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.

A Size-Based Criteria for Flap Reconstruction After Thigh-Adductor, Soft-Tissue Sarcoma Resection.

BACKGROUND: Resection of soft-tissue sarcomas from the adductor compartment is associated with significant complications. Free/pedicled flaps often are used for wound closure, but their effect on healing is unclear. We compared wound complications, oncologic, and functional outcomes for patients undergoing flap reconstruction or primary closure following resection of adductor sarcomas. METHODS: A total of 177 patients underwent resection of an adductor sarcoma with primary closure (PrC) or free/pedicled flap reconstruction (FR). Patient, tumor, and treatment characteristics were compared, as well as wound complications, oncologic, and functional outcomes (TESS/MSTS87/MSTS93). To examine the relative benefit of flap reconstruction, number needed to treat (NNT) was calculated. RESULTS: In total, 143 patients underwent PrC and 34 had FR, 68% of which were pedicled. There were few differences in demographic, tumor, or treatment characteristics. No significant difference was found in the rate of wound complications. Length of stay was significantly longer in FR (18 days vs. PrC 8 days; p < 0.01). Oncologic and functional outcomes were similar over 5 years follow-up. Uncomplicated wound healing occurred more often in FR compared with PrC for tumors with ≥15 cm (NNT = 8.4) or volumes ≥ 800 ml (NNT = 8.4). Tumors ≤ 336 ml do not benefit from a flap, whereas those > 600 ml are 1.5 times more likely to heal uneventfully after flap closure. CONCLUSIONS: Although flap use prolonged hospitalization, it decreased wound healing complications for larger tumors, and in all sized tumors, it demonstrated similar functional and oncologic outcomes to primary closure. Our size-based treatment criteria can help to identify patients with large adductor sarcomas who could benefit from flap reconstruction. LEVEL OF EVIDENCE III: (Retrospective cohort study).

The eTRANSAFE Project on Translational Safety Assessment through Integrative Knowledge Management: Achievements and Perspectives.

eTRANSAFE is a research project funded within the Innovative Medicines Initiative (IMI), which aims at developing integrated databases and computational tools (the eTRANSAFE ToxHub) that support the translational safety assessment of new drugs by using legacy data provided by the pharmaceutical companies that participate in the project. The project objectives include the development of databases containing preclinical and clinical data, computational systems for translational analysis including tools for data query, analysis and visualization, as well as computational models to explain and predict drug safety events.

Selective Affimers Recognise the BCL-2 Family Proteins BCL-xL and MCL-1 through Noncanonical Structural Motifs*.

The BCL-2 family is a challenging group of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are useful as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody-binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL , BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective recognition of their target BCL-2 protein. For anti-apoptotic targets BCL-xL and MCL-1, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug-bound-like conformation. These proof-of-concept studies indicate that Affimers could be used as alternative templates to inspire the design of selective BCL-2 family modulators and more generally other protein-protein interaction inhibitors.

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.

Probing Protein Surfaces: QSAR Analysis with Helix Mimetics.

α-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.

Hydrocarbon constrained peptides - understanding preorganisation and binding affinity.

The development of constrained peptides represents an emerging strategy to generate peptide based probes and hits for drug-discovery that address challenging protein-protein interactions (PPIs). In this manuscript we report on the use of a novel α-alkenylglycine derived amino acid to synthesise hydrocarbon constrained BH3-family sequences (BIM and BID). Our biophysical and structural analyses illustrate that whilst the introduction of the constraint increases the population of the bioactive α-helical conformation of the peptide in solution, it does not enhance the inhibitory potency against pro-apoptotic Bcl-xL and Mcl-1 PPIs. SPR analyses indicate binding occurs via an induced fit mechanism whilst X-ray analyses illustrate none of the key interactions between the helix and protein are disturbed. The behaviour derives from enthalpy-entropy compensation which may be considered in terms of the ground state energies of the unbound constrained and unconstrained peptides; this has implications for the design of preorganised peptides to target protein-protein interactions.

Telehealth in paediatric orthopaedic surgery in Queensland: a 10-year review.

BACKGROUND: Telemedicine is a patient consultation method commonly available to patients in rural and remote areas throughout Australia. Its use in paediatric orthopaedics has been rarely described. The primary aim of this study was to identify the patient cohort accessing the orthopaedic paediatric telehealth service through the Royal Children's Hospital Queensland, so as to better allocate this resource. The secondary aims were to identify the orthopaedic conditions the patients utilizing this service suffered and to follow-up on treatment outcomes to potentially assess clinical benefit. METHOD: A retrospective review of prospectively collected data of paediatric orthopaedic patients consulted using telehealth at the Royal Children's Hospital, Queensland over a 10-year period between January 2004 and September 2012 was conducted. RESULTS: One hundred and twenty-six patient records were assessed with a mean age of 6 years. Results showed that 40% of patients seen using telehealth in paediatric orthopaedics had documented cerebral palsy, an intellectual disability or congenital syndrome. Common paediatric orthopaedic conditions were seen, with lower limb malalignment being the most common presenting complaint. About 58% of patients were seen exclusively via telehealth and did not require in-person consultation or operative therapy. CONCLUSION: We found that the orthopaedic telepaedriatic consultation service at the Royal Children's Hospital reviewed a large proportion of patients with a known disability. We believe there is a role for telehealth medicine for all patients; however, we propose that even greater benefit can be obtained from telehealth consultation in patients with a disability where the cost and inconvenience of patient transport is considerably increased.