XI-006 induces potent p53-independent apoptosis in Ewing sarcoma.

There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma. XI-006 treatment of Ewing and osteosarcoma cell lines (n = 11) resulted in rapid and potent apoptosis at low micro-molar concentrations specifically in Ewing sarcoma cell lines (48 hr IC50 0.099-1.61 µM). Unexpectedly, apoptotic response was not dependent on MDM4 mRNA/protein levels or TP53 status. Alkaline/neutral comet and γH2AX immunofluorescence assays revealed that the cytotoxic effects of XI-006 could not be attributed to the induction of DNA damage. RNA expression analysis revealed that the mechanism of action of XI-006 could be accredited to the inhibition of cell division and cycle regulators such as KIF20A and GPSM2. Finally, potent synergy between XI-006 and olaparib (PARP inhibitor) were observed due to the down-regulation of Mre11. Our findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma.

Primary osteosarcoma of the clavicle and the perils of bone biopsy.

We present a rare case of delayed diagnosis of osteosarcoma of the medial clavicle in a young man. He presented following a pathological fracture with a falsely reassuring core and fine-needle aspiration biopsy. The initial biopsy was suggestive of an aneurysmal bone cyst and was therefore treated conservatively without further follow-up. The rapid increase in size over the next 8 months triggered a repeat presentation and subsequent repeat biopsy. The open biopsy confirmed high-grade osteosarcoma and the patient underwent claviculectomy with neoadjuvant chemotherapy.

A New Approach for Complex Upper Limb Revisions Utilizing the Clavicula Pro Humero Technique: A Case Report.

CASE: A complex case is described involving limb salvage using a combination of the clavicula pro humero technique with a free vascularized fibular graft to span the defect following a failed megaprosthetic reconstruction. This is believed to be the first description of this approach for a very difficult problem. CONCLUSION: In the setting of infection and minimal bone stock, conventional reconstruction options for the proximal aspect of the humerus were unsatisfactory. This new technique provides a biologic, immunocompetent option for limb salvage.

Many faces of osteosarcoma on plain radiographs.

Osteosarcoma is the most common primary malignancy of bone. It is a very rare form of cancer with an annual incidence of 3:1,000,000 and so will not be seen by many surgeons. Coupled with this are the many different subtypes of this cancer that can have different appearances on imaging ranging from densely sclerotic to lytic or even cystic. They can be medullary, cortically or periosteally based. This article demonstrates the various different appearances associated with the different types of osteosarcoma which will assist surgeons in diagnosing this rare cancer.

Multicentric myofibroblastic sarcoma.

We report a case of synchronous, multicentric low-grade myofibroblastic sarcoma presenting in a 62-year-old man. He initially presented with inflammatory symmetric polyarthritis and adhesive capsulitis of his shoulder and hips bilaterally and did not respond to a trial of disease modifying antirheumatic drugs. Over a period of several years he developed progressive restriction of both knees and nodules on his hands, both knees and back. A biopsy of the nodule on his back was inconclusive and subsequent biopsies on his left and then right knee revealed a spindle cell neoplasm with an infiltrative growth pattern, mitotic figures, positive immunostaining for smooth muscle actin and focal myxoid change consistent with myofibroblastic sarcoma. While myofibroblastic sarcoma has been known to metastasise, to our knowledge, a multifocal presentation of this tumour has not been described previously.

A modified ulnar translocation reconstruction technique for Campanacci grade 3 giant cell tumors of the distal radius using a clover leaf plate.

BACKGROUND: Campanacci grade 3 giant cell tumors of the distal radius are locally aggressive and in close proximity to the median nerve, articular cartilage, flexor and extensor tendons, and the radial artery. Although several reconstructive techniques have been described, it is unclear to what degree these procedures restore function. DESCRIPTION OF TECHNIQUE: We present a modified ipsilateral ulna translocation technique using a clover leaf plate, for reconstruction of en bloc resected distal radius. This has the theoretical advantage of ensuring a solid, pain-free wrist arthrodesis, while preserving the forearm rotational axis and minimizing functional loss, without the associated donor site morbidity or allograft rejection issues of other reconstructive techniques. PATIENTS AND METHODS: Between 2006 and 2013, 3 patients underwent this procedure for Campanacci grade 3 giant cell tumors. All patients were right hand-dominant females, aged 24, 35, and 46 years, respectively. Two cases involved the right radius. Patients were reviewed retrospectively with clinical examination, functional assessment [the Toronto Extremity Salvage Score (TESS) for upper limb], and radiographs. The review period was 30, 51, and 41 months, respectively. RESULTS: The length of distal radius resected was 70, 50, and 35 mm, respectively. All achieved clear margins. There were no complications and there have been no recurrences. All ulnocarpal translocations achieved radiographic fusion. Patient's averaged 80-degree pronation, 70-degree supination, and clinical TESS scores of 86 at most recent follow-up. CONCLUSIONS: This technique achieved a painless and functional wrist arthrodesis with partially restored wrist motion, without complications. This technique has the advantage of negating remote donor site morbidity and/or allograft rejection issues of other techniques. LEVEL OF EVIDENCE: Level III, therapeutic study.

Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling.

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists.

Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy.

The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin-3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre-clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy.

Aqueous calcium sulphate as bone graft for voids following open curettage of bone tumours.

INTRODUCTION: Reported strategies for void filling in bone include autograft, allograft, synthetic bone substitutes or various combinations of these materials, but poor response rates and donor morbidity have created a desire to find a better option. Calcium sulphate as a stand-alone graft material reconstruct bone following curettage has not been previously reported. The purpose of this study was to assess the efficacy and radiological quality of healing, the time to healing, the functional outcomes and the complications following curettage and grafting using an injectable aqueous calcium sulphate (BonePlast; Biomet, Warsaw, IN, USA) as the sole grafting strategy. METHODS: The procedure of curettage and grafting with an aqueous solution of calcium sulphate was undertaken. The patients were regularly reviewed clinically and radiologically for a minimum of 12 months (range: 12-85 months). Forty-six procedures in 46 patients were reviewed. Radiological outcomes of healing were established and functional outcomes were obtained from each patient at annual follow-up review. RESULTS: A complete response was seen in 38 patients (83%) at a median of 6 months following the procedure (range: 1-24 months). Seven patients (15%) displayed only a partial response after a median of 13 months post-surgery (range: 12-53 months). There was one non-response to treatment (2%) after 40 months of follow-up. The mean functional score was 99%. DISCUSSION: Aqueous calcium sulphate as a sole grafting agent for void management after curettage simplifies current treatment practices and displays good bone reconstruction in a comparatively short time frame, with excellent functional results and acceptable complication rates in the setting of tumour surgery.

The toronto extremity salvage score in unoperated controls: an age, gender, and country comparison.

The Toronto Extremity Salvage Score (TESS) is widely used for the functional assessment of patients following surgery for musculoskeletal tumours. The aim of this study was to determine if there are gender and/or age-specific changes, unrelated to surgery, that may influence this score and the appropriateness of the questions. The TESS for lower limb was carried out in two different countries to see if there was variation between them. There were no statistically significant differences between the scores obtained between the respondents from Australia or Britain either in total or between the corresponding age groups. There were statistically significant differences in the TESS obtained between age groups with a lower score at older age groups but there was no difference between the sexes. Patients in the age group 70+ were more likely to record activities as "not applicable" and also have a lower score. This study has shown that age is the major factor in determining the TESS in both an Australian and British populations of otherwise healthy people. As there were no differences between the two populations, it supports the TESS as an international scoring system. There may be also an argument for age-specific questions.

Can the Toronto Extremity Salvage Score produce reliable results when used online?

BACKGROUND: Web-based questionnaires have become popular, however, access to the Internet can be biased regarding age, gender, and education, among other factors. Therefore, it is unknown whether this is a reasonable avenue to administer a questionnaire to patients or whether Web-based can be a reliable alternative to paper-based. QUESTIONS/PURPOSES: We determined whether the Internet version of the Toronto Extremity Salvage Score is reproducible compared with the paper-based version and the compliance and completion rates. PATIENTS AND METHODS: The study population consisted of 81 adults who had had surgery for a musculoskeletal tumor of the lower extremity more than 12 months earlier. The Toronto Extremity Salvage Score was administered by paper at a baseline interview and then readministered via Internet 7 to 14 days later to those with access. RESULTS: Sixty of the 81 patients (74%) were able to use the Internet. Increasing age and lower education levels were correlated with a lower likelihood of using the Internet. Questionnaires were done online and on paper by 56 patients but 10 were excluded because of self-reported change in circumstances. The mean TESS was 85.7 (range, 41.1-100; SD, 17.26) for the paper-based questionnaire and 85.2 (range, 42.5-100; SD, 17.47) for the Internet-based questionnaire. The intraclass correlation coefficient was 0.97. CONCLUSIONS: The questionnaire can be transferred successfully to the Internet and can be used reliably instead of a paper-based instrument. Recruitment to use an Internet-based questionnaire is limited only by the percentage of patients able to access and use the Internet.

Open incisional biopsy is a safe and accurate technique for soft tissue tumours.

BACKGROUND: Accurate diagnosis of musculoskeletal tumours is important for successful treatment. Studies have reported a high risk of complications following open biopsy and have advocated core biopsy as a safer alternative; however, accuracy may be reduced with the smaller sample. The aims of this study were to determine the accuracy of open incisional biopsy, the complications (overall and those that affected subsequent management) including local recurrence and the need for further surgery. METHODS: This study was a retrospective audit of 135 consecutive open incisional biopsies of soft tissue tumours. The complications, including changes to surgical management as a direct result of complications of the biopsy, were recorded for all 135 cases. The accuracy of the open biopsy was determined by comparing the histology of the biopsy with the final histology of the 88 cases that proceeded to definitive surgical resection. RESULTS: There were two complications attributable to the biopsy (complication rate 1.5%). No complication affected the definitive management. There were three cases where the biopsy incorrectly reported a benign condition when it was malignant (benign versus malignant accuracy 96%). There were no cases of benign initially being reported as malignant. The tissue diagnosis was correct in 72 of the excised specimens (accuracy 82%). The false positive rate for malignant versus benign was 0%, sensitivity 93%, specificity 100% and positive predictor value 100%. DISCUSSION: Open incisional biopsy remains a safe and accurate method of obtaining a tissue diagnosis when the principles of biopsy are adhered to.

The survivorship of protrusio cages for metastatic disease involving the acetabulum.

BACKGROUND: Metastatic disease commonly affects the proximal femur and occasionally the acetabulum. Surgical options include the use of a protrusio cage with a THA. However, the complications and survivorship of these cages for this indication is unknown. QUESTIONS/PURPOSES: The purpose was to report the restoration of function, complications and implant survival. METHODS: The medical records of 29 patients undergoing insertion of a protrusio cage for metastatic pelvic disease were reviewed. Complications were recorded. The most common diagnosis was metastatic breast cancer. During the review process, all but 10 of the 29 patients died 1-73 months after surgery. The median length of survival was 12 months (range, 3 days-100 months) after the procedure; 11 patients were alive at last followup at a median of 16 months (range, 1-100 months). RESULTS: One patient had loss of fixation owing to disease progression. Five patients had dislocations, four of which were treated. There were three deep infections (two that led to dislocation, which proceeded to revision surgery). Ten patients of the 29 patients became household ambulators, 17 became community ambulators, two remained chair-bound, and one bed-bound. CONCLUSIONS: The protrusio cage allowed most patients to return to walking with only one mechanical failure.

Vascular reconstruction in lower limb musculoskeletal tumours.

BACKGROUND: Individual experience in the investigative, planning and operative aspects of lower limb musculoskeletal tumours is often small, making comparison between results difficult. The aim of the study was to describe the recent experience of a single tertiary referral unit performing limb salvage surgery, to identify areas of concern that are amenable to intervention and to provide clinicians an understanding of the surgical options. METHODS: Nine patients with peripheral limb musculoskeletal tumours are described. Four patients had a leiomyosarcoma, and one each of osteosarcoma, synovial chondrosarcoma, synovial sarcoma, liposarcoma and recurrent malignant peripheral nerve sheath tumour. RESULTS: Thirty-day mortality was nil. Two patients (one with a leiomyosarcoma and one with an osteosarcoma) died at 6 months follow-up because of pulmonary metastases. One patient with synovial chondrosarcoma developed a local recurrence and underwent an above-knee amputation. Six patients at 18 months follow-up are alive with no evidence of local recurrence and a functional lower limb. CONCLUSION: These cases are a challenge to the clinicians, radiologists and pathologists. Review by a multidisciplinary team can produce successful results with low post-operative morbidity and mortality. Longer follow-up is required to determine the long-term implications.

Injectable form of calcium sulphate as treatment of aneurysmal bone cysts.

BACKGROUND: Aneurysmal bone cysts (ABC) are a rare condition in adolescents and teenagers but may result in pain, fracture and growth abnormalities. The gold standard of open curettage carries the risk of surgical complications and still a local recurrence rate of 20-30%. Percutaneous treatment of ABC have rarely been reported and a poor response the usual outcome. This study investigated a new technique of percutaneous aspiration and injection of ABC using an aqueous solution of calcium sulphate. METHODS: A radiological diagnosis of a bone cyst was made in 15 consecutive patients and pathologically confirmed as ABC. Most had already sustained a fracture and/or had been previously unsuccessfully treated by minimally invasive techniques including embolization or methylprednisolone injection. The procedure of aspiration and injection with calcium sulphate was undertaken, and the patients were reviewed regularly both clinically and radiologically for a minimum of 2 years. RESULTS: The calcium sulphate cement was reabsorbed completely within 8 weeks. The first osseous response was periosteal new bone formation circumferentially followed by gradual opacification of the cystic cavity. All except one patient that described pain before the procedure reported complete relief of symptoms by 4 weeks. Two patients developed a local recurrence of the cyst, and one subsequently developed a pathological fracture. Two patients sustained pathological fractures through healed cysts, 12 and 22 months after the procedure, respectively. CONCLUSIONS: This new technique has shown good early clinical and radiological responses and a low complication rate in a consecutive group of patients with ABC.

Protecting a patellar ligament reconstruction after proximal tibial resection: a simplified approach.

UNLABELLED: Limb salvage in tumor surgery has encouraged the development of megaprostheses. However, reattaching the ligamentum patellae poses a particular problem: avulsion and/or extensor lag may lead to poor function. We describe a new technique of patellar ligament reconstruction. The technique involves reattachment of the patellar ligament to the tibial tuberosity of the proximal tibial megaprosthesis, which has a porous surface created, and the repair is protected with a cerclage wire through the patella and the prosthesis. In 10 consecutive patients, the range of motion averaged 95 degrees (median, 90 degrees ; range, 70 degrees -120 degrees ), and the mean extension lag averaged 4 degrees (median, 0 degrees ; range, 0 degrees -20 degrees ). We had one case of patellar ligament avulsion. This technique resulted in good quadriceps function and a low incidence of complications. LEVEL OF EVIDENCE: Level IV, therapeutic study.