[New melanoma immunotherapies: mechanisms of action, efficiency and management of toxicities]. / Nouvelles immunotherapies du mélanome: mécanismes d'action, efficacité et prise en charge des toxicities.

In recent years the therapy of metastatic melanoma has been revolutionized from a disease with very few efficient treatment options to one with access to multiple therapies which can impact on patient survival. Two main classes of therapies have been developed: 1. Immunotherapy by immune checkpoint inhibitors and 2. Small molecule inhibitors of the MAPK pathway. Immunotherapies achieved by either inhibition of CTLA-4 or the PD1/PD-Ll axes are impacting the overall survival in an important fraction of patients. In addition, the side effects of these immune therapy approaches require early detection by all the specialists involved as well as early management according to precise guidelines for optimal outcome.

Dermoscopy of acral melanoma: a multicenter study on behalf of the international dermoscopy society.

BACKGROUND: Most studies on dermoscopy of acral lesions were conducted in Asian populations. In this study, we analyzed these features in a predominantly Caucasian population. OBJECTIVE: Estimate the prevalence of dermoscopic features in acral lesions, and assess their level of agreement between observers. METHODS: In this retrospective multicenter study, 167 acral lesions (66 melanomas) were evaluated for 13 dermoscopic patterns by 26 physicians, via a secured Internet platform. RESULTS: Parallel furrow pattern, bizarre pattern, and diffuse pigmentation with variable shades of brown had the highest prevalence. The agreement for lesion patterns between physicians was variable. Agreement was dependent on the level of diagnostic difficulty. CONCLUSION: Lesions with a diameter >1 cm were more likely to be melanoma. We found as well that a benign pattern can be seen in parts of melanomas. For this reason one should evaluate an acral lesion for the presence of malignant patterns first.

PIDD orchestrates translesion DNA synthesis in response to UV irradiation.

PIDD has been implicated in survival and apoptotic pathways in response to DNA damage, and a role for PIDD was recently identified in non-homologous end-joining (NHEJ) repair induced by γ-irradiation. Here, we present an interaction of PIDD with PCNA, first identified in a proteomics screen. PCNA has essential functions in DNA replication and repair following UV irradiation. Translesion synthesis (TLS) is a process that prevents UV irradiation-induced replication blockage and is characterized by PCNA monoubiquitination and interaction with the TLS polymerase eta (polη). Both of these processes are inhibited by p21. We report that PIDD modulates p21-PCNA dissociation, and promotes PCNA monoubiquitination and interaction with polη in response to UV irradiation. Furthermore, PIDD deficiency leads to a defect in TLS that is associated, both in vitro and in vivo, with cellular sensitization to UV-induced apoptosis. Thus, PIDD performs key functions upon UV irradiation, including TLS, NHEJ, NF-κB activation and cell death.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites.

BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a long half-life of 5-10 years in human beings as a result of its high lipophilicity, and little or no metabolism. We monitored TCDD, its form, distribution, and elimination in Victor Yushchenko after he presented with severe poisoning. METHODS: In late December, 2004, a patient presented with TCDD poisoning; the levels in his blood serum (108000 pg/g lipid weight) were more than 50 000-fold greater than those in the general population. We identified TCDD and its metabolites, and monitored their levels for 3 years using gas chromatography and high-resolution mass spectrometry in samples of blood serum, adipose tissue, faeces, skin, urine, and sweat, after they were extracted and cleaned with different organic solvents. FINDINGS: The amount of unmodified TCDD in the samples that were analysed accounted for about 60% of TCDD eliminated from the body during the same period. Two TCDD metabolites-2,3,7-trichloro-8-hydroxydibenzo-p-dioxin and 1,3,7,8-tetrachloro-2-hydroxydibenzo-p-dioxin-were identified in the faeces, blood serum, and urine. The faeces contained the highest concentration of TCDD metabolites, and were the main route of elimination. Altogether, the different routes of elimination of TCDD and its metabolites accounted for 98% of the loss of the toxin from the body. The half-life of TCDD in our patient was 15.4 months. INTERPRETATION: This case of poisoning with TCDD suggests that the design of methods for routine assessment of TCDD metabolites in human beings should be a main aim of TCDD research in the metabolomic era. FUNDING: University of Geneva Dermatology Fund, and Swiss Centre for Applied Human Toxicology.

[Inflammation and auto-immunity: an update on the NOD-like receptors and their clinical role]. / Inflammation et auto-immunité: les NOD-like receptors et leur impact en clinique.

Clinical and molecular research on inflammation has soared tremendously thanks to the discovery of Toll-like receptors (TLRs). These efforts have resulted in the recent identification and characterization of a new class of proteins called NOD-like receptors (NLR), which are intracellular analogs of the TLRs. These molecules act as true sensors of the dangers encountered by the cell and are essential for the initiation of the inflammatory response. Their implication in the pathogeny of numerous auto-inflammatory and autoimmune diseases revolutionizes our understanding of the mechanisms underlying the development of these diseases. We discuss here these major discoveries as well as their clinical implications.

Can automated dermoscopy image analysis instruments provide added benefit for the dermatologist? A study comparing the results of three systems.

BACKGROUND: Instruments designed to provide computer program-driven diagnosis of dermoscopic images of lesions are now commercially available. Multiple publications tout the improved diagnostic accuracy of these instruments compared with that of clinicians. OBJECTIVES: Our aim was to evaluate the actual usefulness of these instruments for dermatologists practising in a pigmented lesion clinic. METHODS: Over a 4-month period we subjected lesions, which were being evaluated in one of our clinics, to automated computer diagnosis performed by three commercially available instruments. We intentionally included three groups of lesions: group 1 lesions were suspicious melanocytic lesions that were scheduled to be excised; group 2 lesions were nonmelanocytic lesions; group 3 lesions were clinically obvious melanomas. The automated diagnoses provided by the instruments were compared with the dermoscopy diagnosis of experienced physicians and with histopathology. RESULTS: We included a total of 107 lesions. One imaging system's computer algorithm was unable to analyse one third of the lesions. All three instruments' computer algorithms were able to identify the clinically obvious melanomas (group 3) correctly. However, all three systems tended to overdiagnose by incorrectly classifying most seborrhoeic keratoses (group 2) as potential malignant lesions. Concerning the suspect melanocytic lesions (group 1), which are precisely the lesions for which a dermatologist would welcome a second opinion, we found significant variability in the diagnostic accuracy of the instruments tested. However, all three systems providing computer-assisted diagnosis had a tendency to overdiagnose benign melanocytic lesions as potential melanomas. CONCLUSIONS: Although the image analysis systems tested by us correctly identified the clinically obvious melanomas, they were not able to discriminate between most dysplastic naevi and early malignant melanoma. Thus, for the moment these computer-assisted diagnostic imaging machines provide little to no added benefit for the experienced dermatologist/dermoscopist.

The significance of multiple blue-grey dots (granularity) for the dermoscopic diagnosis of melanoma.

BACKGROUND: The presence of multiple blue-grey dots (MBGD) is widely used by clinicians to decide if a pigmented lesion should be removed, but only little is known about their significance. OBJECTIVES: To evaluate the significance of MBGD for the dermoscopic diagnosis of melanoma. METHODS: In part 1 we retrospectively evaluated 340 pigmented lesions for the presence and morphological appearance of granularity. One hundred and seventy melanomas were included and matched with 170 benign and dysplastic naevi which were randomly chosen from our collection. In part 2, 3773 lesions were examined prospectively in at-risk patients: all lesions with granularity were recorded, surgically removed and subjected to histopathological examination. RESULTS: In part 1, granularity was found in 26.5% of the benign lesions and 93.5% of melanomas. The presence of granularity, granularity at the periphery, irregularly distributed granularity and granularity in association with red and white colour were statistically highly significant for the diagnosis of melanoma (P < 0.001). In part 2, granularity was found in 1.08% of the 3773 lesions and more frequently in sun-damaged skin. Sensitivity for the diagnosis of melanoma was 85% and specificity 99%. CONCLUSIONS: After the revision of many lesions with MBGD, we concluded that the term 'granularity' better describes this entity. Lesions with irregular granularity (periphery, irregularly distributed) should be removed especially if they are associated with red, blue or white colour. Lesions with a benign dermoscopy pattern which have granularity with a regular appearance and involving only a small portion of the lesion do not require surgical excision.

[Follow-up of melanoma lesions]. / Surveillance des lésions mélanocytaires.

Due to the early diagnosis, melanomas can be diagnosed in early stages. Most melanomas tend not to show morphological criteria of malignancy in the very early stages. They rather resemble benign moles. For patients with hundreds of atypical lesions, follow-up examinations using digital dermoscopy are very helpful. This technique enables the physician to monitor lesions and to detect microscopic change. Lesions with microscopic change are thought to be high risk lesions and should be removed this will represent important savings for the health system because this will allow to make the diagnosis of melanoma in earlier stages and to save costs for unnecessary surgery. In this article we are going to review the technique.

NF-kappaB signals induce the expression of c-FLIP.

Activation of the transcription factor NF-kappaB is a major effector of the inducible resistance to death receptor-mediated apoptosis. Previous evidence indicates that the combined transcriptional activation of TRAF-1, TRAF-2, IAP-1, and IAP-2 is required to suppress cell death by tumor necrosis factor (TNF). Here we show that NF-kappaB activation upregulates the caspase 8 inhibitor FLIP, resulting in increased resistance to Fas ligand (FasL) or TNF. Restoration of either the full-length 55-kDa long form of FLIP or an alternatively spliced short form of FLIP in NF-kappaB null cells inhibits TNF- and FasL-induced cell death efficiently, whereas the expression of IAP or TRAF family members only partially rescues cells from death. Resistance to either FasL- or TNF-induced apoptosis is overcome when cells are incubated in the presence of the protein synthesis inhibitor cycloheximide. This treatment leads to the rapid downregulation of FLIP but not to that of TRAF2. Our findings suggest that FLIP is an important mediator of NF-kappaB-controlled antiapoptotic signals.

Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation.

Bcl10, a caspase recruitment domain (CARD)-containing protein identified from a breakpoint in mucosa-associated lymphoid tissue (MALT) B lymphomas, is essential for antigen-receptor-mediated nuclear factor kappaB (NF-kappaB) activation in lymphocytes. We have identified a novel CARD-containing protein and interaction partner of Bcl10, named Carma1. Carma1 is predominantly expressed in lymphocytes and represents a new member of the membrane-associated guanylate kinase family. Carma1 binds Bcl10 via its CARD motif and induces translocation of Bcl10 from the cytoplasm into perinuclear structures. Moreover, expression of Carma1 induces phosphorylation of Bcl10 and activation of the transcription factor NF-kappaB. We propose that Carma1 is a crucial component of a novel Bcl10-dependent signaling pathway in T-cells that leads to the activation of NF-kappaB.

Equine herpesvirus protein E10 induces membrane recruitment and phosphorylation of its cellular homologue, bcl-10.

v-E10, a caspase recruitment domain (CARD)-containing gene product of equine herpesvirus 2, is the viral homologue of the bcl-10 protein whose gene was found to be translocated in mucosa-associated lymphoid tissue (MALT) lymphomas. v-E10 efficiently activates the c-jun NH(2)-terminal kinase (JNK), p38 stress kinase, and the nuclear factor (NF)-kappaB transcriptional pathway and interacts with its cellular homologue, bcl-10, via a CARD-mediated interaction. Here we demonstrate that v-E10 contains a COOH-terminal geranylgeranylation consensus site which is responsible for its plasma membrane localization. Expression of v-E10 induces hyperphosphorylation and redistribution of bcl-10 from the cytoplasm to the plasma membrane, a process which is dependent on the intactness of the v-E10 CARD motif. Both membrane localization and a functional CARD motif are important for v-E10-mediated NF-kappaB induction, but not for JNK activation, which instead requires a functional v-E10 binding site for tumor necrosis factor receptor-associated factor (TRAF)6. Moreover, v-E10-induced NF-kappaB activation is inhibited by a dominant negative version of the bcl-10 binding protein TRAF1, suggesting that v-E10-induced membrane recruitment of cellular bcl-10 induces constitutive TRAF-mediated NF-kappaB activation.

Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A.

Mutations in the epithelial morphogen ectodysplasin-A (EDA), a member of the tumor necrosis factor (TNF) family, are responsible for the human disorder X-linked hypohidrotic ectodermal dysplasia (XLHED) characterized by impaired development of hair, eccrine sweat glands, and teeth. EDA-A1 and EDA-A2 are two splice variants of EDA, which bind distinct EDA-A1 and X-linked EDA-A2 receptors. We identified a series of novel EDA mutations in families with XLHED, allowing the identification of the following three functionally important regions in EDA: a C-terminal TNF homology domain, a collagen domain, and a furin protease recognition sequence. Mutations in the TNF homology domain impair binding of both splice variants to their receptors. Mutations in the collagen domain can inhibit multimerization of the TNF homology region, whereas those in the consensus furin recognition sequence prevent proteolytic cleavage of EDA. Finally, a mutation affecting an intron splice donor site is predicted to eliminate specifically the EDA-A1 but not the EDA-A2 splice variant. Thus a proteolytically processed, oligomeric form of EDA-A1 is required in vivo for proper morphogenesis.