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.

Adrenal function in women with idiopathic acne.

The adrenal secretion of androgens were examined in 9 women (ages 19-39 yr) with postadolescent idiopathic acne and compared to age and sex-matched normal controls. Plasma dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), androstenedione (delta 4-delta), cortisol, 17-hydroxyprogesterone, 11-deoxycortisol, and testosterone were measured by radioimmunoassay in the basal state and during a 48 hr ACTH infusion. The mean plasma and time-integrated plasma levels of the 3 adrenal androgens in patients with acne were 15-25% higher than normal controls, but the groups were not significantly different (p greater than .05). The plasma testosterone values, on the other hand, were similar in both groups. In addition, cortisol, 11-deoxycortisol and 17-hydroxyprogesterone basal plasma values and responses to ACTH in patients with acne were similar to the normal control values. These findings suggest that adrenal androgen secretion is at most mildly elevated in patients with idiopathic acne and is unlikely to be the sole cause of acne since many patients without acne have similar hormone levels. Increased sensitivity of the sebaceous gland to androgens or increased local metabolism of androgen hormones in the skin to potent androgen metabolites may offer alternative mechanisms for the pathogenesis of this disorder.

Etretinate: effect of milk intake on absorption.

Since etretinate, an aromatic retinoid useful in the treatment of psoriasis and other skin disorders is lipid-soluble, it may be poorly absorbed in the absence of a fat load. We therefore studied serum concentrations of etretinate and its major metabolite (Ro 10-1670) after the controlled administration of etretinate. After an overnight fast, 6 Darier's disease and 4 psoriatic patients received a 1 mg/kg morning dose of etretinate with water or 1 pint of whole milk (fat load). There was a 260% increase (p less than 0.0005) in the mean of each patient's increase in the baseline-corrected peak serum concentration of etretinate after administration with milk (115 +/- 15 micrograms/dl) compared to after administration with water (32 +/- 4 micrograms/dl). Over a 24-h period there was an overall 296 +/- 26% (p less than 0.0005) increase in serum etretinate after administration with milk compared to water in 5 patients with Darier's disease. In contrast to the serum etretinate, there was a 17% mean decrease (p less than 0.025) in the corrected peak serum concentration of Ro 10-1670 in all 10 patients after administration of etretinate with milk compared to water. The net result of these alterations is that the mean corrected serum concentration of etretinate is higher than Ro 10-1670 at all time points measured after milk administration. In contrast, after administration of etretinate with water the major retinoid in the serum is Ro 10-1670. Establishing the clinical significance of these alterations may require controlled clinical trials.

Abnormal retinal function associated with fenretinide, a synthetic retinoid.

Five patients with basal cell carcinoma received fenretinide. Two patients while receiving the drug had evidence of abnormal rod photoreceptor function that reversed rapidly on cessation of therapy. We speculate that fenretinide may interfere with the binding of vitamin A to opsin or with the transport of vitamin A.

Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin. A prospective study.

Twenty men with nodulocystic acne were treated with oral isotretinoin (13-cis-retinoic acid) for four months. Plasma lipids and lipoprotein determinations were obtained before and during treatment to quantitate the effects of oral isotretinoin on lipid metabolism. Maximum isotretinoin-induced elevations in plasma triglyceride and cholesterol levels were 67% and 16%, respectively. Additional maximal changes included very-low-density lipoprotein cholesterol increases of 56%, low-density lipoprotein cholesterol increases of 22%, and high-density lipoprotein decreases of 10% from pretreatment values. Chronic increases in plasma cholesterol levels, increases in low-density lipoprotein cholesterol levels, and decreases in high-density lipoprotein cholesterol levels may predispose subjects to premature atherosclerosis. Because of the potential for unmasking an occult lipid or lipoprotein disorder, the plasma lipid and lipoprotein profiles of subjects receiving isotretinoin should be carefully monitored.

Cutaneous macroglobulinosis.

A patient with Waldenström's macroglobulinemia had firm, translucent papules and nodules on the extremities. Clinically, the skin lesions were suggestive of amyloidosis cutis. Histologically, a homogeneous eosinophilic material was observed in the upper dermis and encasing the hair follicles. Special histochemical stains, electron microscopy, and immunofluorescence microscopy identified the material as IgM.

Retinoids and the eye.

Systemic retinoids are being used more frequently to treat various disorders of the skin, particularly disorders of keratinization. They are promising agents for chemoprevention of cancer and as such may be widely used in the future. Both natural and synthetic retinoids may affect the eye, both on the surface epithelium and the visual metabolism. Three basic effects of pharmacologic doses of synthetic retinoids have been seen. Blepharoconjunctivitis has been particularly prominent with isotretinoin use. Pseudotumor cerebri has been reported sporadically. Recently, night blindness has been reported with both isotretinoin and fenretinide. The greater use of isotretinoin may be more important in explaining the increased incidence of these side effects than is the individual metabolism of the different available synthetic retinoids. These three major side effects of the eye will be carefully evaluated as newer synthetic retinoids are proposed for further trials. Fortunately, it seems that all of these ocular manifestations are dose dependent and reversible, giving the clinician several alternatives to adjust the treatment regimen.

Onychomycosis in diabetes. Management considerations.

With exciting recent developments in the field of medical mycology and a new generation of oral antifungal agents, there has been renewed interest in the management of onychomycosis. Epidemiologic surveys report an overall disease prevalence of 2% to 13% and evidence of steadily rising incidence worldwide. Onychomycosis, beyond being a mere cosmetic nuisance, as it has been labeled historically, can be a serious infection that may have a deleterious impact on patients' overall quality of life and well-being. Across medical disciplines, onychomycosis is well recognized as being arduous both to diagnose and to manage. In addition to the importance of treating onychomycosis in the general population, there is strong clinical impetus to treat patients with concomitant conditions in order to prevent primary disease-related complications that, ultimately, can be life-threatening.

The safety of itraconazole in the diabetic population.

This study examined the safety of itraconazole for the treatment of onychomycosis in patients with diabetes mellitus compared with standard palliative treatment. Fifty-two diabetic subjects in a large Veterans Affairs health system who had been diagnosed as having lower-extremity complications and distal dermatophytic subungual onychomycosis of the toenail were randomized to receive either intermittent itraconazole, 200 mg twice daily, or standard palliative care, consisting of toenail trimming, cleaning, and soaking. Adverse events were reported in 4 of the 27 itraconazole subjects; no adverse events were reported in the 25 palliative treatment subjects. One itraconazole subject was withdrawn from the study because of elevated liver function test results; the other three adverse events (rash, diarrhea, and pedal edema) were considered self-limiting and did not interfere with protocol completion. Analyses of prestudy and poststudy hemoglobin A1c and liver function test results in both treatment groups were comparable, with no statistically significant differences. Itraconazole was found to be safe for the treatment of distal dermatophytic subungual onychomycosis in diabetic patients with lower-extremity complications having multiple concomitant disorders and requiring concurrent pharmacologic regimens.

Cervical motion assessment: a new, simple and accurate method.

Accurate assessment of head motion can be a useful tool in clinical studies. Since the head moves on a combination of axes in the cervical spine, evaluation of neck motion is difficult. Assessment of cervical mobility is further complicated because of inadequate reference points on the head from which to measure. Hence, numerous methods for approximating cervical range have been devised. These methods include visual estimation, radiographic analysis, schematography, photography, and a variety of goniometer devices. Disadvantages of these techniques are lack of accuracy and objectivity, radiation exposure, expense, time consumption, and equipment availability. To measure cervical mobility, a standard gravity goniometer with spirit level and head adapter was used, which allowed stabilization. The gravity goniometer can be obtained in a variety of sizes at most hardware stores. The head adapter consists of a wood block into which an arc is carved and elastic straps suspended for securing on the head. The reliability of this instrument was tested and compared to the universal goniometer, and correlation coefficients were determined. When two experienced examiners used the universal goniometer to assess cervical motion, significant intraclass correlation coefficients (ICC) were found with three of the six criteria measures (p less than 0.05). When one experienced and one novice examiner used the gravity goniometer with head adapter, highly significant ICC values were found for all six criteria measures (p less than 0.01). A single experienced examiner comparing both instruments on the same subjects produced significant ICC values in four of the six criterion measures (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Minocycline-associated tooth discoloration in young adults.

After observing a patient with adult-onset tooth discoloration coincident with minocycline administration, we retrospectively surveyed a cohort of patients with severe cystic acne during therapeutic trials with isotretinoin. Four of 72 patients who had minocycline therapy during adolescence were found to have minocycline-associated tooth discoloration, which occurred in one case after only four weeks of treatment. Thus, minocycline must be considered as an uncommon cause of tooth staining in adults.

Chemoprevention of basal cell carcinoma with isotretinoin.

Three patients with multiple basal cell carcinomas, due either to excessive sunlight exposure, the nevoid basal cell carcinoma syndrome, or arsenical insecticide exposure, were treated with oral isotretinoin for 2 1/2 to 4 years. Although higher doses were used initially, approximately 1.5 mg/kg/day was used for long-term therapy in all three patients. Therapeutic effects on existing tumors varied between each patient, and only nine of sixty-five lesions underwent complete clinical regression. No tumors enlarged in two patients; a few tumors enlarged slightly in the third patient, particularly during the later courses of therapy when isotretinoin was given at lower dosage. No new lesions have been observed in any of these three patients. With these encouraging preliminary data, it now may be appropriate to perform larger trials for longer periods of time to determine the usefulness of isotretinoin in the chemoprevention of basal cell carcinoma in patients with multiple tumors.

Influence of topical and systemic retinoids on basal cell carcinoma cell membranes.

Although much recent work suggests that retinoids can prevent the development of epithelial cancers, their mechanism of action remains unknown. Since malignancy has been associated with alterations in gap junctions, desmosomes, microfilaments, and hemidesmosomes, the authors examined freeze-fracture replicas and thin sections of cell membranes of: (1) 11 basal cell cancers (BCC) treated twice daily for two weeks with topical 1.0% retinoid acid (RA); (2) 21 BCC treated for 2 to 17 weeks with oral 13-cis retinoic acid (CRA) (1.0-8.0 mg/kg/day); and (3) 17 BCC prior to retinoid treatment and/or after applications of vehicle alone. Both thin sections and replicas were examined and photographed in a single-blind fashion, and the density and size distribution of gap junctions and desmosomes were computed planimetrically. Topical RA treatment induced a two-fold increase in gap junction density (P less than 0.025) over controls. In contrast, RA produced a concurrent = 35% decrease in desmosome density. Systemic CRA did not significantly alter either gap junction or desmosome density or size. Finally, neither RA nor CRA treatment appeared to influence hemidesmosome or microfilament populations. Structural changes in both treatment groups did not correlate with either tumor regression or inflammation. Topical and systemic retinoids may exert their antineoplastic activity by different cellular mechanisms.

Histopathology of an adverse reaction to a eutectic mixture of the local anesthetics lidocaine and prilocaine.

A unique histopathologic reaction to the topical application of a eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA), used for topical anesthesia prior to biopsy in two children is described. Standard application of EMLA cream under occlusion for 1 h was given to both patients. The biopsies in both cases demonstrate focal vacuolization of the upper spinous and granular layers. The epidermis was focally separated from the dermis in areas of basal vacuolar alteration. Electron microscopy performed in one case demonstrated the dermal-epidermal cleft to be secondary to alteration of the basal cells with condensation of the cytoplasm and cytologic degeneration similar to that seen in epidermolysis bullosa simplex.

The effects of topical and oral L-selenomethionine on pigmentation and skin cancer induced by ultraviolet irradiation.

This study was conducted to determine whether oral and/or topical selenium (Se) supplementation can reduce the incidence of acute and/or chronic damage to the skin (i.e., sunburn and pigmentation and/or skin cancer, respectively) induced by ultraviolet (UV) irradiation in mice. Groups of 38 BALB:c female mice or 16 Skh:2 hairless pigmented mice were treated with 1) lotion vehicle, 2) 0.02% L-selenomethionine (SeMet) lotion, or 3) vehicle and 1.5 ppm SeMet in the drinking water. Within each group, 30 BALB:c mice or 12 Skh:2 mice were given UV irradiation (Westinghouse FS 40 bulbs) three times per week in doses of 0.575 and 0.24 J/cm2, respectively. The animals' weights and food intakes and the Se concentrations of skin and liver were measured. Skin biopsies were taken from the backs and abdomens of all animals to evaluate the relative amounts of Se and the damage by UV irradiation. Skin pigmentation was scored, and the total number of clinically detectable skin tumors per animal was counted weekly. Results showed that the skin Se concentrations in areas of application of the lotion containing SeMet were greater than those of animals given comparable oral doses, while the Se concentrations of untreated skin and liver were similar to those of animals receiving oral Se. Mice treated with Se showed no signs of toxicity and had significantly less skin damage by UV irradiation, as indicated by reduced inflammation and pigmentation and by later onset and lesser incidence of skin cancer.

Liquid-chromatographic assay for retinol (vitamin A) and retinol analogs in therapeutic trials.

A "high-performance" liquid-chromatographic separation of retinoids (retinol, isotretinoin, all-trans retinoic acid, retinal, etretinate, and retinyl acetate) in serum is described. The separation was used in developing a quantitative assay for retinol (vitamin A) and two therapeutic analogs, isotretinoin (13-cis-retinoic acid) and etretinate (Ro 10-9359). The procedure requires 1 mL of serum. Overall analytical recovery for retinol, isotretinoin, and etretinate from serum was 100% (SD 7%). The between-day coefficient of variation for specimens with concentrations ranging from 0.70 to 0.95 mg/L was less than 4%. Normal reference intervals for serum retinol in men and women are 0.61 to 1.33 and 0.44 to 1.19 mg/L, respectively.

Vertebral abnormalities associated with synthetic retinoid use.

Frequent symptoms of back and neck stiffness led to a radiographic investigation of the vertebral spine in patients receiving synthetic retinoids, isotretinoin and etretinate. X-ray examination of fifty patients with various skin disorders who received retinoids for at least 2 years were compared with seventy-two age- and sex-matched untreated patients. Differences in frequencies of defined abnormalities, which included anterior spinal ligament calcification and presence of osteophyte at two or more vertebral levels in the absence of joint space narrowing, were determined for treated and untreated patients. When the entire group of treated patients was compared with the entire group of those untreated, no statistically significant differences were observed. When only patients with basal cell nevus syndrome ( BCNS ) or basal cell carcinoma (BCC) who had never received retinoid were compared with those who received isotretinoin, the frequency of the defined abnormalities was significantly higher in the treated group (P less than 0.01). This study suggests that the ingestion of isotretinoin at mean total dose of 150,060 mg for an average of 2.9 years is associated with a statistically significant increase in developing an associated ossifying diathesis in patients with BCNS or BCC, when compared with matched, untreated controls.

Treatment and prevention of basal cell carcinoma with oral isotretinoin.

Twelve patients with multiple basal cell carcinomas resulting from varying causes were treated with high-dose oral isotretinoin (mean daily dosage: 3.1 mg/kg/day) for a mean of 8 months. Of the 270 tumors monitored in these patients, only 8% underwent complete clinical and histologic regression. All patients developed moderate to severe acute toxicities, leading five patients to withdraw from the study. Retinoid skeletal toxicity was identified in two patients who were examined after long-term therapy. Lower doses of isotretinoin (0.25 to 1.5 mg/kg/day) were ineffective for chemotherapy but demonstrated a chemopreventive effect in a subset of three patients who received these lower doses for 3 to 8 years. Two of these three patients have been observed after discontinuation of therapy. In one patient with a history of arsenic exposure, only one new tumor has appeared in a 27-month posttreatment observation period; in the other patient with the nevoid basal cell carcinoma syndrome, 29 new tumors have appeared within a 13-month period. This suggests that the need for long-term maintenance therapy with isotretinoin for chemoprevention of basal cell carcinoma may depend on the underlying cause of the skin cancers.