PubMed Health⌕ Search

Biomedical subjects

D J Leffell

Publications and source records attributed to D J Leffell.

At least 19 recordsLinked to original sources
PubMed2005

PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer.

BACKGROUND: The PTCH tumour suppressor gene is involved in the development of nearly all basal cell carcinomas (BCCs) of the skin and a fraction of squamous cell carcinomas (SCCs). A nonconservative Pro/Leu nucleotide polymorphism within PTCH exon 23 at codon 1315 was recently reported to be potentially important for the development of breast epithelial cell cancers. Objectives Accordingly, the status of PTCH codon 1315 was analysed for a possible association with the development of nonmelanoma skin cancers (NMSCs) in a pilot study. Because skin cancer risk is affected by specific population-dependent phenotypes such as skin and hair colour, codon 1315 was also analysed for normal allele frequency variation in human populations having differing extents of eumelanin vs. phaeomelanin. METHODS: The single nucleotide polymorphism in codon 1315 of the human PTCH gene was analysed in genomic DNA from six different populations comprising 472 blood samples and from 170 patients in four different categories with NMSC. Polymerase chain reaction and pyrosequencing were used to determine the allele frequencies. Allelic loss was furthermore determined in tumours following microdissection. RESULTS: The Pro/Pro genotype frequency ranged from 30% to 65% between populations, with a significant trend for a reduced frequency of the Pro/Pro genotype in populations having lighter pigmentation (P = 0.020). Pro/Pro frequency showed an increasing trend with increasing tumour case severity (P = 0.027). In 260 samples from 180 Swedish patients with NMSC and a control group of 96 healthy ethnically matched volunteers, no statistically significant pairwise differences between groups were detected in the PTCH codon 1315 allelic distribution, neither was a difference seen for multiple or early onset cases of BCC in the Swedish population. In Swedish patients with single tumours, allelic loss (loss of heterozygosity) was observed in 20 of 30 (67%) patients with BCC and four of 22 (18%) patients with SCC, with no preference in the allele lost. In contrast, the Pro/Pro genotype was frequent in seven U.S. patients having multiple independent BCCs. One of these patients was heterozygous, enabling allelic loss studies. Of 20 independent tumours, 11 had lost an allele; 10 of the 11 had lost Leu, suggesting nonrandom loss that favoured retention of Pro (P = 0.0059). CONCLUSIONS: Our results indicate an association between the eumelanin-to-phaeomelanin shift and a shift from the Pro/Pro genotype to Leu-containing genotypes. Failure to lose Pro during the shift to phaeomelanin may be associated with an increased population risk for BCC and increased individual risk for multiple BCC. During development of a tumour, the effect of Pro may be magnified by loss of the Leu allele.

Basal Cell Carcinoma↗
PubMed2000

Electrosurgical facial resurfacing: a prospective multicenter study of efficacy and safety.

BACKGROUND: A novel electrosurgical technology that uses a bipolar electrode-tipped stylet to deliver relatively low-radiofrequency energy through an electrically conductive medium has been developed. OBJECTIVE: To evaluate the efficacy and safety of the radiofrequency resurfacing system for the treatment of facial wrinkles. DESIGN: Multicenter, prospective, noncomparative study with longitudinal follow-up. SETTING: Four US academic dermatologic surgery clinics. PATIENTS: Ninety-five patients with mild to severe photodamage (Fitzpatrick classes I-III) involving periorbital (75 treatment sites) and perioral (50 sites) facial skin. INTERVENTION: Radiofrequency resurfacing with the use of 2 to 3 passes at 125 or 139 V. MAIN OUTCOME MEASURES: Wrinkle and cosmetic improvements evaluated by patients, investigators, and, by means of photographs, an independent panel of 5 evaluators. RESULTS: All evaluators determined a positive mean improvement in wrinkles for both periorbital and perioral anatomic sites, with greater improvement for patients with more severe wrinkles at baseline. An increased number of passes and higher voltage settings had a positive impact on wrinkle improvement. Transient postinflammatory hyperpigmentation occurred in 26% of periorbital and 4% of perioral sites. Hypertrophic scars occurred in 3.8% of treatment sites, with all but 1 scar resolving by 6 months. For the most part, healing was rapid, pain was minimal, and erythema largely resolved within 2 months. Other untoward effects were relatively few and short-lived. CONCLUSIONS: At the study settings used, radiofrequency resurfacing is an effective modality in the treatment of periorbital and perioral wrinkles in patients with Fitzpatrick class I, II, and III photodamage. There is less severe postoperative morbidity than seen with carbon dioxide or coagulating erbium:YAG lasers. The potential risks are similar to those seen with other resurfacing modalities.

Electrosurgery↗
PubMed2000

The scientific basis of skin cancer.

BACKGROUND: Mutations in tumor suppressor gene p53 are very common in many human cancers. They are present in more than 90% of squamous cell carcinomas (SCCs) and are usually found in actinic keratoses (AKs). Data demonstrate a strong relationship between the early effects of ultraviolet radiation (UVR) on p53 in skin and the development of AK and SCC. OBJECTIVE: The purpose of this article is to review specific data about the p53 tumor suppressor gene, UVR, and their interaction to cause AKs. METHODS: The published, peer-reviewed literature is reviewed and a published proposal for the mechanism for UVR-induced carcinogenesis is explained. RESULTS: The specific effect of UVR on the p53 tumor suppressor gene, including its impact on apoptosis, in humans, and in animals, suggests a cause-effect relationship between UVR and the earliest mutations seen in AKs. CONCLUSION: AKs result from UVR in a process by which UVR mutates a known tumor suppressor gene (p53). It is likely that the mutated cells expand preferentially in a clonal fashion at the expense of the normal surrounding keratinocytes to develop into a clinical lesion of AK.

Apoptosis↗
PubMed1999

Use of a lyophilized bovine collagen matrix in postoperative wound healing.

BACKGROUND: Immediate reconstruction is the preferred approach to the management of defects following Mohs micrographic surgery. In a minority of patients, however, reconstruction is contraindicated, and a long-term biological dressing that stimulates wound healing and minimizes wound care is desirable. OBJECTIVE: We wanted to assess the utility of a lyophilized, type I bovine collagen matrix (SkinTemp) in wound care and wound healing following Mohs micrographic surgery. METHODS: Fifteen patients were treated with a bovine collagen matrix following Mohs micrographic surgery. Study wounds were evaluated for time to complete granulation, time to complete epithelialization, and adverse reactions including infection and allergy. The time to complete healing (granulation and epithelialization) for this group was compared to 15 size- and site-matched surgical defects. RESULTS: The use of bovine collagen matrix provided more rapid wound healing than traditional second intention healing at all anatomic sites studied. The time to complete healing averaged 6.1 weeks with bovine collagen matrix versus 9.4 weeks for the control group. Use of bovine collagen matrix required an average of 3.0 dressing changes weekly compared to 7.0 changes weekly in the control group. There were no wound infections or allergic reactions to it. CONCLUSIONS: A Type I bovine collagen matrix provided a safe, readily available alternative to traditional methods of second intention healing. It minimized wound care while reducing the time for complete healing. A larger study should be performed to confirm the results of this pilot study.

Aged↗
PubMed1997

Preoperative assessment of the elderly patient.

Preoperative assessment of the elderly patient for surgery is vital to the success of the surgical procedure. A thorough evaluation must first begin with an understanding of the physiologic and pathophysiologic changes unique to the elderly patient and the aging skin. A complete preoperative assessment entails assessing the patient and dermatologic problem, preparing the patient and caregivers for the surgery and its expected outcomes, and highlighting issues and problems that need to be managed prior to the procedure. With the continued growth of the geriatric population, all dermatologic surgeons should be aware of the special issues related to their geriatric patients. With heightened awareness of and screening for potential pitfalls in the elderly surgical patient, adverse outcomes can be avoided.

Aged↗
PubMed1997

The molecular basis of nonmelanoma skin cancer: new understanding.

Nonmelanoma skin cancers, including basal cell carcinomas and squamous cell carcinomas, represent the most common malignant neoplasms in humans. Although many environmental and genetic factors contribute to the development of skin cancers, the most important is chronic exposure to UV radiation in sunlight. We now appreciate that the role of UV in the development of nonmelanoma skin cancers is 2-fold. First, UV radiation causes mutations in cellular DNA. Failure to repair these genetic alterations ultimately leads to unrestrained growth and tumor formation. Second, UV radiation has profound effects on the cutaneous immune system, inducing a state of relative immunosuppression that prevents tumor rejection. The purpose of this review is to educate clinical dermatologists about the recent developments in molecular biology and immunology that have greatly enhanced our understanding of how skin cancers arise. The clinical implications of this new knowledge are far-reaching and likely to soon impact the diagnosis, treatment, and prevention of a variety of benign and malignant skin conditions. It will be important for the clinician to understand the biological mechanisms underlying these new therapeutic developments to implement them effectively.

Carcinoma↗
PubMed1996

Frequent clones of p53-mutated keratinocytes in normal human skin.

The multiple genetic hit model of cancer predicts that normal individuals should have stable populations of cancer-prone, but noncancerous, mutant cells awaiting further genetic hits. We report that whole-mount preparations of human skin contain clonal patches of p53-mutated keratinocytes, arising from the dermal-epidermal junction and from hair follicles. These clones, 60-3000 cells in size, are present at frequencies exceeding 40 cells per cm2 and together involve as much as 4% of the epidermis. In sun-exposed skin, clones are both more frequent and larger than in sun-shielded skin. We conclude that, in addition to being a tumorigenic mutagen, sunlight acts as a tumor promoter by favoring the clonal expansion of p53-mutated cells. These combined actions of sunlight result in normal individuals carrying a substantial burden of keratinocytes predisposed to cancer.

Adult↗
PubMed1996

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

Alleles↗
PubMed1996

Relationship between sunlight exposure and a key genetic alteration in basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. Epidemiologic studies implicate sunlight exposure as one risk factor, but the limited association between BCCs and UVB radiation (i.e., UV radiation of a wavelength of 280-320 nm) suggests that additional factors must be involved. At the molecular level, not much is known about the role of specific environmental agents in the pathogenesis of BCCs. Point mutations of the types produced by UVB radiation are seen in the p53 gene (also known as TP53; chromosome 17p) of 40%-56% of BCCs. Loss of heterozygosity (LOH) on chromosome 9q22, however, is the most frequent genetic alteration in these tumors, and its causative agent is unknown. PURPOSE: We investigated whether the genetic alteration in chromosome 9 is common to all clinical subtypes of BCCs and whether inactivation of this putative tumor suppressor is related to sunlight exposure. The presence of UVB radiation-related point mutations in the p53 gene was used as an internal control for sunlight exposure to the precursor cells. METHODS: Tumor and blood samples were obtained from skin cancer patients by a surgeon who used Mohs' micrographic surgical technique. Clinical information on each tumor included location, size, histologic, subtype and whether it was primary or recurrent and sporadic or hereditary. Sixty BCCs from 58 patients were evaluated for LOH with 12 polymorphic markers that span chromosome 9. A subset of 18 tumors was evaluated for point mutations in exons 2-11 of the p53 gene, and a subset of 26 tumors was evaluated for LOH by use of a polymorphism in exon 4 of the p53 gene. Associations between tumor characteristics and molecular alterations were tested by a two-tailed chi-squared analysis or a two-tailed Fisher's exact test, depending on sample size. RESULTS: In a clinically diverse series of 47 informative tumors, 32 (68%) showed LOH for chromosome 9q markers, irrespective of histologic characteristics or clinical behavior. Forty-four (94%) of the 47 tumors were from sun-exposed areas of the body, defined as the head and neck in both sexes, shoulders or chest in males, and legs in females. No association was found between chromosome 9q LOH and sunlight exposure, as assessed by either the location of tumors on the body or the presence of UVB radiation-related p53 mutations. Of note, there was a striking difference between the frequency of LOH on chromosome 17p (two [12.5%] of 16 informative tumors) and on chromosome 9q (32 [68%] of 47 informative tumors; P < .001). CONCLUSIONS: Inactivation of a gene on chromosome 9q22 may be a necessary event for basal cell carcinogenesis. The pathogenesis of mutations in this gene may involve factors other than sunlight in a large proportion of tumors. IMPLICATIONS: The limited association between sunlight exposure and BCC incidence may reflect an etiologic contribution of additional environmental agents.

Adult↗
PubMed1996

The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas.

Basal cell carcinoma (BCC) is the most common cancer in humans. The majority of sporadic BCCs have allele loss on chromosome 9q22 implying that inactivation of a tumour suppressor in this region is an important step in BCC formation. The gene for nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder characterized by multiple BCCs, maps to the same region and is presumed to be the tumour suppressor inactivated at this site. NBCCS has been identified recently and encodes a protein with strong homology to the Drosophila segment polarity gene, patched. Analysis of Drosophila mutants indicates that patched interacts with the hedgehog signalling pathway, repressing the expression of various hedgehog target genes including wingless, decapentaplegic and patched itself. Using single strand conformational polymorphism (SSCP) to screen human patched in 37 sporadic BCCs, we detected mutations in one-third of the tumours. Direct sequencing of two BCCs without SSCP variants revealed mutations in those tumours as well suggesting that inactivation of patched is probably a necessary step in BCC development. Northern blots and RNA in situ hybridization showed that patched is expressed at high levels in tumour cells but not normal skin suggesting that mutational inactivation of the gene leads to overexpression of mutant transcript owing to failure of a negative feedback mechanism.

Animals↗
PubMed1996

Sunlight and sunburn in human skin cancer: p53, apoptosis, and tumor promotion.

Sunlight is a carcinogen to which everyone is exposed. Epidemiology indicates that most carcinogenic sunlight exposure takes place several decades before the tumor arises. Some of the early events have been identified by searching for genes having ultraviolet (UV)-specific mutations. Over 90% of squamous cell carcinomas and more than 50% of basal cell carcinomas from New England patients contain UV-like mutations in the p53 tumor suppressor gene. From the mutation pattern, it can be concluded that the carcinogenic DNA lesions were pyrimidine-cytosine photoproducts caused by the UVB portion of sunlight. Particular codons of the p53 gene are most susceptible, apparently because of slower DNA repair at specific sites. Sunlight is sufficiently mutagenic often to mutate both p53 alleles. These mutations are also found in the precancer for squamous cell carcinoma, actinic keratosis, implying an early role. The function of p53 in normal skin is indicated by the observation that inactivating p53 in mouse skin reduces the appearance of sunburn cells, apoptotic keratinocytes generated by UV overexposure. Skin thus appears to possess a p53-dependent "cellular proofreading" response to DNA damage in which precancerous cells self-destruct. If this response is reduced in a single cell by a prior p53 mutation, sunburn can thereafter select for clonal expansion of the p53-mutated cell into an actinic keratosis. Sunlight appears to act twice: as tumor initiator and as tumor promoter.

Animals↗