Pulmonary carcinosarcoma with an aggressive heterologous angiosarcoma component: A case report.

Pulmonary carcinosarcomas are rare biphasic lung tumors comprised of malignant epithelial and malignant mesenchymal components. The most common heterologous sarcomatous elements are osteosarcoma, rhabdomyosarcoma, and chondrosarcoma; a heterologous angiosarcoma component in a pulmonary carcinosarcoma is exceedingly rare. We report a case of a pulmonary carcinosarcoma containing adenocarcinoma, squamous cell carcinoma, undifferentiated malignant spindle cell, and heterologous angiosarcoma components. The patient, a 64-year-old woman, had initially presented to medical attention with hemoptysis. Although the tumor was thought to be confined to the lung at resection (pT3N0), she developed multiple metastatic foci within 3 weeks of lobectomy and required the evacuation of an intraparenchymal left occipital hematoma secondary to a hemorrhagic intra-axial focus of metastatic carcinosarcoma. She died 6 weeks after her primary lung resection from rapidly progressive metastatic disease. We hope the description and discussion provided herein will further the medical community's understanding of this rare malignancy.

EBV-positive T/NK-associated lymphoproliferative disorders of childhood: A complete autopsy report.

INTRODUCTION: Epstein-Barr Virus (EBV)-associated systemic T-cell lymphoproliferative disorder of childhood is a rare but severe manifestation of chronic EBV infection. Despite several case reports characterizing this rare hematological neoplasm, the literature describes extensive heterogeneity in the presentation of this disease. CASE PRESENTATION: Here we present a complete autopsy of a 16-year-old girl who ultimately succumbed to EBV-associated systemic T-cell lymphoproliferative disorder of childhood. Her clinical presentation demonstrated a non-specific pharyngitis with positive mono spot test, evolving into fulminant multi-organ failure, disseminated intravascular coagulopathy, sepsis, and ultimately death. CONCLUSIONS: Post-mortem findings included extensive hemorrhage, and infiltration of the liver, spleen, lymph nodes and bone marrow with neoplastic T-cells. There was extensive hemophagocytic lymphohistiocytosis (HLH) within these organs, suggesting overlap between the EBV-associated systemic T-cell lymphoproliferative disorder of childhood and EBV-associated HLH. We hope these findings provide a more comprehensive overview of several possible manifestations of EBV-associated systemic T-cell lymphoproliferative disorder of childhood.

Activity-based labeling of matrix metalloproteinases in living vertebrate embryos.

Extracellular matrix (ECM) remodeling is a physiologically and developmentally essential process mediated by a family of zinc-dependent extracellular proteases called matrix metalloproteinases (MMPs). In addition to complex transcriptional control, MMPs are subject to extensive post-translational regulation. Because of this, classical biochemical, molecular and histological techniques that detect the expression of specific gene products provide useful but limited data regarding the biologically relevant activity of MMPs. Using benzophenone-bearing hydroxamate-based probes that interact with the catalytic zinc ion in MMPs, active proteases can be covalently 'tagged' by UV cross-linking. This approach has been successfully used to tag MMP-2 in vitro in tissue culture supernatants, and we show here that this probe tags proteins with mobilities consistent with known MMPs and detectable gelatinolytic activity in homogenates of zebrafish embryos. Furthermore, because of the transparency of the zebrafish embryo, UV-photocroslinking can be accomplished in vivo, and rhodamated benzophenone probe is detected in striking spatial patterns consistent with known distributions of active matrix remodeling in embryos. Finally, in metamorphosing Xenopus tadpoles, this probe can be used to biotinylate active MMP-2 by injecting it and cross-linking it in vivo, allowing the protein to be subsequently extracted and biochemically identified.

Differential in vivo zymography: a method for observing matrix metalloproteinase activity in the zebrafish embryo.

Investigations into the molecular mechanisms of, and cellular signaling pathways modulating ECM remodeling are especially challenging due to the complex post-translational regulation of the primary effectors of ECM catabolism - the matrix metalloproteinases (MMPs). Recently a variety of approaches to the detection of MMP activity have been developed, and the prospect of visualizing ECM remodeling activity in living tissues is now opening exciting avenues of research for matrix biologists. In particular the use of FRET-quenched MMP substrates, which generate a fluorescent signal upon hydrolysis, is becoming increasingly popular, especially because linkers with defined and/or restricted proteolytic sensitivity can be used to bind fluorophore-quencher pairs, making these probes useful in characterizing the activity of specific proteases. We have taken advantage of the transparency and amenability to reverse genetics of the zebrafish embryo, in combination with these fluorogenic MMP substrates, to develop a multiplex in vivo assay for MMP activity that we dub "differential in vivo zymography."

The zebrafish embryo: a powerful model system for investigating matrix remodeling.

Extracellular matrix (ECM) remodeling is a process that is crucial to the development of embryos, the growth and metastasis of tumors, and wound healing and homeostasis of tissues in adults. As such, it involves dozens of gene products that are regulated by mechanisms operating at transcriptional and multiple posttranslational levels. This complexity of regulation has made the development of a comprehensive understanding of the biology of ECM remodeling in vivo an unusually challenging task, yet such an understanding would be of profound value to our knowledge of and clinical approaches to the treatment of many cancers. The primary effectors of ECM remodeling are the matrix metalloproteinases (MMPs). Homologs of this gene family have been identified in every metazoan examined. We propose that the zebrafish embryo is an ideal system for the study of the regulation of MMP activity, and we present some progress we have made in the development of this organism as a platform for MMP research. We have identified 25 genes encoding MMPs in the zebrafish genome, and 5 genes encoding their endogenous inhibitors, the tissue inhibitors of MMPs. Based on a phylogenetic analysis, we have identified the most probable homologies of these sequences and found that there are two that are of equivocal identity. We have developed 17 antibodies specific to zebrafish MMPs and have begun characterizing the ontogeny of these molecules. Finally, we have developed two novel assays that allow the detection and characterization of active MMPs in vivo (differential in vivo zymography and activity-based protease profiling). In combination with the array of powerful biochemical, genomic, cell, and molecular biological techniques available to zebrafish researchers already, we feel that these new reagents and techniques make the zebrafish the best model system for the study of MMP regulation currently available.