Patrick Walsh

Pediatric melanoma : Are recent advances in the management of adult melanoma relevant to the pediatric population

Purpose Although melanoma in childhood is a rare condition, there is evidence that it is increasing in frequency. As advances are being made in the understanding and therapy of adult melanoma, we need to consider the relevance of these advances to the pediatric population. Patients and Methods We have reviewed our experience at the University of Colorado Health Sciences Center with the clinical parameters, therapy, and outcomes of melanoma in 27 patients age 16 years or younger and contrasted these to the adult experience. Results Most cases were diagnosed early with the median thickness of the primary melanoma being 0.75 mm. Six of seven patients who had lymph node metastases develop remain alive at a median follow-up of 62 months. Durable complete responses to a variety of therapies were seen in three of five patients with advanced disease outside the central nervous system. Our experience with sentinel node biopsy, adjuvant interferon, and new therapies for metastatic melanoma were also reviewed and appear to be relevant for younger patients. Conclusions The behavior of melanoma in the pediatric population at our center is similar to that seen in adults. The integration of recent advances in the staging and therapy of melanoma in adults would be of benefit to children with this condition.

Reversible Resistance to Apoptosis in Cutaneous T Cell Lymphoma

Abstract: Mycosis fungoides and its leukemic variant, Sézary syndrome, represent the most common forms of cutaneous T cell lymphomas (CTCL). These disorders are clonal neoplasms characterized by the progressive accumulation of cells that resemble activated/memory CD4+ T cells. Unlike their normal counterparts, these malignant lymphocytes have prolonged life spans and are resistant to dying following treatment with most chemotherapeutic agents. This suggests that CTCL undergo abnormal programmed cell death; however, data regarding apoptotic defects in CTCL are limited. Regulation of apoptosis in lymphocytes that regularly undergo clonal expansion is necessarily complex and will be reviewed here. Clonally expanded lymphocytes rely primarily on Fas‐mediated pathways to initiate apoptosis. Factors leading to the resistance of apoptosis in CTCL and new therapeutic approaches for reversing this resistance will be discussed, including the important role that the Fas death pathway may play in the pathogenesis and treatment of CTCL.

Newer strategies for effective evaluation of primary melanoma and treatment of stage III and IV disease.

Our objective in this article is to update dermatologists on the clinical management of malignant melanoma, including the role of sentinel node biopsy and options for the treatment of stage III and stage IV disease. The role of the dermatologist throughout the continuum of care is emphasized, and the essential partnership with medical oncology in recognizing promising new options for patients with advanced disease is examined.

CUSP/p63 expression in basal cell carcinoma

Abstract: Chronic ulcerative stomatitis protein (CUSP), the most abundant cutaneous isoform of p63, is a p53‐related gene essential for epithelial development. CUSP lacks the N‐terminal transactivation domain found on other p53 family members and has been shown to inhibit p53 function in vitro. In this study, biopsies of normal skin (21 of 21), benign neoplasms [seborrheic keratosis (3 of 3), acrochordon (2 of 3), and verruca plana (3 of 3)], and squamous cell carcinomas (SCC) (4 of 4) displayed strong nuclear CUSP immuno‐reactivity in epidermal cells. In contrast few basal cell carcinomas (BCC) (7 of 27) and sebaceous nevi (1 of 2) displayed this pattern of CUSP immunoreactivity. Thus, biopsies of cutaneous conditions characterized by sonic hedgehog (SHH) pathway dysregulation were more than 86 times as likely to lack CUSP/p63 immunofluorescence as were other cutaneous samples. Adjacent normal‐appearing skin from patients with basal cell nevus syndrome (BCNS) (2 of 3) also lacked CUSP immuno‐staining. Lastly, a BCC arising in a patched heterozygous mouse also lacked CUSP immuno‐staining. Because CUSP mRNA and protein were detected via Northern and Western analysis in BCC samples lacking CUSP immuno‐staining, we sequenced the coding region of CUSP from two non‐staining BCCs but found no mutations. Therefore, CUSP appears to be present, unmutated, and yet frequently undetectable by immunofluorescence in cutaneous lesions in both humans and mice that are associated with SHH pathway dysregulation (BCCs, BCNS, and nevus sebaceous).

Candida albicans induces selective expansion of human T lymphocytes expressing the T-cell receptor variable region Vβ 5.1

Candida albicans is a common pathogen which can present major problems as an opportunistic skin pathogen in patients with immunodeficiency. The exact nature of the T cell responses to C. albicans is poorly understood. The purpose of this study was to determine whether C. albicans could stimulate the selective expansion of T lymphocytes expressing particular V beta gene segments. Human T lymphocytes stimulated in vitro with an extract of C. albicans were analyzed for T cell receptor V beta gene expression by using a quantitative PCR technique. We found that stimulation of peripheral blood mononuclear cells (PBMC) produced a selective increase in the expression of V beta 5.1 and 5.2 gene transcripts. Using cytofluorographic analysis with available anti-V beta monoclonal antibodies, we verified that there was a significant selective expansion (P = 0.035) of V beta 5.1 positive T lymphocytes in PBMC from six subjects stimulated in vitro with C. albicans. PCR analysis of V beta 5.1 expansion in 10 subjects showed increases in V beta 5.1 gene transcripts in 7/10 subjects. More importantly, analysis of the T cell infiltrate 48 h after intradermal injections with C. albicans also showed significant expression of V beta 5.1 in the infiltrates, along with the infiltration of V beta 8.1 + T cells. The selective expansion of V beta 5.1 bearing T lymphocytes in PBMC stimulated with C. albicans and in skin test reactions to C. albicans suggests that a restricted population of T cells react to C. albicans. Furthermore, our present data raise the provocative possibility that one or more antigens in C. albicans can act as a superantigen, producing selective expansion of a population of T lymphocytes bearing a particular V beta specificity.

The CUSP ΔNp63α isoform of human p63 is downregulated by solar-simulated ultraviolet radiation

Background: In normal human keratinocytes, a p53-like protein, ΔNp63α, also known as CUSP, is constitutively and abundantly expressed. The significant constitutive expression of ΔNp63α in stratified epithelium has been proposed to maintain the proliferative capacity of basal cells, blocking the consequences of inappropriate p53 activation. Objective: To determine the response of keratinocyte ΔNp63α to ultraviolet radiation (UVR), a stimulus for p53 activation. Methods: Cultured normal human keratinocytes were exposed to graded doses of solar-simulated UVR. The expression of ΔNp63α protein and mRNA were measured with Western and Northern blotting. Normal mouse skin was exposed to UVR, and ΔNp63α expression assessed with immunohistochemistry. Results: Increasing doses of UVR virtually shut off ΔNp63α protein and mRNA expression in cultured normal human keratinocytes and in normal mouse skin in vivo. Conclusion: This study supports the hypothesis that in situations where p53 activation is desirable, as with DNA-damaging UVR, ΔNp63α downregulation occurs and may possibly allow for better target gene transcription by p53.