Inflammatory Myofibroblastic Tumor Arising in the Cul-De-Sac, Mimicking Ectopic Decidua.

Extra-ovarian neoplasms incidentally discovered during cesarean section are very rare. Here we report a case of inflammatory myofibroblastic tumor found during cesarean section of a 30-year-old, full-term woman, forming a mass in her cul-de-sac. Histology revealed an extensively decidualized spindle cell process, positive for anaplastic large cell lymphoma kinase (ALK) through immunohistochemistry and fluorescent in situ hybridization (FISH). To the best of our knowledge, this is the first presentation of inflammatory myofibroblastic tumor in this location without concurrent intrauterine component, that additionally demonstrates this degree of decidualization, mimicking ectopic decidua.

Ossifying fibromyxoid tumor metastatic to the thyroid: a case report and review of the literature.

Ossifying fibromyxoid tumors are rare soft-tissue neoplasms, usually with an indolent course. However, atypical/malignant variants have been described, showing either local recurrence after complete excision or metastasis to the lungs, mediastinum, adrenals, or soft tissue. We report the case of an ossifying fibromyxoid tumor of the left ankle that metastasized to the lung and thyroid gland 12 years after the initial diagnosis and surgical treatment. To our knowledge, this is the first reported case of this neoplasm metastasizing to the thyroid gland.

PAX-8 expression in cutaneous ciliated cysts: evidence for Müllerian origin.

Cutaneous ciliated cysts (CCC) are exquisitely rare, benign cystic lesions demonstrating simple, ciliated epithelial linings reminiscent of fallopian tube epithelium. Most commonly, CCC show a predilection for the lower extremities of young reproductive age women and demonstrate immunohistochemical positivity for estrogen and progesterone receptors, supporting the theory that they are derived from ectopic Müllerian rests. PAX-8 is a paired box gene, important in the development of Müllerian and thyroid organs and has utility in the identification of tumors of Müllerian, renal, and thyroid origin. Prompted by the precedent studies on PAX-8 immunohistochemical expression in tumors of Müllerian origin, this article aimed to explore the utility of this antibody in defining the histogenesis of 2 bona fide cases of CCC, both occurring in young reproductive age women. Herein, 2 prototypic index cases of CCC with strong nuclear positivity for estrogen and progesterone receptors are shown to also have positive nuclear staining for PAX-8, further supporting their likely Müllerian origin. These data support the designation of these lesions as cutaneous Müllerian cysts, distinct from potential ciliated cysts of eccrine origin.

CD40·FasL and CTLA-4·FasL fusion proteins induce apoptosis in malignant cell lines by dual signaling.

Evolution of apoptosis resistance in both lymphoma and leukemia cells is well documented, and induction of apoptosis in malignant cells is a major goal of cancer therapy. Up-regulation of anti-apoptotic signals is one of the mechanisms whereby resistance to apoptosis emerges. We have previously described the fusion proteins CD40·FasL and CTLA-4·FasL, which are formed from two functional membrane proteins and induce apoptosis of activated T cells. The present study explores the potential use of CD40·FasL and CTLA-4·FasL for the killing of malignant cells of lymphatic origin. Using malignant B and T cell lines that differ in surface expression of costimulatory molecules, we found that CTLA-4·FasL induces effective apoptosis of cells expressing CD95 and activates caspases 3, 8, and 9. Only B7-expressing B cells responded to CTLA-4·FasL with rapid abrogation of cFLIP expression. CD40·FasL effectively killed only the T cells that express high levels of CD40L in addition to CD95. In these cells, CD40·FasL significantly diminished cFLIP expression. Importantly, each of the fusion proteins is more potent than its respective components parts, alone or in combination. Thus, the proteins with their two functional ends deliver a pro-apoptotic signal and, in parallel, inhibit an anti-apoptotic signal, thus optimizing the wanted, death-inducing effect. Therefore, these proteins emerge as promising agents to be used for targeted and specific tumor cell killing.

Analysis of HIF-1a and its regulator, PHD2, in retroperitoneal sarcomas: clinico-pathologic implications.

Hypoxia is known to play important role in cancer biology.  In sarcomas, hypoxia-induced protein biomarkers such as Hypoxia Inducible Factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), and Erythropoietin (Epo) have been previously reported in only a few studies.  Moreover, the biologic significance and relationship to tumorigenesis of these hypoxia-induced biomarkers is not well understood in the context of sarcoma. The HIF negative regulator, Prolyl Hydroxylase Domain protein 2 (PHD2) has not been evaluated in sarcomas.  We examined the expression of PHD2, HIF-1a, and several other hypoxia induced biomarkers in a series of clinically characterized, retroperitoneal sarcomas with immunohistochemical methods.  Expression of these proteins was analyzed and correlated with clinical outcome.  Increased HIF-1a expression was associated with shorter overall and disease free survival.  PHD2 expression was detected in the majority of sarcoma cases, with increased expression correlating with high tumor grade but not with survival.  Though changes in PHD2 expression alone did not correlate with overall and disease free survival, reduced/absent PHD2 expression in the presence of HIF-1a expression was associated with shorter overall and disease-free survival than that of other HIF-1a/PHD2 expression profiles.  These observations suggest that regulation and expression of both PHD2 and HIF-1a are important to the biology of sarcomas, and that loss of PHD2 function has an additional adverse effect in the prognosis of sarcomas in tumors expressing HIF-1a.  The biologic and therapeutic implications of HIF-1a and PHD2 expression in retroperitoneal sarcomas warrant further investigation.

Primary cardiac sarcomas: a clinicopathologic analysis of a series with follow-up information in 17 patients and emphasis on long-term survival.

Although cardiac sarcomas are rare in comparison to their soft tissue counterparts, they are the second most common type of primary cardiac neoplasm. Of the few hundred cases reported, most has been based on autopsy series. A series of 27 cardiac sarcomas removed at surgery for curative and diagnostic intent were reviewed for clinicopathologic features with correlation to available postoperative follow-up data in 17 patients. There were 6 angiosarcomas, 6 myxofibrosarcomas, 3 malignant peripheral nerve sheath tumors, 3 leiomyosarcomas, 2 synovial sarcomas, 1 epithelioid hemangioendothelioma, 1 chondrosarcoma, 1 osteosarcoma, and 4 poorly differentiated sarcomas. There was a wide age and size range with slight female predilection. There were 20 cases that arose in the atria/pulmonary vessels, 4 in the ventricles, 1 in mitral valve, and 2 in epi/pericardium. There was a slight left predilection. The histologic grade was low in 4, moderate in 3, and high in 20 cases. Six high-grade and 1 low-grade tumors were also treated with adjuvant chemotherapy and/or radiation. In 17 patients with follow-up data, 6 of 12 patients with high-grade tumor died (4 within 5 days of the initial surgery, 1 in 21 months, and 1 in 131 months), and 1 patient with moderate-grade tumor and all 4 patients with low-grade tumor were alive without evidence of disease at the end of follow-up. Tumor grade appeared to be prognostically important in cardiac sarcoma. Long survival was achieved in patients who survived the initial surgery well.

CTLA-4 . FasL induces early apoptosis of activated T cells by interfering with anti-apoptotic signals.

The fusion protein CTLA-4 . FasL, a paradigmatic "trans signal converter protein", can attach to APC surfaces and in effect convert B7-activating costimulator signals into inhibitory Fas receptor-generated signals. The present study investigates CTLA-4 . FasL's mechanism of action. A combination of p27(kip) and proliferating cell nuclear Ag Western blot and propidium iodide flow cytometric analysis showed no CTLA-4 . FasL effect on cell cycle entry and progression, pointing away from the kind of classical anergy associated with CTLA-4 . Ig. Significantly, CTLA-4 . FasL elicited apoptosis (as detected by annexin-V/propidium iodide costaining) as early as 24 h after T cell activation, suggesting that some coordinate signaling might be capacitating the Fas receptor. Significantly, CTLA-4 . FasL, but not CTLA-4 . Ig, anti-Fas mAb, or the two in combination, abrogated the usual increase in expression of the anti-apototic protein, cFLIP. Furthermore, activation of caspases 8 and 3 were not affected by CTLA-4 . FasL. These findings suggest a model for CTLA-4 . FasL action wherein there is coordinate triggering of a death receptor and suppression of a proapoptotic protein.

New designs for cancer vaccine and artificial veto cells: an emerging palette of protein paints.

Antigen-presenting cells (APC) can be refaced with "protein paints" that change the appearance of their T cell-oriented trans signal arrays. Our group has developed three categories of protein paints suitable for this kind of APC engineering: artificial glycosylphosphatidylinositol (GPI) proteins, palmitated-protein A:Fc*1 fusion protein conjugates, and trans signal converter proteins. Protein paints have been devised with either immune enhancement or suppression in mind. Costimulator * GPI and palmitated-protein A costimulator * Fcgamma1 conjugates can be used to augment the immune-activating potential of tumor cells. Alternatively, protein paints can be designed to transform APC into artificial veto cells, in essence creating Trojan horses capable of inhibiting pathogenic T cells. Trans signal converter proteins (TSCP) have been devised for this purpose. Our first paradigmatic inhibitory TSCP, CTLA-4 * Fas ligand, binds to APC, and in so doing, simultaneously blocks B7 costimulation (via CTLA-4) and sends inhibitory trans signals (via Fas ligand) to T cells with dramatic efficacy. Protein transfer offers a number of advantages over gene transfer in facilitating quantitative and combinatorial protein expression and simplifying in vivo applications; the palette of protein paints with immunotherapeutic potential will undoubtedly continue to evolve.

CTLA-4. FasL induces alloantigen-specific hyporesponsiveness.

The APC:T cell interface can be effectively targeted with immunotherapeutic proteins. We previously described a unique trans signal converter protein, CTLA-4. Fas ligand (FasL), that has the inherent capacities to tether the T cell inhibitor FasL (CD95 ligand) to the surfaces of B7 (CD80 and CD86)-positive APC (via CTLA-4:B7 interaction), and in so doing, to simultaneously interfere with B7-to-CD28 T cell activation signals. Given the continuing need for agents capable of inducing allograft tolerance without generalized immunosuppression, we have explored in depth the functional activity of CTLA-4. FasL in human allogeneic MLR. CTLA-4. FasL inhibits 1 degrees MLR and induces specific hyporesponsiveness in 2 degrees MLR, with both effects only partially reversible with exogenous IL-2. Moreover, the presence of exogenous IL-2 during the 1 degrees MLR does not affect the induction of hyporesponsiveness upon restimulation. Furthermore, CTLA-4. FasL enables partial activation of allostimulated T cells, reduces the fraction of actively dividing cells, and increases the percentage of dead cells among dividing T cells. Taken together, these findings suggest that CTLA-4. FasL-mediated inhibition of secondary alloantigenic responses involves both anergy induction and clonal deletion. Thus, CTLA-4. FasL, a paradigmatic trans signal converter protein, manifests unique functional properties and emerges as a potentially useful immunotherapeutic for modulating alloresponsiveness.