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.

Fournier's gangrene associated with intradermal injection of cocaine.

INTRODUCTION: Cocaine abuse is associated with a number of medical complications, most notably arrhythmias, myocardial infarction, and cerebral hemorrhages. The injection of cocaine in the penis has been predominantly recorded into the corpus cavernosae and is associated with priapism. AIM: Here we describe the injection of subcutaneous cocaine within the penile shaft skin producing ischemic necrosis and Fournier's gangrene. MAIN OUTCOME MEASURES: We sought to highlight the effects of cocaine use within the penis and emphasize the different effects that may ensue. METHODS: We reviewed a recent clinical case and conducted a literature review on the use of cocaine within the penis. RESULTS: The use of cocaine has been reported previously within the literature and is mainly limited to case reports. Cocaine use within the corpora and the subcutaneous tissues produces significantly different consequences ranging from priapism to Fournier's gangrene. CONCLUSIONS: The case illustrates the growing use of cocaine and other illicit drugs and emphasizes the importance of this issue to all clinicians.

The story of the condom.

Condoms have been a subject of curiosity throughout history. The idea of safer sex has been explored in ancient and modern history, and has been used to prevent venereal diseases. We conducted a historical and medical review of condoms using primary and secondary sources as well as using the RSM library and the internet. These resources show that the first use of a condom was that of King Minos of Crete. Pasiphae, his wife, employed a goat's bladder in the vagina so that King Minos would not be able to harm her as his semen was said to contain "scorpions and serpents" that killed his mistresses. To Egyptians, condom-like glans caps were dyed in different colours to distinguish between different classes of people and to protect themselves against bilharzia. The Ancient Romans used the bladders of animals to protect the woman; they were worn not to prevent pregnancy but to prevent contraction of venereal diseases. Charles Goodyear, the inventor, utilized vulcanization, the process of transforming rubber into malleable structures, to produce latex condoms. The greater use of condoms all over the world in the 20(th) and 21(st) centuries has been related to HIV. This account of the use of condoms demonstrates how a primitive idea turned into an object that is used globally with a forecast estimated at 18 billion condoms to be used in 2015 alone.

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.

Proteus: Mythology to modern times.

AIMS: It is common knowledge that proteus bacteria are associated with urinary tract infections and urinary stones. Far more interesting however, is the derivation of the word proteus. This study examines the origin of the word proteus, its mythological, historical and literary connections and evolution to present-day usage. MATERIALS AND METHODS: A detailed search for primary and secondary sources was undertaken using the library and internet. RESULTS: Greek mythology describes Proteus as an early sea-god, noted for being versatile and capable of assuming many different forms. In the 8(th) century BC, the ancient Greek poet, Homer, famous for his epic poems the Iliad and Odyssey, describes Proteus as a prophetic old sea-god, and herdsman of the seals of Poseidon, God of the Sea. Shakespeare re-introduced Proteus into English literature, in the 15(th) century AD, in the comedy The Two Gentleman of Verona, as one of his main characters who is inconstant with his affections. The 'elephant man' was afflicted by a severely disfiguring disease, described as 'Proteus syndrome'. It is particularly difficult to distinguish from neurofibromatosis, due to its various forms in different individuals. The Oxford English Dictionary defines the word 'protean' as to mean changeable, variable, and existing in multiple forms. Proteus bacteria directly derive their name from the Sea God, due to their rapid swarming growth and motility on agar plates. They demonstrate versatility by secreting enzymes, which allow them to evade the host's defense systems. CONCLUSIONS: Thus proteus, true to its name, has had a myriad of connotations over the centuries.

Functional outcome of arthrodesis with a vascularized fibular graft and a rotational latissimus dorsi flap after proximal humerus sarcoma resection.

BACKGROUND: The prognosis of humeral sarcomas has improved greatly in the past 20 years. As a result, the challenges for orthopedic oncologists include long-term handicap and local morbidity. METHODS: Shoulder reconstruction after the resection of sarcomas with the proximal humerus was evaluated for 55 patients from 1990 to 2007 at two universities. After S34(5)B resections (intra-articular resection of the proximal humerus and the abductor mechanism), the shoulders were reconstructed with arthrodesis, prosthesis, or allograft-prosthesis composites (APC). RESULTS: At the time of the latest follow-up examination, the average duration of follow-up was 86.73 months for the 39 patients who were still alive and whose limbs were salvaged. The local recurrence rate was 7.27% (4 of 55). Functional evaluation was conducted on the 39 patients who had the postreconstructions: 12 arthrodeses, 17 prostheses, and 10 APC. Statistical analysis showed that the functional score of shoulder reconstruction significantly varied among the three groups by the test of homogeneity of variances with P = 0.222, by analysis of variance with P < 0.01, and by post hoc test (Student-Newman-Keuls) with α = 0.05. Primary arthrodesis resulted in better function and increased strength than the prostheses and the APC. Insertion of an allograft, a vascularized fibular graft, a rotational latissimus dorsi flap, and cancellous autograft bone were the preferred arthrodesis techniques used to achieve fusion and reduce complications. CONCLUSIONS: After resection of the sarcoma with the proximal humerus with the abductor apparatus, shoulder arthrodesis is recommended above other reconstructions for better functional outcome as well as increased strength and capacity to position the hand.

Surgical margin and its influence on survival in soft tissue sarcoma.

BACKGROUND: The goal of surgeons treating soft tissue sarcoma is to gain local control, to avoid risk of local recurrence and to avoid compromise of the patient's potential survival. The aim of the investigation was to assess the significance of the extent of surgical margin on the chance of death, metastasis and local recurrence. METHODS: Two hundred and seventy-nine patients who presented with soft tissue sarcoma without metastatic disease were analysed. RESULTS: The extent of the surgical margin was not clinically or statistically significant in the development of metastatic disease. The presence of a contaminated surgical margin led to a significantly higher rate of local recurrence (as did a narrow surgical margin less than 1 mm). A margin greater than 1 mm allowed a satisfactory outcome in terms of low local recurrence rates. In terms of overall survival, the failure to achieve a wide surgical margin (wide contaminated margin) led to an increased relative death rate. However, when the margin was not contaminated (even if the margin was very close, less than 1 mm), the overall survival rate was similar across all groups. Patients who had radical resections did poorly; they generally belonged to a group in which palliative surgery was carried out, and they showed very high relative metastasis and death rates. CONCLUSION: The present study provides statistically significant evidence that increasing the width of resection improves local control and overall survival.

[Functional outcome following shoulder tumor resection and reconstruction].

OBJECTIVE: To analyze the long-term limb sparing outcomes of various reconstructive procedures and complications associated with extensive excision in bone tumours of the shoulder girdle. METHODS: Shoulder reconstruction following resection of bone tumors of the shoulder girdle was reviewed retrospectively for 32 patients at the Wesley Hospital or Princess Alexandra Hospital. The reconstructions were including arthrodesis (8 cases), allograft-prosthetic composite (7 cases), spacer (6 cases), no bone reconstruction (5 cases), prosthesis (3 cases), vascular fibular graft (2 cases) and allograft (1 case). RESULTS: The average duration of follow-up was 81 months for the 23 patients who were still alive at the time of the latest follow-up examination. Functional results were related to the type of resection and the method of shoulder reconstruction. After intra-articular resection of the proximal humerus with loss of the abductor mechanism, arthrodesis resulted in 87% functional score and more strength was found after reconstruction with prosthesis or allograft-prosthetic composite. Allograft-prosthetic composite had better function (Score 79%) than prosthesis alone after intra-articular resection of the humerus because reconstruction of the deltoid and the rotator cuff could be performed without increased prevalence of complication related to the allograft. After extra-articular resection of the glenoid cavity and the proximal humerus with abductor mechanism, reconstruction with a functional spacer frequently resulted in superior subluxation of the implant and only fair function (Score 66%) of the shoulder. With two teen-aged patients, a free fibular graft inserted after intra-articular resection of the proximal humerus led to fair function (Score 73%), to be followed by secondary arthrodesis when growth was complete. CONCLUSIONS: Indications for the method of reconstruction depend on type of resection, age, gender, occupation, the expected functional level and restriction of activity. After resection of the abductor mechanism, arthrodesis results in more strength and is the preferred option for the young active demanding patients. If the abductor mechanism is preserved, allograft-prosthetic composite gives good results.

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.

Fibroblast growth factor receptor 4 (FGFR4) expression in newborn murine calvaria and primary osteoblast cultures.

Fibroblast growth factor receptor (FGFR) signalling is important in the initiation and regulation of osteogenesis. Although mutations in FGFR1, 2, and 3 genes are known to cause skeletal deformities, the expression of FGFR4 in bony tissue remains unclear. We have investigated the expression pattern of FGFR4 in the neonatal mouse calvaria and compared it to the expression pattern in cultures of primary osteoblasts. Immunohistochemistry demonstrated that FGFR4 was highly expressed in rudimentary membranous bone and strictly localised to the cellular components (osteoblasts) between the periosteal and endosteal layers. Cells in close proximity to the newly formed osteoid (preosteoblasts) also expressed FGFR4 on both the endosteal and periosteal surfaces. Immunocytochemical analysis of primary osteoblast cultures taken from the same cranial region also revealed high levels of FGFR4 expression, suggesting a similar pattern of cellular expression in vivo and in vitro. RT-PCR and Western blotting for FGFR4 confirmed its presence in primary osteoblast cultures. These results suggest that FGFR4 may be an important regulator of osteogenesis with involvement in preosteoblast proliferation and differentiation as well as osteoblast functioning during intramembranous ossification. The consistent expression of FGFR4 in vivo and in vitro supports the use of primary osteoblast cultures for elucidating the role of FGFR4 during osteogenesis.

Synovial sarcoma--towards a simplified approach to prognosis.

BACKGROUND: Synovial sarcoma is a high grade sarcoma that usually occurs in adults. Numerous studies have attempted to identify prognostic factors that might allow more effective treatment for particular subgroups of patients. METHODS: We studied 25 histologically confirmed cases of synovial sarcoma in an attempt to identify particular patient, tumour or treatment characteristics that might have a prognostic significance using Cox proportional hazards regression modelling to identify differences in survival rates. All patients received their definitive surgical treatment from a single orthopaedic surgeon reducing the likelihood of bias related to variations in surgical technique. RESULTS: Statistically significant higher survival rates were seen in female patients (P = 0.040) and in patients aged <50 years (P = 0.028). There was also a tendency towards higher survival rates in those cases with upper limb tumours, tumours less than 50 mm in size, and tumours that histologically showed low grade tumour nuclei. Differences in survival were not seen with the percentage of epithelioid, spindled or poorly differentiated areas present, the number of mitoses, or the presence of necrosis. No treatment characteristics were associated with differences in survival. CONCLUSIONS: The present study has confirmed that male sex and older age are unfavourable prognostic features in synovial sarcoma. Additionally, the histological grade of synovial sarcomas might be more accurately and simply determined based on an assessment of nuclear grade alone.

Bone Regeneration Based on Tissue Engineering Conceptions - A 21st Century Perspective.

The role of Bone Tissue Engineering in the field of Regenerative Medicine has been the topic of substantial research over the past two decades. Technological advances have improved orthopaedic implants and surgical techniques for bone reconstruction. However, improvements in surgical techniques to reconstruct bone have been limited by the paucity of autologous materials available and donor site morbidity. Recent advances in the development of biomaterials have provided attractive alternatives to bone grafting expanding the surgical options for restoring the form and function of injured bone. Specifically, novel bioactive (second generation) biomaterials have been developed that are characterised by controlled action and reaction to the host tissue environment, whilst exhibiting controlled chemical breakdown and resorption with an ultimate replacement by regenerating tissue. Future generations of biomaterials (third generation) are designed to be not only osteoconductive but also osteoinductive, i.e. to stimulate regeneration of host tissues by combining tissue engineering and in situ tissue regeneration methods with a focus on novel applications. These techniques will lead to novel possibilities for tissue regeneration and repair. At present, tissue engineered constructs that may find future use as bone grafts for complex skeletal defects, whether from post-traumatic, degenerative, neoplastic or congenital/developmental "origin" require osseous reconstruction to ensure structural and functional integrity. Engineering functional bone using combinations of cells, scaffolds and bioactive factors is a promising strategy and a particular feature for future development in the area of hybrid materials which are able to exhibit suitable biomimetic and mechanical properties. This review will discuss the state of the art in this field and what we can expect from future generations of bone regeneration concepts.

Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis.

PURPOSE: Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease. EXPERIMENTAL DESIGN: We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status. RESULTS: We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification. CONCLUSIONS: Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists.

Electromyographic assessment of Gait function following limb salvage procedures for bone sarcoma.

Bone sarcomas are the fourth most common cancer in individuals under 25 years of age. Limb salvage procedures have become increasingly popular for the treatment of osteosarcomas as they have functional and physiological benefits over traditional amputative procedures. The purpose of this study was to assess locomotor patterns post lower limb salvage surgery via electromyographic and energetic measurement techniques on a group of intra-articular knee osteosarcoma patients greater than one year post surgery. A retrospective outcome study was undertaken on 20 limb salvage patients (10 female, 10 male) recruited from the Queensland Bone Tumour Registry. Results showed prolonged activation of rectus femoris and prolonged co-contraction of the rectus femoris and hamstring muscles (p>0.05) in the affected limb of the limb salvage group compared to a control group. Prolonged rectus femoris activation and co-contraction was also evident in the unaffected lower limb suggesting alterations in gait programming within higher neuronal centres. The results are important for the development of rehabilitation programs as they suggest an overall reprogramming of the gait pattern, thereby limiting the impact of conventional strength and stretching interventions.

Centralization and the relationship between volume and outcome in knee arthroplasty procedures.

BACKGROUND: Centralization aims to reduce adverse patient outcomes by concentrating complex surgical procedures in specified hospitals. OBJECTIVES: This review assessed the efficacy of centralization for knee arthroplasty by examining the relationship between hospital and surgeon volume and patient outcomes. DATA SOURCES AND REVIEW METHODS: The systematic review identified studies using multiple databases, including Medline and Embase. Two independent researchers ensured studies met the inclusion criteria. Morbidity, mortality, length of stay, financial outcomes and statistical rigour were examined. Correlations between volume and outcome were reported. RESULTS: Twelve primary knee arthroplasty studies examined hospital volume, which was significantly associated with decreased morbidity (five of seven studies), mortality (two of five studies) and length of stay (two of three studies). Three primary knee arthroplasty studies examined surgeon volume, which was significantly associated with decreased morbidity (two of three studies), mortality (zero of two studies) and length of stay (one of one study). Two revision knee arthroplasty studies examined hospital volume. One study examined but did not test for significance between hospital volume and patient morbidity; both studies examined volume and patient mortality reporting inconclusive results; and one study reported no significant association between volume and length of stay. None of the revision knee arthroplasty studies examined surgeon volume. CONCLUSIONS: Significant associations between increased hospital and surgeon volume and improved patient outcomes were reported. However, when these results were separated by arthroplasty type, the association appeared tenuous. Judgements regarding centralization of knee arthroplasty should be made with caution until further evidence is published.

Radical prostatectomy: a systematic review of the impact of hospital and surgeon volume on patient outcome.

BACKGROUND: To assess the impact of hospital and surgeon volume on mortality, morbidity, length of hospital stay and costs of radical prostatectomy (RP). METHODS: This systematic review identified relevant studies published between 1997 and June 2007. Inclusion of papers was established through application of a predetermined protocol, independent assessment by two reviewers, and a final consensus decision. RESULTS: Compared with low volume hospitals, the included studies showed high volume hospitals demonstrated lower rates of mortality, postoperative complications and readmissions, and lower overall hospital costs. High volume surgeons similarly showed lower rates of postoperative complications and shorter length of stay compared with low volume surgeons, but no difference in mortality. CONCLUSIONS: From the literature obtained, patients undergoing RP performed by high volume providers may have better outcomes compared to low volume providers; however, any move to centralize RP must be further evaluated.

Systematic review of the impact of volume of oesophagectomy on patient outcome.

PURPOSE: This systematic review aims to assess whether overall survival, mortality, morbidity, length of stay and cost of performing oesophagectomy are related to surgical volume. METHODS: A systematic search strategy from 1997 until December 2006 was used to retrieve relevant studies. Inclusion of articles was established through application of a predetermined protocol, independent assessment by two reviewers and a final consensus decision. RESULTS: A total of 55 studies were identified of which 27 studies, representing 68 882 patients, met the inclusion criteria. Twenty-one of these solely examined hospital volume, 5 examined both hospital and surgeon volume, and 1 examined surgeon volume in isolation. All but one of the studies were retrospective in nature, and because of the heterogeneity of the literature, no meta-analysis could be performed. Of the studies exploring the relationship between hospital volume and mortality, 20 reported a statistically significant benefit to large volume centres. Five of six included studies showed significant evidence for a reduced mortality risk with greater surgeon volume. CONCLUSIONS: Based on the evidence from these retrospective studies, oesophagectomy performed in high volume centres would appear to be associated with better outcome compared with low volume centres.

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.