Ginger E. Holt

Fractures Following Radiotherapy and Limb-salvage Surgery for Lower Extremity Soft-tissue Sarcomas: A Comparison of High-dose and Low-dose Radiotherapy

BACKGROUND The purpose of the present retrospective study was to determine the correlation between radiation therapy and the risk of postradiation fracture following combined therapy for the treatment of soft-tissue sarcomas of the lower extremity. METHODS Three hundred and sixty-four patients with lower extremity sarcomas that had been treated with combined external beam radiation therapy and limb-salvage surgery were evaluated on the basis of a combined chart and data-base review. For the purposes of analysis, high-dose radiation was defined as 60 or 66 Gy and low-dose radiation was defined as 50 Gy. The timing of irradiation was defined as preoperative, postoperative, or preoperative followed by a postoperative boost. Univariate and multivariate analyses were used to determine which factors were associated with fracture risk. RESULTS Twenty-seven fractures occurred in twenty-three patients. Twenty-four fractures occurred in twenty patients who had been managed with high-dose radiation. Seventeen of these patients had received postoperative radiation (with fifteen patients receiving 66 Gy and two receiving 60 Gy), and three had received preoperative radiation with a postoperative boost (total dose, 66 Gy). Three fractures occurred in three patients who had received preoperative, low-dose radiation (50 Gy). Of the twenty-three patients who sustained a pathologic fracture, eighteen were female and five were male. The crude median time to fracture was forty-three months. Most fractures occurred in the femoral shaft (thirteen) or the femoral neck (eight). High-dose radiation was associated with a greater risk of fracture when compared with low-dose radiation (p = 0.007). CONCLUSIONS Women more than fifty-five years of age who are managed with removal of a thigh sarcoma combined with radiation therapy have a higher risk of pathologic fracture. The frequency of pathologic fractures associated with higher doses (60 or 66 Gy) of radiation is significantly higher than that associated with lower doses (50 Gy).

Delayed proximal repair and distal realignment after patellar dislocation.

Twenty athletes with distal malalignment who sustained unilateral traumatic patellar dislocation remained impaired by chronic instability. Surgery was performed at a mean age of 18 years. Posttraumatic attenuation of the medial patellofemoral ligament was repaired near the margin of the patella in 10 knees and avulsion or attenuation posterior to the vastus medialis obliquus in 10 knees. Advancement of the medial patellomeniscal ligament at the margin of the patella and normalization of the Q angle to 10° by tibial tubercle osteotomy were performed in each knee. Distal lateral retinacular release without release of the normal vastus lateralis tendon was performed. Results were judged according to Turba et al, and activity levels were evaluated per guidelines of the International Knee Documentation Committee. Eighteen (90%) patients achieved good or excellent results and were unimpaired at a minimum of 24 months. Two patients achieved fair subjective results with some impairment in vigorous activity. There was no recurrent instability. Radiographically, the mean preoperative patellofemoral congruence angle improved from 20° to 0°. Athletes who sustain an initial traumatic patellar dislocation after physeal closure and in whom conservative management fails can be treated successfully by repair of the medial patellofemoral ligament at the site of disruption and advancement of the medial patellomeniscal ligament combined with correction of an elevated Q angle.

Use of custom triflanged acetabular components in revision total hip arthroplasty

Difficulty persists in consistently treating massive acetabular defects in revision total hip arthroplasty. A relatively new treatment option for these complex cases is a custom triflanged acetabular component created from anatomic data derived from a computed tomography scan of the pelvis. The custom triflanged acetabular component achieves fixation on the remaining ilium, ischium, and pubis with multiple fixation screws while the acetabular defect is filled with cancellous allograft bone. A retrospective review was done of 26 hips (26 patients) with massive periacetabular bone loss (Paprosky Type 3B) reconstructed with a custom triflanged acetabular component. Twenty-three of 26 patients (88.5%) were considered clinically successful at short-term followup (average, 54 months; range, 24 to 85 months), with stable fixation and reconstruction of periacetabular bone. Three failures occurred from loss of ischial fixation in two patients with a preoperative pelvic discontinuity and one patient with severe osteopenia. These devices should be used with caution in patients with a preoperative pelvic discontinuity unless additional column plating is done.

Benign Synovial Disorders

Abstract Collectively, benign synovial disorders are not uncommon, and they may be seen in general orthopaedic practices. Symptoms are nonspecific, often delaying diagnosis. In fact, synovial chondromatosis, pigmented villonodular synovitis, synovial hemangioma, and lipoma arborescens often mimic each other as well as other, more common joint disorders in presentation, making diagnosis extremely difficult. It is important to diagnose these disorders correctly in order to provide appropriate treatment and avoid secondary sequelae, such as bone erosion and cartilage degeneration.

Osteoclast-derived matrix metalloproteinase-7, but not matrix metalloproteinase-9, contributes to tumor-induced osteolysis.

The matrix metalloproteinases MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 are highly expressed in the tumor-bone microenvironment, and, of these, MMP-7 and MMP-9 were found to be localized to bone-resorbing osteoclasts in human breast-to-bone metastases. In a bid to define the roles of host-derived MMP-7 and MMP-9 in the tumor-bone microenvironment, the tibias of MMP-7 and MMP-9 null mice were injected with osteolytic luciferase-tagged mammary tumor cell lines. Our data show that osteoclast-derived MMP-7 significantly contributes to tumor growth and tumor-induced osteolysis whereas osteoclast-derived MMP-9 had no effect on these processes. MMP-7 is capable of processing a number of nonmatrix molecules to soluble active forms that have profound effects on cell-cell communication, such as RANKL, a crucial mediator of osteoclast precursor recruitment and maturation. Therefore, the ability of osteoclast-derived MMP-7 to promote RANKL solubilization in the tumor-bone microenvironment was explored. Results revealed that levels of soluble RANKL were significantly lower in the MMP-7 null mice compared with wild-type (WT) controls. In keeping with this observation, MMP-7 null mice had significantly fewer osteoclast numbers at the tumor-bone interface compared with the WT controls. In summary, we propose that the solubilization of RANKL by MMP-7 is a potential mechanism through which MMP-7 mediates mammary tumor-induced osteolysis. Our studies indicate that the selective inhibition of MMP-7 in the tumor-bone microenvironment may be of benefit for the treatment of lytic breast-to-bone metastases.

Synthesis, characterization, and remodeling of weight-bearing allograft bone/polyurethane composites in the rabbit

The process of bone healing requires the restoration of both anatomy and physiology, and there is a recognized need for innovative biomaterials that facilitate remodeling throughout this complex process. While porous scaffolds with a high degree of interconnectivity are known to accelerate cellular infiltration and new bone formation, the presence of pores significantly diminishes the initial mechanical properties of the materials, rendering them largely unsuitable for load-bearing applications. In this study, a family of non-porous composites has been fabricated by reactive compression molding of mineralized allograft bone particles (MBPs) with a biodegradable polyurethane (PUR) binder, which is synthesized from a polyester polyol and a lysine-derived polyisocyanate. At volume fractions exceeding the random close-packing limit, the particulated allograft component presented a nearly continuous osteoconductive pathway for cells into the interior of the implant. By varying the molecular weight of the polyol and manipulating the surface chemistry of the MBP via surface demineralization, compressive modulus and strength values of 3-6 GPa and 107-172 MPa were achieved, respectively. When implanted in bilateral femoral condyle plug defects in New Zealand White rabbits, MBP/PUR composites exhibited resorption of the allograft and polymer components, extensive cellular infiltration deep into the interior of the implant, and new bone formation at 6 weeks. While later in vivo timepoints are necessary to determine the ultimate fate of the MBP/PUR composites, these observations suggest that allograft bone/polymer composites have potential for future development as weight-bearing devices for orthopedic applications.

The clinical and functional outcome for patients with radiation-induced soft tissue sarcoma

Radiation‐induced soft tissue sarcomas (RI‐STS) are rare, and it is believed that they are associated with a poor prognosis.The authors of this report compared the clinical and functional outcomes of adults who had extremity RI‐STS with the outcomes of adults with sporadic STS.

Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma

Radiation-induced sarcoma of bone (RISB) is thought to be associated with a poor prognosis. The purpose of this study was to determine disease-free and overall survival of patients treated for RISB, and whether there is a role for limb sparing surgery. Twenty-four patients had a mean latency of 16 years between radiation for their index cancer and RISB diagnosis. The most common tumor was osteosarcoma (n = 17). Ten patients with localized disease treated aggressively with chemotherapy and surgical resection had estimated 5-year disease-free and overall survival rates of 58% and 69% respectively. Patients treated by surgery alone or those with metastases at diagnosis had inferior outcomes. Patients who received a complete course of chemotherapy demonstrated better histologic tumor response and improved survival. There was no difference in survival between the limb sparing surgery (n = 12) or amputation (n = 8) groups. However, limb salvage patients had slightly higher rates of local tumor relapse and post-operative complications. Functional outcome following limb sparing surgery for 10 patients with RISB was similar to a matched cohort treated for primary osteosarcoma. An aggressive treatment approach for patients with RISB may provide similar rates of local recurrence and metastasis and functional outcomes compared to patients with primary osteosarcoma.Level of Evidence: Therapeutic study, level IV-1. See Guidelines for Authors for a complete description of levels of evidence.

Human Mesenchymal Stromal Cells: Identifying Assays to Predict Potency for Therapeutic Selection

Multipotent mesenchymal stromal cells (MSCs) have the potential to repair and regenerate damaged tissues, making them attractive candidates for cell‐based therapies. To maximize efficacy of MSCs, prediction of their therapeutic abilities must be made so that only the best cells will be used. Our goal was to identify feasible and reproducible in vitro assays to predict MSC potency. We generated cell lines from 10 normal human bone marrow samples and used the International Society for Cellular Therapys minimal criteria to define them as MSCs: plastic adherence, appropriate surface marker expression, and trilineage differentiation. Each MSC line was further characterized by its growth, proliferation, and viability as determined by cell count, bromodeoxyuridine incorporation, and cellular ATP levels, respectively. To determine whether these tests reliably predict the therapeutic aptitude of the MSCs, several lines were implanted in vivo to examine their capacity to engraft and form granulation tissue in a well‐established murine wound model using polyvinyl alcohol sponges. Long‐term engraftment of MSCs in the sponges was quantified through the presence of the human‐specific Alu gene in sponge sections. Sections were also stained for proliferating cells, vascularity, and granulation tissue formation to determine successful engraftment and repair. We found that high performance in a combination of the in vitro tests accurately predicted which lines functioned well in vivo. These findings suggest that reliable and reproducible in vitro assays may be used to measure the functional potential of MSCs for therapeutic use.

Prophylactic antibiotic regimens in tumour surgery (PARITY): protocol for a multicentre randomised controlled study

Introduction Limb salvage with endoprosthetic reconstruction is the standard of care for the management of lower-extremity bone tumours in skeletally mature patients. The risk of deep postoperative infection in these procedures is high and the outcomes can be devastating. The most effective prophylactic antibiotic regimen remains unknown, and current clinical practice is highly varied. This trial will evaluate the effect of varying postoperative prophylactic antibiotic regimens on the incidence of deep infection following surgical excision and endoprosthetic reconstruction of lower-extremity bone tumours. Methods and analysis This is a multicentre, blinded, randomised controlled trial, using a parallel two-arm design. 920 patients 15 years of age or older from 12 tertiary care centres across Canada and the USA who are undergoing surgical excision and endoprosthetic reconstruction of a primary bone tumour will receive either short (24 h) or long (5 days) duration postoperative antibiotics. Exclusion criteria include prior surgery or infection within the planned operative field, known colonisation with methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus at enrolment, or allergy to the study antibiotics. The primary outcome will be rates of deep postoperative infections in each arm. Secondary outcomes will include type and frequency of antibiotic-related adverse events, patient functional outcomes and quality-of-life scores, reoperation and mortality. Randomisation will be blocked, with block sizes known only to the methods centre responsible for randomisation, and stratified by location of tumour and study centre. Patients, care givers and a Central Adjudication Committee will be blinded to treatment allocation. The analysis to compare groups will be performed using Cox regression and log-rank tests to compare survival functions at α=0.05. Ethics and dissemination This study has ethics approval from the McMaster University/Hamilton Health Sciences Research Ethics Board (REB# 12-009). Successful completion will significantly impact on clinical practice and enhance patients’ lives. More broadly, this trial will develop a network of collaboration from which further high-quality trials in Orthopaedic Oncology will follow.