Detection theory for accurate and non-invasive skin cancer diagnosis using dynamic thermal imaging.

Skin cancer is the most common cancer in the United States with over 3.5M annual cases. Presently, visual inspection by a dermatologist has good sensitivity (> 90%) but poor specificity (< 10%), especially for melanoma, which leads to a high number of unnecessary biopsies. Here we use dynamic thermal imaging (DTI) to demonstrate a rapid, accurate and non-invasive imaging system for detection of skin cancer. In DTI, the lesion is cooled down and the thermal recovery is recorded using infrared imaging. The thermal recovery curves of the suspected lesions are then utilized in the context of continuous-time detection theory in order to define an optimal statistical decision rule such that the sensitivity of the algorithm is guaranteed to be at a maximum for every prescribed false-alarm probability. The proposed methodology was tested in a pilot study including 140 human subjects demonstrating a sensitivity in excess of 99% for a prescribed specificity in excess of 99% for detection of skin cancer. To the best of our knowledge, this is the highest reported accuracy for any non-invasive skin cancer diagnosis method.

Treatment-refractory actinic keratoses successfully treated using simultaneous combination topical 5-fluorouracil cream and imiquimod cream: a case-control study.

BACKGROUND: Most actinic keratoses (AKs) respond to standard treatments, but a subset persist and require further intervention. We report a series of 10 patients with AKs that failed to respond to conventional treatment with cryotherapy and topical monotherapy but responded completely to simultaneous therapy with topical 5-fluorouracil (5-FU) and imiquimod creams. OBJECTIVE: To report the success of this combination therapy in refractory AKs and to determine whether any clinical or histologic features predict for treatment resistance. METHODS: Case-control study with two control groups matched to each patient according to lesion location and sex. RESULTS: Mean lesion diameter (p < .001), lesion diameter greater than 1 cm (p < .001), and the presence of pain (p = .01) were statistically associated with failure of cryotherapy and topical monotherapy. None of the histologic features evaluated were found to be statistically significant, although thicker epidermis was nearly so (p = .054). CONCLUSIONS: In patients who have failed standard therapy for AKs, combination treatment using topical 5-FU and imiquimod cream may be an effective alternative therapeutic strategy. Larger lesion diameter, specifically greater than 1 cm, and the presence of pain predict conventional treatment resistance.

Microarray analysis of cutaneous squamous cell carcinomas reveals enhanced expression of epidermal differentiation complex genes.

Gene expression profiles were determined for 12 cutaneous squamous cell carcinomas (SCC) removed from sun-exposed sites on nonimmunosuppressed patients. Gene expression in each SCC was compared to that in sun-exposed skin from the same patient using the Affymetrix HGU133 2.0 PlusGeneChip. We identified 440 genes with increased expression in SCC and 738 with decreased expression; overall we identified a large number of small changes in gene expression rather than a few marked changes that distinguished SCC from sun-exposed skin. Analyzing this robust data set according to biofunctional pathways using DAVID, transcriptional control elements using oPOSSUM, and chromosomal location using GSEA suggested genetic and epigenetic mechanisms of gene expression regulation in SCC. Some altered patterns of gene expression in SCC were consistent with regulation of spatially separated genes by a number of developmentally important transcription factors (forkhead, HMG, and homeo factors) that negatively regulated gene expression and to a few factors that positively regulated expression (Creb-1, NFkappaB, RelA, and Sp-1). We also found that coordinately enhanced expression of epidermal differentiation complex genes on chromosome 1q21 was a hallmark of SCC. A novel finding in our study was enhanced expression of keratin 13 in SCC, a result validated by immunohistochemical staining of an SCC tumor tissue array.

Gene expression patterns of normal human skin, actinic keratosis, and squamous cell carcinoma: a spectrum of disease progression.

OBJECTIVES: To identify and compare the gene expression profiles of actinic keratosis (AK) and squamous cell carcinoma (SCC) and to further clarify critical genetic alterations in the evolution of SCC from normal sun-damaged human skin. DESIGN: Observational study. SETTING: University practice. PATIENTS: Skin biopsy specimens were obtained from 16 patients. The specimens included 14 normal non-sun-exposed skin samples, 14 normal sun-exposed skin samples, 5 AKs, and 15 cutaneous SCCs. MAIN OUTCOME MEASURES: Gene expression profiles from normal non-sun-exposed skin, normal sun-exposed skin, AKs, and SCCs. RESULTS: Using a highly astringent shrunken centroid threshold of 6.52 and the prediction analysis of microarrays, we identified 89 unique genes that most likely contribute to the molecular evolution of SCC. Our model was cross-validated using data from a separate study and clearly distinguishes between skin tumors (AK and SCC) and normal skin independent of sun exposure. Genes that were upregulated in AK and SCC were downregulated in normal skin, and genes that were downregulated in AK and SCC were upregulated in normal skin. CONCLUSIONS: The finding of similar differentially expressed genes in AK and SCC confirms that AK is a precursor lesion of SCC and indicates that they are closely related genetically. Clear elucidation of these relationships will be critical to improving therapeutic approaches.

Evaluation of a novel Arg-Gly-Asp-conjugated α-melanocyte stimulating hormone hybrid peptide for potential melanoma therapy.

UNLABELLED: The purpose of this study was to determine whether Arg-Gly-Asp (RGD)-conjugated α-melanocyte stimulating hormone (α-MSH) hybrid peptide could be employed to target melanocortin-1 (MC1) receptor for potential melanoma therapy. METHODS: The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys(3,4,10), DPhe(7), Arg(11)]α-MSH(3-13) {(Arg(11))CCMSH} to generate RGD-Lys-(Arg(11))CCMSH hybrid peptide. The MC1 receptor binding affinity of RGD-Lys-(Arg(11))CCMSH was determined in B16/F1 melanoma cells. The internalization and efflux, melanoma targeting and pharmacokinetic properties and single photon emission computed tomography/CT (SPECT/CT) imaging of (99m)Tc-RGD-Lys-(Arg(11))CCMSH were determined in B16/F1 melanoma cells and melanoma-bearing C57 mice. Clonogenic cytotoxic effect of RGD-Lys-(Arg(11))CCMSH was examined in B16/F1 melanoma cells. RESULTS: RGD-Lys-(Arg(11))CCMSH displayed 2.1 nM MC1 receptor binding affinity. (99m)Tc-RGD-Lys-(Arg(11))CCMSH showed rapid internalization and extended retention in B16/F1 cells. The cellular uptake of (99m)Tc-RGD-Lys-(Arg(11))CCMSH was MC1 receptor-mediated. (99m)Tc-RGD-Lys-(Arg(11))CCMSH exhibited high tumor uptake (14.83 ± 2.94% ID/g 2 h postinjection) and prolonged tumor retention (7.59 ± 2.04% ID/g 24 h postinjection) in B16/F1 melanoma-bearing mice. Nontarget organ uptakes were generally low except for the kidneys. Whole-body clearance of (99m)Tc-RGD-Lys-(Arg(11))CCMSH was rapid, with approximately 62% of the injected radioactivity cleared through the urinary system by 2 h postinjection. Flank melanoma tumors were clearly imaged by small animal SPECT/CT using (99m)Tc-RGD-Lys-(Arg(11))CCMSH as an imaging probe 2 h postinjection. Single treatment (3 h incubation) with 100 nM of RGD-Lys-(Arg(11))CCMSH significantly (p < 0.05) decreased the clonogenic survival of B16/F1 cells by 65% compared to the untreated control cells. CONCLUSION: Favorable melanoma targeting property of (99m)Tc-RGD-Lys-(Arg(11))CCMSH and remarkable cytotoxic effect of RGD-Lys-(Arg(11))CCMSH in B16/F1 cells warranted the further evaluation of (188)Re-labeled α-MSH hybrid peptides as novel therapeutic peptides for melanoma treatment once the strategies of amino acid coinjection or structural modification of peptide sequence substantially reduce the renal uptake.

Arsenic-induced skin conditions identified in southwest dermatology practices: an epidemiologic tool?

Populations living in the Southwest United States are more likely to be exposed to elevated drinking water arsenic levels compared to other areas of the country. Skin changes, including hyperpigmentation and generalized hyperkeratosis, are the most common signs of chronic arsenic ingestion from drinking water. The purpose of this study was to determine the feasibility of using dermatology practices in New Mexico, Arizona, and western Texas as a surveillance system for arsenical skin disorders related to drinking water. Postcard questionnaires were mailed to practicing dermatologists. The number of cases of arsenical hyperpigmentation/keratoses seen by these dermatologists during the past 10 years and the past year were estimated. Of 240 dermatologists who were mailed questionnaires, 37 reported seeing 237 patients with arsenical hyperpigmentation/keratoses in the past 10 years and 35 patients in the past year. Since approximately one-eighth of dermatologists practicing in the Southwest saw at least one patient with arsenical hyperpigmentation/keratoses during one year, it appears feasible to complete a population-based study of these conditions.

Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study.

BACKGROUND: Stevens-Johnson syndrome (SJS) is a severe cutaneous drug reaction associated with considerable morbidity, possible transition to toxic epidermal necrolysis (TEN) and death in certain cases. OBJECTIVE: To determine whether treatment with high-dose IVIG in SJS patients may improve outcome. METHODS: Data from 12 patients (collected between January 1997 and November 2000 from 7 university dermatology centers in Europe and North America) diagnosed with SJS according to a recent consensus definition was analyzed retrospectively. All patients had progressive ongoing epidermal detachment at the time of treatment initiation. Patients with overlap syndromes and TEN were excluded. Tolerance, survival at 45 days after onset and total healing time were assessed. RESULTS: Twelve SJS patients (mean age 44 years) were treated with IVIG at a mean dose of 0.6g/kg/day for an average of 4 days. An objective response to IVIG infusion was observed in all patients within a mean of 2 days, and the overall survival rate was 100%. Total skin healing occurred, on average, within 8.3 days. Time to total healing was shorter in a group of patients with fewer severe underlying diseases who had received IVIG infusion rapidly after the onset of skin lesions. CONCLUSION: High-dose IVIG may be effective in blocking the progression of SJS and reducing the time to complete skin healing.

Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases.

OBJECTIVE: To evaluate the effect of high-dose intravenous immunoglobulin (IVIG) in toxic epidermal necrolysis (TEN), parameters that may affect response to treatment, and the effect of different IVIG batches on Fas-mediated cell death. DESIGN: Multicenter retrospective analysis of 48 consecutive TEN patients treated with IVIG. SETTING: Fourteen university hospital dermatology centers in Europe and the United States. PATIENTS: Forty-eight patients with TEN (skin detachment >10% of their body surface [mean, 44.8%; range, 10%-95%]). INTERVENTIONS: Infusion of IVIG in all patients (range, 0.8-5.8 g/kg), and analysis of the ability of different IVIG batches to inhibit Fas-mediated cell death. MAIN OUTCOME MEASURES: Objective response to IVIG treatment, final outcome at day 45, parameters that may affect response to IVIG treatment, and tolerance. RESULTS: Infusion of IVIG (mean total dose, 2.7 g/kg [range, 0.65-5.8 g/kg]; mean consecutive days, 4 [range, 1-5 days]) was associated with a rapid cessation (mean, 2.3 days [range, 1-6 days]) of skin and mucosal detachment in 43 patients (90%) and survival in 42 (88%). Patients who responded to IVIG had received treatment earlier in the course of disease and, on average, higher doses of IVIG. Furthermore, analysis of 35 IVIG batches revealed significant batch-to-batch variations in the capacity of IVIG to inhibit Fas-mediated cell death in vitro. CONCLUSIONS: Early infusion of high-dose IVIG is safe, well tolerated, and likely to be effective in improving the survival of patients with TEN. We recommend early treatment with IVIG at a total dose of 3 g/kg over 3 consecutive days (1 g/kg per day for 3 days).

A case of primary mucinous carcinoma of the scalp treated with mohs surgery.

BACKGROUND: Primary mucinous carcinoma of the skin is a rare sweat gland malignancy that is associated with locally aggressive behavior and a high rate of local recurrence following simple excision. OBJECTIVE: A patient with primary mucinous carcinoma of the scalp, which was treated with Mohs micrographic surgery (MMS), is described. METHODS: Case report and literature review. RESULTS: The patient underwent MMS to remove the tumor. Thirty months after the procedure, the patient remains tumor free. CONCLUSION: Simple excision of primary mucinous carcinoma of the skin is associated with a high recurrence rate. Given the low rate of metastasis and characteristic histologic tumor continuity associated with primary mucinous carcinoma of the skin, as well as the tendency for the tumor to involve cosmetically sensitive areas, such as the face and eyelids, MMS appears to represent a preferable treatment alternative for this particular sweat gland tumor. MMS appears to be associated with a very low risk of tumor recurrence.

Giant dermatofibroma with monster cells.

We report a case of a 64-year-old woman with a giant dermatofibroma on her back with the unusual histologic feature of monster cells. The firm, exophytic, 3-cm nodule had purple and yellow components with surface telangiectasia. Histologic examination demonstrated characteristic findings of a dermatofibroma, including rete ridge flattening and bridging; a stroma containing scattered, large, round, eosinophilic collagen bundles; and a polymorphous dermal infiltrate of spindle and xanthomatous cells with scattered siderophages. Some xanthomatous cells demonstrated features consistent with monster cells, including huge bizarre nuclei and one or more nucleoli. Immunohistochemical staining for factor XIIIa was positive. A diagnosis of giant dermatofibroma with monster cells (DFMC) was made. Giant dermatofibromas are rare, with monster cells being an uncommon finding in dermatofibroma. To our knowledge, this is the first report of DFMC.