Our goal is to repurpose drugs to block the growth of lung metastases, the lethal process in osteosarcoma. We therefore screened the NCI-panel of 114 FDA-approved oncology drugs to identify agents that potently reduce growth of osteosarcoma spheroids (sarcospheres). We first developed a system to routinely generate large numbers of highly-uniform spherical sarcospheres (1/well) with a 400um diameter, to most closely simulate micrometatases. Our primary drug screen (Z’-factor=0.70+0.10) utilized sarcospheres from three highly-metastatic human osteosarcoma cell lines (LM7, 143B, and MG63.3) in the presence and absence of MAP chemotherapeutics. Dose-response experiments with 13 of the most effective drugs confirmed initial results and allowed comparison with each drug's toxicity on normal human osteoblasts and normal small airway epithelial cells. Romidepsin, a HDAC inhibitor (HDACi), had the most favorable toxicity/efficacy ratios (TD50/IC50=57–580, depending on cell line). The only other HDACi in the panel of FDA-approved drugs (vorinostat) also ranked highly in the screen. Since newer HDACi's may have improved toxicity/efficacy ratios, we compared romidepsin and vorinostat with the three other HDACi's that are FDA-approved (belinostat, panobinostat, and valproic acid) plus one that is in clinical trials (entinostat). Romidepsin (Cmax/IC50=36–360) and belinostat (Cmax/IC50=14–20) reduced sarcosphere growth at clinically-achievable levels, in the presence or absence of MAP. Importantly, both romidepsin and belinostat were synergistic with MAP (BLISS scores=5–15). Propidium iodide staining showed that both romidepsin and MAP substantially induced cell death throughout the sarcospheres. Our results strongly support future studies to determine effects of romidepsin and belinostat on growth of lung metastases
Dunkin Hartley guinea pigs, a commonly used animal model of osteoarthritis,
were used to determine if high frequency ultrasound can ensure intra-articular
injections are accurately positioned in the knee joint. A high-resolution small animal ultrasound system with a 40 MHz
transducer was used for image-guided injections. A total of 36 guinea
pigs were anaesthetised with isoflurane and placed on a heated stage.
Sterile needles were inserted directly into the knee joint medially,
while the transducer was placed on the lateral surface, allowing
the femur, tibia and fat pad to be visualised in the images. B-mode
cine loops were acquired during 100 µl. We assessed our ability
to visualise 1) important anatomical landmarks, 2) the needle and
3) anatomical changes due to the injection. Objective
Methods
Recently there has been interest in an alternative method of aligning a total knee arthroplasty (TKA) referred to as kinematic alignment. The theoretical appeal of this method is that alignment of each patient's knee can be individualized through the use of preoperative imaging and computer software, with the goal of achieving pre-arthritic alignment through restoration of the axes of rotation of each particular knee. Clinical studies have evaluated the outcomes of this new alignment technique, but to date there have been no randomized controlled trials comparing kinematic alignment to mechanical alignment. This randomized controlled trial was conducted to compare kinematically aligned and mechanically aligned TKA outcomes of knee pain, function and motion at two years' post-op, along with a comparison of limb, knee, and implant alignment of the two methods. Forty-four patients were surgically treated with kinematically aligned TKA (figure 1) with the use of patient specific guides, and forty-four patients were surgically treated with mechanically aligned TKA with the use of conventional instruments. All patients underwent CT long leg scanograms after surgery, and outcomes data were collected at a minimum of 2 years. The patient, radiographic evaluator, and clinical evaluator were blinded as to the alignment method.Introduction:
Methods and Materials:
The coronoid and collateral ligaments are key elbow stabilizers. When repair of comminuted coronoid fractures is not possible, prosthetic replacement may restore elbow stability. A coronoid prosthesis has been designed with an extended tip in an effort to augment elbow stability in the setting of residual collateral ligament insufficiency. The purpose of this biomechanical study, therefore, was to compare an anatomic coronoid replacement with an extended tip implant both with and without ligament insufficiency. Two coronoid prostheses were designed and developed based on CT-derived images adjusted for cartilage thickness: an anatomical implant and an extended-tip implant. Passive elbow extension was performed in 7 cadaveric arms in the varus and valgus positions. Varus-valgus laxity of the ulna relative to the humerus was quantified with a tracking system with an intact coronoid, a 40% coronoid deficiency, an anatomical prosthesis, and an extended prosthesis, with the collateral ligaments sectioned and repaired.Purpose
Method
Limited information is available regarding the functional outcomes of radial head fractures managed with open reduction and internal fixation (ORIF). The purpose of this study was to determine the functional outcomes of radial head fractures treated with ORIF. Fifty-two patients, with a mean age of 4412 years, who were treated with radial head ORIF were evaluated at a mean of 4.42.4 years. Thirty were isolated radial head fractures (Group A), 13 (Group B) were associated with a complex fracture-dislocation (terrible triad variants), and 5 (Group C) were associated with a proximal ulnar fracture (Monteggia/trans-olecranon variants). Fourty-four were partial articular fractures and 8 were complete articular fractures. Outcomes were assessed with physical and radiographic examination, and validated self-reported questionnaires.Purpose
Method
Radial head implant over-lengthening, a common cause of capitellar wear and clinical failure, is difficult to diagnose using radiographs of the injured elbow. The purpose of this study was to determine if a novel measurement technique based on contralateral elbow radiographs, termed the RACER method, could be used to accurately estimate the magnitude of radial head implant over-lengthening. Part I of this study examined the side-to-side consistency of radiographic landmarks used in the measurement technique. Part II of this study validated the technique using simulated radial head implant over-lengthening in a cadaveric model. Part I: A side-to-side comparison of elbow joint dimensions was performed in 50 patients (100 radiographs). Part II: Radial head prostheses of varying lengths (0,+2mm,+4mm,+6mm,+8mm) were implanted in 4 paired cadaveric specimens (8 elbows). Radiographs were obtained and measurements were performed by 2 examiners blinded to implant size to determine if contralateral radiographs could diagnose and provide a valid estimate of the magnitude of implant over-lengthening. Intra and inter-rater reliability was determined.Purpose
Method
There have been a number of described techniques for sizing the diameter of radial head implants. All of these techniques, however, are dependent on measurements of the excised native radial head. When accurate sizing is not possible due to extensive comminution or due to a previous radial head excision, it has been postulated that the proximal radioulnar joint (PRUJ) may be used as an intraoperative landmark for correct sizing. The purpose of this study was to: 1) determine if the PRUJ could be used as a reliable landmark for radial head implant diameter sizing when the native radial head in unavailable, and (2) determine the reliability of measurements of the excised radial head. Twenty-seven fresh-frozen denuded ulnae and their corresponding radial heads (18 males, 9 females) were examined. The maximum diameter (MaxD), minimum diameter (MinD) and dish diameter (DD) of the radial heads were measured twice, 3–5 weeks apart, using digital calipers. Two fellowship-trained upper extremity surgeons, an upper extremity fellow and a senior orthopedic resident were then asked to independently select a radial head implant diameter based on the congruency of the radius of curvature of the PRUJ to that of the radial head trial implants. The examiners were blinded to the native radial head dimensions. This selection was repeated 3–5 weeks later by two of the investigators. Correlation between radial head measurements and radial head implant diameter sizes was assessed using Pearsons correlation coefficient (PCC) and inter and intra-observer reliability were assessed using intra-class correlation coefficient (ICC).Purpose
Method
Current coronoid fracture classification systems are based on fragment size and configuration using plain radiographs and/or CT. During surgery, coronoid fracture fragments appear much larger than anticipated because cartilage is radiolucent and therefore not taken into account with preoperative imaging. The purpose of this study was to quantify the articular cartilage thickness of the coronoid process, with reference to coronoid fracture classifications. Twenty-four cadaveric ulnae were dissected, imaged, and analyzed using the OsiriX software program (3.6–64 bit, Geneva). Thirteen identifiable landmarks were chosen on the coronoid, olecranon and proximal radioulnar joint to measure articular cartilage thickness. Intra-observer and inter-observer reliability were calculated.Purpose
Method
The coronoid process is an integral component for elbow stability. In the setting of a comminuted coronoid fracture, where repair is not possible, a prosthetic device may be beneficial in restoring elbow stability. The hypothesis of this in-vitro biomechanical study was that an anatomic coronoid prosthesis would restore stability to the coronoid deficient elbow. A metal coronoid prosthesis was designed and developed based on CT-derived images adjusted for cartilage thickness. The kinematics and stability of eight fresh-frozen male cadaveric arms (mean age 77.4 years, range 69–92 years) were quantified in the intact state; after collateral ligament sectioning and repair (control state); after a simulated 40% transverse coronoid fracture; and after implantation of a coronoid prosthesis. Elbow flexion was simulated passively with the arm oriented in the varus position and the forearm in pronation. Varus-valgus angulation (VV) and internal-external rotation (IE) of the ulna relative to the humerus were quantified with an electromagnetic tracking system (Flock of Birds, Ascension Technologies, Burlington, VT, static accuracy: 1.8mm position, 0.5 orientation).Purpose
Method
Capitellum hemiarthroplasty is an emerging concept. The current metallic capitellar implants have spherical surface shapes, but the native capitellum is not spherical. This study evaluated the effect of capitellar implant shape on the contact mechanics of the radiocapitellar joint when articulating with the native radial head. Eight paired radii and humeri were potted in a custom jig. Articular casts were made with medium-viscosity resin while 85 N of axial load was applied to the reduced radiocapitellar joint at 0, 45, and 90 of elbow flexion, and at neutral, 50 pronation and 50 supination at each flexion angle. The native radiocapitellar articulation was compared to capitellar hemiarthroplasties of two surface designs (anatomical and spherical). Contact area and shape (circularity) were determined. Circularity was defined as the ratio of the minor axis and major axis of the shape.Purpose
Method
Release of tight lateral structures is an integral part of balancing the valgus knee during knee replacement surgery. The posterolateral capsule is released through an inside-out technique. The common peroneal nerve is in close proximity to the capsule during this step. This study was undertaken to determine the distance of the nerve and the safe level for the posterolateral release. MR scans of the knee of 100 patients were evaluated. The age range of selected patients was 50 to 70 years. The distance of the nerve was measured to the closest point on the posterolateral capsule. Two separate measurements were taken - one 9mm above the joint line indicating the distal femoral resection level and the other 9mm distal to the joint line indicating the level of tibial resection. A third point was at the joint line level. The position of the nerve was also recorded in relation to the cross section of the femur/tibia on a ‘clock-like’ reference.Purpose of the study
Methods
Rapid prototyping (RP), especially useful in surgical specialities involving critical three-dimensional relationships, has recently become cheaper to access both in terms of file processing and commercially available printing resources. One potential problem has been the accuracy of models generated. We performed computed tomography on a cadaveric human patella followed by data conversion using open source software through to selective-laser-sintering of a polyamide model, to allow comparative morphometric measurements (bone No significant differences in the dimensional measurements could be demonstrated. These data provide us with optimism as to the accuracy of the technology, and the feasibility of using RP cheaply to generate appropriate models for operative rehearsal of intricate orthopaedic procedures.
Hip resurfacing arthroplasty is an established and effective intervention for osteoarthritis of the hip in the young active patient, relying on the principle of femoral bone-stock preservation. A recognised mode of failure is neck thinning leading to radiological evidence of neck collapse and clinical failure. We report on a series of these slow-neck-failure patients and highlight the increased incidence of this phenomenon in post-menopausal female patients. This is a single operator, single implant series; 172 cases were identified from databases at our institution. 76 were female, mean (SD) age 52 (7) years. 96 were male, mean (SD) age 51(12) years. 15 (8.7%) patients required revision. 12 (80%) were female, 9 (75%) of these were due to slow neck failure. In the men one patient developed ALVAL requiring removal of his bilateral hip resurfacings, the other failure mode was early femoral neck failure. Mean time to failure was 6 months in men and 37 months in women. This difference in failure rates is also seen in the NJR figures. This review confirms the relatively high incidence of premature failure in post-menopausal females. NICE guidance in 2003, currently under review, stated that resurfacing is indicated in male patients up to 65 and female patients up to 60. As a result of this study we are currently advising post-menopausal patients that this risk of early failure may make total hip replacement a preferable option to resurfacing arthroplasty.
Osteonecrosis (ON) is a disease that ultimately results in bone collapse. We investigated the correlation between SNPs and osteonecrosis. In this study, 109 patients with systematic lupus erythematosus (SLE) (21 with and 88 without osteonecrosis) were collected for genotype analysis of 7 genes including Introduction
Methods
Osteonecrosis (ON) is one of the most debilitating skeletal disorders. Most patients with ON of the femoral head eventually require surgery, usually total hip arthroplasty, within a few years of disease onset. Previous reports have shown that alendronate reduces osteoclastic activity and reduces the incidence of femoral head collapse in osteonecrotic hips. A randomized study to examine the ability of alendronate to delay or prevent femoral head collapse was performed. From June 2005 to December 2006, sixty four patients were enrolled and randomly assigned to alendronate or placebo. Five patients were excluded from the analysis because of their failure to adhere to the study protocol. Disease progression was evaluated using radiographs and magnetic resonance imaging (MRI).Introduction
Methods