Growth in the Lower Limb Following Chemotherapy for a Malignant Primary Bone Tumour: A Straight-Line Graph

Purpose. The aim of this paper was to assess the growth in the unaffected lower limb of children who had received chemotherapy for a malignant primary bone tumour around the knee

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity

Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma

Background: Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. Methods: Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). Results: Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54–5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19–3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42–3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01–4.68, P = 0.04). Conclusions: This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.</p

Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, paraffin-embedded tissue in a series of 18 cases of alveolar soft part sarcoma: Useful diagnostic tools in cases with unusual histological features

Alveolar soft part sarcoma (ASPS) is a rare malignancy; diagnostic problems may occur when cases present as a metastasis or with unusual morphologic features. In this study, a series of 18 cases with follow-up information were analysed with regard to the ASPL/TFE3 fusion transcripts and immuno-detection of TFE3 using archival formalin-fixed, paraffin-embedded tissues. Novel primers to detect ASPL/TFE3 fusion transcripts, type 1 and 2, were designed. The patients, ten female and eight male, ranged in age from 3 to 46 years; 16 involved soft tissues of the extremities (nine, lower; seven, upper), one involved the uterine cervix and one was a primary bone tumour of the foot. Seven ASPS had unusual morphologic features lacking the typical alveolar pattern. Seven had lung metastases at the time of diagnosis, and three developed lung and brain metastases later. Four patients died of disease (after 1-5 years); four are alive with metastases (after 2-15 years), and ten are alive and well (after 1-10 years). Vascular invasion correlated with metastatic disease. All 18 ASPS, four granular cell tumours (one of which was malignant) and one adrenal cortical carcinoma showed TFE3 immuno-positivity. The 18/18 ASPS showed ASPL/TFE3 fusion transcripts (nine, type 1; nine, type 2), four of which had a balanced translocation. ASPL/TFE3 fusion transcripts were not detected in 25 controls. We conclude that immuno-detection of TFE3 and RT-PCR-based identification of ASPL/TFE3 fusion transcripts in formalin-fixed, paraffin-embedded tissues are powerful tools in the diagnosis of ASPS, particularly in cases with unusual morphologic features. © Springer-Verlag 2010

Proximal femoral replacements for metastatic bone disease: financial implications for sarcoma units

Metastatic pathological fractures of the proximal femur are increasingly treated by endoprosthetic proximal femoral replacement. We report the results and the costs incurred performing these procedures at our supra-regional sarcoma unit. Sixty-two patients underwent 63 proximal femoral replacements for metastatic bone disease over a seven-year period. Breast cancer was the most common primary pathology. One patient underwent a revision procedure for infection. Twenty-two patients suffered dislocations, most commonly those undergoing a conventional arthroplasty articulation. The estimated cost of a proximal femoral replacement is £18,002 at our centre. Less than half of this is reimbursed under Payment by Results. Endoprosthetic replacement of the proximal femur is an effective treatment of metastases, but is poorly reimbursed under current funding arrangements