What Factors Are Associated With Stem Breakage in Distal Femoral Endoprosthetic Replacements Undertaken for Primary Bone Tumors?

BACKGROUND: The advantages of distal femoral replacement prostheses for reconstructions after tumors are well known; one such implant, the Global Modular Replacement System (GMRS), has been widely used since 2003. Although implant breakage has been reported, the frequency of this event has varied across different studies. QUESTIONS/PURPOSES: (1) What percentage of patients who underwent distal femur resection and replacement using the GMRS for primary bone tumors at one center experienced stem breakage? (2) At what timepoints did these breakages occur, and what factors were common among the stems that broke? METHODS: We performed a retrospective study of all patients who underwent distal femur resection and replacement using the GMRS for a diagnosis of primary bone sarcoma by the Queensland Bone and Soft-tissue Tumor service from 2003 to 2020 who had a minimum of 2 years of follow-up. Standard follow-up for primary bone sarcoma involves radiographic imaging of the femur at 6 weeks and 3 months postoperatively and yearly thereafter. From a chart review, we identified patients with femoral stem breakage. Patient and implant details were recorded and analyzed. A total of 116 patients had undergone a distal femoral replacement with the GMRS prosthesis for primary bone sarcoma; however, 6.9% (eight of 116 patients) died before completing the 2-year follow-up period and were excluded. Of the remaining 108 patients, 15% (16 patients) had died at the time of this review; however, given that they completed the 2-year follow-up period and did not experience stem breakage, they were included. Furthermore, 15% (16 patients) were considered lost to follow-up and excluded because they have not been seen in the past 5 years but were not known to have died or experienced stem breakage. This left 92 patients for analysis. RESULTS: Stem breakages were identified in 5.4% (five of 92) of patients. All stem breakages occurred in stem diameters 11 mm or less with a porous body construct; the percentage of patients with breakage in this group was 16% (five of 31). All patients with stem fracture demonstrated minimal ongrowth to the porous coated body. The median time to stem fracture was 10 years (range 2 to 12 years); however, two of the five stems broke within 3 years. CONCLUSION: We recommend the use of a larger-diameter GMRS cemented stem (> 11 mm), and either the line-to-line cementing method or an uncemented stem from an alternative company should be considered in order to achieve this larger stem in smaller canals. If a stem less than 12 mm in diameter must be used or there is evidence of minimal ongrowth, then close follow-up and prompt investigation of new symptoms should occur. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Constrained or unconstrained shoulder replacement for musculoskeletal tumor resections?

BACKGROUND: Many options exist for reconstructing the shoulder after large bony resections of the proximal humerus. One of the more widely used is endoprosthetic replacement. Proximal migration of unconstrained hemiarthroplasty articulations may cause difficulties particularly in the setting of loss of the rotator cuff and/or deltoid musculature. To attempt to overcome these issues, a fixed-fulcrum constrained reverse shoulder replacement option may be considered. METHODS: A retrospective review of prospectively collected data from the Queensland Bone and Soft Tissue Sarcoma Service was undertaken to compare the function, implant survivorship, and reoperation rate of constrained reverse and unconstrained hemiarthroplasty-type endoprostheses in patients with tumors. RESULTS: We retrospectively reviewed data on 41 consecutive proximal or total humeral endoprosthetic replacements undertaken between January 2003 and July 2018. One patient was excluded as lost to follow-up prior to 24 months. There were 21 unconstrained implants and 19 constrained shoulder replacements (Stanmore Modular Endoprosthesis Tumour System with Bayley-Walker articulation). Proximal migration of the unconstrained hemiarthroplasty articulation occurred in 8 patients (38%), and dislocation or failure of the constrained mechanism occurred in 5 (26%). Reoperation for implant-related issues was required in 5 patients in the constrained group and none in the unconstrained group. Of the 18 patients alive at the time of review, 12 provided functional scores. The mean follow-up period for surviving patients was 4.2 years (standard deviation, 2.7 years), with a minimum of 2 years' follow-up. Functional scores were similar between the 2 groups. CONCLUSION: Constrained reverse prostheses were associated with a higher reoperation rate in this series without any functional benefit compared with unconstrained hemiarthroplasty-type articulations. We favor the use of unconstrained hemiarthroplasty-type endoprostheses for reconstruction after resection of destructive lesions of the proximal humerus.

Is an Acetabular Cage and Cement Fixation Sufficiently Durable for the Treatment of Destructive Acetabular Metastases?

BACKGROUND: Destructive bony acetabular metastases cause pain, pathological fractures, and loss of mobility. Although multiple fixation options are available, we have favored a rigid stainless steel partial pelvic cage for acetabular fixation in these patients; however, little is known about the durability of this approach. QUESTION/PURPOSES: (1) How common was loss of fixation in a small series of metastatic acetabular defects treated with an acetabular cage and cemented total hip replacement? (2) What is the implant survival free from reoperation or revision at 2 and 4 years using a competing-risks survivorship estimator in patients thus treated? (3) What complications were associated with the treatment? (4) What level of postoperative mobility was achieved? METHODS: Between 2006 and 2017, we treated all acetabular metastases that needed surgical intervention, not amenable to conventional cemented THA alone with our single technique of acetabular partial pelvic cage and cemented total hip replacement. We treated 47 hips in 46 patients whose acetabular metastasis led to acetabular collapse or who were unresponsive to nonoperative measures of radiation therapy and analgesia. Routine followup occurred at 3 and 12 months; 17 of 46 patients (37%) died before 1 year, and all other patients were followed beyond 1 year. Only one patient who remains alive has not been seen in the past 5 years. Loss of fixation was determined by radiological or clinical signs of cage loosening. Survivorship free from reoperation or revision at 2 and 4 years was determined using competing-risks analysis. We did not assess patient-reported outcomes, but we did have data on the proportion of patients who were able to ambulate in the community and if so, what assistive devices they used, which we obtained by chart review. RESULTS: One patient experienced cage loosening identified 8 years postoperatively as a result of local disease progression and has been managed with observation. No patients underwent revision for loss of acetabular fixation. The cumulative incidence of reoperation or revision was 8% at 2 years (95% CI, 3.6-12.6) and 16% at 4 years (95% CI, 9.2-23.2). Four patients had postoperative dislocations, of which three underwent reoperation. One patient developed a postoperative deep infection and underwent reoperation. One patient died within 30 days of surgery. Only one patient did not ambulate in the community postoperatively; 23 ambulated independently, 10 with the use of a walking stick and 12 using a walker. CONCLUSIONS: In this small series, we found this approach sufficiently durable to continue its use for patients with acetabular metastases with collapse or those not responding to nonoperative measures. However, comparison studies are needed to determine whether it is superior or inferior to other available alternatives. LEVEL OF EVIDENCE: Level IV, therapeutic study.

High accuracy of positioning custom triflange acetabular components in tumour and total hip arthroplasty revision surgery.

Aims: Custom triflange acetabular components (CTACs) play an important role in reconstructive orthopaedic surgery, particularly in revision total hip arthroplasty (rTHA) and pelvic tumour resection procedures. Accurate CTAC positioning is essential to successful surgical outcomes. While prior studies have explored CTAC positioning in rTHA, research focusing on tumour cases and implant flange positioning precision remains limited. Additionally, the impact of intraoperative navigation on positioning accuracy warrants further investigation. This study assesses CTAC positioning accuracy in tumour resection and rTHA cases, focusing on the differences between preoperative planning and postoperative implant positions. Methods: A multicentre observational cohort study in Australia between February 2017 and March 2021 included consecutive patients undergoing acetabular reconstruction with CTACs in rTHA (Paprosky 3A/3B defects) or tumour resection (including Enneking P2 peri-acetabular area). Of 103 eligible patients (104 hips), 34 patients (35 hips) were analyzed. Results: CTAC positioning was generally accurate, with minor deviations in cup inclination (mean 2.7°; SD 2.84°), anteversion (mean 3.6°; SD 5.04°), and rotation (mean 2.1°; SD 2.47°). Deviation of the hip centre of rotation (COR) showed a mean vector length of 5.9 mm (SD 7.24). Flange positions showed small deviations, with the ischial flange exhibiting the largest deviation (mean vector length of 7.0 mm; SD 8.65). Overall, 83% of the implants were accurately positioned, with 17% exceeding malpositioning thresholds. CTACs used in tumour resections exhibited higher positioning accuracy than rTHA cases, with significant differences in inclination (1.5° for tumour vs 3.4° for rTHA) and rotation (1.3° for tumour vs 2.4° for rTHA). The use of intraoperative navigation appeared to enhance positioning accuracy, but this did not reach statistical significance. Conclusion: This study demonstrates favourable CTAC positioning accuracy, with potential for improved accuracy through intraoperative navigation. Further research is needed to understand the implications of positioning accuracy on implant performance and long-term survival.

Treatment of long bone defects and non-unions: from research to clinical practice.

The treatment of long bone defects and non-unions is still a major clinical and socio-economical problem. In addition to the non-operative therapeutic options, such as the application of various forms of electricity, extracorporeal shock wave therapy and ultrasound therapy, which are still in clinical use, several operative treatment methods are available. No consensus guidelines are available and the treatments of such defects differ greatly. Therefore, clinicians and researchers are presently investigating ways to treat large bone defects based on tissue engineering approaches. Tissue engineering strategies for bone regeneration seem to be a promising option in regenerative medicine. Several in vitro and in vivo studies in small and large animal models have been conducted to establish the efficiency of various tissue engineering approaches. Neverthelsss, the literature still lacks controlled studies that compare the different clinical treatment strategies currently in use. However, based on the results obtained so far in diverse animal studies, bone tissue engineering approaches need further validation in more clinically relevant animal models and in clinical pilot studies for the translation of bone tissue engineering approaches into clinical practice.

Auranofin improves overall survival when combined with standard of care in a pilot study involving dogs with osteosarcoma.

Osteosarcoma is the most common paediatric primary bone malignancy. The major cause of death in osteosarcoma is drug-resistant pulmonary metastasis. Previous studies have shown that thioredoxin reductase 2 is a driver of metastasis in osteosarcoma and can be inhibited by auranofin (AF). Moreover, studies have shown that AF significantly reduces pulmonary metastases in xenotransplant models. Here, we describe a phase I/II study of AF in canine osteosarcoma, a well-recognized spontaneous model of human osteosarcoma. We performed a single-arm multicentre pilot study of AF in combination with standard of care (SOC) (amputation + carboplatin). We recruited 40 dogs to the trial and used a historical SOC-only control group (n = 26). Dogs >15 kg received 9 mg AF q3d PO and dogs <15 kg received 6 mg q3d. Follow-up occurred over at least a 3-year period. Auranofin plus SOC improved overall survival (OS) (P = .036) in all dogs treated. The improved outcome was attributable entirely to improved OS in male dogs (P = .009). At the time of writing, 10 dogs (25%) survive without measurable disease in the treatment group with survival times ranging between 806 and 1525 days. Our study shows that AF improves OS in male dogs when combined with SOC. Our findings have translational relevance for the management of canine and human osteosarcoma. Our data justify a larger multicentre phase 2 trial in dogs and a phase I/II trial in human patients with refractory disease at the time of initial surgery.

Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype.

Primary intraosseous rhabdomyosarcomas (RMSs) are extremely rare. Recently 2 studies reported 4 cases of primary intraosseous RMS with EWSR1/FUS-TFCP2 gene fusions, associated with somewhat conflicting histologic features, ranging from spindle to epithelioid. In this study we sought to further investigate the pathologic and molecular abnormalities of a larger group of intraosseous RMSs by a combined approach using targeted RNA sequencing analysis and fluorescence in situ hybridization (FISH). We identified 7 cases, 3 males and 4 females, all in young adults, age range 20 to 39 years (median, 27 y). Three cases involved the pelvis, 2 involved the femur and 1 each involved the maxilla and the skull. Molecular studies identified recurrent gene fusions in all 7 cases tested, including: a novel MEIS1-NCOA2 fusion in 2 cases, EWSR1-TFCP2 in 3 cases, and FUS-TFCP2 gene fusions in 1 case. One case showed a FUS gene rearrangement, without a TFCP2 gene abnormality by FISH. The MEIS1-NCOA2-positive cases were characterized by a more primitive and fascicular spindle cell appearance, while the EWSR1/FUS rearranged tumors had a hybrid spindle and epithelioid phenotype, with more abundant eosinophilic cytoplasm and mild nuclear pleomorphism. Immunohistochemically, all tumors were positive for desmin and myogenin (focal). In addition, 4 tumors with TFCP2-associated gene fusions also coexpressed ALK and cytokeratin. In conclusion, our results suggest a high incidence of gene fusions in primary RMSs of bone, with 2 molecular subsets emerging, defined by either MEIS1-NCOA2 or EWSR1/FUS-TFCP2 fusions, showing distinct morphology and immunophenotype. Additional studies with larger numbers of cases and longer follow-up data are required to definitively evaluate the biological behavior of these tumors and to establish their relationship to other spindle cell RMS genetic groups.

Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney.

We describe 2 cases of a distinct sarcoma characterized by a novel MEIS1-NCOA2 gene fusion. This gene fusion was identified in the renal neoplasms of 2 adults (21-y-old male, 72-y-old female). Histologically, the resected renal neoplasms had a distinctively nodular appearance, and while one renal neoplasm was predominantly cystic, the other demonstrated solid architecture, invasion of perirenal fat, and renal sinus vasculature invasion. The neoplasms were characterized predominantly by monomorphic plump spindle cells arranged in vague fascicles with a whorling pattern; however, a more primitive small round cell component was also noted. Both neoplasms were mitotically active and one case showed necrosis. The neoplasms did not have a distinctive immunohistochemical profile, though both labeled for TLE1. The morphologic features are distinct from other sarcomas associated with NCOA2 gene fusions, including mesenchymal chondrosarcoma, congenital/infantile spindle cell rhabdomyosarcoma, and soft tissue angiofibroma. While we have minimal clinical follow-up, the aggressive histologic features of these neoplasms indicate malignant potential, thus warranting classification as a novel subtype of sarcoma.

The impact of non weight bearing: A prospective cohort study.

BACKGROUND: Patients with lower limb injuries are commonly advised to non weight bear (NWB) on their injured limb as part of treatment. Occasionally, patients complain that offloading one limb, associated with the use of crutches or other mobility aids, may lead to pain on one of the other supporting limbs. This has led to compensation claims (1) but has never been the subject of formal research. METHODS: A prospective cohort trial was undertaken to address this question. Patients were recruited from two Metropolitan Hospital Orthopaedic Fracture Clinics and Orthopaedic Wards. A survey was administered at two time points; the first at the point of definitive orthopaedic treatment and commencement of the NWB phase. The second after the NWB phase was completed. The surveys included a pain Visual Analogue Scale (VAS), Short Form (SF)12, a pain body chart and a health questionnaire. RESULTS: A total of 55 patients were enrolled in the study. Seven patients developed new joint pain after a period NWB. These patients scored significantly lower on the follow up SF12 when compared to those who did not develop new pain (p=0.045). Follow up phone calls at least 6 months following completion of the second survey revealed that all initial and new pain areas in these participants had resolved. The main limitation of this study was the limited numbers. CONCLUSION: This study supports the idea that crutches, prescribed in the short term to allow a limb to be NWB, achieve this aim with minimal impact. Their use may be associated with new other joint pain however it can be anticipated this will resolve after cessation of crutch use.

Single institution retrospective review of perioperative chemotherapy in adult and adolescent patients with operable osteosarcoma.

AIMS: Perioperative chemotherapy has improved the prognosis for patients with operable osteosarcoma. The literature is conflicting about which regimen is optimal. The aim of this study was to evaluate the survival outcomes of two cohorts of patients with operable osteosarcoma treated with different perioperative chemotherapy regimens. METHODS: This was a retrospective review of patients diagnosed with operable osteosarcoma treated at the Princess Alexandra Hospital from 1986 to 2009. The standard perioperative chemotherapy regimen changed from the modified T10 Rosen protocol to cisplatin/doxorubicin in 1997. Using the Kaplan-Meier method, overall survival (OS) and disease-free survival (DFS) curves were generated for the cisplatin/doxorubicin and the modified T10 Rosen cohorts. RESULTS: Seventy-one patients were identified of whom 63 had potentially curable disease. Of these, 24 received the modified T10 Rosen regimen and 39 received cisplatin/doxorubicin. There was a non-significant trend toward better OS and DFS in the patients who received the modified T10 Rosen protocol. CONCLUSION: The trend toward poorer survival in the cisplatin/doxorubicin cohort, in combination with current evidence, has prompted our institution to change its practice.

Management and outcome after local recurrence of osteosarcoma.

We report on the management and outcome of 96 patients who developed local recurrence (LR) after having definitive primary treatment with chemotherapy and surgery for non-metastatic osteosarcoma. LR developed at a median of 11 months from initial surgical treatment. 18% of patients had metastases prior to the diagnosis of LR and 23% were found to have metastases synchronously. The prognosis for this group with metastases was 14% survival at 2 years. In the 57 patients without metastases at the time of development of LR, survival was 51% at 2 years and 41% at 5 years. Treatment was by excision of the LR and radiotherapy or by amputation. The only significant prognostic factors identified were the presence of metastases at the time of development of LR (P < 0.0001) and small size of the LR. The role of adjuvant chemotherapy was unclear. Whilst every attempt should be made to avoid LR, patients who develop LR are curable, particularly if they do not have metastases at the time of diagnosis of the LR.

Clinical outcomes of deep atypical lipomas (well-differentiated lipoma-like liposarcomas) of the extremities.

AIM: Controversy exists with regard to the nomenclature, treatment and outcome of a group of well-differentiated lipomatous tumours sometimes labelled as atypical lipomas. The purpose of the present paper is to attempt to clarify these controversies by reporting our experience with this lesion. METHODS: The clinical features and follow up of 61 patients with the diagnosis of deep atypical lipoma and a minimum two-year follow up were examined. RESULTS: All patients were treated by marginal excision alone. A local recurrence was seen in five patients (8%). Three recurred once and two recurred twice. No patient had a metastasis or died as a result of the tumour. No lesion dedifferentiated. CONCLUSION: We believe the term atypical lipoma is appropriate for these tumours, as they appear not to have any metastatic potential, merely a propensity to recur locally. The chance of dedifferentiation is small and radiotherapy may play a role in its causation. We suggest that a simple marginal resection (shelling-out) is adequate treatment for these lesions. Radiotherapy should not be used.

Loss of osteoclasts contributes to development of osteosarcoma pulmonary metastases.

We conducted a transcriptomic screen of osteosarcoma (OS) biopsies and found that expression of osteoclast-specific tartrate-resistant acid phosphatase 5 (ACP5/TRAP) is significantly downregulated in OS compared with nonmalignant bone (P < 0.0001). Moreover, lesions from OS patients with pulmonary metastases had 2-fold less ACP5/TRAP expression (P < 0.018) than lesions from patients without metastases. In addition, we found a direct correlation (P = 0.0166) between ACP5/TRAP expression and time to metastasis. Therefore, we examined whether metastasis-competent (MC) OS cells could induce loss of ACP5(+) osteoclasts and contribute to metastasis. We found that MC OS cell lines can inhibit osteoclastogenesis in vitro and in vivo. In addition, osteoclasts can inhibit the migration of MC OS cells in vitro. Finally, ablation of osteoclasts with zoledronic acid increases the number of metastatic lung lesions in an orthotopic OS model, whereas fulvestrant treatment increases osteoclast numbers and reduces metastatic lesions. These data indicate that the metastatic potential of OS is determined early in tumor development and that loss of osteoclasts in the primary lesion enhances OS metastasis.

Establishment of a preclinical ovine model for tibial segmental bone defect repair by applying bone tissue engineering strategies.

Currently, well-established clinical therapeutic approaches for bone reconstruction are restricted to the transplantation of autografts and allografts, and the implantation of metal devices or ceramic-based implants to assist bone regeneration. Bone grafts possess osteoconductive and osteoinductive properties; however, they are limited in access and availability and associated with donor-site morbidity, hemorrhage, risk of infection, insufficient transplant integration, graft devitalization, and subsequent resorption resulting in decreased mechanical stability. As a result, recent research focuses on the development of alternative therapeutic concepts. The field of tissue engineering has emerged as an important approach to bone regeneration. However, bench-to-bedside translations are still infrequent as the process toward approval by regulatory bodies is protracted and costly, requiring both comprehensive in vitro and in vivo studies. The subsequent gap between research and clinical translation, hence, commercialization, is referred to as the "Valley of Death" and describes a large number of projects and/or ventures that are ceased due to a lack of funding during the transition from product/technology development to regulatory approval and subsequently commercialization. One of the greatest difficulties in bridging the Valley of Death is to develop good manufacturing processes and scalable designs and to apply these in preclinical studies. In this article, we describe part of the rationale and road map of how our multidisciplinary research team has approached the first steps to translate orthopedic bone engineering from bench to bedside by establishing a preclinical ovine critical-sized tibial segmental bone defect model, and we discuss our preliminary data relating to this decisive step.

E2F7 can regulate proliferation, differentiation, and apoptotic responses in human keratinocytes: implications for cutaneous squamous cell carcinoma formation.

The E2F family of transcription factors plays a crucial role in the regulation of genes involved in cell proliferation, differentiation, and apoptosis. In keratinocytes, the inhibition of E2F is a key step in the control and initiation of squamous differentiation. Because the product of the recently identified E2F7a/E2F7b gene has been shown to repress E2F-regulated promoters, and to be abundant in skin, we examined its role in the epidermis. Our results indicate that E2F7b mRNA expression is selectively associated with proliferation-competent keratinocytes. Moreover, E2F7 was able to antagonize E2F1-induced proliferation and apoptosis. In contrast, although E2F7 was able to inhibit proliferation and initiate differentiation, it was unable to antagonize the differentiation suppression induced by E2F1. These data indicate that E2F7-mediated suppression of proliferation and apoptosis acts through E2F1-dependent pathways, whereas E2F7-induced differentiation acts through an E2F1-independent pathway. These data also suggest that proliferation, differentiation, and survival of primary human keratinocytes can be controlled by the relative ratio of E2F1 to E2F7. Because deregulated proliferation, differentiation, and apoptosis are hallmarks of cancer, we examined the expression levels of E2F1 and E2F7 in cutaneous squamous cell carcinomas (CSCC). We found that both genes were overexpressed in CSCCs compared with normal epidermis. Furthermore, inhibition of E2F7 in a SCC cell line sensitized the cells to UV-induced apoptosis and doxorubicin-induced apoptosis. Combined, these data suggest that the selected disruption of E2F1 and E2F7 in keratinocytes is likely to contribute to CSCC formation and may prove to be a viable therapeutic target.

Contralateral total hip arthroplasty after hindquarter amputation.

We describe the management and outcome of a 62-year old lady who developed severe osteoarthritis of the hip, nine years after a hindquarter amputation for radiation-induced sarcoma of the contralateral pelvis. The difficulties of stabilising the pelvis intraoperatively and the problems of postoperative rehabilitation are outlined. The operation successfully relieved her pain and restored limited mobility.

Possible metastasis of osteosarcoma to a remote biopsy site: a case report.

In a patient who presented with an osteosarcoma of the proximal humerus, systemic staging revealed a lesion in the contralateral humerus, which was shown to be an enchondroma after open biopsy. The patient had a local recurrence develop, which necessitated forequarter amputation. Shortly thereafter, the patient had pain develop at the contralateral biopsy site, and examinations and repeat biopsy revealed metastatic osteosarcoma. We think it is likely that surgical trauma contributed to the development of this unusual metastasis. In this clinical situation, consideration should be given to doing the biopsy and definitive resection on separate occasions.

The management of extra-abdominal desmoid tumours.

We performed a retrospective analysis of 35 cases of desmoid tumours (aggressive fibromatoses) that underwent treatment at our institutions between 1987 and 2002. The purpose was to evaluate the rate of local recurrence of desmoid tumours treated with surgical excision, to assess the impact of surgical margins on local recurrence and to define the role of radiotherapy in the treatment. Nine patients experienced a recurrence at an average of 16 months after initial treatment. Seven of the 15 patients with a less-than-wide margin had a local recurrence. Comparatively, only two of the 20 patients with a wide margin had a local recurrence. Thirty-three of the 35 patients were disease free at the last follow-up. We recommend wide excision with clear margins whenever possible. Marginal resections are appropriate when wide excision would severely compromise the function of the limb. Surgical resections and selective supplementation of adjuvant radiotherapy give excellent control rates.