Evaluation of the role and cost-effectiveness of end-of-life orthopaedic interventions in cancer patients with skeletal metastases to the hip.

This study aimed to evaluate the effect of hip reconstruction on patients with skeletal metastases to the hip. We investigated the effect of hip reconstruction on quality of life and ambulatory status, as well as cost-effectiveness of hip reconstruction in this group of patients.

Cancer-related ectopic expression of the bone-related transcription factor RUNX2 in non-osseous metastatic tumor cells is linked to cell proliferation and motility.

INTRODUCTION: Metastatic breast cancer cells frequently and ectopically express the transcription factor RUNX2, which normally attenuates proliferation and promotes maturation of osteoblasts. RUNX2 expression is inversely regulated with respect to cell growth in osteoblasts and deregulated in osteosarcoma cells. METHODS: Here, we addressed whether the functional relationship between cell growth and RUNX2 gene expression is maintained in breast cancer cells. We also investigated whether the aberrant expression of RUNX2 is linked to phenotypic parameters that could provide a selective advantage to cells during breast cancer progression. RESULTS: We find that, similar to its regulation in osteoblasts, RUNX2 expression in MDA-MB-231 breast adenocarcinoma cells is enhanced upon growth factor deprivation, as well as upon deactivation of the mitogen-dependent MEK-Erk pathway or EGFR signaling. Reduction of RUNX2 levels by RNAi has only marginal effects on cell growth and expression of proliferation markers in MDA-MB-231 breast cancer cells. Thus, RUNX2 is not a critical regulator of cell proliferation in this cell type. However, siRNA depletion of RUNX2 in MDA-MB-231 cells reduces cell motility, while forced exogenous expression of RUNX2 in MCF7 cells increases cell motility. CONCLUSIONS: Our results support the emerging concept that the osteogenic transcription factor RUNX2 functions as a metastasis-related oncoprotein in non-osseous cancer cells.

Three-dimensional spatial configuration of tumour cells confers resistance to chemotherapy independent of drug delivery.

Anticancer drug discovery has been hampered by the lack of reliable preclinical models, which routinely use cells grown in two-dimensional (2D) culture systems. However, many of the characteristics of cells in 2D culture do not translate into the findings in animal xenografts. Three-dimensional (3D) growth may be responsible for some of these changes, and models using cells grown in 3D may form a more representative step in tumouricidal validation prior to animal implantation and human testing. For the 3D model, we cultured 143.98.2, SaOS2 or U2OS osteosarcoma cells seeded in porous Bombyx mori silk sponges. We conducted real-time PCR on cells grown in 2D culture and 3D scaffolds for the proliferation markers cyclin B1 and E2F1 and the actin regulator RhoA, and found a significant decrease in expression levels for the 3D tumour models (p = 0.02, < 0.001 and 0.008 for cyclin B1, E2F1 and RhoA for 143.98.2; p = 0.02, 0.002 and 0.02 for cyclin B1, E2F1 and RhoA for U2OS, respectively). In contrast, p21 was upregulated when SaOS2 and U2OS were cultured in the 3D scaffolds (p < 0.001) and there was no increase in DNA quantity during the culture period. We correspondingly observed G1 arrest when cell cycle analysis was conducted. Cytotoxicity results for cells treated with serial dilutions of doxorubicin and cisplatin showed that cells in 3D scaffolds were less sensitive to drug treatment than in 2D culture, and the difference was more pronounced for cell cycle specific agents. Copyright © 2013 John Wiley & Sons, Ltd.

The dominant role of IL-8 as an angiogenic driver in a three-dimensional physiological tumor construct for drug testing.

The induction of angiogenesis and the promotion of tumor growth and invasiveness are processes critical to metastasis, and are dependent on reciprocal interactions between tumor cells and their microenvironment. The formation of a clinically relevant tumor requires support from the surrounding stroma, and it is hypothesized that three-dimensional (3D) tumor coculture models offer a microenvironment that more closely resembles the physiological tumor microenvironment. In this study, we investigated the effects of tissue-engineered 3D architecture and tumor-stroma interaction on the angiogenic factor secretion profiles of U2OS osteosarcoma cells by coculturing the tumor cells with immortalized fibroblasts or human umbilical vein endothelial cells (HUVECs). We also carried out Transwell migration assays for U2OS cells grown in monoculture or fibroblast coculture systems to study the physiological effect of upregulated angiogenic factors on endothelial cell migration. Anti-IL-8 and anti-vascular endothelial growth factor (VEGF)-A therapies were tested out on these models to investigate the role of 3D culture and the coculture of tumor cells with immortalized fibroblasts on the efficacy of antiangiogenic treatments. The coculture of U2OS cells with immortalized fibroblasts led to the upregulation of IL-8 and VEGF-A, especially in 3D culture. Conversely, coculture with endothelial cells resulted in the downregulation of VEGF-A for cells seeded in 3D scaffolds. The migration of HUVECs through the Transwell polycarbonate inserts increased for the 3D and immortalized fibroblast coculture models, and the targeted inhibition of IL-8 greatly reduced HUVEC migration despite the presence of VEGF-A. A similar effect was not observed when anti-VEGF-A neutralizing antibody was used instead, suggesting that IL-8 plays a more critical role in endothelial cell migration than VEGF-A, with significant implications on the clinical utility of antiangiogenic therapy targeting VEGF-A.

An unusual presentation of a simple bone cyst in the scapula.

A 38-year-old man presented with pain in the left shoulder following a fall. A rotator cuff tear was suspected but roentgenograms revealed a lytic, expanded, multiseptate lesion of the scapula adjacent to glenoid. This was compatible with a giant cell tumor, aneurysmal bone cyst or simple bone cyst. The MRI showed rim enhancement and clinched the diagnosis of simple bone cyst. An infraspinous approach to scapula was undertaken and open biopsy confirmed the diagnosis of simple bone cyst. Definitive treatment in the form of curettage and calcium phosphate cementation was carried out. The postoperative period was uneventful. Early mobilization was started. Patient remained well on follow-up and has returned to work in a physically demanding capacity.

Collagen membranes for host-graft integration: an animal study.

PURPOSE: To evaluate the biocompatibility of collagen membranes for host-graft integration. METHODS: 18 Achilles tendons in 9 rats were used. Five tendons were controls and repaired with prolene 3-0 sutures only. The remaining 13 tendons were cases, and a 10-mm section was excised. A 15x5 mm bovine pericardial collagen membrane (Tutomesh; Tutogen Medical, Germany) was laid circumferentially around the tendon and secured with prolene 3-0 sutures. Tendons were harvested after 4 and 6 weeks. Only the repair interfaces (i.e. cut ends and immediate surrounding tissue) were evaluated. Integration of the membranes to the tendons was evaluated using a semi-quantitative wound maturation scale (1-4) based on the presence of inflammatory cells, vascularisation, fibroblasts, and the amount and alignment of collagen fibrils. The presence of fibroblasts and vascularisation were positive parameters, whereas inflammatory cell ratios were regarded as negative parameters. Immunohistochemical study was also performed. RESULTS: There was no host-graft reaction or wound complication (infection, abscess or seroma). Histological and immunohistochemical assessment confirmed re-approximation of the cut tendon ends and incorporation of the membrane onto the tendon as early as week 4. At week 4, the mean maturation scale scores were 2.7 for controls and 3.3 for cases (p=0.11). At week 6, the corresponding values were 3.8 and 3.0 (p=0.004). A reparative process involving formation of blood vessels and invasion by fibroblasts was noted in both control and case tendons. In controls, T- and B-lymphocytes were present. In cases, inflammatory cells were noted at the junction of the host and membrane without invasion of the graft material. There was no lymphocytic infiltration on the graft. The foreign body reaction was localised and minimal. CONCLUSION: The collagen membrane achieved favourable host-graft integration as early as week 4, with a minimal foreign body reaction.

Collagen membranes for host-implant integration: a pilot clinical study.

PURPOSE: To evaluate host-implant integration with collagen membranes in 14 patients who underwent limb salvage surgery for musculoskeletal oncological disease. METHODS: 8 females and 6 males aged 10 to 69 (mean, 30) years underwent limb savage surgery with collagen membranes (Tutomesh; Tutogen Medical, Germany) for osteosarcoma (n=7), chondrosarcoma (n=3), giant cell tumour (n=1), malignant fibrous histiocytoma (n=1), arteriovenous malformation (n=1), and pigmented villonodular synovitis (n=1). The procedures performed were proximal humeral resection (n=3), partial scapulectomy (n=1), proximal femoral resection (n=2), total femoral resection (n=2), proximal tibial resection (n=3), and wide resection of soft tissues of the knee (n=3). In addition, 10 patients underwent endoprosthesis reconstruction. Reconstruction of musculoskeletal defects was classified into type I (intercalary, n=2), type II (joint, n=4), and type III (both, n=8). Graft incorporation and local recurrence were monitored. Clinical outcome measures entailed the Short Form-36, Toronto Extremity Salvage Score (TESS), and Musculoskeletal Tumor Society Score (MSTS). RESULTS: Two patients with proximal tibial resection and one with total femoral resection had wound healing problems. No patient had any infection or any foreign body reaction necessitating implant removal. Eight patients with type II or III reconstruction were followed up for a mean of 11 (range, 1-23) months. Their scores in the Short Form-36, TESS, and MSTS were similar to those who had undergone reconstructions without the membrane, with the exception of type II reconstructions for which the membrane conferred good results. CONCLUSION: The Tutomesh membrane facilitated host-implant integration and provided a feasible anatomic reconstruction for ligaments in the shoulder, knee, and hip.

The need for a system of prognostication in skeletal metastasis to decide best end-of-life care - a call to arms.

INTRODUCTION: The near terminal patient with skeletal metastasis may suitably be palliated with an intramedullary nail whereas another patient with good survival potential may benefit from a more extensive resection and reconstructive procedure. In a previous study by the senior author (Nathan et al, 2005), life expectancy in patients operated on for bone metastases correlated with clinical and haematological parameters in a normogram. We performed a cross-cultural comparison to validate this normogram. MATERIALS AND METHODS: We randomly selected 73 patients who had undergone surgery for metastatic bone disease between 28 December 2000 and 11 March 2009. The time to deaths was recorded from hospital records and telephone interviews. Multiple parameters including clinical, radiological and haematological were evaluated for significant prognostic value using Kaplan-Meier survivorship analysis. Statistically significant parameters were entered into a Cox regression model for statistically independent significance. A multi-tier prediction of survival was performed by workers from various levels of seniority. RESULTS: At the time of analysis, there were 40 deaths (55%). Median survival was 15.8 (95% CI, 7.9 to 23.7) months. Kaplan-Meier analysis showed that low haemoglobin (P = 0.0000005), presence of lymph node metastases (P = 0.00008), multiple bone metastases (P = 0.003), presence of visceral metastases, (P = 0.007), low lymphocyte count (P = 0.02) and low serum albumin (P = 0.02) were significantly associated with poor survival. By Cox regression analysis, presence of visceral metastases (P = 0.002), presence of lymph node metastases (P = 0.0002) and low haemoglobin (P = 0.01) were shown to be independent factors in the prediction of survival. Survivorship readings were superimposed onto the previous normogram and found to be similar. Independent blinded use of the normogram allowed good prediction of survival. There was a tendency to underestimate survival when patients survived beyond 1 year of skeletal metastasis. CONCLUSION: Our findings are similar to that of the previous study in showing a relationship between the above-mentioned parameters and survival. This is despite differences in patient demographic characteristics and management protocols. Use of the tools may allow better siting of most appropriate surgery in metastatic bony disease.

Active unicameral bone cysts in the upper limb are at greater risk of fracture.

PURPOSE: To elucidate the natural history of unicameral bone cyst (UBC) and risk factors for pathological fracture. METHODS: 14 males and 8 females (mean age, 9 years) diagnosed with UBC were reviewed. Cyst location, symptoms, and whether there was any fracture or surgery were recorded. Cyst parameters were measured on radiographs, and included (1) the cyst index, (2) the ratio of the widest cyst diameter to the growth plate diameter, and (3) the adjusted distance of the cyst border from the growth plate. RESULTS: There were 11 upper- and 11 lower-limb cysts. 13 patients had pathological fractures and 9 did not. 20 patients were treated conservatively with limb immobilisation; 2 underwent curettage and bone grafting (one resolved and one did not). Seven cysts resolved (5 had fractures and 2 did not). The risk of fracture was higher in the upper than lower limbs (100% vs 18%, p<0.001). Fractured cysts were larger than unfractured cysts (mean cyst index, 4.5 vs. 2.2, p=0.07). Active cysts were more likely to fracture. CONCLUSION: Conservative management had a 30% resolution rate. Surgery should be considered for large active cysts in the upper limbs in order to minimise the fracture risk.