Effectiveness of lenalidomide in relapsed primary cutaneous diffuse large B-cell lymphoma, leg type.

The primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) has a poor prognosis. R-CHOP with or without radiotherapy is the available recommendations for first-line treatment. Relapses/refractory cases are frequent with no standardized therapeutic guidelines. Lenalidomide seems to be an excellent therapeutic option as a second-line treatment of relapsed PCDLBCL-LT.

Impact of a store-and-forward teledermatology intervention versus usual care on delay before beginning treatment: A pragmatic cluster-randomized trial in ambulatory care.

Introduction In France, 66% of patients forego getting specialized care by dermatologists because of difficulty obtaining appointments. Store-and-forward teledermatology could improve how promptly treatment begins by reducing the delay in obtaining a specialist's opinion. In this study, we compared the delay before care between general practitioners (GPs) using a store-and-forward teledermatology intervention and GPs addressing their patients with a standard referral letter. Methods We performed an open-label, pragmatic cluster-randomized controlled trial with two parallel arms. GP clinics in Paris (France) were randomly assigned to use either teledermatology referral (use of electronics to send clinical images taken using a mobile phone) or conventional referral (using standard letters) to care for patients for whom a dermatologist's advice was needed for the diagnosis or treatment of skin lesions. Dermatologists integrated responses to teledermatology requests in their usual schedule. Patients were followed up for three months. Primary outcome was the delay, in days, between the GP's consultation and a reply by the specialist allowing treatment to begin. Analyses were adjusted for clustering of GPs and identities of dermatologists. Results Between February and June 2014, 103 patients were included in the study (53 patients of 20 GPs in the intervention group). The median delay between the initial GP's consultation and the reply allowing for treatment to begin was four days in the intervention group and 40 days in the control group (adjusted hazard ratio = 2.55; p < 0.011). Discussion We showed that a simple store-and-forward teledermatology intervention significantly reduced the delay before beginning care (ClinicalTrials.gov identifier: NCT02122432).

Retrospective Multicentric Study of 25 Kimura Disease Patients: Emphasis on Therapeutics and Shared Features with Cutaneous IgG4-Related Disease.

BACKGROUND: Kimura disease (KD) is a rare lymphoproliferative inflammatory disease of unknown etiology. Data regarding therapeutic modalities and pathophysiology are scarce. OBJECTIVES: Analyze therapeutic and follow-up data and compare KD with cutaneous IgG4-related disease (IgG4-RD). METHODS: Multicentric retrospective study of 25 KD patients with analysis of treatment, follow-up and IgG4 immunostaining. Comparison with published cases of cutaneous IgG4-RD. RESULTS: Patients were mostly male (84%), median-aged 42 years with lymph node, lacrimal/salivary gland and kidney involvements in 45, 24 and 12%, respectively. Surgical excision had 100% complete response and 60% relapse. Oral corticosteroids had 100% response with 50% relapse. Thalidomide, cyclosporine or interferon-α had 100% response, but 100, 20 and 50% relapse, respectively. KD showed clinicopathological similarities with 27 published cases of cutaneous IgG4-RD. CONCLUSION: Surgery may be used in resectable KD cases, whereas cyclosporine or thalidomide may represent interesting alternatives to oral corticosteroids in other cases. KD shares features with cutaneous IgG4-RD.

Sézary syndrome without erythroderma.

BACKGROUND: Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement. OBJECTIVE: We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma. METHODS: Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied. RESULTS: Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred. LIMITATIONS: Retrospective design and small sample size are limitations. CONCLUSION: Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.

Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin.

A major deleterious side effect of glucocorticoids is skin atrophy. Glucocorticoids activate the glucocorticoid and the mineralocorticoid (MR) receptor, both present in the epidermis. We hypothesized that glucocorticoid-induced epidermal atrophy may be related to inappropriate occupancy of MR by glucocorticoids. We evaluated whether epidermal atrophy induced by the topical glucocorticoid clobetasol could be limited by coadministration of MR antagonist. In cultured human skin explants, the epidermal atrophy induced by clobetasol was significantly limited by MR antagonism (canrenoate and eplerenone). Blockade of the epithelial sodium channel ENaC by phenamil was also efficient, identifying a role of MR-ENaC cascade in keratinocytes, acting through restoration of clobetasol-induced impairment of keratinocyte proliferation. In the SPIREPI randomized double-blind controlled trial, gels containing clobetasol, the MR antagonist spironolactone, both agents, or placebo were applied on four zones of the forearms of 23 healthy volunteers for 28 days. Primary outcome was histological thickness of the epidermis with clobetasol alone or clobetasol+spironolactone. Spironolactone alone did not affect the epidermal thickness but coapplication of clobetasol and spironolactone significantly limited clobetasol-induced atrophy and was well tolerated. Altogether, these findings identify MR as a factor regulating epidermal homeostasis and suggest that topical MR blockade could limit glucocorticoid-induced epidermal atrophy.

Clinical activity of lenalidomide in visceral human immunodeficiency virus-related Kaposi sarcoma.

IMPORTANCE: Curative treatment of aggressive Kaposi sarcoma (KS) with conventional chemotherapy in human immunodeficiency virus (HIV)-infected patients remains difficult. The administration of thalidomide, an immunomodulatory drug with antiangiogenic effects, is limited by its toxicity. This engenders interest in evaluating thalidomide analogues such as lenalidomide with better toxicity profiles. To our knowledge, we describe for the first time a patient with visceral KS successfully treated with lenalidomide. OBSERVATIONS: A man with advanced visceral HIV-related KS progressing after 11 months of highly active antiretroviral therapy (HAART) and 2 lines of conventional chemotherapy (pegylated liposomal doxorubicin and docetaxel) was treated with lenalidomide on a compassionate use basis. He showed a rapid partial response without any substantial adverse effect but experienced relapse after 5 months of treatment, in a context of virologic failure. CONCLUSIONS AND RELEVANCE: Similar to our observation, good partial response without toxic effects has been reported in 3 patients with only skin involvement. Because immune reconstitution syndrome may occur in HIV-infected patients with KS undergoing HAART, KS improvement may be partly explained by immune recovery. An ongoing US phase 1/2 trial will better evaluate the efficacy and tolerance of lenalidomide in patients with HIV-related KS with and without visceral involvement.

Prognostic factors of paraneoplastic pemphigus.

OBJECTIVE: To identify the prognostic factors of overall survival in a series of patients with paraneoplastic pemphigus (PNP). DESIGN: Multicenter retrospective cohort study. SETTING: Twenty-seven dermatology departments in France. PATIENTS: A total of 53 patients (31 men and 22 women; median age, 59 years; age range, 30-88 years) were diagnosed as having PNP between 1992 and 2010. MAIN OUTCOME MEASURES: Overall Kaplan-Meier survival rates were estimated, and features associated with survival were assessed using univariate (log-rank test) and multivariate (Cox regression) analyses. RESULTS: The study included 53 patients with PNP. Thirty-six patients (68%) died during the study. The 1-, 3-, and 5-year overall survival rates were 49%, 41%, and 38%, respectively. The main causes of death were infections (n=21) and evolution of neoplasia (n=6). In univariate analysis, the main detrimental prognostic factors identified were erythema multiforme­like skin lesions (P=.05) and histologic keratinocyte necrosis (P=.03). None of the 5 patients with Castleman disease died during the study. After adjustment for age and sex in multivariate analysis, erythema multiforme­like skin lesions remained predictive of fatal outcome, with a 2-fold increase in death rate (hazard ratio [HR], 2.3; 95% CI, 1.05-5.03; P=.04). The prognosis of patients with PNP was even poorer when erythema multiforme­like skin lesions were associated with severe skin or mucosal involvement at presentation (HR of death, 3.0; 95% CI, 1.01-8.92; P=.049). CONCLUSION: Patients with PNP with erythema multiforme­like skin lesions and histologic keratinocyte necrosis, especially when associated with extensive lesions at presentation, are likely to have a more severe and rapid fatal outcome and should be managed very carefully.

Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family.

BACKGROUND: Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. OBJECTIVE: We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). METHODS: We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. RESULTS: The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. LIMITATIONS: The study was not population based. CONCLUSIONS: This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.

Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin.

PURPOSE: To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin (SCCS). PATIENTS AND METHODS: Thirty-six patients received cetuximab (initial dose of 400 mg/m(2) followed by subsequent weekly doses of 250 mg/m(2)) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated. RESULTS: Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes. CONCLUSION: As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.

Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro.

Amoxicillin is known to induce exanthema in patients with EBV-induced infectious mononucleosis. It is widely recognized that the reactivation of herpesviruses, including HHV-6 (Human Herpesvirus 6) and EBV (Epstein Barr virus) is associated with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). We report 7 cases of amoxicillin-induced flare in patients with DRESS induced by other drugs and investigate whether amoxicillin may have a direct effect on HHV-6 replication in vitro. 7 cases of DRESS with amoxicillin-induced flare were retrospectively analysed. The influence of amoxicillin on HHV-6 HST strain replication was studied in vitro in a human T lymphoblastoid MT4 cell line. The viral replication was quantified by immunofluorescence assay and by real-time polymerase chain reaction (PCR). Comparisons were performed using the Student's t test. Amoxicillin-induced flare was observed in 7 patients with DRESS induced by other drugs. In two cases HHV-6 reactivation was studied and was demonstrated by PCR. Amoxicillin neither modified cell viability nor cell proliferation for the range of tested concentrations. Amoxicillin increased the replication of HHV-6 at 25 microg*mL-1 and 50 microg*mL-1. Amoxicillin may induce a flare of DRESS, possibly by acting directly on herpesvirus replication.

Characteristics of the coexistence of melanoma and renal cell carcinoma.

BACKGROUND: Patients with melanoma (MM) have an increased risk of kidney cancer, and there is an excess risk of MM among patients with renal cell carcinoma (RCC). The objective of the current study was to analyze a series of 42 patients with both MM and RCC to identify clinical and pathologic features as well as risk factors of this association. METHODS: Clinical and pathologic characteristics of 42 patients who developed both MM and RCC (the MM + RCC series) were compared with 2 published series in each cancer alone: a series of 293 patients with MM (MM series) and a series of 1527 patients with RCC (RCC series). RESULTS: RCC was diagnosed concomitantly or after MM in 83% of patients in the MM + RCC series. Those patients displayed a high proportion of asymptomatic RCC at diagnosis (70%) and a higher frequency of stage I tumors (61%) than patients in the RCC series. Compared with the MM series, patients in the MM + RCC series more often were men, had a higher frequency of blond/red hair, had poor tanning ability, and had a higher number of nevi. In addition, patients in the MM + RCC series had a high aggregation of other malignancies (mainly skin cancers) and a significantly higher frequency of family history of MM (P = .005). Only 2 cyclin-dependent kinase 2A gene (CDKN2A) germline mutations were identified among patients in the MM + RCC series who also were members of MM-prone families. CONCLUSIONS: The high aggregation of cancers among patients in the MM + RCC series and the familial clustering of MM argued for a genetic predisposition that may be partly independent of CDKN2A.

Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure.

BACKGROUND: Factors implicated in the severity of drug reaction with eosinophilia and systemic symptoms (DRESS) have not been identified. We retrospectively describe and analyze severe cases of DRESS defined by history of intensive care unit admission and death due to DRESS. OBSERVATIONS: Of 15 patients retrospectively recruited in France, 14 were admitted to the intensive care unit and 3 died. The culprit drugs were already known to cause or trigger DRESS: allopurinol, minocycline hydrochloride, anticonvulsants, sulfonamides, and antibiotics. Visceral involvement with severe manifestations responsible for intensive care unit admission or death was variable and often multiple (pneumonitis, hepatitis, renal failure, encephalitis, hemophagocytosis, cardiac failure, and pancytopenia) and resulted in multiorgan failure in 11 patients. These severe complications sometimes developed late in DRESS. Human herpesvirus 6 infection was demonstrated in 6 of 7 patients. In addition, human herpesvirus 6 infection was demonstrated in involved viscera in 2 patients. CONCLUSIONS: Severe DRESS is rare. Some specificities of visceral involvement were associated with allopurinol and minocycline. However, visceral involvement comprising multiorgan failure seemed to be unpredictable. Better knowledge of DRESS is necessary to propose specific and prompt treatment. Early demonstration of human herpesvirus 6 reactivation could be considered a prognostic factor for identifying patients at higher risk and, hence, needs to be evaluated.

Association of androgenetic alopecia and hypertension.

Androgenetic alopecia is considered to be associated with coronary heart disease but the explanation of this association remains unknown. Hypertension is highly prevalent in patients with coronary heart disease. Essential hypertension is linked to hyperaldosteronism and spironolactone, an antihypertensive drug which is a mineralocorticoid receptor antagonist, has been used for a long time in the treatment of androgenic alopecia. We recently observed in a double transgenic mouse model that overexpression of a mineralocorticoid receptor targeted to the skin induced the development of alopecia. We prospectively studied the association of hypertension and androgenetic alopecia in Caucasian men. Two hundred and fifty Caucasian men aged 35-65 years were consecutively recruited by 5 general practitioners (50 per practitioner). Data collected included age, androgenetic alopecia score with a simplified Norwood's score (0-4), blood pressure or history of hypertension, smoking, history of diabetes mellitus or hyperlipidemia, familial history of androgenetic alopecia, and treatment. Chi-square, Fisher exact tests and linear regression model were used for statistical analysis. Hypertension was strongly associated to androgenetic alopecia (p < 0.001). Linear regression tests confirmed that this association was independent of age : odds ratio was 2.195 (95% CI : 1.1-4.3). Familial history of androgenetic alopecia was also strongly associated with androgenetic alopecia : odds ratio was 10.870 (95% CI : 4.3-27.1). Other variables (diabetes mellitus, hyperlipidemia, smoking, treatment) were not associated with androgenetic alopecia. We were limited by a relatively small study sample but in this study androgenetic alopecia was strongly associated with hypertension. Association of androgenetic alopecia and hyperaldosteronism warrants additional studies. The use of specific mineralocorticoid receptor antagonists could be of interest in the treatment of androgenetic alopecia.

Effect of neonatal phototherapy on melanocytic nevus count in children.

BACKGROUND: Melanocytic nevus is the strongest risk factor for the development of cutaneous melanoma. Fair skin and exposure to UV light, especially in childhood, are correlated with the development of childhood nevi. OBJECTIVE: To assess the role of blue light neonatal phototherapy used to treat hyperbilirubinemia in nevus acquisition in childhood. DESIGN: Case-control prospective study. SETTING: University hospital. PARTICIPANTS: Fifty-eight children were included in this study. Selection criteria included the following: age, 8 to 9 years; and skin type, less than IV by Fitzpatrick classification (ie, brown, always tans, rarely burns). The case group consisted of 18 children exposed to neonatal phototherapy (mostly intensive phototherapy) retrospectively found by review of consecutive neonatal medical records at Saint-Antoine Hospital, Paris, France. The control group was composed of 40 nonexposed children consecutively recruited from a public school in the same geographic area. MAIN OUTCOME MEASURES: Total body nevus count in children, phenotypic characteristics, solar exposure, and demographic data were assessed by the same dermatologist. RESULTS: A comparison of both groups showed that the number of nevi larger than 2 mm was significantly higher in the exposed group. The mean (SD) nevus count was 3.5 (3.05; median, 3.0) per child in the exposed group, compared with 1.45 (1.99; median, 1.0) per child in the nonexposed group (P(mean) = .02 and P(median) = .01). Multivariate analysis confirmed these results, with a statistically significant correlation with nevus count, especially with nevi 2 to 5 mm in greatest diameter. The association between neonatal phototherapy and nevus count was not significant for nevi smaller than 2 mm or larger than 5 mm. Solar exposure, especially during vacations, was strongly associated with total nevus count and all nevus sizes (2-5 mm, <2 mm, and >5 mm). At univariate analysis, hair color was significantly associated with nevus size smaller than 2 mm (P(mean) = .03). CONCLUSIONS: Intensive neonatal phototherapy is a strong risk factor for nevus development in childhood. While childhood development of nevi is correlated with fair skin and solar light exposure, and having many nevi is a recognized risk factor in persons with melanoma, we must be careful not to equate childhood nevi development in response to neonatal phototherapy with an individual's risk of developing melanoma. The treatment of hyperbilirubinemia remains neonatal phototherapy. Exposed children should undergo dermatologic preventive measures and surveillance for the development of melanoma.

Mixed nonseminomatous germ cell tumor presenting as a subcutaneous tissue mass.

Extragonadal germ cell tumors most commonly arise in the midline of the retroperitoneum or the mediastinum. Primary tumors involving the skin are very rare. Only one case of malignant primary germ cell tumor located in the skin has been reported. We present the case of a 44-year-old white man with a primary subcutaneous mixed nonseminomatous germ cell tumor. This man had a long-lasting subcutaneous lump of the breast, which became painful. Surgery revealed 3 juxtaposed nodules. Microscopic examination showed a mixed germ cell tumor with a 90% immature teratoma component and a 10% embryonal carcinoma component. Testicular ultrasound and computed tomography of the chest, abdomen, pelvis, and brain were normal. Serum human chorionic gonadotrophin, beta-human chorionic gonadotrophin, alpha-fetoprotein, and lactate dehydrogenase were within normal ranges. A further surgical excision was performed. The patient is presently alive with no evidence of disease after a follow-up of 7 years. Review of the literature indicates that primary cutaneous extragonadal germ cell tumors usually occur as cutaneous or subcutaneous solitary nodules or as ulcerated lesions. They mainly consist of mature teratomas in children. Only 2 cases have been reported in adults.

Association of hypogammaglobulinemia with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).

The association of hypogammaglobulinemia was recently reported in anticonvulsant-associated DRESS. Hypogammaglobulinemia could be the consequence of hypoproteinemia in patients with erythroderma. To ascertain the association of hypogammaglobulinemia with DRESS we compared the prevalence of hypogammaglobulinemia in DRESS and in other cause of erythroderma. In a retrospective study, 39 consecutive patients with DRESS were compared to 52 patients with other causes of erythroderma hospitalized in the same period. Hypogammaglobulinemia was statistically significantly associated with DRESS (p = 0.022). This association was not limited to anticonvulsants (phenytoin, carbamazepin) and was observed with other drugs (allopurinol, tazocillin, ibuprofen, celecoxib, vancomycin).

Association between endothelin receptor B nonsynonymous variants and melanoma risk.

The endothelin signaling pathway plays a crucial role in melanocyte differentiation and migration. In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM). The coding region of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched Caucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 patients (11%), but only two were found in four control subjects (3%, odds ratio [OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 out of 15 MM patients carried EDNRB mutations reported in HSCR, some of which had previously been shown to lead to loss of function. In multivariable logistic regression analysis including skin type, eye and hair color, number of nevi, and dorsal lentigines (freckles), the association between EDNRB mutations and MM risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = .03). Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.