Minimally invasive stabilization of pelvic metastatic bone disease: A review of an emerging technique.

Percutaneous pelvic stabilization is an emerging technique that provides mechanical stability to pathologic fractures of the pelvic ring and acetabulum. Variability exists in procedural technique among institutions; however, early case series consistently demonstrate an acceptable complication profile and significant improvement in patients' pain and function. This minimally invasive approach is less morbid than traditional, open acetabular and pelvic reconstructions. Therefore, this procedure is an encouraging palliative intervention for a growing patient population in need.

Minimally invasive management of pathologic fractures of the pelvis and sacrum: Tumor ablation and fracture stabilization.

BACKGROUND: Pathologic fractures of the pelvis/sacrum due to metastatic bone disease (MBD) cause pain and dysfunction due to mechanical instability of the pelvic ring. This study presents our multi-institutional experience with percutaneous stabilization of pathologic fractures and osteolytic lesions from MBD throughout the pelvic ring. METHODS: The records of patients undergoing this procedure from 2018 to 2022 were reviewed retrospectively from two institutions. Surgical data and functional outcomes were recorded. RESULTS: Fifty-six patients underwent percutaneous stabilization, with a median operative duration of 119 min (interquartile range [IQR]: 92.8, 167) and median estimated blood loss of 50 mL (IQR: 20, 100). The median length of stay was 3 days (IQR: 1, 6), and 69.6% (n = 39) of patients were discharged home. Early complications included one partial lumbosacral plexus injury, three acute kidney injuries, and one case of intra-articular cement extravasation. Late complications included two infections and one revision stabilization procedure for hardware failure. Mean Eastern Cooperative Oncology Group (ECOG) scores improved from 3.02 (SD 0.8) preoperatively to 1.86 (SD 1.1) postoperatively (p < 0.001). Ambulatory status also improved (p < 0.001). CONCLUSIONS: Percutaneous stabilization of pathologic fractures and osteolytic defects of the pelvis and sacrum is a procedure that improves patient function, ambulatory status and is associated with a limited complication profile.

A Novel Method to Prevent Terminal Appositional Overgrowth Following Pediatric Below Knee Amputations A Case Series and Review of the Literature.

The terminal overgrowth of the tibia following pediatric transtibial amputation is a common problem leading to pain, disability, and repeat surgical procedures. We present three patients who underwent transtibial amputation due to sarcoma of the lower extremity followed by compress osseointegration prosthesis fixation. The minimum follow-up was 1 year. The average age of patients was 10.8 years. There were no complications that required surgical revision. To date, there has been no evidence of terminal appositional overgrowth in this series. The application of an end-cap implant utilizing compressive osseointegration fixation can prevent terminal bone overgrowth in pediatric transtibial amputations.

PROMIS® scores in operative metastatic bone disease patients: A multicenter, prospective study.

BACKGROUND: The prevalence of metastatic bone disease (MBD) grows each year as treatments improve. Little has been published about functional and pain outcomes in this group after surgery. Patient-Reported Outcomes Measurement Information System (PROMIS® ) can collect information, in just minutes, about patient's physical, mental, and social health. This study evaluated PROMIS® pain and functional scores in surgically treated patients with MBD. METHODS: Basic demographics and PROMIS® scores were recorded from a total of 13 patients at 9 periods of time over 6 months. RESULTS: The average change in physical function at week 1 was -2.5 (standard deviation [SD] = 5.4), at 2 weeks 1.7 (SD = 7.6), after 4 weeks 6.9 (SD = 10), after 6 weeks 6.4 (SD = 10.9), after 10 weeks 15.3 (SD = 3.1), and after 3 months 8.6 (SD = 7.6). The average change in pain inference at week 1 was -1.2 (SD = 7.3), at 2 weeks -2.1 (SD = 9.5), after 4 weeks -12.6 (SD = 4.5), after 6 weeks -8.3 (SD = 10.2), after 10 weeks -16.6 (SD = 4.3), and after 3 months -11.4 (SD = 8.2). CONCLUSIONS: PROMIS® provides a feasible means to collect data in this population. Trends of improved function and decreased pain were seen after surgery. Continuing this study will hopefully elucidate more insight into the surgical treatment of MBD.

Limb Salvage Versus Amputation in Conventional Appendicular Osteosarcoma: a Systematic Review.

The overall survivorship in patients with appendicular osteosarcoma has increased in the past few decades. However, controversies and questions about performing an amputation or a limb salvage procedure still remain. Using three peer-reviewed library databases, a systematic review of the literature was performed to evaluate all studies that have evaluated the outcomes of appendicular osteosarcoma, either with limb salvage or amputation. The mean 5-year overall survivorship was 62% for salvage and 58% for amputation (p > 0.05). At mean 6-year follow-up, the local recurrence rates were 8.2% for salvage and 3.0% for amputation (p > 0.05). Additionally, at mean 6-year follow-up, the rate for metastasis was 33% for salvage and 38% for amputation (p > 0.05). The revision rates were higher with salvage (31 vs. 28%), and there were more complications in the salvage groups (52 vs. 34%; p > 0.05). Despite the heterogeneity of studies available for review, we observed similar survival rates between the two procedures. Although there was no significant statistical difference between rates of recurrence and metastasis, the local recurrence rate and risk of complications were higher for limb salvage as compared to amputation. Cosmetic satisfaction is often higher with limb salvage, whereas long-term expense is higher with amputation. Overall, current literature supports limb salvage procedures when wide surgical margins can be achieved while still retaining a functional limb.

Is cold blood cardioplegia absolutely superior to cold crystalloid cardioplegia in aortic valve surgery?

BACKGROUND: Experimental evidence suggests that blood cardioplegia (BCP) may be superior to cold crystalloid cardioplegia (CCP) for myocardial protection. However, robust clinical data are lacking. We compared postoperative outcome of patients undergoing aortic valve replacement (AVR) using cold anterograde-retrograde intermittent BCP versus anterograde (CCP). METHODS: Adult consecutive isolated AVR performed between April 2006 and February 2011 at the Royal Infirmary Hospital of Edinburgh were retrospectively analyzed. The use of anterograde CCP was compared with that of intermittent anterograde-retrograde cold BCP. End points were intra-operative mortality, 30-day hospital re-admission, need for RBC or platelet transfusion, mechanical ventilation time and renal failure. RESULTS: Of total 774 cases analyzed, 592 cases of BCP and 182 cases of CCP were identified. Demographics did not differ between groups (mean age: 67±12 years in CCP and 69±12 years in BCP). Groups (BCP vs. CCP) were indistinguishable (P>0.05, not significant) based on: average aortic cross clamp time 77.01±14.47 vs. 75.78±18.78 minutes, cardiopulmonary bypass time 104.07±43.70 vs. 100.34±25.90 minutes, surgery time 190.53±61.80 vs. 204.04±51.09 minutes and postoperative total blood consumption 1.38±2.11 vs. 1.61±2.4 units. The percentage of patients who required platelets' transfusion was similar: 12.8% BCP and 18.7% CCP (Fisher's exact test, P=0.053). Prevalence of respiratory failure was lower in BCP than in CCP: 2.6% vs. 6.3% (P=0.028). Admission time (days) at ICU was 3.63± 21.90 in BCP and 3.07±8.04 in CCP (not significant). Intra-hospital mortality, 30-day hospital re-admission, renal failure, sepsis, wound healing and stroke did not differ between groups. CONCLUSIONS: BCP was strictly not superior to CCP in every aspect. In particular it was definitely not superior in terms of postoperative ventricular function. Our results question the absolute superiority of BCP over CCP in terms of hard outcomes. Likelihood of serious complications should be considered to improve risk profile of patients before choosing a cardioplegic solution.

What is the Optimal Reconstruction Option after the Resection of Proximal Humeral Tumors? A Systematic Review.

PURPOSE: The proximal humerus is a common location for both primary and metastatic bone tumors. There are numerous reconstruction options after surgical resection. There is no consensus on the ideal method of reconstruction. METHODS: A systematic review was performed with a focus on the surgical reconstructive options for lesions involving the proximal humerus. RESULTS: A total of 50 articles and 1227 patients were included for analysis. Reoperation rates were autograft arthrodesis (11%), megaprosthesis (10%), RSA (17%), hemiarthroplasty (26%), and osteoarticular allograft (34%). Mechanical failure rates, including prosthetic loosening, fracture, and dislocation, were highest in allograft-containing constructs (APC, osteoarticular allograft, arthrodesis) followed by arthroplasty (hemiarthroplasty, RSA, megaprosthesis) and lowest for autografts (vascularized fibula, autograft arthrodesis). Infections involving RSA (9%) were higher than hemiarthroplasty (0%) and megaprosthesis (4%). Postoperative function as measured by MSTS score were similar amongst all prosthetic options, ranging from 66% to 74%, and claviculo pro humeri (CPH) was slightly better (83%). Patients were generally limited to active abduction of approximately 45° and no greater than 90°. With resection of the rotator cuff, deltoid muscle or axillary nerve, function and stability were compromised even further. If the rotator cuff was sacrificed but the deltoid and axillary nerve preserved, active forward flexion and abduction were superior with RSA. DISCUSSION: Various reconstruction techniques for the proximal humerus lead to relatively similar functional results. Surgical choice should be tailored to anatomic defect and functional requirements.

End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.

Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.

The Impact of Microenvironment on the Synovial Sarcoma Transcriptome.

Synovial sarcoma (SS) is initiated by a t(X;18) chromosomal translocation and resultant SS18-SSX fusion oncogene. Only a few SS cell lines exist. None has been compared to its source tumor. In order to compare matched tumor and cell line pairs, we performed RNAseq on 3 tumor/cell line pairs from a genetically engineered mouse model of SS, as well as 2 pairs from human SS tumors. Transcriptomes of mouse tumors and derivative cell lines deviated significantly. Differentially expressed genes highlighted inflammatory infiltrates and metabolism. The same was found for the human tumor and cell line pairs. More was shared between different tumors than between any tumor and its cell line. Direct xenografting generated transcriptomes that more closely resembled the primary tumor than did its derivative cell line. SS tumor transcriptomes are powerfully impacted by the environment wherein they reside, especially with regard to immune interaction and metabolism.

Use of Compressive Osseointegration Endoprostheses for Massive Bone Loss From Tumor and Failed Arthroplasty: A Viable Option in the Upper Extremity.

BACKGROUND: Endoprostheses using principles of compressive osseointegration have shown good survivorship in several studies involving the lower extremity; however, no series to our knowledge have documented the use of this technology in the management of massive bone loss in the upper limb. QUESTIONS/PURPOSES: (1) What proportion of upper extremity implants using compressive osseointegration fixation principles achieved durable short-term fixation, and what were the modes of failure? (2) What surgical complications resulted from reconstruction using this technique? METHODS: A multiinstitutional retrospective review identified nine patients (five women; four men) who underwent 13 endoprosthetic replacements between 2003 and 2014 using compressive osseointegration (Compliant® Pre-stress Device [CPS]; Biomet Inc, Warsaw, IN, USA) in the upper extremity, including two proximal humeri, two humeral diaphyses, seven distal humeri, and two proximal ulna. During the early part of that period, the indication for use of a compressive prosthesis in our centers was revision of a previous tumor reconstruction (allograft-prosthetic composite or stemmed endoprosthetic reconstruction) (three patients; five implants), or revision arthroplasty with massive bone loss (three patients, four implants); more recently, indications became somewhat more permissive and included posttraumatic bone loss (one patient, one implant), primary bone sarcoma, and resections with very short remaining end segments after diaphyseal resections (two patients, three implants). Minimum followup was 24 months; one patient (one implant) was lost to followup before that time with the implant intact at 14 months and no patients have died. The mean age of the patients was 45 years (range, 21-62 years). Mean followup was 68 months (range, 24-141 months). Implant revision for any cause and for failure of the CPS mechanism was recorded. Modes of failure were categorized as soft tissue, aseptic loosening, structural, infection, and tumor progression; CPS modes of failure were defined as lack of fixation, with or without bone or implant fracture. RESULTS: Of the 12 implants accounted for beyond 2 years, six had undergone revision of any kind. Only two revisions in two patients were attributable to lack of CPS fixation at the bone-implant interface; one of the patients also had periprosthetic and implant fracture develop through the traction bar. Other modes of failure were aseptic loosening of the standard ulnar component (two patients, two implants), bushing wear (one patient; one implant) and infection resulting in two-stage exchange and free soft tissue transfer with retention of the CPS spindle (one patient, one implant). Complications for all nine patients included one transient radial nerve palsy, one ulnar nerve sensory neurapraxia, one superficial infection, and two glenohumeral subluxations, one underwent revision surgery with implantation of a constrained liner. CONCLUSIONS: A compressive osseointegration endoprosthesis is an option for very difficult revisions or sarcoma resection in the upper extremity in which the remaining segment of host bone is too short for a conventional prosthesis. However, surgeons must inform patients that these are salvage operations, and revision surgery is common. Long-term followup of more patients is necessary to further document the survivorship of these implants in the upper extremity. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Has the Level of Evidence of Podium Presentations at the Musculoskeletal Tumor Society Annual Meeting Changed Over Time?

BACKGROUND: Level of evidence (LOE) framework is a tool with which to categorize clinical studies based on their likelihood to be influenced by bias. Improvements in LOE have been demonstrated throughout orthopaedics, prompting our evaluation of orthopaedic oncology research LOE to determine if it has changed in kind. QUESTIONS/PURPOSES: (1) Has the LOE presented at the Musculoskeletal Tumor Society (MSTS) annual meeting improved over time? (2) Over the past decade, how do the MSTS and Orthopaedic Trauma Association (OTA) annual meetings compare regarding LOE overall and for the subset of therapeutic studies? METHODS: We reviewed abstracts from MSTS and OTA annual meeting podium presentations from 2005 to 2014. Three independent reviewers evaluated a total of 1222 abstracts for study type and LOE; there were 577 abstracts from MSTS and 645 from OTA. Changes in the distributions of study type and LOE over time were evaluated by Pearson chi-square test. RESULTS: There was no change over time in MSTS LOE for all study types (p = 0.13) and therapeutic (p = 0.36) study types during the reviewed decade. In contrast, OTA LOE increased over this time for all study types (p < 0.01). The proportion of Level I therapeutic studies was higher at the OTA than the MSTS (3% [14 of 413] versus 0.5% [two of 387], respectively), whereas the proportion of Level IV studies was lower at the OTA than the MSTS (32% [134 of 413] versus 75% [292 of 387], respectively) during the reviewed decade. The proportion of controlled therapeutic studies (LOE I through III) versus uncontrolled studies (LOE IV) increased over time at OTA (p < 0.021), but not at MSTS (p = 0.10). CONCLUSIONS: Uncontrolled case series continue to dominate the MSTS scientific program, limiting progress in evidence-based clinical care. Techniques used by the OTA to improve LOE may be emulated by the MSTS. These techniques focus on broad participation in multicenter collaborations that are designed in a comprehensive manner and answer a pragmatic clinical question.

Cardiac Repair and Regeneration: The Value of Cell Therapies.

Ischaemic heart disease is the predominant contributor to cardiovascular morbidity and mortality; one million myocardial Infarctions occur per year in the USA, while more than five million patients suffer from chronic heart failure. Recently, heart failure has been singled out as an epidemic and is a staggering clinical and public health problem associated with significant mortality, morbidity and healthcare expenditures, particularly among those aged ≥65 years. Death rates have improved dramatically over the last four decades, but new approaches are nevertheless urgently needed for those patients who go on to develop ventricular dysfunction and chronic heart failure. Over the past decade, stem cell transplantation has emerged as a promising therapeutic strategy for acute or chronic ischaemic cardiomyopathy. Multiple candidate cell types have been used in preclinical animal models and in humans to repair or regenerate the injured heart, either directly or indirectly (through paracrine effects), including: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), neonatal cardiomyocytes, skeletal myoblasts (SKMs), endothelial progenitor cells, bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (MSCs) and, most recently, cardiac stem cells (CSCs). Although no consensus has emerged yet, the ideal cell type for the treatment of heart disease should: (a) improve heart function; (b) create healthy and functional cardiac muscle and vasculature, integrated into the host tissue; (c) be amenable to delivery by minimally invasive clinical methods; (d) be available 'off the shelf' as a standardised reagent; (e) be tolerated by the immune system; (f) be safe oncologically, i.e. not create tumours; and (g) circumvent societal ethical concerns. At present, it is not clear whether such a 'perfect' stem cell exists; what is apparent, however, is that some cell types are more promising than others. In this brief review, we provide ongoing data on agreement and controversy arising from clinical trials and touch upon the future directions of cell therapy for heart disease.

Using Na3PO4 to Enhance In vitro Animal Models of Aortic Valve Calcification.

BACKGROUND/OBJECTIVES: The pathogenesis of calcific aortic valvular disease (CAVD) involves an active inflammatory process of valvular interstitial cells (VICs) characterized by the activation of specific osteogenic signaling pathways and apoptosis. This process can be studied by analyzing certain molecular markers and gene expression pathways of spontaneous calcification. The purpose of our study is to investigate the role of sodium phosphate (Na3PO4) as a calcification promoter, with the aim of improving in vitro animal models for testing potential calcification inhibitors. MATERIALS AND METHODS: VICs were extracted from 6 healthy 6-month-old fresh porcine hearts by serial collagenase digestion. Quantitative polymerase chain reaction (qPCR) was used to quantify trans-differentiation of genes of interest during spontaneous calcification of VICs. Spontaneous calcification of VICs was increased by adding Na3PO4 (3 mM, pH 7.4). The degree of calcification was estimated by Alizarin Red staining for calcium deposition, and Sirius Red staining for collagen. Colorimetric techniques were used to determine calcium and collagen deposition quantitatively. Additionally, the enzymatic activity of alkaline phosphatase (ALP) was measured by a kinetic assay. For statistical analysis we used SPSS and Microsoft Office Excel 2013. RESULTS: Porcine VICs calcify spontaneously with demonstrable calcium and collagen deposition. In this study we observed an increase of calcium and collagen deposition from day 0 to day 14 (calcium: 376%; P<0.001, collagen: 3553%; P<0.001). qPCR analysis of mRNA by day 14 showed the following results: α-actin, a marker of myoblast phenotype, was increased to 1.6-fold; P<0.001. Runx2, an osteoblast marker, rose to 1.3 fold; P<0.05, TGF-ß, a promoter of osteogenesis, increased to 3.2-fold; P<0.001, and RhoA, a regulator of nodular formation in myoblasts, increased to 4.5-fold; P<0.001, compared to their levels at day 0. RANKL mRNA and calponin did not change significantly. Treatment of porcine VICs with Na3PO4 (3 mM, pH 7.4) led to a marked increase in calcium deposition by day 14 (522%; P<0.001), and a significant increase in ALP activity by day 7 (228%; P<0.05). There were no significant changes in ALP activity between the groups by day 14. CONCLUSION: This study has demonstrated the upregulation of some specific molecules during spontaneous calcification of aortic VICs with an active increase of calcium, collagen and ALP activity. In this in vitro model it was possible to increase spontaneous VICs calcification with Na3PO4 (3 mM, pH 7.4) to a level in which inhibitors of calcification could be tested to identify a novel potential therapeutic strategy against calcific aortic stenosis.

Denosumab could be a Potential Inhibitor of Valvular Interstitial Cells Calcification in vitro.

OBJECTIVE: Denosumab is a fully human monoclonal antibody and novel antiresorptive agent that works by binding receptor activator of nuclear factor kappa-ß ligand (RANKL) and inhibiting the signaling cascade that causes osteoclast maturation, activity, and survival. We aimed to elucidate the effect of Denosumab in the process of spontaneous and induced calcification in an in vitro porcine valvular interstitial cells (VICs) model. MATERIALS AND METHODS: VICs were extracted from fresh porcine hearts by serial collagenase digestion. Spontaneous calcification of VICs was increased in vitro by adding Na3PO4 (3 mM, pH 7.4) and different concentrations (0.1, 1 and 10 ng/ml) of transforming growth factor beta (TGFß). The degree of calcification before and after treatment with Denosumab was estimated by Alizarin Red staining for calcium deposition, and Sirius Red staining for collagen. Colorimetric techniques were used to determine calcium and collagen deposition quantitatively. For statistical analysis we used SPSS and Microsoft Office Excel 2013. RESULTS: Porcine aortic VICs in vitro were induced to calcify by the addition of either 3 mM Na3PO4, showing a 5.2 fold increase by 14 days (P<0.001), or 3 mM Na3PO4 + 10 ng/ml of TGFß, showing a 7 fold increase by Day 14 (P<0.001). Denosumab inhibited induced calcification by 3 mM Na3PO4 and 3 mM Na3PO4 with the addition of TGFß at either 0.1, 1 or 10 ng/ml to basal levels only at a concentration of 50 µg/ml (P<0.001). CONCLUSION: This study has proved that Denosumab could be a potential inhibitor of the calcification of VICs in vitro. A fuller understanding of the actions of Denosumab may identify a novel therapeutic strategy for clinical intervention against aortic valve calcification and aortic stenosis.

Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification.

Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.