Primary cutaneous γδ T-cell lymphomas (PCGD-TCLs) are considered a subgroup of aggressive cytotoxic T-cell lymphomas (CTCLs). We have taken advantage of a new, commercially available antibody that recognizes the T-cell receptor-γ (TCR-γ) subunit of the TCR in paraffin-embedded tissue. We have analyzed a series of 146 primary cutaneous T-cell lymphomas received for consultation or a second opinion in the CNIO Pathology Department. Cases were classified according to the World Health Organization 2008 classification as mycosis fungoides (MF; n=96), PCGD-TCLs (n=5), pagetoid reticulosis (n=6), CD30(+) primary cutaneous anaplastic large cell lymphomas (n=5), primary cutaneous CD8 aggressive epidermotropic CTCLs (n=3), primary cutaneous CTCL, not otherwise specified (n=4), and extranodal nasal-type NK/T-cell lymphomas primarily affecting the skin or subcutaneous tissue (n=11). Sixteen cases of the newly named lymphomatoid papulosis type D (LyP-D; n=16) were also included. In those cases positive for TCR-γ, a further panel of 13 antibodies was used for analysis, including TIA-1, granzyme B, and perforin. Clinical and follow-up data were recorded in all cases. Twelve cases (8.2%) were positive for TCR-γ, including 5 PCGD-TCLs, 2 MFs, and 5 LyP-Ds. All 5 PCGD-TCL patients and 1 MF patient died of the disease, whereas the other MF patient and all those with LyP-D were alive. All cases expressed cytotoxic markers, were frequently CD3(+)/CD8(+), and tended to lose CD5 and CD7 expressions. Eight of 12 and 5 of 11 cases were CD30(+) and CD56(+), respectively. Interestingly, 5/12 TCR-γ-positive cases also expressed TCR-BF1. All cases analyzed were negative for Epstein-Barr virus-encoded RNA. In conclusion, TCR-γ expression seems to be rare and is confined to cytotoxic primary cutaneous TCLs. Nevertheless, its expression is not exclusive to PCGD-TCLs, as TCR-γ protein can be found in other CTCLs. Moreover, its expression does not seem to be associated with bad prognosis by itself, as it can be found in cases with good and bad outcomes.

The online version of this paper has a Supplementary Appendix. BackgroundVorinostat (suberoylanilide hydroxamic acid, SAHA), an inhibitor of class I and II histone deacetylases, has been approved for the treatment of cutaneous T-cell lymphoma. In spite of emerging information on the effect of vorinostat in many types of cancer, little is yet known about this drug's mechanism of action, which is essential for its proper use in combination therapy. We investigated alterations in gene expression profile over time in cutaneous T-cell lymphoma cells treated with vorinostat. Subsequently, we evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of cutaneous T-cell lymphoma. Design and MethodsThe genes significantly up-or down-regulated by vorinostat over different time periods (2-fold change, false discovery rate corrected P value<0.05) were selected using the short-time series expression miner. Cell viability was assessed in vitro in cutaneous T-cell lymphoma cells through measuring intracellular ATP content. Drug interactions were analyzed by the combination index method with CalcuSyn software. ResultsThe functional analysis suggests that vorinostat modifies signaling of T-cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. With regards to effects on cutaneous T-cell lymphoma cells, combining vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when vorinostat was combined with HSP90 inhibitor. ConclusionsThese results demonstrate the potential targets of vorinostat, underlining the importance of Tcell receptor signaling inhibition following vorinostat treatment. Additionally, we showed that combination therapies involving histone deacetylase inhibitors and inhibitors of PI3K are potentially efficacious for the treatment of cutaneous T-cell lymphoma.Key words: vorinostat, gene expression, cutaneous T-cell lymphoma, synergy, HDAC inhibitors. T-cell lymphoma. Haematologica. 2010;95:613-621. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Citation: Wozniak MB, Villuendas R, Bischoff JR, Aparicio CB, Martínez Leal JF, de La Cueva P, Rodriguez ME, Herreros B, Martin-Perez D, Longo MI, Herrera M, Piris MÁ, and Ortiz-Romero PL. Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancerassociated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer. ª 2019 Steunstichting ESOT

Background Although considered as a first‐group carcinogen, indoor tanning is a common practice in Europe. Euromelanoma is a pan‐European skin cancer prevention campaign. Objectives To compare several European countries in terms of the prevalence and determinants of sunbed use. Methods Participants in the Euromelanoma campaigns filled in questionnaires containing demographics and risk factors, including type/duration of sunbed use. Multivariate analyses adjusted for age, gender, education, skin type and year of survey were employed to assess factors independently associated with sunbed use in each country. Results In total, 227 888 individuals (67.4% females, median age 44, 63.4% highly educated, 71.9% skin types III–VI) from 30 countries participated. Overall, the prevalence of sunbed ever use was 10.6% (≤19‐year‐olds: 5.9%; 20 to 35‐year‐olds: 17.0%; >35‐year‐olds: 8.3%). Females displayed a higher prevalence than males in all countries. Balkan countries displayed the highest female/male ratios (≥4). Sunbed use was significantly more prevalent among skin type III–VI (14/30 countries) and highly educated participants (11/30 countries). Significant correlations were found between sunbed use prevalence and countries’ latitude (P < 0.001) and sunshine (P = 0.002); Italy and Spain represented exceptions towards excessive exposure. Very different prevalence rates were found for Spain (19.3%) and Portugal (2.0%). Scandinavian countries ranked highest in sunbed use among ≤19‐year‐olds, Baltic countries among 20 to 35‐year‐olds. Conclusions Sunbed use prevalence was higher in northern, sun‐deprived countries, with the exception of Italy and Spain. The main determinants of sunbed use were age (young adults) and gender (females), whereas education and skin type had a less relevant effect. Geographic particularities were found in four regions: Iberian (prevalence ten times higher in Spain than Portugal), Balkan (prevalence disproportionately higher among women), Baltic (highest prevalence among young adults) and Scandinavian (highest prevalence among adolescents). These data have public health relevance for future interventions aimed at reducing sunbed use in Europe.