Skin melanoma induced by 7,12-dimethylbenzanthracene in albino guinea pigs and its similarities to skin melanoma of humans.

A model for a metastasizing melanoma was developed, and its characteristics were established. Sixty-five albino guinea pigs were painted with 7,12-dimethylbenzanthracene in acetone. There was evidence that, after 18 months, 40% of the animals developed melanomas. Melanomas arose by a malignant transformation of junctional nevus cells and/or by transformation of amelanotic melanocytes. Metastases to the skin and internal organs were multiple and eventually fatal for the animals. Histology and electron microscopy of induced melanomas were reviewed in detail. Clinical and histological events leading to development of melanoma in albino guinea pigs were found to be similar to human melanomas in a number of aspects. Fragments of melanomas were successfully transplanted to "nude" mice and healthy albino guinea pigs. The described model could be used for study of the various cellular and tissue events which precede nevus, lentigo maligna, and melanoma formation. It could also be useful in studying carcinogenic potential, for studying development of metastases, and presumably for trials of treatment.

Junctional and compound pigmented nevi induced by 9, 10-dimethyl-1,2-benzanthracene in skin of albino guinea pigs.

Seventy albino guinea pigs were used in the experiment to investigate the influence of 9,10-dimethyl-1,2-benzanthracene on amelanotic melanocytes. A field 5 sq cm was marked on the flank of each animal. Hairs from these fields were clipped twice a week and painted for 20 consecutive weeks with 0.3 ml of 1% 9,10-dimethyl-1,2-benzanthracene in acetone. During the 1-year observation period, pigmented sports appeared in 40 animals. Biopsies were taken under local anesthesia, and sections were prepared for light and electron microscopic observations. Melanin formation of unknown mechanism took place in the epidermal melanocytes and in the melanocytes from the outer root sheath. These melanocytes also formed junctional and compound nevi; serial sections revealed various stages of pigmented nevi development. Schwann cells did not participate in the formation of nevi. Evidence is presented that 9,10-dimethyl-1,2-benzanthracene can convert amelanotic melanocytes into melanin-producing cells in the albino guinea pig skin. In addition, this system produces an animal model for the development of junctional and compound nevi.

Effects of ultraviolet-visible irradiation in the presence of melanin isolated from human black or red hair upon Ehrlich ascites carcinoma cells.

The present study is an attempt to investigate the possibility that ultraviolet irradiation in the presence of pheomelanin may be more harmful to cells than the irradiation in the presence of eumelanin. The effects of UV-visible irradiation upon Ehrlich ascites carcinoma cells in the presence of the melanin isolated from human black hair (eumelanin) or from red hair (pheomelanin) were investigated. Irradiation of these cells was found to produce cell lysis, as observed by leakage of 51Cr from labeled cells and intracellular lactic dehydrogenase from the cells and decrease in cell viability demonstrated by the trypan blue exclusion test. The three parameters were quantitatively parallel to one another under various experimental conditions, namely different periods of irradiation and irradiation in the presence of different concentrations of melanin. The above effects were more pronounced when the irradiation was carried out in the presence of melanin from red hair than in the presence of black-hair melanin. In the absence of either melanin, the irradiation did not produce any significant effect in cell viability or cell lysis. Irradiation of the cells in the presence of red-hair melanin also decreased the transplantability of these cells. These observations clearly show that irradiation of cells in the presence of pheomelanin could produce cytotoxic effects. The present experimental design may have application in the development of in vitro models for the study of UV radiation-induced cutaneous carcinogenesis. The reactions of pheomelanin may be related to the susceptibility of "Celtic" skin to UV radiation-induced skin damage and carcinogenesis.

Heterotransplantation of human basal cell carcinomas in "nude" mice.

Human basal cell carcinomas, obtained from 10 subjects were transplanted to 25 "nude" mice. Two methods of transplantation were used and compared. Grafting gave better results than subcutaneous implantation. Tumor cells were identified in 5 mice, however only 2 of them developed lesions with histology similar to human basal cell carcinoma. Grafts, in which tumors developed, were obtained from superficial basal cell carcinoma. No reasons for the cause of the low percentage of successful transplantation and slow rates of growth of the transplants are found; however, possible immunological, vascular and environmental factors are discussed.

Simple and sensitive test for the determination of phenolic compounds in urine and its application to melanoma.

A simple procedure is outlined for the determination of phenolic compounds in urine. The method involves the diazotization of p-nitroaniline and subsequent coupling of the diazonium chloride with phenolic compounds. The diazo compound formed is determined by measuring the absorbance at 400 nm. The extinction coefficients for several compounds have been determined. Application of this method to determine the levels of phenolic compounds in urine in patients with melanoma showed that the assay may be of diagnostic value. The amounts of phenols in 24-hr urine samples from patients with melanoma, patients with various other diseases, and healthy individuals were determined. A statistical analysis of these results showed that the results for patients with melanoma were higher than those for healthy individuals and patients with other diseases at 1 percent probability level. A comparison of this test with three other methods (Thormählen test, ferric chloride test, and ferrocitrate test) for determination of melanogens showed that the diazo test is the most sensitive one for detecting melanoma.

Familial vulvar dystrophy of lichen sclerosus type.

Lichen sclerosus et atrophicus (LS&A) of the vulva and perianal skin is an atrophic condition that con occur alone or in association with additional lesions situated elsewhere on the skin surface. The cases of three sisters with LS&A of the vulva are reported herein; in one a squamous cell carcinoma developed in a hyperplastic area of mixed dystrophy (LS&A with foci of hyperplasia). Familial occurrences of LS&A are rare. Malignant neoplasms arising in areas of LS&A have been reported previously. Squamous cell carcinoma arises in hyperplastic areas of mixed dystrophy where there is evidence of both LS&A and epithelial hyperplasia.

Proliferating angioendotheliomatosis. Case with long survival and review of literature.

A 30-year-old woman developed cutaneous proliferating angioendotheliomatosis without endocarditis. She was treated with local excision and radiotherapy 42 months ago. There is no recurrence eight years after clinical onset of the lesion, making this one of the longest documented cases of survival. A literature review of the disease, including its controversial histiogenesis, treatment, and survival, is presented. In view of the rarity of the disease, only by studying more patients can we better understand the disease. Since more than one disease process may be included under this diagnosis, clearer clinical and histogenetic separation is required, with immunohistochemical techniques potentially helping to provide a more precise diagnosis.

Cutaneous malignant neoplasms in patients with renal transplants.

There is an increased risk of developing cutaneous neoplasms in patients with renal transplants who are receiving immunosuppressive therapy. We studied 523 consecutive white patients who had received renal transplants at a Canadian medical center. Malignant neoplasms developed in 7.5% of these patients, and 72% of these neoplasms were cutaneous in origin. Compared with the general population, the rate of development of all skin cancers, squamous cell carcinoma, and basal cell carcinoma was 3.2, 18.4, and 1.4 times, respectively. In our study the squamous cell carcinoma to basal cell carcinoma ratio was 2.3:1, compared with 0.2:1 in the general population. There was no significant difference in the site of development of skin cancer in patients with renal transplants compared with the general population. There was, however, a propensity for the development of multiple skin cancers at an earlier age, especially on sun-exposed areas. The results of this study have been compared with those of other world medical centers.

Dermatologic signs in anorexia nervosa and bulimia nervosa.

The dermatologic changes in anorexia nervosa and bulimia nervosa may be the first signs to give the clinician a clue that an eating disorder is present, as many of these patients either deny their symptoms or secretly refuse to comply with treatment. The dermatologic signs are a result of (1) starvation or malnutrition, eg, lanugolike body hair, asteatotic skin, brittle hair and nails, and carotenodermia; (2) self-induced vomiting, eg, hand calluses, dental enamel erosion, gingivitis, and a Sjögrenlike syndrome; (3) use of laxatives, diuretics, or emetics and their dermatologic side effects; and (4) other concomitant psychiatric illness, eg, hand dermatitis from compulsive handwashing. Further, as most of the cutaneous signs are not specific to anorexia nervosa and bulimia nervosa, failure to include eating disorders in the differential diagnosis may lead to misdiagnosis of the cutaneous symptoms.

Role of iron in the photosensitization by uroporphyrin.

The role of iron in the mechanism of photosensitivity due to uroporphyrin was investigated. There is frequently increased levels of Fe in the serum from patients with porphyria cutanea tarda, where the photosensitivity is due to uroporphyrin. It has been reported that H2O2 has a major role in the uroporphyrin induced photosensitivity. Hence we examined the hypothesis that Fe would catalyze the production of OH from H2O2 and the OH thus formed may have a significant role in the uroporphyrin photosensitivity. This was examined by studying the effects of the Fe chelating compound deferoxamine in an in vitro system. Our results show that deferoxamine inhibited the uroporphyrin photosensitivity, but not the photosensitivity due to protoporphyrin. This indicates that Fe may play a role in the uroporphyrin photosensitization in the skin, by accelerating the formation of OH, which may be a major reactive species responsible for the photosensitization in porphyria cutanea tarda.

Quantitation of hydrogen peroxide formed during UV-visible irradiation of protoporphyrin, coproporphyrin and uroporphyrin.

Free porphyrins are strong photosensitizers. Previously reported findings indicate that the in vitro cell lysis induced by irradiation in the presence of coproporphyrin (CP) and uroporphyrin (UP) is mediated by H2O2 and that induced by irradiation with protoporphyrin (PP) is not mediated by H2O2. In the present study the possible role of H2O2 in the porphyrin photosensitization was investigated by direct measurement of the H2O2 formed during the irradiation of PP, CP and UP. Our results show that the amount of H2O2 formed decreased in the following order: UP, CP, PP. The amounts of H2O2 formed during irradiation of CP and PP were approximately 86% and 38% respectively in comparison to the H2O2 formed during the irradiation of UP. The formation of H2O2 was inhibited by sodium azide, a strong quencher of singlet oxygen. These observations are in good agreement with the previous report that the in vitro photolysis of Ehrlich ascites carcinoma cells by UP and CP, but not that by PP, was inhibited by catalase and clinical findings with patients with erythropoietic protoporphyria (EPP) and porphyria cutanea tarda (PCT). The patients with EPP, where the photosensitivity is due to PP, respond well to beta-carotene while beta-carotene does not protect against the photosensitivity in PCT, in which case the photosensitivity is due to uroporphyrin.

Modulation of 8-methoxypsoralen-photoinduced cutaneous inflammatory reactions by various chemotherapeutic agents in vivo.

Exposure of albino rabbits to UVA-VIS (320-700 nm) radiation after the topical application of 8-methoxypsoralen (8-MOP) cream is associated with acute cutaneous inflammatory reactions in situ. In the present studies the effects of various agents on 8-MOP plus light induced cutaneous inflammatory response viz. increase in vascular permeability (iVP), accumulation of polymorphonuclear leukocytes (aPMN) and erythema formation were investigated. The inflammatory reactions were induced by a single exposure of 8-MOP-sensitized sites to UVA-VIS (9.4J/cm2) light. Indomethacin, p-bromophenacyl bromide (BPAB), MK886 (trade name of Merck Sharpe & Dome), ibuprofen (IB), nordihydroguaiaretic acid (NDGA) or quinacrine were applied topically in cream base at various times prior to 8-MOP application. The iVP and aPMN were quantitated 24 h postirradiation using 125I-HSA and 51Cr-labeled PMN respectively, while erythema was graded visually. The rate of iVP, aPMN and erythema was inhibited almost completely by indomethacin (7.5-10%) when applied twice, 18 h and 3 h prior to 8-MOP. At lower concentrations of indomethacin (< or = 5%) iVP was inhibited whereas aPMN was augmented. The BPAB (0.25%) inhibited more than 90% of 8-MOP-photoinduced iVP and aPMN while there was partial reduction in erythema. The MK886 (0.1%) cream inhibited about 50% of iVP and aPMN but erythema persisted. The agents that are somewhat nonspecific such as IB, quinacrine and NDGA inhibited 8-MOP-photoinduced inflammation only marginally at the concentrations tested. The fact that iVP, aPMN and erythema can be dissociated suggests that there are independent variables in 8-MOP-photoinduced reactions, which involve multifactorial mechanisms probably controlled by different cell-signalling pathways and mediators.

The self-inflicted dermatoses: a critical review.

The self-inflicted dermatoses, namely dermatitis artefacta, neurotic excoriations, and trichotillomania, have been reported to be associated with various degrees of psychopathology in the dermatologic literature, but have received surprisingly little emphasis in the psychiatric literature. This probably reflects, firstly the fact that most of these patients initially deny any psychologic problems and hence may not receive psychiatric interventions, and secondly a lack of adequate collaboration between the psychiatrist and dermatologist. These disorders may be associated with serious sequelae, such as suicide and repeated major surgical procedures. Their treatment is also primarily psychiatric. This article critically reviews the literature and comments upon the salient clinical features and treatments for these disorders, which are relevant for the psychiatrist doing consultation-liaison work. Knowledge of these disorders is important in the evaluation of any psychiatric patient, as these disorders are essentially a cutaneous sign of psychopathology.

Psoriasis and psychiatry: an update.

Psychosocial factors are important in the onset and/or exacerbation of psoriasis in 40%-80% of cases. Yet psoriasis has received little attention in the recent psychiatric literature. A subgroup of psoriatics appear to be "stress reactors" and these patients may have a better long-term prognosis. Identification of such patients early in the course of treatment and incorporation of specific psychosocial interventions in their overall treatment regimen may improve the course of illness. Psoriasis has also been associated with suicide and an increased prevalence of alcoholism. The disturbances in body image perception and the effect of psoriasis on interpersonal, social, and occupational functioning can further contribute to the overall morbidity, especially if psoriasis first occurs during a developmentally critical period like adolescence. Certain biochemical and physiologic correlates of psoriasis of interest to the psychiatrist such as exacerbation of psoriasis with lithium therapy and increased cutaneous blood flow are discussed. Finally, some practical guidelines are provided for psychosocial interventions in psoriasis.

Comparative studies on the tolerance to photoinduced cutaneous inflammatory reactions by psoralen and rose bengal.

The photochemotherapeutic value of topical 8-methoxypsoralen (8-MOP) plus UVA irradiation has been well recognized. The phototoxicity associated with psoralen plus UVA (PUVA) therapy is hallmarked by an increase in vascular permeability (iVP), the accumulation of polymorphonuclear leukocytes (aPMN) and erythema formation in situ. Rose bengal (RB) plus UVA-VIS light (320-700 nm) produces a similar acute inflammatory response, but without immediate or delayed erythema and perceptible edema. This study describes some of the parameters involved in inflammatory reactions evoked by PUVA and the results are compared with RB-induced phototoxic reactions. The rates of iVP and aPMN with a 3 h pulse were quantified using 125I-albumin and 51Cr-labelled PMNs respectively. The erythemal response was graded visually. 8-MOP cream was applied topically, while RB was injected intradermally in rabbit skin before UVA-VIS (9.4 J cm-2) irradiation. The data show that there is no significant difference in the rates of iVP, aPMN and erythema formation between normal skin sites and mast cell-depleted skin sites when challenged with 8-MOP plus light. These results suggest that in situ mast cells do not play a significant role in 8-MOP-photoinduced acute cutaneous inflammatory reactions, in contrast with RB-photoinduced reactions. The iVP and aPMN responses are minimal or absent in sites subjected to repeated exposure to 8-MOP plus light for three or more consecutive days, suggesting the establishment of a desensitized/unresponsive state. Moreover, 8-MOP-photo-desensitized sites do not produce iVP and aPMN of the same magnitude as the normal (naive) skin sites when challenged with RB plus light. Similarly, RB-photo-desensitized sites do not produce iVP and aPMN of the same magnitude as the native skin sites when challenged with 8-MOP plus light. The desensitization and cross-desensitization of skin sites to 8-MOP- or RB-photoinduced reactions suggest that there is either direct attack on the target cell(s), thereby removing the ability to express adhesion molecules, such as endothelial leukocyte adhesion molecule 1 (ELAM-1) or intercellular adhesion molecule 1 (ICAM-1), involved in the accumulation of inflammatory cells, or downregulation of the secretion/release of putative agent(s), such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), responsible for the initiation and progression of cutaneous inflammations.

Photoinduced cutaneous inflammatory response by psoralens.

Our studies describe the inflammatory response in rabbit skin induced by topical application of 8-methoxypsoralen (8-MOP) and UVA-visible irradiation (320-700 nm). Increase in vascular permeability (iVP) and accumulation of polymorphonuclear leucocytes (aPMN) at the test sites were quantitated using 125I-albumin and 51Cr-labelled PMNs respectively. Erythema was graded visually. 8-MOP cream was applied topically and irradiated. The erythemal response, aPMN and iVP at the test sites were quantitated at 6, 24, 48 and 72 h post-irradiation. The iVP and aPMN were maximal at 24 h; the erythemal response was the same at 24-48 h. The responses were dependent on 8-MOP concentration and irradiation dose. Topical application of 200 micrograms 8-MOP cream followed by irradiation for 2 h (9.4 J cm-2) produced 3-7 times iVP, 2-4 times aPMN and intense erythema at the test sites after 24 h. Neither aPMN nor iVP was detected before 6 h and erythemal response was not observable up to 16 h after irradiation. The aPMN and iVP gradually subsided in 72 h, although the erythemal response was still present. The repeated exposure of 8-MOP-treated sites for three consecutive days 24 h apart did not produce appreciable iVP or aPMN at 72 h or 24 h after the last exposure; however, erythema persisted. The 8-MOP-treated sites previously exposed for three consecutive days on reapplication of 8-MOP cream plus irradiation showed significantly less response compared with non-pretreated sites. Our results suggest that the erythemal response is not directly related to either iVP or aPMN.

Endogenous porphyrins in murine skin and transplanted PAM-212 squamous cell carcinoma tissues after injection of delta-aminolevulinic acid.

After intraperitoneal (IP) injection of delta-aminolevulinic acid (ALA), the endogenous porphyrins in murine skin and tumor tissues were determined by a method involving solvent and acid extractions. The results showed that the total amount of porphyrins in the tumor tissues after ALA injection was much higher than that in the skin from the same mice, although the amount of porphyrins in the skin from the ALA-injected mice was higher than that from the saline-injected (control) mice. The porphyrins in the tumor were mostly protoporphyrin and coproporphyrin, with only a small amount of uroporphyrin. The optimum period for porphyrin accumulation in the tumor as well as in the skin was 1 hour after the injection of ALA. As the period was extended to 3 and 6 hours, the amount of porphyrins in these tissues decreased considerably. These findings could be valuable for further application of ALA in the photodynamic therapy of skin cancer.

Yellow nail syndrome.

The case of a patient with yellow nail syndrome (YNS), an infiltrating duct carcinoma of the breast, and giant cell interstitial pneumonitis (GIP) is presented. YNS has not been previously described in association with GIP. There was improvement of the yellow fingernails following surgery and chemotherapy for the breast cancer. The possible pathogenesis of the yellow nails in this case and its management are presented. A wide variety of conditions are associated with YNS, which has been reported to respond to various treatment modalities. The most likely cause in our case is impaired lymphatic drainage. However, treatments that do not affect lymphatic drainage also have been reported to be successful.