Désirée Ratner

The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

Sunscreens: An overview and update

Sunscreens are an important aspect of photoprotection. Their efficacy in reducing photocarcinogenesis and photoaging is widely documented. Although there are concerns regarding long-term sunscreen safety, the advantages of sunscreen use are far more compelling. In addition, novel technologies and ultraviolet filters are improving the aesthetics and efficacy of modern products.

SKIN GRAFTING: From Here to There*

Free skin grafts for soft tissue reconstruction can be classified into four types: full-thickness skin grafts, split-thickness skin grafts, composite grafts, and free cartilage grafts. The indications, techniques, donor site considerations, and postoperative complications of each type of skin graft are reviewed.

The uses of digital photography in dermatology

Digital photography is a powerful tool that is transforming the specialty of dermatology by integrating patient and practice management. The fundamentals of digital imaging are discussed, and an approach to the selection of a digital camera and its associated hardware and software is provided. The applications of this technology to patient and practice management are addressed, and the ethical implications of digital tampering are also discussed.

What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion

Perineural invasion (PNI) in cutaneous squamous cell carcinoma (SCC) is infrequent, occurring in 2.5% to 14% of patients, but it is important prognostically, because it carries an increased risk of recurrence and metastasis. Although both excision and Mohs micrographic surgery (MMS) are used to treat SCC with PNI, postoperative radiation therapy (XRT) often is recommended to minimize the risk of recurrence. To date, the effectiveness of adjuvant XRT in this setting has not been determined definitively.

Role of PTCH and p53 Genes in Early-Onset Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common skin cancer in the Western world. Ultraviolet (UV) exposure, race, age, gender, and decreased DNA repair capacity are known risk factors for the development of BCC. Of these, UVB irradiation from sunlight is the most significant risk factor. The incidence of sporadic BCC increases in individuals older than age 55, with the greatest incidence reported in individuals who are older than 70, and is rare in individuals who are younger than 30. In this study, we analyzed 24 BCC samples from individuals who had BCC diagnosed by the age of 30. Fifteen single-stranded conformation polymorphism variants in the PTCH gene were identified in 13 BCC samples. Sequence analysis of these single-stranded conformation polymorphism variants revealed 13 single nucleotide changes, one AT insertion, and one 15-bp deletion. Most of these nucleotide changes (nine of 15) were predicted to result in truncated PTCH proteins. Fifteen p53 mutations were also found in 11 of the 24 BCC samples. Thirty-three percent (five of 15) and 60% (nine of 15) of the nucleotide changes in the PTCH and p53 genes, respectively, were UV-specific C-->T and CC-->TT nucleotide changes. Our data demonstrate that the p53 and PTCH genes are both implicated in the development of early-onset BCC. The identification of UV-specific nucleotide changes in both tumor suppressor genes suggests that UV exposure is an important risk factor in early onset of BCC.

Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.

The Immunosuppressive Surface Ligand CD200 Augments the Metastatic Capacity of Squamous Cell Carcinoma

CD200 (OX-2) is a cell surface glycoprotein that imparts immune privileges by suppressing alloimmune and autoimmune responses through its receptor, CD200R, expressed primarily on myeloid cells. The ability of CD200 to suppress myeloid cell activation is critical for maintaining normal tissue homeostasis but may also enhance the survival of migratory neoplastic cells. We show that CD200 expression is largely absent in well-differentiated primary squamous cell carcinoma (SCC) of the skin, but is highly induced in SCC metastases to the lymph node and other solid tissues. CD200 does not influence the proliferative or invasive capacity of SCC cells or their ability to reconstitute primary skin tumors. However, loss of CD200 impairs the ability of SCC cells to metastasize and seed secondary tumors, indicating that the survival of CD200(+) SCC cells may depend on their ability to interact with CD200R(+) immune cells. The predominant population of CD200R(+) stromal cells was CD11b(+)Gr-1(+) myeloid-derived suppressor cells, which release elevated levels of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor when in the presence of SCC cells in a CD200-dependent manner. Collectively, our findings implicate CD200 as a hallmark of SCC metastasis and suggest that the ability of CD200(+) SCC keratinocytes to directly engage and modulate CD200R(+) myeloid-derived suppressor cells is essential to metastatic survival.

Neoadjuvant Imatinib Therapy for Dermatofibrosarcoma Protuberans

BACKGROUND Dermatofibrosarcoma protuberans (DFSP) is an unusual soft-tissue tumor with a propensity for subclinical extension and local recurrence. Surgical excision, even with tissue-sparing techniques, may cause significant deformity or disability because of the infiltrative nature of DFSP. In this study, we evaluate retrospective data obtained from 4 patients with locally advanced or recurrent DFSP who received neoadjuvant imatinib mesylate therapy before undergoing Mohs micrographic surgery. OBSERVATIONS Patients treated with neoadjuvant imatinib therapy had an average tumor size reduction of 36.9%. This clinical response was paralleled by histopathologic changes, including decreased cellularity in 100% of the total area as well as significant hyalinization. Imatinib therapy for DFSP before Mohs micrographic surgery was associated with 100% local control at a maximum follow-up of 4 years. CONCLUSIONS Neoadjuvant imatinib therapy is a well-tolerated, novel approach to DFSP that reduces tumor burden and facilitates resection. Larger prospective studies are needed to confirm and expand on these results.

Complete Clinical Response to Cetuximab in a Patient with Metastatic Cutaneous Squamous Cell Carcinoma

Metastatic cutaneous squamous cell carcinoma (cSCC) is a difficult clinical problem. With no established first-line agents, interest in targeted therapies for metastatic cSCC has increased. It has been shown that cetuximab, an epidermal growth factor receptor (EGFR) antibody, is effective in treating epidermal growth factor–expressing solid tumors. Metastatic cSCC expresses EGFR at high levels, but no study has examined cetuximab efficacy in this setting. We report a patient with in-transit and distant metastases from cSCC whose disease regressed completely after serial infusions of cetuximab, indicating a possible role for this agent in treating metastatic cSCC.