowship design and delivery. METHODS: Spine surgery fellowship includes trainees from orthopaedic and neurosurgical backgrounds and is increasingly indicated for individuals wishing to pursue spine surgery as a career, recognizing how spinal surgery evolved significantly in scope and complexity. We combine expert opinion with a review of the literature and international experience to expound spine fellowship training. RESULTS: Contemporary learning techniques include boot camps at the start of fellowship which may reinforce previous clinical learning and help prepare fellows for their new clinical roles. There is good evidence that surgical specialty training boot camps improve clinical skills, knowledge and trainee confidence prior to embarking upon new clinical roles with increasing levels of responsibility. Furthermore, as simulation techniques and technologies take on an increasing role in medical and surgical training, we found evidence that trainees' operative skills and knowledge can improve with simulated operations, even if just carried out briefly. Finally, we found evidence to suggest a role for establishing competence-based objectives for training in specific operative and technical procedures. Competence-based objectives are helpful for trainees and trainers to highlight gaps in a trainee's skill set that may then be addressed during training. CONCLUSIONS: Spinal fellowships may benefit from certain contemporary strategies that assist design and delivery of training in a safe environment. Interpersonal factors that promote healthy teamwork may contribute to an environment conducive to learning. These slides can be retrieved under Electronic Supplementary Material.

Versican 3'-untranslated region (3'UTR) promotes dermal wound repair and fibroblast migration by regulating miRNA activity.

Versican is an extracellular chondroitin sulfate proteoglycan which functions as a structural molecule but can also regulate a variety of cellular activities. This study was designed to explore the roles of versican in the process of dermal wound repair. To elevate levels of versican, we ectopically expressed the versican 3'-untranslated region (3'UTR) as a competitive endogenous RNA to modulate expression of versican. We demonstrated that wounds closed faster in transgenic mice expressing the versican 3'UTR, as compared to those in wildtype mice. We stably expressed versican 3'UTR in NIH3T3 fibroblasts and found that the 3'UTR-transfected cells showed increased migratory capacity relative to vector-transfected cells. Interestingly, we found that the 3'UTRs of versican and ß-catenin shared common microRNAs (miRNAs) including miR-185, miR-203*, miR-690, miR-680, and miR-434-3p. Luciferase assays showed that all of these miRNAs could target the 3'UTRs of both versican and ß-catenin, when the luciferase constructs contained fragments harboring the miRNA binding sites. As a consequence, expression of both versican and ß-catenin was up-regulated, which was confirmed in vitro and in vivo. Transfection with small interfering RNAs (siRNAs) targeting the versican 3'UTR abolished the 3'UTR's effects on cell migration and invasion. Taken together, these results demonstrate that versican plays important roles in wound repair and that versican messenger RNAs (mRNAs) could compete with endogenous RNAs for regulating miRNA functions.

Development and validation of a radiofrequency ablation treatment planning system for vertebral metastases.

PURPOSE: Bone-targeted radiofrequency ablation (RFA) is widely used in the treatment of vertebral metastases. While radiation therapy utilizes established treatment planning systems (TPS) based on multimodal imaging to optimize treatment volumes, current RFA of vertebral metastases has been limited to qualitative image-based assessment of tumour location to direct probe selection and access. This study aimed to design, develop and evaluate a computational patient-specific RFA TPS for vertebral metastases. METHODS: A TPS was developed on the open-source 3D slicer platform, including procedural setup, dose calculation (based on finite element modelling), and analysis/visualization modules. Usability testing was carried out by 7 clinicians involved in the treatment of vertebral metastases on retrospective clinical imaging data using a simplified dose calculation engine. In vivo evaluation was performed in a preclinical porcine model (n = 6 vertebrae). RESULTS: Dose analysis was successfully performed, with generation and display of thermal dose volumes, thermal damage, dose volume histograms and isodose contours. Usability testing showed an overall positive response to the TPS as beneficial to safe and effective RFA. The in vivo porcine study showed good agreement between the manually segmented thermally damaged volumes vs. the damage volumes identified from the TPS (Dice Similarity Coefficient = 0.71 ± 0.03, Hausdorff distance = 1.2 ± 0.1 mm). CONCLUSION: A TPS specifically dedicated to RFA in the bony spine could help account for tissue heterogeneities in both thermal and electrical properties. A TPS would enable visualization of damage volumes in 2D and 3D, assisting clinicians in decisions about potential safety and effectiveness prior to performing RFA in the metastatic spine.

Beyond radiation therapy: photodynamic therapy maintains structural integrity of irradiated healthy and metastatically involved vertebrae in a pre-clinical in vivo model.

Spinal metastasis commonly occurs in advanced breast cancer. Treatment is often multimodal including radiation therapy (RT), bisphosphonates (BPs), and surgery, yet alternative minimally invasive local treatments are needed. Photodynamic therapy (PDT) has been shown to ablate tumor cells and enhance bone formation secondary to metastatic breast cancer, demonstrating potential as a treatment for spinal metastasis. Combined with previous BP treatment, bone formation was further enhanced by PDT. This study aimed to determine the effects of PDT in combination with previous RT on healthy and metastatically involved vertebrae. Forty-six athymic rats underwent RT (4 Gy on day-7), twenty-three of them were inoculated with MT-1 human breast cancer cells on day 0. Thirteen healthy and ten metastatically involved rats underwent PDT treatment on day 14. All rats were sacrificed on day 21. L2 vertebrae were analyzed using µCT imaging, mechanical testing, and histological methods. In healthy vertebrae, while modest increases in trabecular structure were found in RT + PDT compared to RT only, mechanical stability was negatively affected. The 4 Gy RT dose was found to ablate all tumor cells and prevent further vertebral metastasis. As such, in metastatically involved rats, no differences in stereological or mechanical properties were detected. RT + PDT and RT-only treatment resulted in greatly improved vertebral structural and mechanical properties versus untreated or PDT-only treatment in metastatically involved rats, due to early tumor destruction in RT-treated groups. Increased amounts of woven bone and osteoid volume were found in PDT-treated vertebrae. Further investigation is needed to understand if structural improvements seen in RT + PDT treatment can translate into longer-term improvements in strength to support the potential of PDT as a viable adjuvant treatment for spinal metastasis postradiation.

Intraoperative Ultrasound in Spine Decompression Surgery: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVE: The aim of this study was to review the current spine surgery literature to establish a definition for adequate spine decompression using intraoperative ultrasound (IOUS) imaging. SUMMARY OF BACKGROUND DATA: IOUS remains one of the few imaging modalities that allows spine surgeons to continuously monitor the spinal cord in real-time, while also allowing visualization of surrounding soft tissue anatomy during an operation. Although this has valuable applications for decompression surgery in spinal canal stenosis, it remains unclear how to best characterize adequacy of spinal decompression using IOUS. METHODS: We conducted a systematic search of multiple databases including: Medline, Embase, and Cochrane Central Register of Controlled Trials Strategy. Our search terms were spine, spinal cord diseases, decompression surgery, ultrasonogra-phy, and intraoperative period. We were interested in studies that used intraoperative use of ultrasound imaging in spinal decompression surgery for the cervical, thoracic, and lumbar spine. Study quality was evaluated using the Methodological Index for Non-Randomized Studies (MINORS). RESULTS: Our search strategy yielded 985 of potentially relevant publications, 776 underwent title and abstract screening, and 31 full-text articles were reviewed. We found IOUS to be useful in spine surgery for decompression of degenerative cases in all regions of the spine. The thoracic spine was unique for IOUS-guided decompression of fractures, and the lumbar spine for decompressing nerve roots. Although we did not identify a universal definition for adequate decompression, there was common description of decompression that qualitatively described the ventral aspect of the spinal cord being "free floating" within the cerebrospinal fluid. Other measurable definitions, such as spinal cord diameter or spinal cord pulsatility, were not good definitions given there was insufficient evidence and/or poor reliability. CONCLUSION: The systematic review examines the current literature on IOUS and spinal decompression surgery. We identified a common qualitative definition for adequate decompression involving a "free floating" spinal cord within the cerebrospinal fluid which indicates that the spinal cord is free from contact of the anterior elements.Level of Evidence: 1.

Femoral Antegrade Starting Tool (FAST) for intramedullary nailing.

Intramedullary (IM) nailing is the standard of care for adult lower extremity long bone fracture stabilisation. Key to this procedure is obtaining the correct entry point and trajectory for initial guide pin insertion. This work presents the Femoral Antegrade Starting Tool (FAST), a surgical tool that addresses the lack of connectivity in utilising sequential 2D fluoroscopic images to achieve 3D alignment of femoral guide pin placement. The user centred design and development of FAST is introduced and the performance of this device evaluated during guide pin insertion for femoral IM nailing in a series of sawbones and cadaveric models leading to a first in human clinical cohort study. The results demonstrated the potential of FAST to improve time and consistency of the guide pin insertion for femoral IM nailing for less experienced surgeons and trainees. Overall, FAST was found to be easy to use with a high degree of clinical interest (particularly for use in large patients) and acceptance motivating continued development of this new technology.

Detection of SARS-CoV-2 contamination in the operating room and birthing room setting: a cross-sectional study.

BACKGROUND: The exposure risks to front-line health care workers caring for patients with SARS-CoV-2 infection undergoing surgery or obstetric delivery are unclear, and an understanding of sample types that may harbour virus is important for evaluating risk. We sought to determine whether SARS-CoV-2 viral RNA from patients with SARS-CoV-2 infection undergoing surgery or obstetric delivery was present in the peritoneal cavity of male and female patients, in the female reproductive tract, in the environment of the surgery or delivery suite (surgical instruments or equipment used, air or floors), and inside the masks of the attending health care workers. METHODS: We conducted a cross-sectional study from November 2020 to May 2021 at 2 tertiary academic Toronto hospitals, during urgent surgeries or obstetric deliveries for patients with SARS-CoV-2 infection. The presence of SARS-CoV-2 viral RNA in patient, environmental and air samples was identified by real-time reverse transcription polymerase chain reaction (RT-PCR). Air samples were collected using both active and passive sampling techniques. The primary outcome was the proportion of health care workers' masks positive for SARS-CoV-2 RNA. We included adult patients with positive RT-PCR nasal swab undergoing obstetric delivery or urgent surgery (from across all surgical specialties). RESULTS: A total of 32 patients (age 20-88 yr) were included. Nine patients had obstetric deliveries (6 cesarean deliveries), and 23 patients (14 male) required urgent surgery from the orthopedic or trauma, general surgery, burn, plastic surgery, cardiac surgery, neurosurgery, vascular surgery, gastroenterology and gynecologic oncology divisions. SARS-CoV-2 RNA was detected in 20 of 332 (6%) patient and environmental samples collected: 4 of 24 (17%) patient samples, 5 of 60 (8%) floor samples, 1 of 54 (2%) air samples, 10 of 23 (43%) surgical instrument or equipment samples, 0 of 24 cautery filter samples and 0 of 143 (95% confidence interval 0-0.026) inner surface of mask samples. INTERPRETATION: During the study period of November 2020 to May 2021, we found evidence of SARS-CoV-2 RNA in a small but important number of samples obtained in the surgical and obstetric operative environment. The finding of no detectable virus inside the masks worn by the health care teams would suggest a low risk of infection for health care workers using appropriate personal protective equipment.

In-hospital mortality and surgical utilization in severely polytraumatized patients with and without spinal injury.

BACKGROUND: Patients who sustain major trauma experience multisystem injuries including those affecting the spine. We hypothesize that recovery after spinal injuries differs from those affecting other systems. The purpose of our study was to compare in-hospital mortality and surgical resource utilization in severely polytraumatized patient with and without spinal injury. METHODS: We assembled a cohort of patients with severe polytrauma (Injury Severity Score [ISS]>15) and spinal injury and matched them to a cohort without spinal injury for age, gender, ISS, and mechanism of injury. In patients presenting to a Level I trauma center, we compared in-hospital patient mortality, the number of surgical procedures, and duration required for ventilatory support, intensive care unit (ICU) length of stay (LOS), and in-hospital LOS comparing matched groups. We performed a subanalysis of those who sustained severe fracture types and those with neurologic impairment. RESULTS: From 114 matched pairs, we found no significant differences in mortality rates or numbers of surgical procedures performed between the groups. Patients with spine injury, however, were observed to experience a prolonged duration of ventilation, ICU and in-hospital LOS compared with their matched cohort. Severe fracture patterns and the presence of neurologic involvement amplified the effect on these outcomes. CONCLUSIONS: In this study, we conclude that the presence of a spinal injury in the setting of severe polytrauma (ISS>15) is associated with a prolonged course of ventilatory support, ICU, and in-hospital LOS. Trauma hospitals treating patients with spinal fracture should be aware of differences in the use of health services for this patient population.

Beyond bisphosphonates: photodynamic therapy structurally augments metastatically involved vertebrae and destroys tumor tissue.

Breast cancer patients commonly develop metastases in the spine, which compromises its mechanical stability and can lead to skeletal related events. The current clinical standard of treatment includes the administration of systemic bisphosphonates (BP) to reduce metastatically induced bone destruction. However, response to BPs can vary both within and between patients, which motivates the need for additional treatment options for spinal metastasis. Photodynamic therapy (PDT) has been shown to be effective at treating metastatic lesions secondary to breast cancer in an athymic rat model, and is proposed as a treatment for spinal metastasis. The objective of this study was to determine the effect of PDT, alone or in combination with previously administered systemic BPs, on the structural and mechanical integrity of both healthy and metastatically involved vertebrae. Human breast carcinoma cells (MT-1) were inoculated into athymic rats (day 0). At 14 days, a single PDT treatment was administered, with and without previous BP treatment at day 7. In addition to causing tumor necrosis in metastatically involved vertebrae, PDT significantly reduced bone loss, resulting in strengthening of the vertebrae compared to untreated controls. Combined treatment with BP + PDT further enhanced bone architecture and strength in both metastatically involved and healthy bone. Overall, the ability of PDT to both ablate malignant tissue and improve the structural integrity of vertebral bone motivates its consideration as a local minimally invasive treatment for spinal metastasis secondary to breast cancer.

Defining the therapeutic window of vertebral photodynamic therapy in a murine pre-clinical model of breast cancer metastasis using the photosensitizer BPD-MA (Verteporfin).

Breast cancer is known to cause metastatic lesions in the bone, which can lead to skeletal-related events. Currently, radiation therapy and surgery are the treatment of choice, but the success rate varies and additional adjuncts are desirable. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for numerous cancers. Earlier work has shown that the athymic rat model is suitable to investigate the effect of PDT on bone metastasis and benzoporphyrin-derivative monoacid ring A (BPD-MA; verteporfin) has been shown to be a selective photosensitizer. The aim of this study was to define the therapeutic window of photosensitizer with regard to drug and light dose. Human breast carcinoma cells (MT-1)-stable transfected with the luciferase gene-were injected intra-cardiacally into athymic rats. At 14 days, the largest vertebral lesion by bioluminescence imaging was targeted for single treatment PDT. A drug escalating-de-escalating scheme was used (starting drug dose and light energy of 0.2 mg/kg and 50 J, respectively). Outcomes included 48 h post-treatment bioluminescence of remaining viable tumour, histomorphometric assessment of tumour burden, and neurologic evaluation. The region of effect by bioluminescence and histology increased with increasing drug dose and light energy. A safe and effective drug-light dose combination in this model appears to be 0.5 mg/kg BPD-MA and applied light energy of less than 50 J for the thoracic spine and 1.0 mg/kg and 75 J for the lumbar spine. For translation to clinical use, it is an advantage that BPD-MA (verteporfin), a second-generation photosensitizer, is already approved to treat age-related macular degeneration. Overall, PDT represents an exciting potential new minimally-invasive local, safe and effective therapy in the management of patients with spinal metastases.

How do validated measures of functional outcome compare with commonly used outcomes in administrative database research for lumbar spinal surgery?

Clinical interpretation of health services research based on administrative databases is limited by the lack of patient-reported functional outcome measures. Reoperation, as a surrogate measure for poor outcome, may be biased by preferences of patients and surgeons and may even be planned a priori. Other available administrative data outcomes, such as postoperative cross sectional imaging (PCSI), may better reflect changes in functional outcome. The purpose was to determine if postoperative events captured from administrative databases, namely reoperation and PCSI, reflect outcomes as derived by validated functional outcome measures (short form 36 scores, Oswestry disability index) for patients who underwent discretionary surgery for specific degenerative conditions of the lumbar spine such as disc herniation, spinal stenosis, degenerative spondylolisthesis, and isthmic spondylolisthesis. After reviewing the records of all patients surgically treated for disc herniation, spinal stenosis, degenerative spondylolisthesis, and isthmic spondylolisthesis at our institution, we recorded the occurrence of PCSI (MRI or CT-myelograms) and reoperations, as well as demographic, surgical, and functional outcome data. We determined how early (within 6 months) and intermediate (within 18 months) term events (PCSI and reoperations) were associated with changes in intermediate (minimum 1 year) and late (minimum 2 years) term functional outcome, respectively. We further evaluated how early (6-12 months) and intermediate (12-24 months) term changes in functional outcome were associated with the subsequent occurrence of intermediate (12-24 months) and late (beyond 24 months) term adverse events, respectively. From 148 surgically treated patients, we found no significant relationship between the occurrence of PCSI or reoperation and subsequent changes in functional outcome at intermediate or late term. Similarly, earlier changes in functional outcome did not have any significant relationship with subsequent occurrences of adverse events at intermediate or late term. Although it may be tempting to consider administrative database outcome measures as proxies for poor functional outcome, we cannot conclude that a significant relationship exists between the occurrence of PCSI or reoperation and changes in functional outcome.

The who, what and when of surgery for the degenerative lumbar spine: a population-based study of surgeon factors, surgical procedures, recent trends and reoperation rates.

BACKGROUND: Degenerative disease of the lumbar spine (DLS) is a common condition for which surgery can be beneficial in selected patients. With recent surgical trends toward more focused subspecialty training, it is unclear how characteristics of the surgical consultant may impact on treatment and reoperations. Our objective was to understand the relations between surgeon factors (who), surgical procedures (what) and recent trends (when) and their influence on reoperations for DLS surgery. METHODS: We performed a longitudinal population-based study using administrative databases including all patients aged 50 years and older who underwent surgery for DLS. We collected data on surgeon characteristics (specialty, volume), index procedures (decompressions, fusions) and reoperations. RESULTS: We identified 6128 patients who underwent surgery for DLS (4200 who had decompressions, 1928 who had fusions). We observed an increasing proportion of fusions over decompressions while the per capita surgeon supply declined. Orthopedic specialty and higher surgical volume were associated with a higher proportion of fusions (p < 0.001). The overall reoperation rate was 10.6%. Reoperations were more frequent in patients who had decompressions than those who had fusions at 2 years (5.4% v. 3.8%, odds ratio 1.4, p < 0.013), but not over the long-term. Long-term survival analysis demonstrated that a lower surgical volume was related to a higher reoperation rate (hazard ratio 1.28, p = 0.038). CONCLUSION: Lumbar spinal fusion rates for DLS have been increasing in Ontario. There is wide variation in surgical procedures between specialty and volume: namely high-volume and orthopedic surgeons have higer fusion rates than other surgeons. We observed better long-term survival among patients of high-volume surgeons. Referring physicians should be aware that the choice of surgical consultant may influence patients' treatments and outcomes. With increasing rates of spinal surgery, the efficacy and cost benefit of current surgical options require ongoing study.

The Importance of Determining Trainee Perspectives on Procedural Competencies During Spine Surgery Clinical Fellowship.

STUDY DESIGN: Longitudinal survey. OBJECTIVE: It remains important to align competence-based objectives for training as deemed important by clinical fellows to those of their fellowship supervisors and program educators. The primary aim of this study was to determine trainee views on the relative importance of specific procedural training competencies. Secondarily, we aimed to evaluate self-perceived confidence in procedural performance at the commencement and completion of fellowship. METHODS: Questionnaires were administered to 68 clinical fellows enrolled in the AOSNA fellowship program during the 2015-2016 academic year. A Likert-type scale was used to quantify trainee perspectives on the relative importance of specific procedural competencies to their training base on an established curriculum including 53 general and 22 focused/advanced procedural competencies. We measured trainee self-perceived confidence in performing procedures at the commencement and completion of their program. Statistical analysis was performed on fellow demographic data and procedural responses. RESULTS: Our initial survey response rate was 82% (56/68) and 69% (47/68) for the follow-up survey. Although most procedural competencies were regarded of high importance, we did identify several procedures of high importance yet low confidence among fellows (ie, upper cervical, thoracic discectomy surgery), which highlights an educational opportunity. Overall procedural confidence increased from an average Likert score of 4.2 (SD = 1.3) on the initial survey to 5.4 (SD = 0.8) by follow-up survey (P < .0001). CONCLUSIONS: Understanding trainee goals for clinical fellowship remains important. Identification of areas of low procedural confidence and high importance to training experience will better guide fellowship programs and supervisors in the strategic delivery of the educational experience.

The effect of versican G3 domain on local breast cancer invasiveness and bony metastasis.

INTRODUCTION: Increased versican expression has been associated with local breast cancer invasiveness and a more aggressive tumor phenotype. The cellular mechanisms are not fully understood and this study evaluated versican G3 domain with its EGF-like motifs in influencing tumor invasion and metastasis. METHODS: One recombinant construct was synthesized (a signal peptide for product secretion and the versican G3 domain). The construct was stably transfected into human breast carcinoma MT-1 cells. Cell viability in vitro was evaluated in low serum and serum starvation conditions. In vivo study of tumor growth was evaluated in a nude mouse model. G3 effects on rodent vascular endothelial cells were evaluated in vitro on cell survival, apoptosis, migration, and vascular formation. The effects of VEGF, fibronectin, and G3 on vascular formation were examined. An intracardiac injection model of metastatic human breast carcinoma tested the effect of G3 on distant bony and soft tissue metastasis. Analysis of metastatic burden included histology, radiographs, and micro-CT quantification of osteolysis. RESULTS: A greater viability of cancer cells was observed in low serum and serum-free conditions in the presence of versican G3. Larger subcutaneous tumors were obtained in the G3 group following tumor cell injection into CD1 mice. G3 induced a greater degree of rodent vascular endothelial cell proliferation and migration in vitro. Simultaneous presence of fibronectin, VEGF, and G3 promoted endothelial cell migration in wound-healing assays as compared to the treatments containing none, one or two of these molecules. Systemic tumor burden to distant bony and soft tissue metastatic sites was greater in the G3 group using the intracardiac injection metastatic model. CONCLUSION: Versican G3 domain appears to be important in local and systemic tumor invasiveness of human breast cancer. Effects include enhancing cell viability, proliferation, migration and enhancing local tumor growth. Potential effects on angiogenesis include enhancing vascular endothelial proliferation, migration, and vessel formation. The interactions between tumor cells, surrounding stromal components and neo-vascularization in breast cancer may include interactions with VEGF and fibronectin. The propensity of versican G3 to influence tumor invasion to bone and the mechanisms of G3 mediated osteolysis warrants ongoing studies.

Photodynamic therapy of vertebral metastases: evaluating tumor-to-neural tissue uptake of BPD-MA and ALA-PpIX in a murine model of metastatic human breast carcinoma.

Photodynamic therapy has been successfully applied to numerous cancers. Its potential to treat cancer metastases in the spine has been demonstrated previously in a preclinical animal model. The aim of this study was to test two photosensitizers, benzoporphyrin-derivative monoacid ring A (BPD-MA) and by 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), for their potential use to treat bony metastases. The difference in photosensitizer concentration in the spinal cord and the surrounding tumor-bearing vertebrae was of particular interest to assess the risk of potential collateral damage to the spinal cord. Vertebral metastases in a rat model were generated by intracardiac injection of human breast cancer cells. When tumor growth was confirmed, photosensitizers were injected systemically and the animals were euthanized at different time points. The following tissues were harvested: liver, kidney, ovaries, appendicular bone, spinal cord and lumbar vertebrae. Photosensitizer tissue concentration of BPD-MA or PpIX was determined by fluorescence spectrophotometry. In contrast to BPD-MA, ALA-PpIX did not demonstrate an appreciable difference in the uptake ratio in tumor-bearing vertebrae compared to spinal cord. The highest ratio for BPD-MA concentration was found 15 min after injection, which can be recommended for therapy in this model.

Bedside to bench and back to bedside: Translational implications of targeted intervertebral disc therapeutics.

Spinal pain and associated disability is a leading cause of morbidity worldwide that has a strong association with degenerative disc disease (DDD). DDD can begin in early-late adolescence and has a variable course. Biologically based therapies to treat DDD face significant challenges posed by the unique milieu of the environment within the intervertebral discs. Many potential promising therapies are still in the early stages of development with a hostile microenvironment within the disc presenting unique challenges. The translational potential of this article: Patient selection, reasonable therapeutic goals, approach, and timing will need to be discerned in order to successfully translate potential therapeutics.

Volume of Lytic Vertebral Body Metastatic Disease Quantified Using Computed Tomography-Based Image Segmentation Predicts Fracture Risk After Spine Stereotactic Body Radiation Therapy.

PURPOSE: To determine a threshold of vertebral body (VB) osteolytic or osteoblastic tumor involvement that would predict vertebral compression fracture (VCF) risk after stereotactic body radiation therapy (SBRT), using volumetric image-segmentation software. METHODS AND MATERIALS: A computational semiautomated skeletal metastasis segmentation process refined in our laboratory was applied to the pretreatment planning CT scan of 100 vertebral segments in 55 patients treated with spine SBRT. Each VB was segmented and the percentage of lytic and/or blastic disease by volume determined. RESULTS: The cumulative incidence of VCF at 3 and 12 months was 14.1% and 17.3%, respectively. The median follow-up was 7.3 months (range, 0.6-67.6 months). In all, 56% of segments were determined lytic, 23% blastic, and 21% mixed, according to clinical radiologic determination. Within these 3 clinical cohorts, the segmentation-determined mean percentages of lytic and blastic tumor were 8.9% and 6.0%, 0.2% and 26.9%, and 3.4% and 15.8% by volume, respectively. On the basis of the entire cohort (n=100), a significant association was observed for the osteolytic percentage measures and the occurrence of VCF (P<.001) but not for the osteoblastic measures. The most significant lytic disease threshold was observed at ≥11.6% (odds ratio 37.4, 95% confidence interval 9.4-148.9). On multivariable analysis, ≥11.6% lytic disease (P<.001), baseline VCF (P<.001), and SBRT with ≥20 Gy per fraction (P=.014) were predictive. CONCLUSIONS: Pretreatment lytic VB disease volumetric measures, independent of the blastic component, predict for SBRT-induced VCF. Larger-scale trials evaluating our software are planned to validate the results.

Closure of the annulus fibrosus of the intervertebral disc using a novel suture application device-in vivo porcine and ex vivo biomechanical evaluation.

BACKGROUND CONTEXT: Defects in the annulus fibrosus (AF) remain a challenge in the surgical treatment of lumbar disc herniations with persistent defects, allowing potential re herniation of nucleus pulposus (NP) tissue. A cervical porcine model was chosen to simulate human lumbar intervertebral disc (IVD). PURPOSE: The aim of this study was to determine the technical feasibility of closure of the AF of the IVD using a novel minimally invasive Kerrison-shaped suture application device. STUDY DESIGN: Ex vivo biomechanical and in vivo porcine device evaluations were performed. METHODS: Ex vivo biomechanical evaluation: 15 porcine spinal units were explanted and subjected to mock discectomy. The annular defect was closed using 2-0 non-absorbable (ultra-high molecular-weight polyethylene, UHMWPE) suture and Dines knot. The knot was backed up with two, three, or four throws. The spinal unit was subject to 4000 cycles of flexion/extension with 1500 N of axial load, and assessed for knot slippage. In vivo porcine device evaluation: three pigs (53-57 kg) were anesthetized and underwent a ventral surgical approach to the cervical spine. The AF of two discs was incised, and simulated partial NP discectomy was performed. The defect was closed at one level using the AnchorKnot device to apply the suture with a Dines knot and four throws. The pigs were observed for 4 weeks before euthanasia, allowing 7T magnetic resonance imaging (MRI) and histological evaluation. RESULTS: A Dines knot with four throws experienced no slippage after 4000 cycles. This configuration was tested in vivo. Clinically, the neurological examination in treated pigs was normal following surgery. Histological and MRI assessment confirmed sustained defect closure at 4 weeks. There was no reaction to the suture material and no NP extrusion at any of the sutured levels. CONCLUSIONS: This study demonstrates that it is technically feasible to perform AF defect closure in a porcine model. This novel device achieved AF defect closure that was maintained through 4 weeks in vivo.