[Acquired hypertrichosis lanuginosa and gastric adenocarcinoma]. / Hypertrichose lanugineuse acquise et adénocarcinome gastrique.

INTRODUCTION: Acquired hypertrichosis lanuginosa is a form of obligatorily paraneoplastic disease characterised by the recurrence of lanuga hair during adulthood. We report a case in which this hypertrichosis allowed diagnosis of gastric cancer. OBSERVATION: A 51 year-old woman was seen for hypertrichosis present for 3 months. Clinical examination led to diagnosis of acquired hypertrichosis lanuginosa, which subsequently resulted in the discovery of gastric adenocarcinoma. Surgical excision of the tumour resulted in the disappearance of hypertrichosis with no recurrence during the ensuing 13 months. DISCUSSION: Acquired hypertrichosis lanuginosa is rare, with only 50 or so cases reported in the literature since the condition was first described in 1865 by Turner. These cases confirm the obligatorily paraneoplastic nature of this particular dermatosis. Our finding is original since it is the first recorded case of association with gastric adenocarcinoma. It is also unique in terms of the strictly parallel development of acquired hypertrichosis lanuginosa and the tumour, with complete disappearance of the hypertrichosis in the weeks following surgical removal of the tumour, and in terms of prolonged survival (complete remission 17 months after the onset of symptoms). The mechanism responsible for acquired hypertrichosis lanuginosa is unknown. Two hypotheses have nevertheless been suggested: acquired hypertrichosis lanuginosa could be associated with secretion by the tumour of an as yet unidentified serum factor, or with a nutritional deficiency that may accompany this form of cancer.

Use of allogenic epidermal sheets for difficult wound healing: selection and testing of relevant growth factors.

The clinical interest of using allogenic epidermal sheets (AES) has largely been shown [1,2,3]. As well as covering, they also stimulate healing, by simultaneously secreting numerous growth factors (GFs), although little is known on their mechanism of action. Our objectives were to: (a) devise a test for the efficacy of AES release, (b) select keratinocyte-secreting strains and optimal culture conditions. Three GFs were selected: IL-1alpha, IL-8 and VEGF. Three different keratinocyte strains were cultured for 3 and 6 days after confluence for 3 passages. Assays were performed after 3 h and 24 h+3 h after dispase treatment (AES conservation for 24 h then change of medium and sampling after 3 h). AES were found to secrete GFs in DMEM and the amounts were greater when cultured for 6 rather than 3 days after confluence. Each strain had different secretory patterns depending on passage and time in culture, this variability being explained by inter-individual heterogeneity.

[Drug hypersensitivity syndrome associated with a primary HHV6 infection]. / Syndrome d'hypersensibilité médicamenteuse associé à une primo-infection HHV6.

INTRODUCTION: Drug hypersensitivity syndrome is a severe life-threatening drug reaction. An association between this syndrome and HHV6 reactivation has been hypothesized. CASE-REPORT: A 45 year-old women was treated with sulfasalazine for polyarthralgia. One month after beginning the treatment, she developed a drug hypersensitivity syndrome with severe acute hepatic failure. HHV6 serology and serum PCR revealed a primary HHV6 infection. DISCUSSION: We report the second case of drug hypersensitivity syndrome associated with a primary HHV6 infection. An immunological disorder may explain such an association by increasing viral replication. Detection and titration of anti-HHV6 antibodies in each case of drug hypersensitivity syndrome should help to confirm this association and possibly modify treatment strategy.

[Nicorandil-associated anal ulceration]. / Ulcérations anales induites par le nicorandil.

BACKGROUND: Nicorandil is a potassium-channel activator used in the treatment of angina pectoris. The first cases of anal ulcerations induced by nicorandil were published in 2002. CASE REPORT: A 71-year-old man presented with a 2-year history of anal ulcerations occurring within a few months of initiation of treatment with Nicorandil. Histological tests on a biopsy sample showed granulation tissue with non-specific chronic inflammation. Nicorandil was stopped and this resulted in complete healing of the ulcers after three months. DISCUSSION: Nicorandil can induce chronic and extensive anal ulcerations. The pathogenesis is unknown. Patients are usually treated with high doses of nicorandil. Dermatologists should be aware of this rare side-effect which heals after withdrawal of the drug.

TGFbeta inhibits CD1d expression on dendritic cells.

The CD1 family of cell surface glycoprotein has been demonstrated to be a third lineage of antigen-presenting molecules for specific T cell responses. They present lipidic, glycolipidic antigen and hydrophobic peptide to T cells. CD1d restricted T cells play a role in autoimmune disease and in tumor immunity. Transforming growth factor beta (TGFbeta), a member of the family of polypeptide growth factors synthetized by human keratinocytes, has inhibitory effects on proliferation and differentiation of immune cells, especially on CD1d-restricted natural killer T cells. These properties led us to investigate the role of TGFbeta in CD1d expression on dendritic cells (DC), which are known to play a key role in initiation of the immune response. Here, we observed CD1d molecules on DC developed from PBMC with GM-CSF and IL4 but not with GM-CSF, IL4 and TGFbeta for 7 d. RT-PCR and FACS analysis (mAb 42.1) performed at various stages of differentiation on CD34+ HPC show that CD1d mRNA levels and CD1d molecule expression at the cell surface decreased progressively during the differentiation process. Thus, while committing DC-precursors differentiation toward the Langerhans cell (LC) pathway, TGFbeta likely inhibits CD1d transcription. Therefore, LC freshly recovered from epidermal sheet were evaluated by flow cytometry. In accordance with in vitro observation, they did not expressed measurable levels of CD1d molecules at the cell membrane. Thus, TGFbeta produced by keratinocytes contribute to selectively downregulate CD1d expression on intraepidermal-resident LC.

[Correction of facial lipoatrophy with a biodegradable material in HIV-infected patients]. / Correction par produit biodégradable des lipoatrophies faciales des malades infectés par le VIH.

INTRODUCTION: Facial lipoatrophy in HIV-infected patients under tri-therapy occurs frequently and alters their quality of life. No systemic treatment is capable of curing this problem. PATIENTS AND METHODS: Eighty-one patients were included in an open, prospective, compassionate study. A strict intradermal injection of a biodegradable, polyacrylamide cationic copolymer was administered in several sessions. RESULTS: In all the patients, the correction of the facial lipoatrophy was considered satisfactory and stable over a period of 6 months using comparative photographic clichés. The thickness of the dermal skin, assessed by sonography, was doubled. No local or systemic side effect was reported. CONCLUSION: Our study shows that is it possible to durably correct the facial lipoatrophy of HIV-infected patients under tri-therapy by using a biodegradable implant.

[Kaposi's sarcoma and organ transplantation: 22 cases]. / Maladie de Kaposi et transplantation d'organes: 22 cas.

BACKGROUND: The discovery of the Human Herpes virus 8 (HHV8) improved our knowledge of the pathogenesis of Kaposi's sarcoma. After organ transplantation, Kaposi's sarcoma exhibits distinctive features compared with other forms of the disease. PATIENTS AND METHODS: We report 22 cases of post-transplant Kaposi's sarcoma (12 kidneys, 2 kidney-pancreas, 6 livers and 2 hearts). The aim of this retrospective study was to analyze clinical and virological characteristics in these transplant patients and to specify the frequency of HHV8 seroconversions in this population. RESULTS: Twenty-one patients showed cutaneous lesions and 9 had visceral involvement. HHV8 serology was positive in 16/20 patients at transplantation and in 21/22 cases at the time of Kaposi's sarcoma diagnosis. Most cases corresponded to viral reactivations whereas seroconversions occurred in 2 cases and may have been linked to viral transmission by the graft. Treatment led to recovery in 68p. 100 of the cases. Two heart-transplant patients died from their disease. We included in our series two cases of re-transplanted patients without recurrence of Kaposi's sarcoma and one case of familial Kaposi's sarcoma. DISCUSSION: Seroconversions after transplantation emphasize the interest of systematic screening of HHV8 serology in transplant recipients and their donors.

Linear IgA bullous dermatosis with IgA antibodies exclusively directed against the 180- or 230-kDa epidermal antigens.

This study describes the presence in sera from patients with linear IgA bullous dermatosis (LABD) of IgA antibodies specific for 230- or 180-kDa epidermal antigens. Of 11 patients' sera with IgA antibodies reactive with the epidermal antigens obtained from cultured keratinocytes, 6 sera recognized the 230-kDa antigen and co-migrated with the polypeptide recognized by a human monoclonal antibody against the 230-kDa bullous pemphigoid antigen (BPAgl). Five sera recognized the 180-kDa antigen and co-migrated with the polypeptide stained by a polyclonal antibody to the 180-kDa bullous pemphigoid antigen (BPAg2). None of these LABD sera contained IgG antibodies reactive with the basement membrane zone antigens and none labeled a 97-kDa epidermal antigen or a 290-kDa dermal antigen. Immunoaffinity-purified IgA antibodies from the 230 kDa band further reacted with the epidermal side of the skin basement membrane zone. Epitope mapping with rBP55, a fusion protein containing the C-terminal end of BPAg1, suggested that the major antigenic epitopes for LABD and BP antibodies on the 230-kDa antigen are different. Only one serum with IgA antibodies was found to label rBP55, contrasting with nine of ten BP sera reacting with this protein. Our study demonstrates the presence of an exclusive IgA response against the 230- or 180-kDa antigens in a subset of patients with LABD.

Identification of a 168-kDa mucosal antigen in a subset of patients with cicatricial pemphigoid.

This study describes the presence of antibodies in sera from patients with cicatricial pemphigoid specific for a 168-kDa antigen expressed by buccal mucosa. Six cicatricial pemphigoid sera unreactive, with epidermal or dermal proteins in immunoblot assay were tested on mucosal protein extracts. Four of these sera labeled a mucosal 168-kDa antigen (M168) under reducing conditions. An additional cicatricial pemphigoid serum with circulating antibodies to 180-kDa bullous pemphigoid antigen (BPAg2) also labeled M168. None of these cicatricial pemphigoid sera reacted with the alpha, beta, or gamma subunits of laminin-5. Nitrocellulose elution studies showed that the M168 antigen is a basement membrane antigen and labeled the epidermal side of salt-split skin. Immunoaffinity-purified anti-M168 antibodies did not bind to the 230-kDa bullous pemphigoid antigen (BPAg1) or to the 180-kDa BPAg2. None of the control sera from healthy individuals or from bullous pemphigoid, pemphigus vulgaris, or pemphigus foliaceus patients reacted with Ml68. This study demonstrates the specificity of some cicatricial pemphigoid sera against a 168-kDa antigen that is different from the laminin-5 subunits and shares no epitopes with the antigens of bullous pemphigoid (BPAg1, BPAg2) or the epidermolysis bullosa acquisita.

Tumour necrosis factor (TNF) soluble receptors in malignant melanoma: correlation with soluble ICAM-1 levels.

It has been recently suggested that soluble tumour necrosis factor receptors (sTNF-Rs) may represent prognostic factors in cancer. In malignant melanoma, the intercellular adhesion molecule (ICAM-1) has been described as involved in progression of the disease and is upregulated by TNF alpha. We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (sICAM-1). Significantly raised sTNF-R1 levels were detected only in patients with metastatic melanoma compared with normal controls (P < 0.002), whereas sTNF-R2 levels were increased both in primary and metastatic melanoma (P < 0.001). The ratio of type 2 to type 1 proteins increased in malignant melanoma compared with the controls but remained constant with the progression of the disease. A correlation between sTNF-Rs and sICAM-1 concentrations in patients' sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumour progression.

Sequential histological and immunohistochemical study of the skin of the first human hand allograft.

BACKGROUND: On September 1998, the first human hand allograft was successfully performed in Lyon. METHODS: A 48-year-old white man who had suffered accidental amputation of the arm in 1984, received a forearm and hand allograft from a 42-year-old white male cadaveric heart-beating donor. Immunosuppressive therapy included prednisone, mycophenolate mofetil, FK506, and antithymocyte globulins. Sequential skin biopsies were taken from the grafted limb and examined (immuno)histologically to detect a possible graft rejection and to evaluate the structural integrity of the skin of the allograft. RESULTS: The skin showed histologically a normal appearance, except on days 57 and 63, when a mononuclear perivascular cell infiltrate was observed in the dermis; this appeared concomitantly with erythematous lesions of the skin that developed after a slight decrease of the immunosuppressive treatment. These changes were considered as signs of graft rejection, and were reversed by an increase of the immunosuppressive treatment. No skin necrosis was seen at any time. Immunohistochemically, the main cell types of the skin were present throughout the study. From day 77 onward the epidermis of the grafted hand harbored some epidermal Langerhans cells of recipient's origin. CONCLUSION: This study shows that the skin of the hand allograft maintains overall a normal histological structure and contains most essential cell types, including cells of recipient origin, such as Langerhans cells. Furthermore, it shows that in this system of composite tissue transplantation, skin biopsies may reveal a starting graft rejection, before the appearance of clinically obvious lesions.

Circulating vascular endothelial growth factor (VEGF) is not a prognostic indicator in malignant melanoma.

Among angiogenic peptides, vascular endothelial growth factor (VEGF) is associated with growth and metastasis of solid tumours. In order to determine whether VEGF could be involved in the clinical course of malignant melanoma, we studied 96 patients with primary or metastatic melanoma and we reported the follow-up of nine cases who initially presented with a primary melanoma and further developed metastasis over a period of 12-25 months. Circulating VEGF levels quantified by enzyme-linked immunosorbent assay were found to be elevated in patients with primary or metastatic melanoma compared to a control group (P < 0.001), but no significant difference occurred between primary and metastatic melanoma. The follow-up of patients who developed metastasis showed high initial VEGF levels (in five out nine cases) which remained increased with the course of the disease. It is conceivable that increased VEGF levels reflect an intense activation of the host immune system but the variations in the concentration of circulating VEGF were not considered as an indicator of disease evolution in malignant melanoma.

Soluble intercellular adhesion molecule 1 (sICAM-1) and malignant melanoma.

A soluble form of the intercellular adhesion molecule-1 (sICAM-1) has been reported to be elevated in malignant melanoma. We have studied the expression of sICAM-1 by ELISAs in a series of 85 consecutive sera derived from patients with primary or metastatic melanomas in comparison with control patients and patients with diffuse acute eczema and psoriasis. Our results showed elevated sICAM-1 concentrations in patients with malignant melanoma but also in patients with extensive inflammatory dermatoses. The diagnostic potential of sICAM-1 in malignant melanoma appears to be limited. Further studies are needed to determine whether increased values of sICAM-1 in primary melanomas may predict a progression of the disease.

Incidence of human papillomavirus type 33 in premalignant and malignant skin lesions from organ transplant recipients.

Human papillomavirus (HPV) type 33 belongs to potentially oncogenic types in genital cancers, but its infection corresponds to an intermediate risk for progression towards malignancy. We studied by in situ hybridization with biotinylated probes the incidence of HPV 33 infection in a series of 106 skin lesions and 12 mucosal lesions from heart and renal transplant recipients, 34 skin lesions and 17 mucosal lesions from normal population. We have shown that skin lesions from both populations could harbor HPV 33. In transplant recipients, HPV 33 was identified in 12/77 premalignant and malignant lesions and one oral leukoplakia; in the normal population, HPV 33 was detected in 2/13 warts and 2/15 mucosal lesions. The analysis of in sial hybridization signal pattern of the 17 HPV 33 positive samples suggests that a strong viral DNA signal was uniformly distributed in the nuclei of positive cell foci in 11 cases and punctate signals were seen in the nuclei of dispersed cells of 6 skin biopsies. The significance of the presence of HPV 33 DNA in skin lesions is not clear; the hybridization signal pattern may be important, mainly in premalignant actinic keratodses of organ transplant recipients although other factors are most likely involved to change the epithelial environment.

Raynaud's phenomenon of the lung. A reality both in primary and secondary Raynaud syndrome.

Vasospasm of RP is thought to occur in the lungs. To assess pulmonary vasospasm, we analyzed the early and late Dsb variations after a digital CPT. Sixteen normal volunteers and 20 patients (7 with primary, 13 with secondary RP) were included. A clinical RP was conducted on ten patients, nine with secondary and one with primary RP. The Dsb analysis showed: no significant variations in control subjects, a quick and short fall in primary RP significant after 15 min and a delayed fall in secondary RP significant after 45 min. A Dsb decrease was noticed even if no clinical RP occurred. The pallor phase of RP was associated with a concomitant decrease in the DCO and the hyperemic phase, with a Dsb increase. These results agree with those of previous studies with a few differences.

Differential expression of the cancer associated antigens T (Thomsen-Friedenreich) and Tn to the skin in primary and metastatic carcinomas.

AIM: To study the immunohistochemical expression of the Thomsen-Friedenreich antigen (T) and its precursor, Tn, in the skin in various cancers. METHODS: T and Tn antigens were studied with monoclonal antibodies in 91 primary premalignant and malignant lesions, 13 cases of Paget's disease, and 26 carcinomas metastatic to the skin. The material had been collected over a 10 year period, formalin fixed, and paraffin embedded. Diagnoses had been made after examination of standard histological sections, supplemented when needed by appropriate immunohistochemical staining. RESULTS: 21% and 29% of the primary cutaneous premalignant and malignant epithelial tumours expressed the Tn and T antigens, respectively. By contrast, 81% of metastatic carcinomas to the skin were Tn positive, while only 23% of them expressed the T antigen. All cases of Paget's disease were Tn positive but only 15% of them expressed the T antigen. The 21 nonepithelial tumours (including melanomas) were as a rule unreactive. CONCLUSIONS: The accumulation of the precursor (Tn) antigen in tumours metastasising to the skin highlights the incomplete glycosylation of carbohydrate antigens occurring in these tumours. The predominant Tn versus T antigen expression appears to be a useful immunohistochemical feature which may aid in the differentiation of primary cutaneous carcinomas from metastatic tumours.

Retinoids for the management of dermatological complications of organ transplantation.

Organ transplant recipients receiving immunosuppressive therapy are prone to skin cancers, especially squamous cell carcinomas on sun-exposed areas. The frequency of skin cancers increases with time after transplantation, reaching 40 to 70% of patients after 20 years. Squamous cell carcinomas tend to be multiple and may have a life-threatening course. They are often associated with warts, premalignant keratoses, Bowen's disease and keratoacanthomas. Repeated excisions of tumours and sessions of cryotherapy are not always satisfactory, as they lead to numerous scars and aesthetic impairment. Systemic retinoids may be used in organ transplant recipients without inducing graft rejection; they prevent the occurrence of dysplastic lesions and skin carcinomas. There is usually relapse following discontinuation of retinoids, raising the question of continuous or intermittent treatment. The long term use of retinoids may be limited by adverse effects which are cumulative with those of immunosuppressive treatment. Hence, systemic retinoids should be reserved for patients developing a great number of lesions over short periods. Topical retinoids probably represent the best way to control the proliferation of premalignant and malignant lesions. Further studies are required to assess the efficacy and safety of new retinoids.

PUVA treatment of alopecia areata.

Twenty-three patients with alopecia areata were treated with photochemotherapy combining oral or topical methoxsalen and UV-A irradiation of the scalp or of the whole body. Eleven of 17 patients with multiple plaques of alopecia areata, alopecia totalis, and alopecia universalis, who were treated with oral methoxsalen and total body irradiation, had complete or more than 90% hair regrowth. Three patients had a relapse. The mean energy required was 505 joules/sq cm. In six cases, topical applications of methoxsalen or oral methoxsalen combined with local irradiation of the scalp were treatment failures. In the patients responding to treatment, the result did not seem to depend on the age of onset or the extent or duration of disease. However, patients with long-lasting alopecia had a higher risk of recurrence notwithstanding a good initial regrowth of hair. Few side effects of psoralens and UV-A (PUVA) treatment were noted. The mean follow-up period was 18.6 months after the completion of treatment. We discuss the possible mechanisms of action of PUVA in the treatment of alopecia areata.

Bullous dermatosis and myeloma. Monoclonal anticytoplasmic antibody activity.

A case of a recurrent bullous eruption in a patient who had myeloma is reported. This eruption was differentiated from pemphigus and bullous pemphigoid by the histological and immunological findings. In addition, antibodies against the cytoplasm of basal cell layer cells in the human epidermis were detected in the patient's serum and in diseased skin. The myelomatous monoclonal protein and the antibody fixed on the cell cytoplasm had an identifical isotypical marker.

Diagnostic value of indirect immunofluorescence on sodium chloride-split skin in differential diagnosis of subepidermal autoimmune bullous dermatoses.

OBJECTIVE: To determine the diagnostic value of indirect immunofluorescence on sodium chloride-split skin (SSS) in differentiating the pemphigoid group of subepidermal autoimmune bullous dermatoses, including bullous pemphigoid (BP), cicatricial pemphigoid, and pemphigoid gestationis, from epidermolysis bullosa acquisita (EBA). DESIGN: Serum samples were tested using immunofluorescence on SSS and immunoblot assay on epidermal and dermal extracts, a recombinant protein corresponding to the C-terminal end of the 230-kd BP antigen, and purified laminin-5. SETTING: An immunodermatology laboratory. PATIENTS: One hundred forty-two serum samples from patients with BP (n = 98), cicatricial pemphigoid (n = 23), pemphigoid gestationis (n = 10), EBA (n = 10), and anti-type IV collagen (n = 1). MAIN OUTCOME MEASURES: Binding sites of serum to the epidermal and/or dermal sides of SSS were correlated with their antigenic specificities. RESULTS: Epidermal staining on SSS was highly specific for pemphigoid. Alternatively, a poor correlation was found for the dermal-reacting serum samples and the diagnosis of EBA; of the 19 serum samples with dermal staining on SSS, only 10 reacted with the EBA antigen. The remaining serum samples were from patients with cicatricial pemphigoid having antibodies to the alpha 3 or beta 3 chains of laminin-5 (n = 5) or patients with BP having antibodies to the 180-kd BP antigen (n = 2). One sample recognized exclusively a 185-kd dermal antigen corresponding to type IV collagen. One more BP serum sample with dermal staining did not recognize any dermal or epidermal antigen. CONCLUSION: In case of immunofluorescent dermal staining, the precise diagnosis should be confirmed by identification of the involved antigen, since it may reveal antibodies to laminin-5 or type XVII or IV collagen, in addition to the EBA antigen.