Cheng-Hsiang Hsiao

Involvement of matrix metalloproteinase-13 in stromal-cell-derived factor 1 alpha-directed invasion of human basal cell carcinoma cells.

Basal cell carcinoma (BCC) is one of the most common skin neoplasms in humans and is usually characterized by local aggressiveness with little metastatic potential, although deep invasion, recurrence, and regional and distant metastases may occur. Here, we studied the mechanism of BCC invasion. We found that human BCC tissues and a BCC cell line had significant expression of CXCR4, which was higher in invasive than non-invasive BCC types. Further, of 19 recurrent tumors among 390 BCCs diagnosed during the past 12 years, 17/19 (89.5%) had high CXCR4 expression. We found that the CXCR4 ligand, stromal-cell-derived factor 1α (SDF-1α), directed BCC invasion and that this was mediated by time-dependent upregulation of mRNA expression and gelatinase activity of matrix metalloproteinase-13 (MMP-13). The transcriptional regulation of MMP-13 by SDF-1α was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the AP-1 component c-Jun. Finally, CXCR4-transfected BCC cells injected into nude mice induced aggressive BCCs that co-expressed CXCR4 and MMP-13. The identification of SDF-1α/CXCR4 as an important factor in BCC invasiveness may contribute insight into mechanisms involved in the aggressive potential of human BCC and may improve therapy for invasive BCCs.

p53 overexpression and mutation in metaplastic carcinoma of the breast: genetic evidence for a monoclonal origin of both the carcinomatous and the heterogeneous sarcomatous components

Metaplastic carcinoma of the breast (MCB) is characterized by the biphasic presence of both a carcinomatous component (CC) and heterogeneous sarcomatous components (HSCs). Although an epithelial or myoepithelial origin of the HSCs has been suggested, molecular evidence for a common origin for the CC and HSCs is limited and the mechanism underlying the sarcomatous or metaplastic change is unknown. The present study investigated the frequency and nature of p53 expression and mutation in 11 biphasic and three monophasic MCBs by immunohistochemistry and either needle‐assisted or laser‐capture microdissection, followed by PCR and direct sequencing. In all 11 biphasic MBCs, staining for p53 was concordant in the CC and HSCs (8/11 positive and 3/11 negative), consistent with a monoclonal origin of both components. Significantly, whenever a component of carcinoma in situ was present (5/11), the p53 staining was always concordant with that in the CC and HSCs. Screening of the 14 cases for p53 mutation identified four mutants, each in a single case of biphasic MCB with concordant p53 overexpression. Both the CC and each of the HSCs revealed identical p53 mutation in all four cases; in addition, one of the four cases also had an in situ component and the same mutant was found simultaneously in the in situ, invasive, and sarcomatous components. The concordant pattern of p53 alteration (overexpression or mutation) implies that early p53 mutation, occurring prior to invasion, was maintained throughout tumour progression and metaplastic change. The findings therefore support a monoclonal histogenesis of the various components, but are neutral regarding the role of p53 alteration in the development of metaplastic change in MCBs. Copyright

Transformation between Kaposiform Hemangioendothelioma and Tufted Angioma

Kaposiform hemangioendothelioma and tufted angioma are viewed as two separate disease entities in the current classification of vascular tumors. However, the concurrence of features of both vascular tumors in the same specimen of some patients raises the question whether these tumors exist on a continuum. Herein, we report a dynamic transformation between both tumors within a single patient, which suggests they are two variants of the same vascular tumor.

Hydroa vacciniforme-like primary cutaneous CD8-positive T-cell lymphoma

An 8‐year‐old Taiwanese girl had a 6‐month history of a relapsing papulovesicular eruption on her face that resembled hydroa vacciniforme (HV). Histologically, there was a dense infiltration of large atypical lymphocytic cells expressing CD8. TCR‐γ gene rearrangement study revealed a monoclonal band present in the DNA extracted from the specimen. A diagnosis of CD8+ cutaneous T‐cell lymphoma (CTCL) was made. The patient was treated with Chinese herbal drugs and her skin lesions waxed and waned. At this writing, 11 months after establishment of the diagnosis, the skin lesions have been limited to the facial area and no definite evidence of systemic involvement is noted. To our knowledge, this is the first case of CD8+ primary CTCL with clinical features resembling HV.

Microbiologic Characteristics, Serologic Responses, and Clinical Manifestations in Severe Acute Respiratory Syndrome, Taiwan

The genome of one Taiwanese severe acute respiratory syndrome-associated coronavirus (SARS-CoV) strain (TW1) was 29,729 nt in length. Viral RNA may persist for some time in patients who seroconvert, and some patients may lack an antibody response (immunoglobulin G) to SARS-CoV >21 days after illness onset. An upsurge of antibody response was associated with the aggravation of respiratory failure.

Identification of a novel protein 3a from severe acute respiratory syndrome coronavirus.

The open reading frame 3 of the severe acute respiratory syndrome coronavirus (SARS‐CoV) genome encodes a predicted protein 3a, consisting of 274 amino acids, that lacks any significant similarities to any known protein. We generated specific antibodies against SARS protein 3a by using a synthetic peptide (P2) corresponding to amino acids 261–274 of the putative protein. Anti‐P2 antibodies and the sera from SARS patients could specifically detect the recombinant SARS protein 3a expressed in Escherichia coli and in Vero E6 cells. Expression of SARS protein 3a was detected at 8–12 h after infection and reached a higher level after ∼24 h in SARS‐CoV‐infected Vero E6 cells. Protein 3a was also detected in the alveolar lining pneumocytes and some intra‐alveolar cells of a SARS‐CoV‐infected patients lung specimen. Recombinant protein 3a expressed in Vero E6 cells and protein 3a in the SARS‐CoV‐infected cells was distributed over the cytoplasm in a fine punctate pattern with partly concentrated staining in the Golgi apparatus. Our study demonstrates that SARS‐CoV indeed expresses a novel protein 3a, which is present only in SARS‐CoV and not in other known CoVs.

Modeling the Early Events of Severe Acute Respiratory Syndrome Coronavirus Infection In Vitro

ABSTRACT The clinical picture of severe acute respiratory syndrome (SARS) is characterized by pulmonary inflammation and respiratory failure, resembling that of acute respiratory distress syndrome. However, the events that lead to the recruitment of leukocytes are poorly understood. To study the cellular response in the acute phase of SARS coronavirus (SARS-CoV)-host cell interaction, we investigated the induction of chemokines, adhesion molecules, and DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin) by SARS-CoV. Immunohistochemistry revealed neutrophil, macrophage, and CD8 T-cell infiltration in the lung autopsy of a SARS patient who died during the acute phase of illness. Additionally, pneumocytes and macrophages in the patients lung expressed P-selectin and DC-SIGN. In in vitro study, we showed that the A549 and THP-1 cell lines were susceptible to SARS-CoV. A549 cells produced CCL2/monocyte chemoattractant protein 1 (MCP-1) and CXCL8/interleukin-8 (IL-8) after interaction with SARS-CoV and expressed P-selectin and VCAM-1. Moreover, SARS-CoV induced THP-1 cells to express CCL2/MCP-1, CXCL8/IL-8, CCL3/MIP-1α, CXCL10/IP-10, CCL4/MIP-1β, and CCL5/RANTES, which attracted neutrophils, monocytes, and activated T cells in a chemotaxis assay. We also demonstrated that DC-SIGN was inducible in THP-1 as well as A549 cells after SARS-CoV infection. Our in vitro experiments modeling infection in humans together with the study of a lung biopsy of a patient who died during the early phase of infection demonstrated that SARS-CoV, through a dynamic interaction with lung epithelial cells and monocytic cells, creates an environment conducive for immune cell migration and accumulation that eventually leads to lung injury.

Merkel cell carcinoma and chronic arsenicism

Arsenic is a well-documented human carcinogen. Bowens disease, squamous cell carcinoma, and basal cell carcinoma are the most common skin cancers found in patients exposed to arsenic over the long term. Merkel cell carcinoma has been documented in Taiwanese patients who resided in an endemic area of black foot disease, another condition found in patients with chronic arsenicism. We collected all cases of Merkel cell carcinoma diagnosed at two medical centers in Taiwan (N = 11) to find a possible association between chronic arsenicism and Merkel cell carcinoma. In our study 6 of the 11 patients were residents of the endemic areas for chronic arsenicism.

Coexisting Sclerosing Angiomatoid Nodular Transformation of the Spleen with Multiple Calcifying Fibrous Pseudotumors in a Patient

Primary tumor or tumor-like lesions of the spleen are rare. Among them, vascular lesions are the most common. Vascular tumor of the spleen is different from the usual hemangioma of soft tissue because the vascular structure of the spleen is unique. Sclerosing angiomatoid nodular transformation (SANT) is a recently described vascular lesion of the spleen. Grossly, it is a multinodular, well-circumscribed tumor containing a hypervascular core. Microscopically, it comprises three types of vessels, and each type recapitulates the immunohistochemical characteristics of the normal vascular elements of the splenic red pulp, i.e. capillaries, sinusoids, and small veins, respectively. Because of the rarity of this entity, its actual pathogenesis is still unknown. In this study, we report a case of SANT occurring in a 43-year-old woman, in whom there were also multiple calcifying fibrous pseudotumors (CFPTs) in the abdominal cavity. Both SANT and CFPT are thought to be variants of inflammatory pseudotumor. Coexistence of these two rare entities in a patient has never been reported, and this fact suggests that there might be a common mechanism contributing to the formation of these two types of lesions.

Poor outcome in post transplant lymphoproliferative disorder with pulmonary involvement after allogeneic hematopoietic SCT: 13 years' experience in a single institute.

EBV-induced post transplant lymphoproliferative disorder (PTLD) continues to be a major complication after transplantation. Between January 1993 and April 2006, 12 cases of B-cell lymphoproliferative disorder were identified among 577 patients after allogeneic hematopoietic SCT (HSCT) with an overall incidence of 2.51% at 1 year. Grades II–IV acute GVHD, CMV antigenemia and the use of antithymocyte globulin (ATG) were independent risk factors for PTLD. At diagnosis, all of the tumors were CD20-positive and 11 (92%) were EBV-encoded RNA (EBER)-positive. Of the 12 patients with B-cell lymphoproliferative disorder, 8 had pulmonary involvement and 10 had extranodal involvement. Eleven patients received weekly rituximab therapy at a dose of 375 mg/m2; the median interval between the onset of symptoms and rituximab therapy was 6 days. The overall mortality rate was 92% and seven (64%) of the deaths were directly attributable to disseminated PTLD within days or weeks of presentation. In our series, pulmonary PTLD followed an extremely aggressive course and poor response to current therapy, even though rituximab was included in the therapeutic regimens.