Introduction

Modular neck (MN) components in total hip arthroplasty (THA) offer intraoperative flexibility, but adverse local tissue reactions (ALTR) due to tribocorrosion at modular junctions are a potential complication of such designs. Serum ion levels and metal artifact reduction sequence (MARS) MRI are used to assess ALTR following modular THA. This study investigates serum ion levels and MARS MRI findings in a series of hips with MN components and differing articulating surfaces.

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

Maintenance of vertebral mechanical stability is of paramount importance to prevent pathologic fractures and resultant neurologic compromise in individuals with spinal metastases. Current non-surgical treatments for vertebral metastases (i.e. chemotherapy, bisphophonates (BP) and radiation) yield variable responses in the tumour and surrounding bone. Photodynamic therapy (PDT) is a novel, minimally-invasive technology that utilizes a drug activated by light at a specific non-thermal wavelength to locally destroy tumour cells. Previously, we observed that PDT can ablate cancer cells within bone and yield short-term (1-week) improvements in vertebral architecture and biomechanical strength, particularly when combined with BP therapy. This study aims to evaluate the effects of PDT in vertebral bone over a longer (6-week) time period, alone and combined with previous BP treatment, to determine if improvements in skeletal architecture and strength are maintained.

Photodynamic therapy is a promising cancer treatment that employs wavelength-specific light in combination with a photosensitizing agent to induce local tumor destruction by photochemical generation of cytotoxic singlet oxygen. Clinical PDT has been evaluated for a variety of primary tumors, however, its use in spinal metastases to our knowledge has not been previously evaluated. A practical consideration is the ability to deliver light to bone. The investigators are evaluating a novel method of applying light to targeted spinal lesions using a minimally invasive technique similar to percutaneous vertebroplasty. This preliminary preclinical study evaluates the feasibility and efficacy of spinal PDT.

To evaluate the feasibility and efficacy of spinal meta-static photodynamic therapy (PDT) using a percutaneous minimally invasive surgical approach similar to that of vertebroplasty in a preclinical model of bone metastases.

A bioluminescent metastatic model was developed (intracardiac injection 2x10⁶ MT-1^Luc human breast cancer cells; rnu/rnu rats). In forty-three tumor bearing rats, a PDT light dose escalation trial (photosensitizer BPD-MA;2mg/Kg IV) was conducted to assess safety and efficacy of tumor ablation in a single treatment via an implanted optical fibre held adjacent to targeted spinal lesions. Pre and forty-eight hours post bioluminescent imaging was performed to gauge PDT related effects followed by post-sacrifice microCT and histology.

Spinal PDT caused a reduction in bioluminescence of targeted lesions (66% to 87% in three hour drug-light group using light fluence rates of 25J and 150J, respectively; p< 0.05). The most selective drug-light interval was twenty-four hours where PDT induced tumor cell apoptosis/necrosis occurred, however, no spinal cord injury was observed. The greatest anti-tumor effect was observed at the three hour drug-light interval but observations of neurologic sequalae (9/22 animals) highlight the importance of ongoing study to closely define the therapeutic window of PDT.

Drug dosimetry and the drug-light interval are critical in establishing an efficacious and safe treatment range for spinal PDT. Bioluminescent reporter imaging provides an in vivo longitudinal assessment of tumor growth kinetics. The feasibility of the minimally invasive approach for spinal PDT in this model has been established.

Funding: this study was support, in part, by a CBCRA (formerly CBCRI) Idea’s grant

Purpose: There is a clinical need for novel effective local therapies to treat spinal metastases at significant risk for fracture. Photodynamic therapy (PDT) is a promising cancer treatment that employs wavelength specific light combined with a photosensitizing agent to induce localized tumour destruction by photochemical generation of singlet oxygen. Using minimally invasive techniques developed for vertebroplasty to deliver light within the vertebral body, PDT is proposed as a potential new treatment for spinal metastases; however, the effects of PDT on bone are largely unknown. This study aims to determine if PDT affects the structural integrity of normal vertebral bone.

Methods: Sixteen Wistar rats were randomly assigned to control, 1-week treatment or 6-week treatment groups. Rats treated with PDT received an intracardiac injection of 2mg/kg BPD-MA activated at 15 minutes post-injection through administration of a non-thermal 690nm diode laser positioned adjacent to the L3 vertebral body via fluoroscopic guidance (150J at 150mW). Rats were sacrificed at 1-week or 6-weeks following a single treatment. |In vitro & #956;CT scans were taken of L2-L4 and 3D stereological quantities measured using a semiautomated volume shrinkage thresholding technique within the trabecular bone centrum. L2, L3 and L4 vertebral bodies were individually tested biomechanically to failure in axial compression. Yield stress and stiffness were calculated from generated load displacement curves.

Results: Bone surface area and bone volume significantly increased with treatment, through trabecular thickening, at both 1-week and 6-weeks vs. control group. The treated group demonstrated an increase in yield stress at 6-weeks vs. control (27%, p=0.023). An increase in stiffness (45%, p=0.010) was found in the 1-week treatment group vs. control, but was not maintained in the 6-week group.

Conclusions: PDT is a promising new treatment for spinal metastases that appears to strengthen vertebral bone. Further research must determine the mechanism of this action and verify if similar effects will occur in metastatically-involved vertebrae. If PDT proves to be effective in both destroying tumour cells and in strengthening remaining bone, it may provide a very attractive minimally invasive treatment option for patients with spinal metastases.

Funding : Other Education Grant

Funding Parties : Canadian Breast Cancer Foundation, Ontario Chapter

Purpose: This study investigates the use of photodynamic therapy (PDT) in regulating bone development with a view to its potential role in treating Juvenile leg length discrepancy (LLD).

Methods: Transgenic mice expressing the luciferase firefly gene upon activation of a promoter sequence specific to the vascular endothelial growth factor (VEGF) gene were subject to benzoporphyrin derivative monoacid (BPD-MA)-mediated PDT in the right, tibial epiphyseal growth plate at the age of 3 weeks. BPD-MA was administered intracardially (2mg/kg) followed 10 mins later by a laser light (690 +/− 5 nm) at a range of doses (5-27J, 50 mW output) delivered either as a single or repeat regimen (x2-3). Contra-lateral legs served as no-light controls. Further controls included animals that received light treatment in the absence of photosensitizer or no treatment. Mice were imaged for VEGF related bioluminescence (photons/sec/steradian) at t= 0, 24, 48, 72 h and 1–4 weeks post PDT. FaxitronÔ x-ray images provided accurate assessment of bone morphometry. Upon sacrifice, the tibia and femur of the treated and untreated limbs were harvested, imaged and measured again and prepared for histology. A number of animals were sacrificed at 24 h post PDT to allow immunohistochemical staining for CD31, VEGF and hypoxia-inducible factor (HIF-1 alpha) within the bone.

Results: PDT-treated (10 J, x2) mice displayed enhanced bioluminescence at the treatment site (and ear nick) for up to 4 weeks post treatment while control mice were bioluminescent at the ear-nick site only. Repeat regimens provided greater shortening of the limb than the corresponding single treatment. PDT-treated limbs were shorter by 3–4 mm on average as compared to the contra lateral and light only controls (10 J, x2). Immunohistochemistry confirmed the enhanced expression VEGF and CD31 at 4 weeks post-treatment although no increase in HIF-1& #945; was evident at either 24 h or 4 weeks post PDT treatment.

Conclusions: Results confirm the utility of PDT to provide localized effects on bone development that may be applicable to other related skeletal deformities.