The spine is a common site of metastasis. Complications include pathologic fracture, spinal cord compression, and neurological deficits. Vertebroplasty (VP) and Balloon Kyphoplasty (KP) are minimally invasive stabilization procedures used as a palliative treatment to improve mechanical stability, quality of life, and reduce pain. Photodynamic therapy (PDT) is a tumour-ablative modality that may complement mechanical stability afforded by VP/KP. This first-in-human study evaluates PDT safety when applied in conjunction with VP/KP.

This dose escalation trial involved one light only control group and four light-drug doses (50,100,150,200J;n=6) delivered at 150mW from a 690nm diode laser by 800-micron optical fibers prior to KP/VP. Patients eligible for VP/KP in treating pathologic fracture or at-risk lesions at a single level were recruited. Exclusion criteria included spinal canal compromise or neurologic impairment. PDT is a two-step binary therapy of systemic drug followed by intravertebral light activation. Light was applied via bone trochar prior to cementation. This study used a benzoporphyrin derivative monoacid (BPD-MA), Verteporfin (VisudyneTm), as the photosensitizer drug in the therapy. Drug/light safety, neurologic safety, generic (SF-36), and disease-specific outcomes (VAS, EORTC-QLQ-BM22, EORTC-QLQ-C15-PAL) were recorded through six weeks. Phototoxicity and the side effects of the BPD-MA were also examined following PDT use.

Thirty (10 male, 20 female) patients were treated (13 KP, 17 VP). The average age was 61 and significantly different between genders (Male 70yrs vs. Female 57yrs: p 0.05), and tumour status (lytic vs. mixed blastic/lytic: p>0.05). In most cases, fluence rates were similar throughout PDT treatment time, indicating a relatively stable treatment. Twelve (40%) of patients experienced complications during the study, none of which were attributed to PDT therapy. This included two kyphoplasty failures due to progression of disease, one case of shingles, one ankle fracture, one prominent suture, one case of constipation due to a lung lesion, one case of fatigue, and five patients experienced pain that was surgically related or preceded therapy.

Vertebral PDT appears safe from pharmaceutical and neurologic perspectives. KP/VP failure rate is broadly in line with reported values and PDT did not compromise efficacy. The 50J group demonstrated an improved response. Ongoing study determining safe dose range and subsequent efficacy studies are necessary.

Purpose: Bony metastases in vertebrae secondary to breast cancer can result in osteolysis and an increase in skeletal related events. Bisphosphonates (BP) are the current standard of care for breast cancer patients with skeletal disease. Photodynamic therapy (PDT) is a non-radiative treatment, which has been successfully applied to various malignancies and shown to successfully ablate vertebral human breast cancer (MT1) metastases in a murine model. Previous in-vitro study has shown that pre-treatment of MT-1 cells with the BP zoledronic acid (Zometa^®) renders them more susceptible to PDT. The aim of this study was to evaluate the influence of pre-treatment with BPs on the effect of PDT treatment on tumour ablation in metastatically involved vertebrae in vivo.

Method: Metastases were induced in fourteen 5–6 weeks old female athymic rats (Hsd:RH-Foxn1rnu) by intra-cardiac injection of 2x10^6 MT-1 cells. Four groups were formed:

control, no treatment;

Seven days after MT-1 injection 60 μg/kg of zoledronic acid was injected. PDT treatment was administered on day 14 using the photosensitizer BPD-MA (1.0 mg/kg; Visudyne). Fifteen minutes later, laser-light (690nm; 75J) was administered to the lumbar vertebrae. The rats were euthanized 7 days after PDT treatment. A total of 45 vertebrae were evaluated using a histomorphometric program (GENIE™, Aperio) to assess tumour burden. Statistical analyses were performed using a one-way ANOVA with a Tukey post hoc test. A p-value p< .05 was considered to be statistically significant..

Results: The total The total tumour burden within vertebrae of rats pre-treated with BP and/or PDT was significantly lower compared to the control rats (p< .001). In addition, the PDT alone treated group demonstrated significantly less tumour burden than the combined BP+PDT group. In the control and BP-only groups, large tumours were found to include regions of necrosis. The PDT treatment groups (PDT and BP+PDT) exhibited areas of necrosis throughout the entire vertebral bodies with adjacent formation of granulation tissue.

Conclusion: BP, PDT and combined BP+PDT treatments resulted in a lower overall tumour burden at day 21 post MT-1 cell injection compared to control rats. A surprising increased level of tumour burden was found in comparing the combined treatment group to the PDT-only group. These findings are in contrast to previous in-vitro results, where the pre-treatment with BPs made the cells more susceptible to PDT. Pre-treatment with BP affects both the bone and tumour cells, and as such may induce different cellular pathways in response to PDT treatment. However, the ability of PDT applied at day 14 to cause a similar reduction in tumour burden compared to BP treatment at day 7, suggests its ability to rapidly and effectively ablate the tumour within the bone, even in the presence of BP.

Purpose: To identify local and systemic risk factors for the development of pathologic fractures and determine the value of the Tokuhashi Score in patients with known asymptomatic lytic spinal metastases secondary to breast cancer.

Method: A prospective cohort study was carried out on 51 patients with lytic spinal metastases secondary to breast cancer identified as having either purely lytic or mixed disease. The Tokuhashi Score, developed to estimate life expectancy for patients with symptomatic spinal metastases being considered for surgery, was calculated for each of the 51 patients. The score consists of six parameters each of which is rated from 0–2. Initial and follow up CT images and pain and function data were obtained every four months for one year. A final review of patient charts was performed two years later to determine if each patient was still alive.

Results: Tumour burden was predominantly blastic and mixed rather than lytic. There was no progression of lytic tumour burden over the 12-month period, however there was progression of blastic tumour load. Eleven compression fractures occurred in seven patients; no burst fractures occurred during the study. No correlation between tumour burden (lytic, blastic or both) and risk of fracture was found. A weak correlation between bone mineral density and length of time elapsed from diagnosis of metastatic disease and fracture risk was found. Pain and functional data results were not related to tumour load. Tokuhashi score did correlate with survival, however actual survival in our population was far longer than that found in previous studies. Negative progesterone status was found to be negatively associated with life expectancy.

Conclusion: Metastatic vertebral disease in breast cancer patients has a predominantly blastic and mixed appearance with current pharmacologic therapies. Pathologic fracture risk appears to be more related to bone mineral density than tumour burden in this population. Tokuhashi score does correlate with life expectancy in patients with relatively asymptomatic spinal metastases. Having a progesterone receptor negative tumour has a significantly negative impact on life expectancy.

Purpose: There is interest in biologic strategies that can potentially treat degenerative disc disease (DDD). A new deacetylated derivative of a marine diatomic glycosaminoglycan (DEAC) was developed and incorporated into two sulphated hydrogel formulations; Gel 1 and 2. These materials were proposed to have a reparative effect on damaged tissue. Biochemical studies were conducted using primary human disc cell (HDC) cultures.

Method: HDCs were isolated from surgical specimens by sequential enzymatic digestion (pronase and collagenase). Time-course in-vitro studies were conducted on cell cultures treated with DEAC, Gel 1 or Gel 2 (28 day period). Proteoglycan content (alcian blue), cellular viability/proliferation (MTT assay), and type collagen II, aggrecan expression (RT-PCR, immunohistochemistry) was assessed.

Results: When compared to controls, the DEAC, Gel 1 and 2 treated HDC groups showed significant increases in proteoglycan content as early as day 12. The greatest effect was observed with Gel 1 (78.4±1.9 fold greater optical density compared to control, p < 0.05). The amount of proteoglycan quantified on DEAC treated HDCs on day 28 was 27.7±0.09 times higher than control (p< 0.05). MTT results demonstrated that Gel 1 group showed the highest viability over the study period (mean optical density 0.13+.01 versus 0.039+0.01 in controls). There were no significant differences in cell proliferation of Gel 2, DEAC and untreated control groups. RT-PCR and immunohistochemistry demonstrated expression of type II collagen and aggrecan consistent with the disc phenotype.

Conclusion: The results of this study demonstrates that formulations derived from poly-N-acetyl glucosamine (pGLcNAc) have positive effects of disc cell metabolism as quantified by proteoglycan content, cellular viability and proliferation, and the expression of key extra-cellular matrix molecules. The sulphated formulation of deacetylated pGLcNAc (Gel 1) appeared to have the greatest in-vitro effect followed by DEAC and the short fiber construct of Gel 2. It is possible that the pGlcNAc fibers in Gel 2 were not as soluble to the extent of DEAC due to their inability to form strong hydrogen bonds. This study shows promise towards ongoing evaluation of novel biomaterials for the potential DDD treatment through tissue regenerative or reparative schemes.

As the population ages, the prevalence of degenerative spinal conditions is estimated to increase. With soaring healthcare costs, we must be vigilant in our accountability for proper resource allocation to ensure universal access. Significant recent increases in lumbar fusion rates have been observed in the US. Less is known regarding the Canadian experience. Our objective was to evaluate recent trends in lumbar fusion and determine how surgeon factors influence reoperation for spinal stenosis (SS) surgery.

Longitudinal follow-up study of lumbar surgical procedures for SS using administrative databases. Data was gathered on patient-hospital encounters from April 1, 1995 to December 31, 2001. We analyzed trends in spinal fusion. Index procedures (decompressions or fusions) and surgeon variables, such as specialty (orthopaedics, neurosurgery) and volume (above or below thirty cases/year), were selected as predictors of patient reoperation for SS. Adjustments were made for age, gender, and comorbidity. Reoperation rates were evaluated at six weeks, one and two years and until maximal follow-up.

6128 patients were identified (4200 decompressions and 1928 fusions). Proportionally more fusions were performed over the study period when compared to decompressions (1:2.6 in 1995 versus 1:1.5 in 2001). Orthopaedic specialty and higher surgical volume were associated with increased proportion of fusions (p< 0.0001). Reoperation rate was higher for decompressions at two years (OR 1.4) but not at long-term follow-up to ten years. Surgeon specialty had no impact on reoperation rates. Lower surgical volume demonstrated a higher reoperation rate after adjusting for specialty (Hazard Ratio 1.28).

Rates of lumbar spinal fusion have been increasing in Ontario, but at a lesser rate compared with the US. There is wide variation in surgical procedures between surgeon specialty and volume. Surgeon specialty had little impact on reoperation rates. Better long-term survival was observed in spinal surgeons with volumes over thirty cases per year after adjusting for surgeon specialty. Due to increasing rates of spinal fusion, the benefit of improved long-term survival in SS surgery with higher volume surgeons requires more detailed analysis before policy recommendations can be made.

Bone is the preferred site of metastases in women with breast cancer, which can cause skeletal-related events (SRE¡¦s) such as pathologic fractures. Bisphosphonates are the current standard of care for treatment of meta-static bone disease by preventing further bone destruction. Photodynamic therapy (PDT) has been applied successfully as a non-radiative treatment for malignancies. In PDT, light is delivered to a tumour after the administration of a photosensitiser. Earlier pre-clinical studies in a metastatic rat model have shown that PDT reduced the tumour burden in the vertebrae. The goal of this investigation was to study the effect of PDT on bisphosphonate pre-treated cancer in-vitro.

Human breast cancer cells, MT-1, were cultured until confluent. The following groups were formed: no treatment; incubation with zoledronic acid (24h; 10 ƒÝmol) only; PDT treatment only and incubation with zoledronic acid and PDT treatment. Prior to light application 1 microg/ml of the photosensitiser BPD-MA was added. PDT was performed with a light dose of 1J and 10 J. The cells were stained with a live/dead stain and analyzed by fluorescence microscope and flowcytometry.

Incubation of the MT-1 carcinoma cells with bisphosphonate zoledronic acid resulted in a significantly higher number of dying cells following PDT treatment when compared cells that were not treated by zoledronic acid (p< 0.05). When comparing cell groups that did not undergo PDT treatment the incubation with zoledronic acid alone did not have a statistically significant effect on cell survival twenty-four hours following zoledronic acid administration.

In-vitro, breast cancer cells appear more susceptible to PDT after they have been incubated with the zoledronic acid. Zoledronic acid, a potent bisphosphonate, inhibits farsenylpyrophosphate (FPP) which is involved in farsenylation of cell membrane proteins. The inhibition of FPP may cause a reduced effect of PDT on cell rescue. The treatment with bisphosphonates seems to have a synergistic effect with PDT treatment. As such, light dosimetry in PDT treatment may need to take into account potential therapeutic interactions between PDT and current medical therapies in the treatment of skeletal metastatic burden.

Versican is a large extracellular proteoglycan that is expressed in a variety of tissues and primary malignancies including infiltrating breast carcinoma. It also appears that versican can inhibit intercellular adhesion of normal as well as malignant cells. With the observation of selectin-like properties of versican G3 the investigators hypothesise that versican G3 influences not only local tumour invasiveness but also systemic metastases including the spread to bony sites. The present study aimed to test the hypothesis of versican G3 associated metastatic invasiveness in a murine osteolytic metastatic model of human breast carcinoma.

Human carcinoma cells (MT-1), transfected with the either a versican-G3-construct (n=7) or a vector-control (n=8) gene, were injected intracardically female athymic rats. The rats were examined clinically at serial time-points following injection and animal weight recorded. Animals were euthanised three weeks after tumour cell injection. On digital lateral radiographs of the scapula osteolytic areas were measured. Additionally, histomorphometry was performed on sections stained with human EGFr antibody to evaluate tumour burden within rodent vertebrae. Statistical analyses were performed using one way ANOVA.

All rats demonstrated weight loss approximately three weeks following tumour cell injection. However, the extent of weight loss observed over time was greater for the versicanG3 group (p< 0.05). Osteolytic metastases were observed using fine detail radiography at the day of euthanasia. Osteolytic burden was greater (p < 0.002) in the G3 transfected group (34.7 %; lytic area scapula) when compared to vector-control animals (8 %).

Versican G3 domain appears to influence the development of metastases to bone and soft tissue. The propensity of versican G3 to influence tumour invasion to bone and the mechanisms of versican G3 mediated osteolysis warrants ongoing study. With the known interactions between versican G3 and beta1 integrin in other cancer cell types and the increasing knowledge regarding several beta3 integrin-expressing cell populations, including osteoclasts in breast cancer tumour progression, the potential interaction between versican G3 and integrin receptors in bone may influence tumour mediating chemotactic and haptotactic migration towards bone factors.