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Introduction: Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor whose clinical presentation, usually a pink nodule, is not specific. We aimed in this study to determine the dermoscopic criteria encountered in MCC. Methods: From our image database we selected the patients diagnosed with MCC and scored the dermoscopic criteria shown by these tumors. Results: Ten patients coming from three different academic hospitals were studied. Vascular structures were the more relevant dermoscopic features. In 8 out of 10 (80%) patients a polymorphic vascular pattern was seen, composed of milky-red clods/areas in association with one or more additional vascular structures. Conclusion: Although an overlap existed between the dermoscopic features observed in MCC and amelanotic melanoma, the presence of a polymorphous vascular pattern may constitute an additional clinical clue to accurately diagnose this rare tumor.

International audience

GA101 is a novel glycoengineered Type II CD20 monoclonal antibody. When compared with rituximab, it mediates less complement-dependent cytotoxicity (CDC). As expected for a Type II antibody, GA101 appears not to act through CDC and is more potent than the Type I antibody rituximab in inducing cell death via nonclassical induction of apoptosis cytotoxicity, with more direct cytotoxicity and more antibody-dependent cell-mediated cytotoxicity. We evaluated the antitumor activity of GA101 against the human-transformed follicular lymphoma RL model in vivo in severe combined immunodeficient mice (SCID) mice. GA101 induced stronger inhibition of tumor growth than rituximab. Combination of GA101 with cyclophosphamide in vivo confirmed the superiority of GA101 over rituximab. Neutralizing the complement system with cobra venom factor partially impaired the antitumor activity of rituximab, but had no impact on the efficacy of GA101. In vitro GA101 more potently induced cell death of RL cells than rituximab. The expression of a limited number of genes was found to be induced by both antibodies after exposure in vitro. Among these, early growth response 1 and activation transcription factor 3 were confirmed to be increased at the protein level, suggesting a possible role of these proteins in the apoptotic signalling of anti-CD20 antibodies. These data imply that GA101 is superior to rituximab not only as a single agent, but also in combination with chemotherapy. These data suggest the presence of novel signalization pathways activated after exposure to anti-CD20 antibodies. Mol Cancer Ther; 10(1); 178–85. ©2011 AACR.

The ability to predict efficacy and safety is crucial for drug discovery and development. To date, there are only a few genetic biomarkers whose clinical validity in predicting drug response has been clearly established; for example, HER-2/neu-positivity in breast cancer as a predictor of response to trastuzumab (Herceptin) [1]. Patient variability in response to medications can range from failure to demonstrate an expected therapeutic effect to development of an adverse reaction, resulting in significant patient morbidity and mortality, as well as increasing healthcare costs. In order to optimize treatment response and decrease adverse drug reactions, pharmacogenetics and pharmacogenomics are being increasingly utilized. Pharmacogenetics is the study of genetic variation and its effects on the response to drugs, vaccines, or other pharmaceutical agents [2]. Pharmacogenomics more broadly involves genome-wide analysis of the genetic determinants of drug efficacy and toxicity. Primary candidate genes of interest include those encoding for drug receptors, metabolizing enzymes, and transporters. However, selection of optimal drug therapy may also involve disease susceptibility genes indirectly affecting drug responses [3].

We report two new cases of cutaneous indeterminate cell histiocytosis (ICH), clinically characterized by a profuse papular eruption, without systemic involment. The first patient, a 59-year-old man, was evaluated for a diffuse, mildly pruritic papular rash of 6 months duration, associated with an impaired general condition. His clinical history was remarkable for a hepatocellular carcinoma (HCC) on NASH treated by hepatic chemoembolization 4 months before the first consultation. No new drug had been [...]

The preservation of a functional pancreatic β-cell mass has become a major point of research in type 2 diabetes (T2D) and the future therapies of T2D notably aim at protecting the β-cell from dysfunction and apoptotic death. β-cell proliferation, survival and insulin secretion are regulated by crucial transcription factors which are activated by signalling pathways engaged by nutrients, G-protein coupled receptors or tyrosine kinase receptors. Among these factors, the cAMP-responsive element-binding protein (CREB) has emerged as a key transcriptional element for the maintenance of an efficient glucose sensing, insulin exocytosis, insulin gene transcription and β-cell survival. CREB activates the transcription of target genes within the β-cells in response to a diverse array of stimuli including glucose, incretin hormones such as the glucagon-like peptide-1 (GLP-1) or the gastric inhibitory polypeptide (GIP), the pituitary adenylate cyclase-activating polypeptide (PACAP), or growth factors such as the insulin like growth factor-1 (IGF-1). All these stimuli phosphorylate CREB at a particular residue, serine 133, which is required for CREB-mediated transcription. However, the molecular mechanisms by which CREB activates gene transcription in β-cells vary according to the nature of the stimulus. These mechanisms involve different protein kinases, scaffold proteins and cofactors which allow CREB to specifically regulate the expression of crucial genes such as insulin, BCL-2, cyclin D1, cyclin A2 or IRS-2. In this review, we summarize the signalling pathways that lead to CREB phosphorylation in β-cells and the molecular features of each signalling pathway that rise specificity at the level of CREB activation and regulation.

Metastatic melanoma is a very aggressive cancer. Dacarbazine has been considered as the standard therapy for decades. Due to a better understanding of melanoma cells signalling and immunological response, new targeted therapies are now proposed. The efficency of these new drugs needs to be confirmed by on larger clinical trials. Ipilimumab (anti-CTLA4 monoclonal antibody) and V600-E- B-raf inhibitor have shown encouraging results, while c-KIT and MEK inhibitors are currently under evaluation. These recently published data shed the light on melanoma management. We review here the latest development of these molecules and the current perspectives in the treatment of metastatic melanoma.

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. Pancreatic β-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. β-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that β-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for β-arrestin-1 in the regulation of insulin secretion and β-cell survival by GPCRs.

Aims: The treatment of dermatofibrosarcoma protuberans (DFSP) involves wide local excision with frequent need for reconstructive surgery. A t(17;22) translocation resulting in COL1A1-PDGFB fusion is present in >95% of cases. Certain patient observations and a report on nine patients suggest that imatinib mesylate, targeting platelet-derived growth factor receptor β, has clinical potential in DFSP. The primary aim of this phase II multicenter study was to define the percentage of clinical responders (Response Evaluation Criteria in Solid Tumors) to a 2-month preoperative daily administration of 600 mg of imatinib mesylate before wide local excision. The secondary aims were to determine tolerance, objective response from imaging results (ultrasound and magnetic resonance imaging), and pathologic responses observed in sequential tissue specimens. Patients and Methods: A two-stage flexible design was used with interim analysis after the recruitment of six patients. Twenty-five adults suffering from primary or recurrent DFSP were included from July 2004 to May 2006. Results: The COL1A1-PDGFB fusion gene was detected in 21 out of 25 patients following fluorescence in situ hybridization analysis (two cases were noninformative). A clinical response was achieved in nine (36%) patients (95% confidence interval, 18.9-57.5). The median relative tumoral decrease was 20.0% (range, −12.5 to 100). Apart from expected grade 1 or 2 side effects, we observed one grade 3 neutropenia, one grade 3 maculopapular rash, and one grade 4 transient transaminitis. Conclusion: Our results support the use of imatinib in a neoadjuvant setting in nonresectable DFSP, or when surgery is difficult or mutilating. These results will be useful for setting hypotheses in the evaluation of new drugs to treat primary or secondary resistance to imatinib. Clin Cancer Res; 16(12); 3288–95. ©2010 AACR.

International audience; OBJECTIVES: To describe circumstances of the diagnosis and access to dermatological care for patients with cutaneous melanoma (CM) and to investigate factors associated with early detection. DESIGN: Retrospective population-based study of incident cases of invasive CM in 2004, using questionnaires to physicians and a survey of cancer registries and pathology laboratories. SETTING: Five regions in northeastern France. PATIENTS: Six hundred fifty-two patients who were referred to dermatologists by general practitioners (group 1) or by other specialists (group 2), who directly consulted a dermatologist for CM (group 3), or who were diagnosed as having CM during a prospective follow-up of nevi (group 4) or when consulting a dermatologist for other diseases (group 5). MAIN OUTCOME MEASURES: Characteristics of patients, tumors, and patients' residence in each group, including the geographical concentration of dermatologists. We performed multivariate analysis of these factors to determine association with Breslow thickness. RESULTS: Age, tumor location, Breslow thickness, ulceration, histological type, and geographical concentration of dermatologists significantly differed among groups. Patients consulting dermatologists directly formed the largest group (45.1%). Those referred by general practitioners (26.1%) were the oldest and had the highest frequency of thick (>3 mm), nodular, and/or ulcerated CM. Patients from groups 4 (8.4%) and 5 (14.1%) had the thinnest CMs. Ulcerated and/or thick tumors were absent in group 4. In multivariate analysis, histological types superficial spreading melanoma and lentigo maligna melanoma, younger age, high concentration of dermatologists, and detection by dermatologists were significantly associated with thinner CMs. CONCLUSION: Easy access of patients to dermatologists, information campaigns targeting elderly people, and education of general practitioners are complementary approaches to improving early detection.

Livedoid vasculitis (LV) may be an isolated condition or associated with an underlying systemic disease, including coagulation disorders, periarteritis nodosa and systemic autoimmune diseases. The classic histological features of LV (fibrin deposition on dermal vessels and the absence of important perivascular infiltrate or leucocytoclasia) argue against a primary vasculitis and is more in keeping with a thrombotic process. Factor V Leiden mutations have rarely been reported in association with LV. We report a patient with LV, who had doubly inherited thrombophilia, with heterozygous mutations in the Factor V Leiden (G1691A) and prothrombin (G20210A) genes.

L YMPHOMATOID PAPULOSIS (LYP) IS CHARACterized by papular, papulonecrotic, and/or nodular skin lesions at different stages of development, predominantly on the trunk and limbs. We prospectively evaluated 8 patients using dermoscopy and histopathologic correlations. The aim of this pilot study was to define dermoscopic criteria associated with the different stages of the disease (erythematous papule, ulcerated and/or necrotic papule, and cicatricial lesion). The dermoscopic pattern was similar in all patients and varied with the different stages of the disease. The initial inflammatory papular lesion (Figure 1A) showed essentially a vascular pattern of tortuous irregular vessels radiating from the center to the periphery of the lesion (Figure 1B). A white structureless area was seen around the vessels (Figure 1B, inset). On histopathologic evaluation, dilated vessels were observed on the upper dermis (Figure 1C and D, arrow) among the tumoral dense infiltrate of large CD30 cells (for type A LyP). Intravascular thrombosis was noted on the small vessels, usually at the beginning of the ischemic process (Figure 1E, arrow). On more mature lesions (hyperkeratotic papules), a whitish structureless area was seen at the center of the papule (Figure 2A). The vessel pattern was still observed, but it spared the middle of the lesion (Figure 2B). This central pattern was correlated with the onset of a hyperkeratosis on histologic samples and the onset of fibrinoid necrosis (Figure 2C, arrow) associated with intravascular thrombosis on the upper dermis. In the third stage, the necrotic ulceration replaced the whitish structureless area (Figure 3A). We observed centrally a brown-gray structureless area corresponding to the fibrinocruoric material; the vessel pattern was strictly limited to the extreme periphery of the lesion (Figure 3B). On histopathologic analysis (Figure 3C), a crust was seen on the center of the lesion, while the tumoral infiltrate and vessels were only seen deeper and at the periphery. Finally, in the cicatricial phase (Figure 4A), we observed no more residual vessel pattern; only a browngray structureless mark suggesting postinflammatory pigmentation persisted (Figure 4B). Histopathologically, findings corresponded to the dermal fibrosis noted in scarring LyP but without residual tumoral infiltrate (Figure 4C). As LyP lesions mature, their histopathologic changes can be well correlated with morphologic features seen on dermoscopy.

Purpose: Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Rituximab is widely used alone or in combination therapy for the treatment of FL. Despite its well-established clinical efficacy, a subpopulation of patients does not respond to rituximab and most patients will relapse after therapy. The mechanisms of action and resistance to rituximab are not fully understood.Experimental Design: To study these mechanisms we developed an in vivo model of FL resistant to rituximab. This model was developed using the human RL line, isolated from a patient with FL, grown as xenotransplants in severe combined immunodeficient mice, exposed weekly to rituximab in vivo, followed by serial reimplantation and reexposure to rituximab, until a resistant phenotype was obtained.Results: RL-derived tumors unexposed to rituximab were grown as controls and compared with the resistant tumors. Although the expression of CD46 and CD55 antigens were not differently expressed in the resistant cells, the complement inhibitor CD59 was overexpressed in a subpopulation and CD20 was found to be expressed at a lower level in a minority of cells. Bcl-XL and YY1 were also found more highly expressed in rituximab-resistant cells.Conclusion: This model provides insight on potential in vivo resistance mechanisms to rituximab and could help contribute to the development of novel therapies in rituximab-refractory diseases.

In pancreatic beta-cells, the pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a potent insulin secretory effect via PAC(1) and VPAC receptors (Rs) through the Galpha(s)/cAMP/protein kinase A pathway. Here, we investigated the mechanisms linking PAC(1)R to ERK1/2 activation in INS-1E beta-cells and pancreatic islets. PACAP caused a transient (5 min) increase in ERK1/2 phosphorylation via PAC(1)Rs and promoted nuclear translocation of a fraction of cytosolic p-ERK1/2. Both protein kinase A- and Src-dependent pathways mediated this transient ERK1/2 activation. Moreover, PACAP potentiated glucose-induced long-lasting ERK1/2 activation. Blocking Ca(2+) influx abolished glucose-induced ERK1/2 activation and PACAP potentiating effect. Glucose stimulation during KCl depolarization showed that, in addition to the triggering signal (rise in cytosolic [Ca(2+)]), the amplifying pathway was also involved in glucose-induced sustained ERK1/2 activation and was required for PACAP potentiation. The finding that at 30 min glucose-induced p-ERK1/2 was detected in both cytosol and nucleus while the potentiating effect of PACAP was only observed in the cytosol, suggested the involvement of the scaffold protein beta-arrestin. Indeed, beta-arrestin 1 (beta-arr1) depletion (in beta-arr1 knockout mouse islets or in INS-1E cells by siRNA) completely abolished PACAP potentiation of long-lasting ERK1/2 activation by glucose. Finally, PACAP potentiated glucose-induced CREB transcriptional activity and IRS-2 mRNA expression mainly via the ERK1/2 signaling pathway, and likewise, beta-arr1 depletion reduced the PACAP potentiating effect on IRS-2 expression. These results establish for the first time that PACAP potentiates glucose-induced long-lasting ERK1/2 activation via a beta-arr1-dependent pathway and thus provide new insights concerning the mechanisms of PACAP and glucose actions in pancreatic beta-cells.

International audience; CDK4-pRB-E2F1 cell-cycle regulators are robustly expressed in non-proliferating beta cells, suggesting that besides the control of beta-cell number the CDK4-pRB-E2F1 pathway has a role in beta-cell function. We show here that E2F1 directly regulates expression of Kir6.2, which is a key component of the K(ATP) channel involved in the regulation of glucose-induced insulin secretion. We demonstrate, through chromatin immunoprecipitation analysis from tissues, that Kir6.2 expression is regulated at the promoter level by the CDK4-pRB-E2F1 pathway. Consistently, inhibition of CDK4, or genetic inactivation of E2F1, results in decreased expression of Kir6.2, impaired insulin secretion and glucose intolerance in mice. Furthermore we show that rescue of Kir6.2 expression restores insulin secretion in E2f1(-/-) beta cells. Finally, we demonstrate that CDK4 is activated by glucose through the insulin pathway, ultimately resulting in E2F1 activation and, consequently, increased expression of Kir6.2. In summary we provide evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in glucose homeostasis, defining a new link between cell proliferation and metabolism.

International audience; Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

Summary Background Desmoplastic melanoma (DM) is a rare variant of cutaneous melanoma. Its diagnosis is often delayed by an unusual clinical presentation. The dermoscopic features of DM have not yet been described. Objective To define the dermoscopic features of DM. Patients and methods A single-institution register-based retrospective study of six cases of histology-proven desmoplastic melanoma for which dermoscopy data were available. The criteria we studied included: network, dots and globules, streaks, regression features, ulceration, number of colours, blue/white veil, and vascular pattern. Results Only three cases exhibited one classical feature for a melanocytic lesion; other cases were recognized on the basis of the presence of figures of regression (all six), i.e. white scar-like areas and ‘peppering’ (three of six), multiple (> 4) colours (five of six), and of melanoma-related vascular patterns (five) such as linear-irregular vessels (four) and milky-red areas (two). Discussion We believe that dermoscopy could help in the accurate diagnosis of this rare neoplasm. In the absence of a pigmented network, attention should be given to the identification of features of regression and to melanoma-associated vascular patterns.

Monoclonal antibodies have yet considerably modified the field of clinical oncology. The growing knowledge of key cellular pathways in tumor induction and progression, targeted therapies represent an increasing proportion of new drugs entering clinical trials. Some molecules such as trastuzumab, rituximab, alemtuzumab, cetuximab are now widely used in clinical practice. These antibodies are now tested in different indications alone or in combination with standard chemotherapy. They are also developed for the treatment of inflammatory diseases (rituximab). Numerous others antibodies are currently in pre-clinical and clinical development phases for several malignancies including renal carcinoma, melanoma, lymphomas, leukaemia, breast, ovarian and colorectal cancer. An alternative approach is to conjugate the monoclonal antibody to a toxin, a cytotoxic agent, or a radioisotope. In other cases these antibodies aim to modify the tumour microenvironnement through inhibition of angiogenesis or enhancing host immune response against cancer. If the molecule targeted by the antibodies is clearly identified, most often the precise mechanism of action of these immunoglobulins is not fully understood.They can have direct effects in inducing apoptosis or programmed cell death. They can block growth factor receptors, efficiently arresting proliferation of tumor cells. Indirect effects include recruiting cells that exert cytotoxicity, such as monocytes and macrophages (ADCC). Monoclonal antibodies also bind complement, leading to toxicity known as complement dependent cytotoxicity (CDC).The side effects associated with these new treatments were in part foreseeable depending on the affected cell or function. But new or surprising side effects emerged from clinical studies. We present an overview of the monoclonal antibodies used in clinical oncology or currently in development phases. We particularly focus on recent development including new indications, clinical trial results and specific side effects of monoclonal antibodies used in the treatment of cancer.

International audience; OBJECTIVE: To describe current management of cutaneous melanoma (CM) and identify factors accounting for disparities. DESIGN: Retrospective population-based study using survey of cancer registries and pathology laboratories, and questionnaires to physicians. SETTING: Five regions covering 19.2% of the French territory and including 8.2 million inhabitants. PATIENTS: Incident cases of patients with stage I to stage II (hereinafter, stage I-II) tumors staged according to the American Joint Committee on Cancer Staging guidelines and nodal stage III CM in 2004. MAIN OUTCOME MEASURES: Modalities of diagnosis and excision, surgical margins, sentinel lymph node biopsy, adjuvant therapies and surveillance procedures, and their variations according to age, sex, residence, location of primary CM, Breslow thickness, type of physicians, modalities of decisions, and health care patterns. RESULTS: Clinical stage I-II CMs (n = 710 cases) slightly predominated in females (53%), with a lower mean Breslow thickness (1.4 mm) than in males (1.9 mm). Initial excisions were most often performed by private dermatologists and wide excisions by surgeons. Narrow margins (8%) were associated with advanced age, higher Breslow thickness, and head location. Sentinel lymph node biopsy was performed in 34% of CMs thicker than 1.0 mm, depending on geographical regions, distance from reference centers, and health care patterns. Adjuvant therapies (mainly low-dose interferon) were proposed in 53% of thick CMs (>1.5 mm), depending on the patient's age and geographical region. In contrast with French recommendations, surveillance procedures frequently included systematic medical imaging. Stage III nodal CMs (n = 89 cases) predominated in males (62%). After lymphadenectomy, adjuvant therapies (including high-dose interferon in 32% of cases and chemotherapies in 24% of cases) were proposed in 68% of cases, depending on the patient's age and geographical region. A complete 1-year high-dose interferon regimen was administered in less than 10% of cases. CONCLUSION: Large disparities still exist in the management of CM in France, depending to a greater extent on medical and geographical environment than on the characteristics of either patients or tumors.

Summary Background Metastatic melanoma of unknown origin is a difficult challenge diagnostically and therapeutically. Diagnosis of the putative primary lesion is difficult. This difficulty increases when the primary lesion has undergone complete regression. Objective To define the dermocopic features of fully regressed melanoma. Patients and methods A single-institution, register-based study of an unselected consecutive series of seven cases of metastatic melanoma in the lymph nodes with no known or visible primary lesion was carried out. Skin examination included dermoscopy; when a suspicious area was found, observed dermoscopic features were recorded and a biopsy was performed. Diagnosis of completely regressive cutaneous melanoma was based on clinical–pathological correlation according to widely accepted criteria. Results Seven dermoscopic features were associated with completely regressive melanoma: scar-like depigmentation (100%); pink coloration of the background (100%); linear-irregular vessels (86%); globular pattern of the vessels (43%); remnants of pigmentation (86%), either macular (43%) or with a peppering aspect (43%); and white lighter transverse bands (43%). The last feature was only observed with polarized light dermoscopy devices. Conclusion Dermoscopy more accurately distinguishes the vascular, pigmentary and scarring changes of fully regressive melanoma. We believe that dermoscopy should be included in the search for a regressive primary lesion in case of metastatic melanoma of unknown origin.

To determine the time required to perform a complete skin examination (CSE) as a means of opportunistic screening for skin cancer both without and with dermoscopy.Randomized, prospective multicenter study.Eight referral pigmented lesion clinics. Patients From June 2006 to January 2007, 1359 patients with at least 1 melanocytic or nonmelanocytic skin lesion were randomly selected to receive a CSE without dermoscopy or CSE with dermoscopy. For each patient, the total number of lesions and the duration of the CSE were recorded. A total of 1328 patients were eligible for analysis (31 were excluded because of missing data).The median time (measured in seconds) needed for CSE with and without dermoscopy and according to total cutaneous lesion count.The median time needed for CSE without dermoscopy was 70 seconds and with dermoscopy was 142 seconds, a significant difference of 72 seconds (P.001). The use of dermoscopy increased the duration of CSE, and this increase was in direct proportion to the patient's total lesion count. In contrast, the time required to perform a CSE without dermoscopy remained the same irrespective of whether the patients had few or many lesions.A CSE aided by dermoscopy takes significantly longer than a CSE without dermoscopy. However, a thorough CSE, with or without dermoscopy, requires less than 3 minutes, which is a reasonable amount of added time to potentially prevent the morbidity and mortality associated with skin cancer.

Objectives To describe clinicopathologic features and to identify prognostic factors in a large series of primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL LT), as defined in the recent World Health Organization–European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. Design Retrospective multicenter study from the French Study Group on Cutaneous Lymphomas. Setting Nineteen departments of dermatology in 10 regions of France. Patients Sixty patients with a PCLBCL LT included in the registry of the French Study Group on Cutaneous Lymphomas. Main Outcome Measures Age, sex, outcome, therapy, B symptoms, cutaneous extent, number of lesions, location (leg vs nonleg), serum lactate dehydrogenase level, and MUM-1 and Bcl-2 expression were recorded. Disease-specific survival was used as the main end point. Prognostic factors were identified using a Cox proportional hazards model. Results Primary cutaneous diffuse large B-cell lymphoma, leg type is characterized by a predilection for the leg (72%), a high proportion of Bcl-2 expression (85%), an advanced age at onset (mean age, 76 years), and frequent relapses and extracutaneous dissemination. The overall 5-year disease-specific survival rate was 41%. Location on the leg and multiple skin lesions were predictive of death in multivariate analysis. Although no variable related to therapy was significantly associated with survival, patients recently treated with combinations of anthracycline-containing chemotherapies and rituximab had a more favorable short-term outcome. Conclusions Primary cutaneous diffuse large B-cell lymphoma, leg type is a distinct entity with a poor prognosis, particularly in patients with multiple tumors on the legs. Despite the advanced age of many patients, the prognosis could be improved with combinations of anthracycline-containing chemotherapies and rituximab.

A 29-year-old woman presented with a 4-month history of a large, approximately 20 8-cm blue patch on her left forearm that had appeared overnight (Figure 1). She told us that she had noticed the blue patch after she had driven “nonstop” from Amsterdam, the Netherlands, to Spain in a state of rage after a fight with her partner. She had a several-year history of diabetes mellitus, for which she injected insulin. She used no other medications. A dissociative disorder had previously been diagnosed by a psychiatrist. Examination of the left forearmshowed striking clear-blue dyschromia of the skin, without induration or any sign of trauma. A skin biopsy was performed (Figure 2). What is your diagnosis?

Acral lentiginous melanoma (ALM) is the fourth histopathological subtype of malignant melanoma, accounting for10% of all melanomas in white-skinned populations. It is characterized by a lentiginous pattern of proliferation of the intraepidermal component of the tumour. Its individualization is still controversial, especially in regard of its prognostic value.To characterize better ALM from a pathological point of view and to assess the prognostic value of all histopathological features of ALM.We performed a review of all cases of ALM followed from 1996 to 2004 at the University Hospital Department of Dermatology, Lyon, France. We examined all haematoxylin, eosin and saffron-stained tissue sections of the primary lesions. Several pathological parameters of interest in melanoma were evaluated for disease-free and specific survival with the Kaplan-Meier method and the Cox proportional hazards regression model.Representative histological material was available for 121 patients. The mean Breslow thickness was 2.5 mm (in situ-20 mm). Fifteen lesions (12%) were in situ, nine (7%) were at Clark level II, 35 (29%) at III, 40 (33%) IV and 22 (18%) V. Extension along adnexal structures was found in almost half of the ALMs (46%), without prognostic significance. Seventeen (14%) lesions showed no microscopic pigmentation. Remnants of pre-existing naevus were found in four (3%) melanomas. The width of the 36 (30%) ulcerated lesions ranged from 1 to 20 mm (mean 7.6). Ulceration and its width were both associated with a large tumour thickness (P0.01), a high level of invasion (P0.01), the presence of vascular invasion (P0.01) and the lack of pigment production (P0.01). Among the 99 ALMs which were in the vertical growth phase (VGP), 21 showed a high mitotic rate (6 mitoses mm(-2)). A high mitotic rate was found to be significantly associated with the presence of ulceration (P0.01). The presence of microscopic satellites was noted in 10 (10%) lesions. The uncommon presence of small cells (8%) in the VGP was statistically significantly (P0.01) associated with a worse prognosis compared with other cell types. Multivariate analysis identified mitotic rate (P0.01), microsatellites (P = 0.05), Clark level (P = 0.01) and gender (P = 0.03) as independent prognostic factors for disease-free survival. Only the presence of microsatellites (P = 0.02) and a high mitotic rate (P0.01) were independently correlated with specific survival in ALM.This is a detailed pathological study of a large cohort with ALM, an uncommon subtype of melanoma. Mitotic activity appears to be of particular importance in predicting the outcome of ALM.

Summary Background Transformation of mycosis fungoides (T-MF) occurs in 8–55% of MF patients. Its early histopathological diagnosis is of tremendous importance to better define the management and to establish the prognosis. Recent studies have demonstrated that advanced-stage MF at diagnosis of transformation is the predominant risk factor of poor outcome. The 5-year survival rates for stage IIB and IV MF are 26·9% and 10·6%, respectively. The prognostic value of the immunophenotypic characterization of the infiltrate has not been thoroughly studied in the literature. Objectives To retrieve clinical, histological and immunophenotypic features of T-MF in our patient population and analyse their prognostic value. Patients and methods A register-based retrospective study was performed including all patients with cutaneous T-cell lymphoma (CTCL) registered in our two departments from January 2000 to December 2005. Among 208 patients with CTCL, 17 patients with proven transformation of their MF were studied. Clinical features and staging as well as immunophenotypic and pathological findings at the time of the initial diagnosis of MF and of the diagnosis of T-MF were analysed. Results Our results, in accordance with previously published material, indicate that the main clinical prognostic factor in T-MF is the stage of the initial disease at the time of the transformation. Patients with stage IIB–IV MF have a poor prognosis. In our study, strong expression of CD30 is linked to a better prognosis. Conclusions We believe that pathological and immunopathological documentation of progressive MF is important in order to identify T-MF early; however, the differential diagnosis is sometimes difficult. Aside from already acknowledged prognostic factors such as older age, advanced initial disease and short delay to transformation, the CD30 immunophenotype could be regarded as a useful additional prognostic marker in T-MF.

Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder affecting the elastic structures in the body, manifesting with cutaneous, ophthalmologic and cardiovascular findings. The association of PXE and systemic disease is rare, as only six cases have been reported in the literature. We describe herein two cases of coexisting PXE and cutaneous lupus and discuss a possible association. Although a fortuitous association cannot be excluded, the calculated prevalence of the association in our area was much less than in our observation. Given the ocular and vascular complications of PXE, clinicians who treat patients with lupus should be aware of this possible association.

Summary Background Sentinel lymph node (SLN) positivity has been found to be strongly associated with a poor prognosis in melanoma. Objectives This large referral centre study was conducted: (i) to confirm the powerful prognostic value of SLN biopsy (SLNB); (ii) to correlate patient prognosis to the micromorphometric features of SLN metastasis in SLN-positive patients; and (iii) to correlate these micromorphometric features to the likelihood of positive completion lymph node dissection (CLND). Patients and methods SLNB was performed in 455 cases of primary melanoma between January 1999 and December 2004; for patients with positive SLN, the following micromorphometric features were registered: size of the largest metastasis (two diameters), depth of metastasis, number of millimetric slices involved, maximum number of metastases on a single section, presence of intracapsular lymphatic invasion and extracapsular spread. Kaplan–Meier survival curves were compared with the log-rank test; multivariate analysis was performed using a Cox regression model. Dependence of CLND status on micromorphometric features of SLN was assessed by the χ2 test and predictive values of the different features were evaluated by multivariate analysis using a logistic regression model. Results A positive SLN was identified in 98 of our 455 cases. Survival was significantly shorter in SLN-positive patients than in SLN-negative patients. Extracapsular invasion was found to be an independent prognostic factor of disease-free survival; ulceration of the primary and the maximum diameter of the largest metastasis were identified as independent predictive factors of disease-specific survival. Age and the lowest diameter of the largest metastasis were identified as independent predictive criteria of positive CLND, whereas depth of metastasis was not. Positivity of CLND was not significantly associated with a worse prognosis. Conclusions Our study confirms the previously demonstrated strong prognostic value of SLNB. It also confirms the relationship between tumour burden in the SLN (evaluated by the maximum diameter of the largest metastasis) and clinical outcome. We point out a new micromorphometric feature of SLN, which seems to be predictive of CLND status: the lowest diameter of the largest metastasis.

The diagnosis of melanonychia striata is often difficult, and a biopsy of the nail matrix is required in doubtful cases. However, dermoscopic examination of the nail plate offers interesting information in order to better select the cases in which pathologic examination is indicated. In the case of brown longitudinal pigmentation with parallel regular lines, the diagnosis of nail apparatus melanocytic nevus could be made. On the other hand, the presence of a brown pigmentation overlaid by longitudinal lines irregular in their thickness, spacing, color, or parallelism is highly in favor of a melanoma. Gray homogeneous lines are observed in case of lentigo, lentiginoses, ethnic or drug-induced pigmentations, and in post-traumatic pigmentations. Blood spots are characterized by their round-shaped proximal edge and their filamentous distal edge and are highly suggestive of subungual hemorrhages. Dermoscopic examination of the free edge of the nail plate gives information on the lesion location; pigmentation of the dorsum of the nail plate is in favor of a proximal nail matrix lesion, whereas pigmentation the lower part of the nail edge is in favor of a lesion of the distal matrix.

Introduction Si les effets immuno-modulateurs des glucocorticoides sont recherches en therapeutique, les effets dits endocriniens sont responsables des effets secondaires nefastes d’une corticotherapie prolongee. Les glucocorticoides agissent en controlant la transcription de genes cruciaux par liaison sur un recepteur nucleaire specifique, exprime notamment dans les cellules beta pancreatiques. Nous avons evalue l’impact d’une exposition prolongee des cellules beta aux glucocorticoides sur la reponse au glucose et au GLP-1. Materiels et methodes Les experiences sont realisees sur la lignee INS-1E et les ilots de souris. La production d’AMPc et la secretion d’insuline sont mesurees par la technologie HTRF. L’expression, la distribution subcellulaire du recepteur GLP-1 sont suivies par western blot, immunofluorescence et microscopie confocale. Resultats L’exposition prolongee (≥ 24 heures) des cellules beta a un glucocorticoide de synthese, la dexamethasone (100 nM), diminue de 40 % la secretion d’insuline induite par le glucose, mais paradoxalement n’impacte pas la secre-tion d’insuline potentialisee par le GLP-1 (20 nM). En lien avec la secretion, les cellules beta exposees a la dexamethasone presentent une augmentation significative de la production d’AMPc en reponse au GLP-1, sans modifier l’expres-sion du recepteur. Cette augmentation n’est pas observee en reponse au glucagon (20 nM), ou a un activateur direct de l’adenylate cyclase, la forskoline (100 nM). La presence d’un inhibiteur des phosphodiesterases, l’IBMX (1 mm), lors de la mesure de l’AMPc indique que cette augmentation n’est pas la conse-quence d’une modulation des phosphodiesterases. L’utilisation d’un antagoniste du recepteur nucleaire des glucocorticoides, le RU486 (1 µM), bloque cette augmentation d’AMPc. Conclusion Cette etude revele que le recepteur nucleaire des glucocorticoides module selectivement le couplage du recepteur GLP-1 avec l’adenylate cyclase dans les cellules beta pancreatiques. Intervenant sur la production d’AMPc, cette modulation pourrait se traduire par une activation differentielle de la PKA et d’Epac2 situees en aval. Declaration d’interet Les auteurs declarent avoir un interet avec un organisme prive, industriel ou commercial en relation avec le sujet presente. Contrat collaboratif avec Cisbio bioassays pour le developpement des KIT HTRF.

Introduction Les kinases ERK1/2 sont connues pour etre impliquees dans la survie des cellules β et pourraient reguler la secretion d'insuline. Neanmoins le role specifique de chaque kinase n'a jamais ete etudie dans les cellules β. Le but de cette etude est de determiner le role de ERK1 en utilisant des souris ERK1-/-. Materiels et methodes La [Ca 2 + ] c et la secretion d'insuline ont ete mesurees sur des ilots perifuses. La masse des ilots a ete quantifiee sur coupes histologiques. Les niveaux d'expression et l'activation des kinases ont ete mesures par western blot et immunocytochimie. Resultats In vivo , les souris ERK1–/– presentent des glycemies comparables aux souris ERK1 +/+. In vitro , les changements de la [Ca 2 + ] c et de la secretion d'insuline en reponse au glucose sont similaires dans les ilots ERK1 +/+ et ERK1–/–. En revanche l'analyse morphometrique des coupes de pancreas de souris ERK1–/– âgees de 5 mois, a montre un nombre comparable mais un appauvrissement en petits ilots et un enrichissement en gros ilots en comparaison des souris ERK1 +/+. Chez les animaux plus âges (10 mois) ce decalage de taille ne s'observe plus. Neanmoins, les souris ERK1–/– semblent protegees de l'inflammation pancreatique liee a l'âge. L'absence de ERK1 n'a pas ete com-pensee par ERK2 (messager, proteine et activation). Par contre les activations de MSK1 ( p p p p Conclusion La kinase ERK1 semble jouer un role dans la regulation de la masse des cellules s mais pas dans la regulation de la secretion d'insuline. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Rituximab is now routinely use in clinical practice for B cell lymphoma and chronic lymphocytic leukaemia treatment. Mechanisms of action of this monoclonal antibody are not fully understood. Antibody dependent cellular cytotoxicity (ADCC), complement dependent toxicity (CDC) and apoptosis have been all shown to play a role. But the prominence of each mechanism is considerably varying among the different reports, the studied cell lines and the experimental models. A lack of explanations still exists between the efficacy observed in vivo and the low reproducible cytotoxicity reproduced shown in vitro. Despite an intensive research, most of the mechanisms of resistance to rituximab are unknown.

Miniglucagon (glucagon 19-29) is the ultimate processing product of proglucagon, present in the glucagon-secreting granules of the alpha cells, at a close vicinity of the insulin-secreting beta cells. Co-released with glucagon and thanks to its original mode of action and its huge potency, it suppresses, inside the islet of Langerhans, the detrimental effect of glucagon on insulin secretion, while it leaves untouched the beneficial effect of glucagon on glucose competence of the beta cell. At the periphery, miniglucagon is processed at the surface of glucagon- and insulin-sensitive cells from circulating glucagon. At that level, it acts via a cellular pathway which uses initial molecular steps distinct from that of insulin which, when impaired, are involved in insulin resistence. This bypass allows miniglucagon to act as an insulin-like component, a characteristic which makes this peptide of particular interest from a pathophysiological and pharmacological point of views in understanding and treating metabolic diseases, such as the type 2 diabetes.

cAMP-responsive element-binding protein (CREB) is required for beta-cell survival by regulating expression of crucial genes such as bcl-2 and IRS-2. Using MIN6 cells and isolated rat pancreatic islets, we investigated the signaling pathway that controls phosphorylation and protein level of CREB. We observed that 10 mmol/l glucose-induced CREB phosphorylation was totally inhibited by the protein kinase A (PKA) inhibitor H89 (2 micromol/l) and reduced by 50% with the extracellular signal-regulated kinase (ERK)1/2 inhibitor PD98059 (20 micromol/l). This indicates that ERK1/2, reported to be located downstream of PKA, participates in the PKA-mediated CREB phosphorylation elicited by glucose. In ERK1/2-downregulated MIN6 cells by siRNA, glucose-stimulated CREB phosphorylation was highly reduced and CREB protein content was decreased by 60%. In MIN6 cells and islets cultured for 24-48 h in optimal glucose concentration (10 mmol/l), which promotes survival, blockade of ERK1/2 activity with PD98059 caused a significant decrease in CREB protein level, whereas CREB mRNA remained unaffected (measured by real-time quantitative PCR). This was associated with loss of bcl-2 mRNA and protein contents, caspase-3 activation, and emergence of ultrastructural apoptotic features detected by electron microscopy. Our results indicate that ERK1 and -2 control the phosphorylation and protein level of CREB and play a key role in glucose-mediated pancreatic beta-cell survival.

Background: Scleromyxedema is an unusual skin disease characterized by mucinous infiltration of the skin. There is no satisfactory treatment for this disorder. Case Report: We report 2 cases of scleromyxedema, both associated with an IgG-λ paraprotein. Treatment with thalidomide was started and great improvement of the lesion was noted as shown by a quality of life questionnaire similar to those used in rheumatoid arthritis. TNF-α value was elevated in both cases during this treatment. Discussion: We hypothesize that the efficiency of thalidomide could be mediated by its costimulatory effect on T cytotoxic lymphocytes.

We report a case of lymphomatoid papulosis (LyP) localized to the face. Only ten cases of localized LyP have been reported, and those involved the extremities. Three of those cases finally evolved to classic LyP with a widespread distribution of the lesions, the other cases remain limited. The evolution into lymphoma for the localized form appears to be equivalent to that reported with the generalized LyP (20 %), underlining the need for long-term followup of these patients. This is the first reported case of LyP localized to the face.

Cutaneous melanoma remains a management challenge. Melanoma is the leading cause of death from skin tumors worldwide. Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma. Among those genes, BRAF is one of the most supposed to be of interest and targeted therapies are ongoing in clinical trials. In familial melanoma, germline mutations in two genes, CDKN2A and CDK4, that play a pivotal role in controlling cell cycle and division. It is hope that this better understanding of the biologic features of melanoma and the mechanisms underlying tumor-induced immunosuppression will lead to efficaceous targeted therapy.

Background: Orthopaedic implants are known to rarely induce or exacerbate dermatitis in metal-allergic patients. In the late 1990s, hypersensitivity to prosthetic material has been suspected to induce recurrent aseptic localized cellulitis. Patients presented with recurrent eruption of the skin overlying the implant, associated with fever. An aseptic origin of this new syndrome was hypothesized as no evidence of microbial involvement could be found and because antibiotic treatment was apparently inefficient. Observations: We observed 4 similar cases. All patients recovered after suppression of factors predisposing to erysipelas (gluteal portal of entry, anti-inflammatory drugs) and appropriate antibiotic therapy. Discussion: Our conviction is that these manifestations are authentic infectious cellulitis. Delayed thigh erysipelas after hip surgery is a distinctive form of cellulitis, characterized by its unusual topography, its rapid outcome and the possibility to be recurrent.

Background: Non-Langerhans cell histiocytoses form a heterogeneous group defined by the proliferation of cells with macrophage characteristics. Diagnosis is easy in typical cases but becomes more complex in unusual forms. Case Report: We report the case of a 53-year-old patient who presented multiple brown-to-yellowish papules and nodules of the trunk, neck, and head evolving for 6 months. No visceral involvement was found. Histopathological examination revealed histiocytic proliferation with features of secondary xanthomization with the presence of giant foamy multinucleated Touton cells. One year later, all lesions cleared spontaneously. Based on the clinical presentation and evolution and on the immunohistologic data, we retain the diagnosis of adult xanthogranuloma (AXG) in a diffuse shape. Discussion: Multiple AXG is a rare entity (15 cases reported since 1963) with a stereotypic presentation. It is important to recognize because of its good prognosis and the absence of visceral involvement therefore requiring no investigations or aggressive treatments. This case is interesting because of the complete and spontaneous healing of all the lesions within 20 months.

Miniglucagon (MG), the C-terminal glucagon fragment, processed from glucagon by the MG-generating endopeptidase (MGE) at the Arg17-Arg18 dibasic site, displays biological effects opposite to that of the mother-hormone. This secondary processing occurs in the glucagon- and MG-producing alpha-cells of the islets of Langerhans and from circulating glucagon. We first characterized the enzymatic activities of MGE in culture media from glucagon and MG-secreting alphaTC1.6 cells as made of a metalloendoprotease and an aminopeptidase. We observed that glucagon is a substrate for N-arginine dibasic convertase (NRDc), a metalloendoprotease, and that aminopeptidase B cleaves in vitro the intermediate cleavage products sequentially, releasing mature MG. Furthermore, immunodepletion of either enzyme resulted in the disappearance of the majority of MGE activity from the culture medium. We found RNAs and proteins corresponding to both enzymes in different cell lines containing a MGE activity (mouse alphaTC1.6 cells, rat hepatic FaO, and rat pituitary GH4C1). Using confocal microscopy, we observed a granular immunostaining of both enzymes in the alphaTC1.6 and native rat alpha-cells from islets of Langerhans. By immunogold electron microscopy, both enzymes were found in the mature secretory granules of alpha-cells, close to their substrate (glucagon) and their product (MG). Finally, we found NRDc only in the fractions from perfused pancreas that contain glucagon and MG after stimulation by hypoglycemia. We conclude that MGE is composed of NRDc and aminopeptidase B acting sequentially, providing a molecular basis for this uncommon regulatory process, which should be now addressed in both physiological and pathophysiological situations.

The p44/p42 MAPKs (ERK1/2) cascade regulates beta-cell nuclear events, which modulates cell differentiation and gene transcription, whereas its implication in processes occurring in the cytoplasm, such as activation of the exocytotic machinery, is still unclear. Using the MIN6 beta-cell line and isolated rat islets of Langerhans, we investigated whether glucose, by activating the ERK1/2 cascade, induces phosphorylation of cytoplasmic proteins implicated in exocytosis of insulin granules such as synapsin I. We observed that the majority of ERK1/2 activity induced by glucose remains in the cytoplasm and physically interacts with synapsin I, allowing phosphorylation of the substrate. Therefore, we reexamined the potential requirement of ERK1/2 for insulin secretion. Blocking activation of ERK1/2 using MEK1/2, the MAPK kinase inhibitor PD98059 or using small interfering RNA-mediated silencing of ERK1 and ERK2 expressions resulted in partial inhibition of glucose-induced insulin release, indicating that ERK1/2 pathway participates also in the regulation of insulin secretion. Moreover, using the pancreatic islet perifusion model, we found that the ERK1/2 activity participates in the first and second phases of insulin release induced by glucose. Taken together, our results demonstrate new aspects of the glucose-dependent actions of ERK1/2 in beta-cells exerted on cytoplasmic proteins, including synapsin I, and participating in the overall glucose-induced insulin secretion.