Benign Notochordal Cell Tumors: A Comparative Histological Study of Benign Notochordal Cell Tumors, Classic Chordomas, and Notochordal Vestiges of Fetal Intervertebral Discs
ABSTRACT Intraosseous benign notochordal cell tumors are recently recognized conditions that may undergo malignant transformation to classic chordomas. This study attempts to define the morphologic and immunohistochemical characteristics of 34 benign notochordal cell tumors by contrasting them with classic chordomas and the notochordal vestiges in fetal intervertebral discs. Benign notochordal cell tumors were characterized by well-demarcated though unencapsulated sheets of adipocyte-like vacuolated and less vacuolated eosinophilic cells within axial bones. The round nuclei were mildly polymorphic but bland. The tumor cells often contained cytoplasmic eosinophilic hyaline globules and lack any intercellular myxoid matrix or necrosis. The involved bone trabeculae were often sclerotic without evidence of bone destruction. The histologic features were different from those of both notochordal vestiges in fetal intervertebral discs and classic chordomas. There was overlap in immunohistochemical reactivity of benign notochordal cell tumors and chordomas, but notochordal vestiges failed to demonstrate cytokeratin 18 positivity. A more appropriate term for the lesions is "benign notochordal cell tumor" rather than "notochordal rest" or "notochordal hamartoma" as they are not rests and do not fulfill the definition of hamartoma. Benign notochordal cell tumors do not need any surgical procedure and must be adequately recognized to prevent unnecessary operations.
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ABSTRACT: Chordoma is a rare malignant bone tumour, showing notochordal differentiation, which occurs in the axial skeleton. Brachyury, a molecule involved in notochordal development, is a highly specific and sensitive marker for chordoma. It is hypothesised that brachyury or genes involved in its activation are implicated in the pathogenesis of chordoma. As there is currently no effective drug therapy for chordoma the aim of this study was to identify genetic events involved in chordoma pathogenesis with a view to identifying potential therapeutic targets. One hundred chordomas (50 skull-based, 50 non-skull based) were studied. Immunohistochemistry showed that the PI3K/AKT/TSC/mTOR pathway was activated in 65% of chordomas, thereby providing a rationale for testing mTOR inhibitors for the treatment of selected cases. DNA sequencing revealed no mutations in PI3KCA or RAS homologue enriched in brain (Rheb) in 23 tumours. Immunohistochemistry and Western blotting showed activation of the fibroblastic growth factor receptor (FGFR)/RAS/RAF/MEK/ERK/ETS2/brachyury pathway in more than 90% of cases, but no mutations were found in the genes analysed (FGFRs, KRAS, BRAF and brachyury) in 23 tumours. Three percent of cases revealed brachyury amplification but nearly half of the cases showed chromosomal abnormalities involving the brachyury locus. Knockdown of brachyury was achieved in the U-CH1 chordoma cell line using shRNA and resulted in premature cell senescence. These findings demonstrate that brachyury plays an important role in chordoma pathology. FISH analysis showed EGFR copy number gain in 45% of chordomas, including 6% with amplification and 39% with high level polysomy. The EGFR inhibitor, tyrphostin (AG1478) significantly inhibited growth of the chordoma cell line, and Western blotting showed this was associated with reduced phosphorylation of EGFR in a dose dependent manner. This study provides evidence for the first time that selected chordomas may be susceptible to treatment with EGFR inhibitors.
Conference Paper: Digital signal processing applied to the subscriber line interface[Show abstract] [Hide abstract]
ABSTRACT: Developments related to the use of digital signal processing techniques for pcm codec circuits have recently yielded a number of IC realisations. Our work in this area, which is a further development of an earlier codec circuit, is described in the paper, together with a discussion of possibilities for further applications of digital signal processing to the subscriber's line interface. Finally the need for an alternative technology partitioning for the line interface is discussed.Acoustics, Speech, and Signal Processing, IEEE International Conference on ICASSP '82.; 06/1982
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ABSTRACT: A technique for reducing the error floor of differential phase-shift-keying (DPSK) receivers impaired by phase noise is introduced and analyzed. In the proposed (optical) DPSK receiver, the bandwidth of integrate-and-dump (I&D) filters are decreased so that multiple samples per symbol duration of the received signal are made available to the post-detection and decision circuitry. The proposed post-detection circuitry, referred to as the one-bit-shifted expanding-window (OBSEW) post-detection processing scheme, correlates the acquired samples that are centered about the signal transition point in a two-symbol signaling interval. For a phase-noise-limited operation, it is shown that the proposed OBS-EW scheme achieves an error floor that is significantly smaller than that of a conventional DPSK receiverSignals, Systems, and Electronics, 1995. ISSSE '95, Proceedings., 1995 URSI International Symposium on; 11/1995