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.

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.

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.

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.

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.

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.

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.

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.

Development of a Competence-Based Spine Surgery Fellowship Curriculum Set of Learning Objectives in Canada.

STUDY DESIGN: Modified-Delphi expert consensus method. OBJECTIVE: The aim of this study was to develop competence-based spine fellowship curricula as a set of learning goals through expert consensus methodology in order to provide an educational tool for surgical educators and trainees. Secondarily, we aimed to determine potential differences among specialties in their rating of learning objectives to defined curriculum documents. SUMMARY OF BACKGROUND DATA: There has been recent interest in competence-based education in the training of future surgeons. Current spine fellowships often work on a preceptor-based model, and recent studies have demonstrated that graduating spine fellows may not necessarily be exposed to key cognitive and procedural competencies throughout their training that are expected of a practicing spine surgeon. METHODS: A consensus group of 32 spine surgeons from across Canada was assembled. A modified-Delphi approach refined an initial fellowship-level curriculum set of learning objectives (108 cognitive and 84 procedural competencies obtained from open sources). A consensus threshold of 70% was chosen with up to 5 rounds of blinded voting performed. Members were asked to ratify objectives into either a general comprehensive or focused/advanced curriculum. RESULTS: Twenty-eight of 32 consultants (88%) responded and participated in voting rounds. Seventy-eight (72%) cognitive and 63 (75%) procedural competency objectives reached 70% consensus in the first round. This increased to 82 cognitive and 73 procedural objectives by round 4. The final curriculum document evolved to include a general comprehensive curriculum (91 cognitive and 53 procedural objectives), a focused/advanced curriculum (22 procedural objectives), and a pediatrics curriculum (22 cognitive and 9 procedural objectives). CONCLUSION: Through a consensus-building approach, the study authors have developed a competence-based curriculum set of learning objectives anticipated to be of educational value to spine surgery fellowship educators and trainees. To our knowledge, this is one of the first nationally based efforts of its kind that is also anticipated to be of interest by international colleagues.

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.

Helical coil electrode radiofrequency ablation designed for application in osteolytic vertebral tumors--initial evaluation in a porcine model.

BACKGROUND CONTEXT: Radiofrequency ablation (RFA) is emerging as a complementary treatment for vertebral metastases. Traditional RFA induces frictional heating leading to local tissue necrosis but often yields small, incomplete, and inhomogeneous zones of ablation in bone. We have developed a new bone-specific RFA electrode that uses a nontraditional frequency (27.12 MHz) and geometry (helical), exploiting a magnetic field and an electric field to generate larger and more comprehensive treatment zones. PURPOSE: The purpose of the study was to evaluate the feasibility and safety of the Bone Coil RFA electrode in the spine. STUDY DESIGN: This is a preclinical in vivo study based on basic science. METHODS: Under institutional approval, six healthy Yorkshire pigs received a sham and an RF treatment in two adjacent cervical vertebrae. To deploy the Bone Coil RFA device in dense porcine vertebrae, a surgical approach was required; an irrigated coring drill bit created a cylindrical path in the vertebral bodies through which the RFA electrodes were placed. The electronic circuit was completed by four grounding pads. Treatment was delivered for 10 minutes at 20 W (n=1), 25 W (n=1), and 30 W (n=4). To monitor the thermal rise and for safety, fiber-optic probes recorded temperatures in the center of each coil and near the spinal foramen. After the procedure, animals were monitored for 2 weeks. Magnetic resonance imaging (MRI) was completed immediately after treatment and at 14 days. Magnetic resonance image segmentation and histology were used to evaluate the ablation volume. RESULTS: Comprehensive treatment of the porcine vertebrae was demonstrated by temperature monitoring, MRI, and histology. Large zones of RF ablation were obtained (RF: 3.72±0.73 cm3 vs. sham: 1.98±0.16 cm3, p<.05), confined within the vertebral body. Internal temperatures were elevated with RF (66.1 °C-102.9 °C), without temperature rise outside of the vertebrae (38.2 °C ± 1.5 °C). Mobility, neurological responses, and behavior were normal, consistent with preprocedural examination. Magnetic resonance imaging best visualized ablation at Day 14. Histology revealed comprehensive homogeneous coagulative necrosis with little peripheral sign of repair. CONCLUSIONS: The Bone Coil RFA device created large intravertebral ablation volumes with no neurologic sequelae. Radiofrequency thermal ablation (clearly distinguished from the much smaller effects arising from core drilling) corresponded to the homogeneous necrosis visible on histology.

Bone targeted bipolar cooled radiofrequency ablation in a VX-2 rabbit femoral carcinoma model.

To determine the effect of bipolar cooled radiofrequency ablation (BCRF) on bone and tumour in a lapine pathologic femoral model. Under institutional approval, twelve New Zealand white rabbits received a single femoral injection of VX2 carcinoma cells (day 0). The rabbit femora, (n = 24), were block-randomized into four experimental groups: tumour-bearing radiofrequency ablation (RFA) treated, healthy bone RFA treated, tumour-bearing shams and healthy bone shams (n = 6 per group). 15 min of thermally regulated (65 °C) BCRF was applied at day 14. Pre- and post-treatment MR imaging was performed and repeated at day 28 prior to euthanasia. Histologic evaluation was used to determine treatment effect on tumour and bone tissue. A thirteenth injected rabbit served as a histologic control (no BCRF electrode placement). Large volumes (12.9 ± 5.5 cm(3)) of thermal ablation were achieved. An eight-fold reduction in tumour growth resulted in RFA treated animals compared to tumour-bearing sham controls (p < 0.001). Osteolysis was controlled in the tumour-treated group. Therapeutic effects were best imaged using MR contrast-enhanced SPoiled Gradient Recalled (SPGR) sequences. Osteoclasts and osteoblasts were observed to be sensitive to BCRF but osteocytes were more resilient. A small number of tumour cells within BCRF treated regions appeared viable post treatment. New bone formation was stimulated in the periphery of the targeted BCRF treatment zone. Structurally large VX2 tumour volumes within bone were successfully ablated with BCRF, stimulating new bone formation in the treatment periphery, although viable appearing osteocytes and tumour cells were observed in some treated regions.

In vitro and in vivo effects of photodynamic therapy on metastatic breast cancer cells pre-treated with zoledronic acid.

BACKGROUND: Photodynamic therapy (PDT), a non-ionizing, minimally invasive drug-light treatment, has recently been shown to successfully ablate tumor within rat vertebrae with concurrent improvements in bone strength and architecture. The bisphosphonate zoledronic acid (zol), a current drug for patients with skeletal metastases, primarily works by inhibiting osteoclast activity, but direct anti-tumor effects have also been reported. However, it is unknown if or how pre-treatment with zol may alter the tumorcidal effect of PDT. The aim of this study was to evaluate the effect of PDT, both in vitro and in vivo, on zol-pretreated cancer cells. MATERIALS AND METHODS: Human metastatic breast cancer cells (MT-1) were cultured in vitro and treated with zol (10µM) for 24h, followed by PDT treatment. Cell viability was assessed by fluorescence microscopy and flow cytometry. In vivo, MT-1 cells were injected (intracardiac) into athymic rats. On day 7, zol (60µg/kg) was administered subcutaneously. On day 14, PDT was applied (1mg/kg verteporfin; 75J; 690nm) to lumbar vertebrae. Histomorphometric assessment of tumor burden was evaluated on day 21. RESULTS: The cell viability measured in vitro after PDT treatment decreased in cells pre-incubated with zol up to 20% compared to treatment with PDT alone. Zol alone had no influence on the MT-1 cell viability. In vivo, all treatments, either alone or combined, had a tumorcidal effect. CONCLUSIONS: Pre-treatment with zol in vivo did not yield a synergistic effect on tumor ablation in contrast to the in vitro results, but neither did it abrogate the positive tumorcidal effect of PDT, so that those therapies may be applied in combination.

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.

Single-stage anterior high sacrectomy for locally recurrent rectal cancer.

STUDY DESIGN: A review of prospectively collected data on a consecutive series of patients undergoing single-stage anterior high sacrectomy for locally recurrent rectal carcinoma (LRRC). OBJECTIVE: To determine the clinical outcome of patients who underwent anterior high sacrectomy for LRRC. SUMMARY OF BACKGROUND DATA: High sacrectomy for oncological resection remains technically challenging. Surgery has the potential to achieve cure in carefully selected patients. Complete (R0) tumor excision in LRRC may require sacrectomy. High sacral resections (S3 and above) typically require a combined anterior/supine and posterior/prone procedure. We investigated our experience performing single-stage anterior high sacrectomy for LRRC. METHODS: A consecutive series of patients with LRRC without systemic metastases who underwent resection with curative intent requiring high sacrectomy were identified. A review of a prospectively maintained colorectal and spine cancer database data was performed. An oblique dome high sacral osteotomy was performed during a single-stage anterior procedure. Outcome measures included surgical resection margin status, hospital length of stay, postoperative complications, physical functioning status, and overall survival. RESULTS: Nineteen consecutive patients were treated between 2002 and 2011. High sacrectomy was performed at sacral level S1-S2 in 4 patients, S2-S3 in 9 patients, and through S3 in 6 patients. An R0 resection margin was achieved histologically in all 19 cases. There was 1 early (<30 d) postoperative death (1/19, 5%). At median follow-up of 38 months, 13 patients had no evidence of residual disease, 1 was alive with disease, and 4 had died of disease. Morbidities occurred in 15 of the 19 patients (79%). CONCLUSION: Although high sacrectomy may require a combined anterior and posterior surgical approach, our series demonstrates the feasibility of performing single-stage anterior high sacrectomy in LRRC, with acceptable risks and outcomes compared with the literature. The procedure described by us for LRRC lessens the need for a simultaneous or staged prone posterior resection, with favorable R0 tumor resections, patient survival, and clinical outcomes. LEVEL OF EVIDENCE: N/A.

Evaluation of a bipolar-cooled radiofrequency device for ablation of bone metastases: preclinical assessment in porcine vertebrae.

BACKGROUND CONTEXT: Cancer spread to the spine affects bone stability and can lead to pathologic fracture and neurologic impairment. Radiofrequency ablation (RFA) recently has gained popularity in treating skeletal tumors. Conventional RFA devices use a monopolar design, which limits the ability to comprehensively treat large tumors in bony tissues and may pose risks to adjacent critical normal neurologic tissues when applied to vertebrae. New bipolar-cooled radiofrequency (BCRF) may generate larger controlled lesions without the same degree of risk to adjacent structures. PURPOSE: The purpose of this study was to evaluate the feasibility, efficacy, and safety of RFA with the use of a new bone-specific, BCRF probe in a porcine vertebral model and to evaluate the ability of magnetic resonance (MR) imaging to represent histologic outcomes of RFA treatment. STUDY DESIGN: Basic science: preclinical in vivo study. METHODS: RFA was evaluated in three noncontiguous lumbar vertebrae in six Yorkshire pigs (25-30 kg). Via a transpedicular approach for probe placement, two vertebrae received BCRF treatment and one vertebrae served as a sham control. MR imaging and neurological assessments were conducted pre- and posttreatment as well as immediately before animal sacrifice (n=3 at day 0, n=3 at day 14). MR ablation zones were compared with hematoxylin and eosin-stained histological sections. RESULTS: With BCRF, large reproducible zones of ablation were achieved, confined within the vertebrae, without damage to adjacent tissues or the spinal cord. All animals demonstrated normal consistent neurologic behavior pre- and posttreatment. External tissue temperatures around targeted vertebrae were not increased. MR imaging after 14 days was more effective in demonstrating ablation effects than images on day 0, with radiologic findings most apparent on T2-weighted sequences. Histologic analysis of samples corresponded well to the zones of ablation observed on MR images (R=0.9, p<.01). CONCLUSIONS: The study demonstrated feasibility, safety, and effectiveness of BCRF ablation of vertebral bone. This motivates ongoing preclinical evaluation in diseased models to further explore the potential for its use in clinical treatment of metastatic vertebrae.

The benefits of photodynamic therapy on vertebral bone are maintained and enhanced by combination treatment with bisphosphonates and radiation therapy.

Photodynamic therapy (PDT) has been shown to ablate tumors within vertebral bone and yield short-term improvements in vertebral architecture and biomechanical strength, in particular when combined with bisphosphonate (BP) treatment. Longer-term outcomes of PDT combined with current treatments for skeletal metastases are essential to understand its therapeutic potential. The objective of this study is to evaluate the response of vertebrae to PDT after a longer (6-week) time period, alone and combined with previous BP or radiation treatment (RT). Sixty-three female rnu/rnu rats were randomized to six treatment groups: untreated control, BP-only, RT-only, PDT-only, combined BP + PDT and combined RT + PDT. L2 vertebrae were structurally analyzed through µCT-based analysis, axial compressive load-to-failure testing and histological analysis of morphology, osteoid formation and osteoclast activity. Combined BP + PDT treatment yielded the largest improvements in bone architecture with combined RT + PDT treatment yielding similar findings, but of a lesser magnitude. Mechanically, ultimate force and stress were correlated to stereological parameters that demonstrated a positive structural effect from combinatory treatment. Increased osteoid formation was observed in both combination therapies without any significant differences in osteoclast activity. Overall, multimodality treatment demonstrated a sustained positive effect on vertebral structural integrity, motivating PDT as a minimally-invasive adjuvant treatment for spinal metastases.

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.