Daniel C. Zedek

CD200 is induced by ERK and is a potential therapeutic target in melanoma

Immune-mediated antitumor responses occur in patients with metastatic melanoma (MM), and therapies designed to augment such responses are clinically beneficial. Despite the immunogenicity of melanoma, immunomodulatory therapies fail in the majority of patients with MM. An inability of DCs to sufficiently activate effector cells may, in part, underlie this failure of the antitumor response seen in most patients. In this work, we show that mutation of N-RAS or B-RAF, signature genetic lesions present in most MMs, potently induced the expression of cell-surface CD200, a repressor of DC function. Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. CD200 mRNA expression correlated with progression and was higher in melanoma than in other solid tumors or acute leukemia. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect. These data indicate that in addition to its effects on growth, survival, and motility, ERK activation in MM attenuates a host antitumor immune response, implicating CD200 and its interaction with the CD200 receptor as a potential therapeutic target for MM.

Validation of the VE1 immunostain for the BRAF V600E mutation in melanoma

BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. We assessed the validity of VE1, a monoclonal antibody against the BRAF V600E mutant protein, in the detection of mutant BRAF V600E melanomas as classified by DNA pyrosequencing.

Clear-cell acanthoma versus acanthosis: a psoriasiform reaction pattern lacking tricholemmal differentiation.

Clear-cell acanthoma (CCA) has been reported to be a benign epidermal neoplasm; however, several authors have suggested alternative differentiation as well as other nosologic categories, including a reactive dermatosis. Fourteen CCAs, ten tricholemmomas, and seven cases of psoriasis were reviewed with conventional microscopy, periodic acid-Schiff stains, and immunohistochemical stains.Twelve of fourteen (86%) CCAs were associated with underlying or adjacent conditions. The CCAs stained immunohistochemically in a pattern similar to normal epidermis and psoriasis. Tricholemmomas stained in a distinctly different pattern with MNF116 and NGFR/p75. These cases demonstrate CCA in settings that reflect chronic inflammation, primarily scars and stasis dermatitis, and with an immunophenotype that parallels psoriasis. These findings support the contention that CCA does not show outer follicular sheath (tricholemmal) differentiation. Furthermore, these cases lend additional support to the contention that CCA represents a psoriasiform reaction pattern, which, in appropriately taken biopsies, usually has a demonstrable associated condition. Nonetheless, the precise nosology of this phenomenon has yet to be elucidated completely.

Cutaneous clear-cell granular cell tumors: the histologic description of an unusual variant

Background:  Granular cell tumors (GCTs) are neoplasms showing nerve sheath differentiation that can arise in the skin but, to our knowledge, have not been associated with significant clear‐cell morphology.

Use of Galactomannan Enzyme Immunoassay for Diagnosis of Invasive Aspergillosis in a Tertiary-Care Center over a 12-Month Period

Invasive pulmonary disease caused by Aspergillus species is an increasing concern for patients who are immunosuppressed, especially patients with neutropenia or hematologic malignancies ([6][1]). Since invasive aspergillosis can be difficult to diagnose, tests have been developed to combat this

The clinical utility of parathyroid hormone-related peptide in the assessment of hypercalcemia

BACKGROUND Hypercalcemia is a common clinical finding with primary hyperparathyroidism and malignancy accounting for most cases. Measurement of parathyroid hormone-related peptide (PTHrP) is often requested for patients with hypercalcemia before confirmation of hypercalcemia and/or determination of parathyroid hormone (PTH) concentrations. We determined a PTH cutoff to guide PTHrP testing in hypercalcemic patients. METHODS Test results for total calcium, intact PTH, and PTHrP tests performed within 2 days of each other were recorded. Chart review determined the etiology of hypercalcemia. The PTH cutoff below which a PTHrP result might be useful was determined. RESULTS Test results from 123 patients were included and 47 had hypercalcemia of malignancy, 15 of which had increased PTHrP. Diagnostic sensitivity and specificity were 32% (95% CI=19-47%) and 95% (95% CI=85-99%), respectively. PTH concentrations were lowest in patients with increased PTHrP compared to those with no increase (25.6+/-69.2 vs. 94.8+/-332.8 ng/l, p<0.01). A cutoff PTH concentration of >26 ng/l predicted a non-increased PTHrp result in 95% of the entire study population which increased to 100% when only patients with hypercalcemia were considered. CONCLUSIONS PTHrP testing is more appropriately performed after assessment of PTH. If the PTH is not low or low normal, testing for PTHrP is usually uninformative.

Original ArticleMucosal Pemphigus Vulgaris Anti-Dsg3 IgG Is Pathogenic to the Oral Mucosa of Humanized Dsg3 Mice

There are two major clinical subsets of pemphigus vulgaris (PV), mucosal PV (mPV) and mucocutaneous PV (mcPV). The mPV subset exhibits anti-human desmoglein (Dsg) 3 autoantibodies that fail to recognize murine Dsg3; thus, passive transfer experiments of mPV IgG into WT mice have been unsuccessful at inducing disease. We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a human Dsg3 transgenic animal crossed to the murine Dsg3 knockout line. Expression of hDsg3 in the mucosa rescues the murine Dsg3 knockout phenotype. Well characterized mPV sera bind mucosal epithelia from the hDsg3 mice, but not mucosal tissues from WT mice by as detected by indirect immunofluorescence. The majority of mPV sera preferentially recognize hDsg3 compared to mDsg3 by immunoprecipitation as well. Passive transfer of mPV IgG into adult hDsg3 mice, but not WT mice, induces suprabasilar acantholysis in mucosal tissues, thus confirming pathogenicity of mPV anti-hDsg3 IgG in vivo. Human anti-hDsg3 antibodies are detected in perilesional mucosa as well as in sera of recipient mice by immunofluorescence. These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human specific. This hDsg3 mouse model will be invaluable in studying the clinical transition from mPV to mcPV.

Mucosal Pemphigus Vulgaris Anti-Dsg3 IgG Is Pathogenic to the Oral Mucosa of Humanized Dsg3 Mice

There are two major clinical subsets of pemphigus vulgaris (PV), mucosal PV (mPV) and mucocutaneous PV (mcPV). The mPV subset exhibits anti-human desmoglein (Dsg) 3 autoantibodies that fail to recognize murine Dsg3; thus, passive transfer experiments of mPV IgG into WT mice have been unsuccessful at inducing disease. We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a human Dsg3 transgenic animal crossed to the murine Dsg3 knockout line. Expression of hDsg3 in the mucosa rescues the murine Dsg3 knockout phenotype. Well characterized mPV sera bind mucosal epithelia from the hDsg3 mice, but not mucosal tissues from WT mice by as detected by indirect immunofluorescence. The majority of mPV sera preferentially recognize hDsg3 compared to mDsg3 by immunoprecipitation as well. Passive transfer of mPV IgG into adult hDsg3 mice, but not WT mice, induces suprabasilar acantholysis in mucosal tissues, thus confirming pathogenicity of mPV anti-hDsg3 IgG in vivo. Human anti-hDsg3 antibodies are detected in perilesional mucosa as well as in sera of recipient mice by immunofluorescence. These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human specific. This hDsg3 mouse model will be invaluable in studying the clinical transition from mPV to mcPV.

Subcutaneous Metastatic Adenocarcinoma: An Unusual Presentation of Colon Cancer - Case Report and Literature Review

Subcutaneous metastasis from a visceral malignancy is rare with an incidence of 5.3%. Skin involvement as the presenting sign of a silent internal malignancy is an even rarer event occurring in approximately 0.8%. We report a case of a patient who presented to her dermatologist complaining of rapidly developing subcutaneous nodules which subsequently proved to be metastatic colon cancer, and we provide a review of the literature.

A Case of Childhood Subcutaneous Pyogenic Granuloma (Lobular Capillary Hemangioma)

Pyogenic granuloma (PG) is a common and benign lesion that most often occurs in children and adolescents. Subtypes of PG exist—cutaneous, intravenous, and subcutaneous. The subcutaneous variant is rare with less than 10 reported incidents of isolated lesions. Clinically, the lesions are often described as a painless and isolated subcutaneous nodule. Histopathologically, these lesions are characterized as noninvasive, lobular masses of capillaries that are separated by thin fibrous bands. In this report, we describe an additional case of subcutaneous PG that presented in an infant with multiple lesions on her chest and back.