In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese.

Although the trace elements zinc, copper and manganese are used in vivo for their healing properties, their mechanism of action is still only partially known. Some integrins expressed by basal layer keratinocytes play an essential part in healing, notably alpha2beta1, alpha3beta1, alpha6beta4 and alphaVbeta5, whose expression and distribution in epidermis are modified during the re-epithelialization phase. This study demonstrates how the expression of these integrins are modulated in vitro by trace elements. Integrin expression was studied in proliferating keratinocytes in monolayer cultures and in reconstituted skin that included a differentiation state. After 48 h incubation with zinc gluconate (0.9, 1.8 and 3.6 microg/mL), copper gluconate (1, 2 and 4 microg/mL), manganese gluconate (0.5, 1 and 2 microg/mL) and control medium, integrin expression was evaluated by FACScan and immunohistochemistry. Induction of alpha2, alpha3, alphaV and alpha6 was produced by zinc gluconate 1.8 microg/mL in monolayers, of alpha2, alpha6 and beta1 by copper gluconate 2 and 4 microg/mL and of all the integrins studied except alpha3 by manganese gluconate 1 microg/mL. Thus, alpha6 expression was induced by all three trace elements. The inductive effect of zinc was particularly notable on integrins affecting cellular mobility in the proliferation phase of wound healing (alpha3, alpha6, alphaV) and that of copper on integrins expressed by suprabasally differentiated keratinocytes during the final healing phase (alpha2, beta1 and alpha6), while manganese had a mixed effect.

[Epstein-Barr virus research by in situ hybridization in 65 cutaneous T cell epidermotropic lymphomas]. / Recherche de l'Epstein-Barr virus par hybridation in situ chez 65 malades atteints de lymphomes cutanés T épidermotropes.

BACKGROUND: The Epstein-Barr virus (EBV) is a highly mutagenic virus known to be the cause of several types of lymphoma. There has been some controversy concerning EBV in cutaneous T-cell lymphomas. The aim of this study was to search for EBV with a sensitive method: in situ hybridization in 65 patients with cutaneous T-cell lymphomas. PATIENTS AND METHODS: From 1990 to 1995, 158 samples from 65 patients with cutaneous T-cell lymphoma (2 stage IA, 12 IB, 4 IIA, 29 IIB, 16 Sézary syndrome, 2 stage IV) were collected. In situ hybridization with EBER and Bam W probes recognizing the viral latency genes were used to search for EBV. RESULTS: EBV was evidenced with at least one of the two probes in 43 samples (26 p. 100). Prior to alpha interferon treatment, 18 p. 100 of the samples were positive for EBER compared with 18 p. 100 for Bam W. After alpha interferon treatment, there was a significantly higher percentage of EBER positive samples (39 p. 100; p = 0.03). Inversely, there was no difference for the Bam W probe (p = 0.2). Clinical stage had no effect on the presence of EBV (p = 0.18). CONCLUSION: Our series evidenced the variable presence of EBV, identified by in situ hybridization, in cutaneous T-cell lymphoma. Few infiltrating cells are infected. This would be an argument in favor of an indirect role of the EBV in the transformation process. In addition, alpha interferon increases the life time of EBERs, sensitizing detection of this latency gene.

Primary cutaneous lymphomas: a study of 37 cases.

BACKGROUND: A retrospective clinical, histologic, and immunohistochemical study was performed in 37 cases of isolated primary cutaneous lymphoma (PCL) (22 B and 15 T phenotype). Patients with epidermotrophic infiltrate (mycosis fungoides and Sézary syndrome) were excluded. METHODS: Patients with PCL were selected according to strict criteria: isolated cutaneous involvement for at least 6 months and a negative exhaustive study of possible spread. Lesions were either limited to a single cutaneous region or were disseminated, involving at least two nonadjacent regions. The diagnosis was confirmed histologically, and an immunohistochemical study was performed. RESULTS: On the basis of the new Willemze classification for prognostic criteria, this study showed similarities between lymphomas of B and T phenotype in clinical features, therapeutic response, course, and overall prognosis. The clinical lesion was usually an erythematous nodule associated, or not, with an infiltrated layer and generally limited to a single cutaneous region. PCLs were highly sensitive to nonaggressive treatment, showing complete or more than 50% partial remission in all cases. CONCLUSIONS: The overall prognosis for these lymphomas was good, even for disseminated cutaneous forms. Patient survival at 48 months was 78% for T and 89% for B phenotype. In the latter group, the prognosis was comparable for CD30+ and CD30- T lymphomas; however, the course of PCL involved frequent cutaneous relapses, particularly with the disseminated forms, raising the problem of adjuvant treatment after complete remission was obtained. Extracutaneous involvement was rare, but always indicative of poor prognosis.

Keratinocyte-lymphocyte interaction in cutaneous T-cell lymphoma. Modulation of keratinocyte antigen My7 by a soluble factor produced by T lymphocytes.

OBJECTIVE: To test the hypothesis that the modulation of My7 antigen in the basal keratinocytes is directly related to the effect of dermal lymphocyte infiltrate of epidermotropic cutaneous T-cell lymphoma (CTCL). DESIGN: In vitro study with reconstituted skin model. SETTING: Department of Dermatology of University Hospital, Nantes, France. PATIENTS: Lymphocytes extracted from 11 skin samples with lesions of epidermotropic CTCL (mycosis fungoides, stages IIa to IV) and 6 skin samples with lesions of atopic dermatitis (control population) together with the supernatants of these infiltrating lymphocytes were incubated with normal reconstituted skin samples either alone or in the presence of interferon alfa-2a (10(2) IU/ mL). Moreover, normal peripheral blood mononuclear cells of 7 patients and 4 controls were incubated with reconstituted skin. INTERVENTION: None MAIN OUTCOME MEASURES: None. RESULTS: Ten of 11 samples of lymphocytes extracted from CTCL and 7 of 11 of their supernatants inhibited partially or completely My7 expression by basal cells. NO inhibition was noted for lymphocytes extracted from inflammatory skin or their supernatants. Addition of interferon alfa-2a in a culture medium of extracted lymphocytes or their supernatants blocked inhibition of My7 expression by keratinocytes in 8 of 10 reconstituted skin samples. No abrogation of My7 expression was noted with peripheral mononuclear cells. CONCLUSIONS: Our in vitro study demonstrated a direct and specific interaction between the tumor infiltrate of CTCL and keratinocytes. Moreover, this interaction appeared to be closely associated with a soluble factor produced by the tumor T-cell infiltrate and was at least partially blocked by interferon alfa-2a.

Increased anti-Epstein-Barr virus antibodies in epidermotropic cutaneous T-cell lymphoma: a study of 64 patients.

Epstein-Barr virus (EBV) is often associated with non-Hodgkin's T-cell lymphomas and has recently been found in the lesions of mycosis fungoides and Sézary syndrome. We sought to determine whether the anti-EBV antibody profile was disturbed in mycosis fungoides and Sézary syndrome and whether there are particular profiles characteristic of disease stage. Anti-EBV antibodies (anti-VCA, -EA and -EBNA) were studied in the sera of 64 patients. An immunoenzymatic technique was used, and the results were compared with the same number of age- and sex-matched healthy controls. Patients with mycosis fungoides and Sézary syndrome developed higher anti-VCA antibody titres (median 1200) than controls (median 320). Thirty-seven patients had anti-VCA > or = 1200 vs. 19 controls (P < 0.01). These elevated anti-VCA antibody titres were associated with positive EA in 19 patients versus three controls. No differences were found between the illness stages. Anti-EBV antibodies were most often found in mycosis fungoides and Sézary syndrome when the serological profile was similar to that of cellular immune deficiencies and EBV-related non-Hodgkin's lymphoma. EBV could be involved, either directly on lymphocytes or, more likely, indirectly by chronic antigenic stimulation.

Skin cancers in transplant patients.

Skin tumors are frequent in transplant patients, and their potential for progression (locoregional recurrences, metastases) is much greater than in the general population. The viral element with HPV probably represents one of the etiologic factors, although other only partially known factors play a role, including the sun and genetic factors. The high frequency of these skin tumors in transplant patients and their potential for progression require preventive and therapeutic measures: regular examination of the skin, strict advice about protection from sun exposure, excision of any suspect lesion, and treatment of warts that might be conducive to the development of skin cancers. Finally, it must be decided whether immunosuppression should be reduced or stopped during treatment of skin tumors with a high risk of progression.

[Ketoprofen-induced contact photosensitivity disorders: 5 cases]. / Photosensibilisation de contract au kketoproféne. 5 Observations.

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAID) are widely used in topical applications for benign diseases. Adverse skin reactions include contact eczema and photocontact dermatitis. Among the NSAID used in topical applications, arylpropionic derivatives, notably ketoprofen, are frequently implicated. CASE REPORTS: We observed 5 patients who developed eczema lesions after application of Ketum, a gel containing ketoprofen used on healthy skin after exposure to sunlight. Photoallergy explorations evidenced positive photopatch-tests for ketoprofen with UVA and total light. The anamnesis suggested a photoallergic mechanism which was confirmed by histological examination of the biopsy of a UVA positive photopatch-test and by negative photopatch-tests in 10 healthy controls. DISCUSSION: The photosensitizing potential of ketoprofen in the UVA spectrum is well known. Although the number of adverse reactions is quite small compared with widespread use, physicians should be aware of this photosensitivity and report all cases to the pharmacovigilance center.

Frequency of mucosal HPV DNA detection (types 6/11, 16/18, 31/35/51) in skin lesions of renal transplant patients.

Human papillomaviruses (HPV) probably play a role in the development of skin cancer in renal transplant recipients. Since some mucosal HPV are strongly related to cervical cancer, we compared the frequency of HPV DNA detection (mucosal types 6/11, 16/18, and 31/33/51) in skin cancer of renal transplant recipients (21 lesions) with that in normal subjects without immunodeficiency (21 lesions) and studied the frequency of these same HPV in benign lesions of renal transplant recipients (34 lesions) and normal subjects (30 lesions). An in situ hybridization technique employing cold biotin probes was used. HPV DNA was not significantly (P = 0.095) more frequent in malignant skin cancer in renal transplant recipients (42.9%) than in normal subjects (19.04%), but was significantly more frequent in benign lesions in renal transplant recipients (32.4%) than in controls (10%; P < 0.05). These results on a limited number of skin lesions do not allow one to confirm the predominant role of mucosal HPV in the development of skin cancer in renal transplant recipients. HPV interaction with other factors related to the immunosuppressive state may play a role.

Long-term interferon-alpha therapy induces autoantibodies against epidermis.

BACKGROUND: While interferon (IFN) is known for its immunoregulatory properties, it has also been shown to induce autoimmune disorders such as lupus erythematosus, hypothyroidism, antiphospholipid syndrome and, recently, bullous pemphigus-like eruptions. OBJECTIVE: The purpose of this study was to determine the percentage of antibodies against epidermis induced by IFN-alpha therapy, as detected by indirect immunofluorescence and Western blotting (WB). METHOD: We have studied the sera of 47 patients treated with low doses of IFN-alpha 2a for malignant melanoma or cutaneous T cell lymphoma for a period of 12 months. These sera were tested by standard IIF and WB. RESULTS: 32% of patient sera were positive after 6 months of treatment. Antibodies against epidermis were most often of the pemphigus type as confirmed by WB. Two types of labeling were noted for anti-basement membrane antibodies: basal cytoplasmic pattern in 4 sera and along the dermal side of the basal keratinocytes in 2 sera. CONCLUSION: This study brings biological arguments to confirm the direct role of IFN-alpha in the development of pemphigus-like eruption, and emphasizes the need for clinical follow-up of patients treated with IFN-alpha over a long period of time.

[Cutaneous and neurologic vasculitis disclosing EBV-selective immunodeficiency]. / Vasculite cutanée et neurologique révélatrice d'un déficit immunitaire sélectif vis-à-vis du virus d'Epstein-Barr.

INTRODUCTION: Purtilo's syndrome or X-linked lymphoproliferative syndrome (XLP) is a rare genetic disorder affecting boys who have a selective immunodeficit towards Epstein Barr Virus (EBV) and who develop extremely severe forms of EBV infection, of which there are four major types: severe or fatal infectious mononucleosis (60 p. 100), lymphoma (23 p. 100), acquired hypo- or agamaglobulinemia (25 p. 100) and anemia or pancytopenia. We report a case of vasculitis (cutaneous and neurologic) which led to the discovery of a selective immunodeficit towards EBV, similar to Purtilo's syndrome. CASE REPORT: A 17 year-old male with no significant past medical history presented with an eruption initially felt to be consistent with pityriasis lichenoid. Treatment with erythromycin was initiated, this did not prevent the subsequent eruptions of cutaneous vasculitis lesions which were severe, prolonged, debilitating, and associated with fever and general deterioration of the patient condition. All etiologic studies were negative. A course of systemic corticosteroids was begun, but the cutaneous eruptions persisted; and in addition the patient developed signs of polyneuropathy in the lower extremities secondary to neurologic vasculitic lesions. New studies revealed an abnormal EBV serology (absence of anti-EBNA antibodies) as well as hypogammaglobulinemia, suggestive of a selective immunodeficit towards EBV resembling Purtilo's syndrome. DISCUSSION: In our patient, the development of an extensive vasculitis, characterized histologically by an intense lymphocytic infiltrate, positive for EBV, associated with hypogammaglobulinemia, and with abnormal serology suggests an anomaly in the immune response to EBV. Although the age of the patient and absence of family history make the Purtilo's syndrome uncertain, the nature of the immunodeficit is very similar and the patient could well develop a lymphoma. This case is significant in that the disease initially manifested itself as a cutaneous vasculitis, which was not been described previously.

[Cardiac metastasis of melanoma disclosed by tamponade]. / Métastases cardiaques d'un mélanome révélées par une tamponnade.

INTRODUCTION: Melanoma is the most frequent cause of neoplastic metastasis to the heart. The diagnosis is however usually made after the patient's death as clinical signs are discrete, non-specific or masked by other visceral metastases. CASE REPORT: A 50-year-old man who was given chemotherapy for metastatic melanoma limited to the mediastinal lymph nodes suddenly developed acute dyspnea due to cardiac tamponnade. Puncture biopsy of the pericardium revealed melanoma cells and nodular infiltration of the pericardium. A pleuro-percardial window gave functional relief. The patient died 5 months later due to a recurrent episode of cardiac tamponnade. DISCUSSION: The diagnosis of metastasis to the heart of a malignant melanoma may be suspected in patients developing heart failure, rhythm or conduction disorders or pericardial effusion. The diagnosis can usually be confirmed with transthoracic sonography. Endocavitary or transmural tumors may require transesophageal echography or magnetic resonance imaging before surgery to determine extension and myocardial infiltration. Despite the severe prognosis, in case of immediate life-threatening emergencies or isolated cardiac metastases, a surgical treatment may be considered.

[Combination of dacarbazine, cisplatin and interferon alpha in the treatment of metastatic melanoma]. / Association dacarbazine, cisplatinium et interféron alpha dans le traitement du mélanome métastatique.

INTRODUCTION: The aim of this work was to study the effectiveness and safety of a combined therapy with dacarbazine, cisplatin and interferon alpha in the treatment of metastatic melanoma. PATIENTS AND METHODS: Sixteen patients, including 15 with one or more visceral metastases, were treated with dacarbazin 400 mg/m2, cisplatin 100 mg/m2 repeated every 28-day and interferon alpha-2a 3.10(6) IU subcutaneously 3 times weekly. Fifty percent of patients had at least 3 different sites of metastases. Ten patients had previously received one or more specific treatment for their melanoma. RESULTS: The overall response was 25 p. 100 (2 complete responses and 2 partial responses). The two complete responses were obtained on liver, lung and cutaneous metastases and remain in sustained, unmaintained remission for 22 and 24 months. Administration of this treatment was well tolerated, the most prevalent toxicity being hematologic. At present, responding patients have a median survival of 26 months+ since the beginning of the treatment, compared to 7 months for non responding patients. DISCUSSION: Dacarbazine and cisplatin combined chemotherapy has been used at various doses with an overall response rate of 14 to 37 p. 100, similar to our results. However, duration of complete response in our study (22 months+ and 24 months+) seem more prolonged than in studies using dacarbazine and cisplatin at dose of 100 mg/m2/21 d (7 to 9 months) and comparable to studies using dacarbazine and cisplatin at dose of 150 mg/m2/28 d or more (15 months+ to 19 months+ and 24 months+) but with less toxicity. Therefore addition of interferon alpha might be of interest in the maintain of complete remissions and perhaps in the prolongation of survival of responding patients as it has already been suggested with the dacarbazine-interferon alpha combination.

Infantile acropustulosis in six immigrant children.

Infantile acropustulosis is a recurrent, pruriginous, vesiculopustular eruption of the palms and soles first described in 1979. We report six cases of infantile acropustulosis in recently emigrated children treated for scabies. Clinical follow-up was obtained by questionnaire addressed to patients' families and general practitioners. Our study suggests infantile acropustulosis is frequent in immigrant infants and could be a non-specific hypersensitivity reaction to Sarcoptes scabiei.