Hypoxia-inducible factors, HIF-1α and HIF-2α, are expressed in the majority of clear-cell renal cell carcinoma (CC-RCC). In vitro, HIFα isoforms regulate a differential set of genes, and their effects in vivo within CC-RCC tumours may affect outcome. The role of angiogenesis and HIFα transcriptional products, including those involved in cell metabolism and morphological dedifferentiation have not been extensively investigated and might have relevance to the development of antiangiogenic or anti-HIFα trials in primary CC-RCC, either before or after radical nephrectomy. We analysed 168 consecutive clear-cell renal tumours from 1983 to 1999 within tissue microarrays and assessed expression of HIF-1α and HIF-2α together with the protein expression of seven of their target genes (BNIP3, CA9, Cyclin D1, GLUT-1, LDH5, Oct-4 and VEGF). The expression of these factors was compared with patient overall survival and CD31 angiogenesis. We found that HIFα antigenicity deteriorated with the age of the paraffin block (P < 0.0001) and in tumours from 1983 to 1992 was deemed not to be reliable. Similar findings were found in aged archival osteosarcoma samples. This might have important implications for retrospective biomarker studies that rely on archival tissue material. HIF-1α(HIGH)/HIF-2α(LOW) tumours had a worse overall survival compared with HIF-1α(LOW)/HIF-2α(LOW) tumours (P = 0.04). Surprisingly, on multivariate analysis, high levels of CD31(+) angiogenesis was shown to be an independent prognostic marker of increased overall survival (P = 0.003). We propose that better differentiation of vascular endothelium may be a reflection of a greater production of vessel stabilization factors versus pro-angiogenic factors, and therefore a less aggressive phenotype.
Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2−/−/γc−/− mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000–5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised “malignant” bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing.
High rates of positive margins and the need for further excision makes this tumour particularly suited to management by multidisciplinary surgical teams. Microscopic tumour can be present up to 29 mm from the macroscopic tumour in fascially-based tumours. Cite this article: Bone Joint J 2016;98-B:1682-8.
Background: Sarcomas are rare, aggressive cancers which can occur in any region of the body. Surgery is usually the cornerstone of curative treatment, with negative surgical margins associated with decreased local recurrence and improved overall survival. Indocyanine green (ICG) is a fluorescent dye which accumulates in sarcoma tissue and can be imaged intraoperatively using handheld near-infrared (NIR) cameras, theoretically helping guide the surgeon’s resection margins. Methods: Patients operated on between 20 February 2019 and 20 October 2021 for intermediate to high grade sarcomas at our centres received either conventional surgery, or were administered ICG pre-operatively followed by intra-operative NIR fluorescence guidance during the procedure. Differences between the unexpected positive margin rates were compared. Results: 115 suitable patients were identified, of which 39 received ICG + NIR fluorescence guided surgery, and 76 received conventional surgery. Of the patients given ICG, 37/39 tumours fluoresced, and surgeons felt the procedure was guided by the intra-operative images in 11 cases. Patients receiving ICG had a lower unexpected positive margin rate (5.1% vs. 25.0%, p = 0.01). Conclusions: The use of NIR fluorescence cameras in combination with ICG may reduce the unexpected positive margin rate for high grade sarcomas. A prospective, multi-centre randomised control trial is now needed to validate these results.
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