Kelly C. Homlar

Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma.

Currently there is no effective chemotherapy for chordoma. Recent studies report co‐expression of insulin‐like growth factor‐1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin‐dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP‐deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin‐embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2‐associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty‐nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR‐positive tumours showed significantly decreased median disease‐free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine‐99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma. Copyright

Osteoblastoma characterized by a three-way translocation: report of a case and review of the literature

Osteoblastoma, an uncommon primary bone tumor, produces both osteoid and primitive woven bone in a background of fibrovascular connective tissue. Although most osteoblastomas are considered benign, a controversial aggressive variant has been described, which may cause diagnostic confusion with malignant tumors such as osteosarcoma. To date, no specific diagnostic cytogenetic or molecular marker has been identified for osteoblastoma to aid in its distinction. Conventional cytogenetic analysis of an osteoblastoma arising in the femur of a 23-year-old woman revealed a novel three-way translocation involving chromosomes 1, 2 and 14 [t(1;2;14) (q42;q13;q24)]. Rearrangement of 1q42 has been identified in a previously reported case.

Signal transduction pathway analysis in desmoid-type fibromatosis: transforming growth factor-β, COX2 and sex steroid receptors.

Despite reports of sex steroid receptor and COX2 expression in desmoid‐type fibromatosis, responses to single agent therapy with anti‐estrogens and non‐steroidal anti‐inflammatory drugs are unpredictable. Perhaps combination pharmacotherapy might be more effective in desmoid tumors that co‐express these targets. Clearly, further understanding of the signaling pathways deregulated in desmoid tumors is essential for the development of targeted molecular therapy. Transforming growth factor–β (TGFβ) and bone morphogenetic proteins (BMP) are important regulators of fibroblast proliferation and matrix deposition, but little is known about the TGFβ superfamily in fibromatosis. A tissue microarray representing 27 desmoid tumors was constructed; 14 samples of healing scar and six samples of normal fibrous tissue were included for comparison. Expression of selected receptors and activated downstream transcription factors of TGFβ family signaling pathways, β–catenin, sex steroid hormone receptors and COX2 were assessed using immunohistochemistry; patterns of co–expression were explored via correlational statistical analyses. In addition to β–catenin, immunoreactivity for phosphorylated SMAD2/3 (indicative of active TGFβ signaling) and COX2 was significantly increased in desmoid tumors compared with healing scar and quiescent fibrous tissue. Low levels of phosphorylated SMAD1/5/8 were detected in only a minority of cases. Transforming growth factor–β receptor type 1 and androgen receptor were expressed in both desmoid tumors and scar, but not in fibrous tissue. Estrogen receptor–β was present in all cases studied. Transforming growth factor–β signaling appears to be activated in desmoid‐type fibromatosis and phosphorylated SMAD2/3 and COX2 immunoreactivity might be of diagnostic utility in these tumors. Given the frequency of androgen receptor, estrogen receptor–β and COX2 co‐expression in desmoid tumors, further assessment of the efficacy of combination pharmacotherapy using hormonal agonists/antagonists together with COX2 inhibitors should be considered.

Morphologic and immunophenotypic analysis of desmoid-type fibromatosis after radiation therapy ☆

The morphologic changes seen in desmoid-type fibromatosis after radiotherapy have not been well studied, and the degree of cytologic atypia, cellularity, mitotic activity, and lesional necrosis found in desmoid-type fibromatosis treated with ionizing radiation has not been thoroughly assessed. Therefore, we evaluated a series of primary and locally recurrent desmoid-type fibromatoses resected at variable intervals after radiation therapy (XRT) and compared their histopathologic and immunophenotypic features with paired pathologic specimens that were obtained before radiotherapy. The morphologic characteristics of desmoid-type fibromatoses resected before and after radiotherapy were not significantly different in 7 of the 8 cases studied. One case resected 191 months after XRT showed morphologic evidence of fibrosarcomatous transformation, with zonal necrosis, hypercellularity, severe nuclear atypia, and increased mitotic activity. No significant differences in the immunophenotype of desmoid-type fibromatosis were observed after XRT. In rare cases of recurrent desmoid-type fibromatosis, the differential diagnosis may include radiation-induced fibrosarcoma. Our data suggest that histomorphologic alterations attributable to the effects of ionizing radiation in desmoid-type fibromatosis are minimal. Therefore, the presence of cytologic features of malignancy in this setting warrants careful examination and consideration of the rare occurrence of postradiation sarcoma. Lesser degrees of nuclear atypia seen in isolation do not necessarily indicate a poor prognosis in irradiated desmoid-type fibromatosis.

Serum Levels of Methyl Methacrylate Following Inhalational Exposure to Polymethylmethacrylate Bone Cement

UNLABELLED Teratogenic effects of polymethylmethacrylate cement at levels used during routine orthopaedic procedures have never been reported, however the hypothetical risk remains a major concern among female surgeons. Our aim was to determine if methyl methacrylate is detectible in the serum during routine cement exposure. METHODS Twenty healthy volunteers were exposed during the mixing of polymethylmethacrylate cement in a simulated operating room environment. Forty serum samples were obtained during the expected peak inhalational exposure and levels of methyl methacrylate were assessed utilizing headspace gas chromatography mass spectrometry. RESULTS Methyl methacrylate was not detected in any of the forty experimental specimens. CONCLUSIONS With a detection level of 0.5 ppm, methyl methacrylate is undetectable in the serum during routine mixing of polymethylmethacrylate cement.

Signal transduction pathway analysis in fibromatosis: receptor and nonreceptor tyrosine kinases ☆

Despite reports of receptor tyrosine kinase activation in desmoid-type fibromatosis, therapeutic benefits of kinase inhibitor therapy are unpredictable. Variability in signal transduction or cellular kinases heretofore unevaluated in desmoid tumors may be responsible for these inconsistent responses. In either case, a better understanding of growth regulatory signaling pathways is necessary to assess the theoretical potential of inhibitor therapy. Immunohistochemical analysis of tyrosine kinases and activated isoforms of downstream signal transduction proteins was performed on a tissue microarray containing 27 cases of desmoid-type fibromatosis and 14 samples of scar; 6 whole sections of normal fibrous tissue were studied for comparison. Platelet-derived growth factor receptor, β type, and focal adhesion kinase 1 were expressed in all desmoid tumors and healing scars but only 80% and 50% of nonproliferative fibrous tissue samples, respectively. Hepatocyte growth factor receptor was detected in 89% of desmoids and all scars tested, but not in any of the fibrous tissue samples. Epidermal growth factor receptor was detected in only 12% of desmoids and not in scar or fibrous tissue. Mast/stem cell growth factor receptor, receptor tyrosine-protein kinase erbB-2, and phosphorylated insulin-like growth factor 1 receptor/insulin receptor were negative in all study cases. Variable levels of phosphorylated downstream signal transduction molecules RAC-α/β/γ serine/threonine-protein kinase, mitogen-activated protein kinase, and signal transducer and activator of transcription-3 were observed in desmoids (58%, 62%, and 67%), scar tissues (100%, 86%, and 86%), and fibrous tissue (33%, 17%, and 17%). These results indicate that tyrosine kinase signaling is active in both fibromatosis and healing scar, but not in most nonproliferating fibrous tissues. Although platelet-derived growth factor receptor, β type, is expressed ubiquitously in desmoids, the kinases driving cell proliferation in desmoids remain unresolved.