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Background: Following the pivotal phase II trial BOLT, the Hedgehog (Hh) inhibitor sonidegib was approved in the EU to treat locally advanced basal cell carcinoma (laBCC) in patients not amenable to surgery or radiotherapy. We report safety data from the interim analysis of the real-world NISSO study., Methods: NISSO is an ongoing non-interventional, multinational, post-authorization safety study (NCT04066504). Patients with laBCC are treated with sonidegib 200 mg orally once daily and followed for 3 years. Dose modifications were allowed according to the local prescribing information., Results: Between May 6, 2019, and March 15, 2022, 321 patients with laBCC were enrolled at 46 European sites (data cut-off: June 22, 2023). Treatment was discontinued in 241 (75.1%) patients, with the main reasons being the patient/guardian decision (n = 69, 28.6%), treatment success (n = 40, 16.6%) and the physician decision (n = 35, 14.5%). The median duration of sonidegib exposure was 8.8 months (4.4-13.7 months). Overall, 284 (88.5%) patients had ≥ one treatment-emergent adverse event (TEAE). Most TEAEs were ≤ grade 2 and the most common were muscle spasms (n = 141; 43.9%), dysgeusia (n = 119; 37.1%), and alopecia (n = 97; 30.2%). After 3 months of treatment, the cumulative rates of muscle spasms, dysgeusia, and alopecia were 21.8%, 16.2%, and 3.7%, respectively. TEAEs led to treatment discontinuation in 59 (18.4%) patients, while 149 (46.4%) patients had at least one TEAE leading to dose reduction or interruption. Serious drug-related TEAEs were reported in 13 (4.1%) patients., Conclusions: These results confirm the safety profile previously observed. Most patients experienced the onset of common TEAEs after 3 months of treatment, and the cumulative incidence of most common TEAEs was 10-20% lower compared to the BOLT study, except for dysgeusia and fatigue that had a similar incidence. The percentage of patients experiencing TEAEs requiring interruption or dose reduction was similar to the BOLT study, while the proportion of patients with TEAE leading to discontinuation of sonidegib was lower. This study demonstrates that the tolerability of sonidegib is manageable in routine clinical practice., Trial Registration: NCT04066504., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by ethics committees of participating study centers: Ethics Committee of the MHH Hannover; Ethics Committee of Westphalia-Lippe; Ethics Committee of the Christian-Albrechts-Universität zu Kiel; Ethics Committee of the Saxony-Anhalt Medical Association; Ethics Committee of the Medical Association of Thuringia; Ethics Committee of the Medical Faculty of the University of Duisburg-Essen; Ethics Committee of the University of Tübingen; Ethics Committee of the Albert-Ludwigs-University Freiburg; Ethics Committee of the Medical Association of Lower Saxony; Ethics Committee of the University of Regensburg; Ethics Committee of the University of Lübeck; Ethics Committee of the Rhineland-Palatinate Medical Association; Ethics Committee of the Medical Association of Hesse; Ethics Committee of the North Rhine Medical Association; Ethics Committee of the Medical Faculty of the Ruhr University Bochum; Ethics Committee of the Goethe University Frankfurt; Ethics Committee Hamburg; Ethics Committee of the University of Ulm; Ethics Committee of the Technical University of Munich; Ethics Committee Bad Oeynhausen; Ethics Committee at the Technical University of Dresden; Ethics Committee Berne; Ethics Committee Zurich; Comitato Etico Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale"; Comitato Etico I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”; Comitato Etico Interaziendale Novara; Comitato Etico Università Federico II; Comitato Etico Fondazione Policlinico Universitario Agostino Gemelli IRCCS – Università Cattolica del Sacro Cuore; Comitato Etico ASL Avezzano/Sulmona/L’Aquila Teramo; Comitato Etico Regionale Liguria; Comitato Etico di Area Vasta Centro; Comitato Etico Fondazione IRCCS “Istituto Nazionale dei Tumori”; Comitato Etico Istituto Dermopatico dell’Immacolata – IRCCS; Comitato Etico di Brescia; Comitato Etico della Romagna (CEROM); Ethics Committee for Clinical Research of Hospital Clínic of Barcelona; Ethics Committee of Hospital of Nuestra Señora de la Candelaria; Ethics Committee of Hospital of Ramón y Cajal; Research Ethics Committee / Ethics Committee for Drug Research of the Dr. Negrín University Hospital of Gran Canaria; Ethics Committee of Galicia (SERGAS); Ethics Committee of the Hospital of Vall d'Hebron; Ethics Committee of University Hospital of La Paz; Ethics Committee of Hospital of Santa Creu i Sant Pau; Ethics Committee of Hospital of La Fe; Ethics Committee of University General Hospital of Valencia; Ethics Committee of Hospital of Germans Trias i Pujol; Ethics Committee of University Hospital of Vírgen de la Macarena (site was not initiated). Consent for publication Not applicable. Competing interests RG served as consultant for BristolMyers Squibb, MerckSharpDohme, Novartis, GlaxoSmithKline, Amgen, Almirall-Hermal, Pierre-Fabre, SUN Pharma, Immunocore, Delcath, Merck Healthcare, Sanofi/Regeneron. RG received honoraria for lectures from BristolMyers Squibb, MerckSharpDohme, Novartis, Amgen, Merck Healthcare, Almirall-Hermal, Pierre-Fabre, Sanofi/Regeneron, SUN Pharma. RG received travel support from Pierre-Fabre, SUN Pharma, Boehringer Ingelheim. RG received research grants from Sanofi/Regeneron, Merck Healthcare, Amgen, SUN Pharma, KyowaKirin, Almirall-Hermal. UL served as a consultant to MSD, Novartis, Sanofi, Sun Pharma, received travel support from Sun Pharma and Pierre Fabre, speakers’ fees from Sun Pharma, Sanofi, MSD, Novartis and institutional grants from MSD, outside the submitted work. PM received honoraria for lectures and presentations from MSD, Novartis, BMS, Pierre Fabre, Sanofi Genzyme, Immunocore, Delcath, Almirall Hermal, Sun Pharma, Regeneron. PM received travel support from MSD, BMS, Sun Pharma, Novartis and served as consultant for Novartis, BMS, Pierre Fabre, Sanofi Genzyme, Beiersdorf, MSD, Beiersdorf, Biotech, Regeneron, Sun Pharma. KCK serves as consultant to Philogen, BMS, MSD, Sanofi Aventis, Immunocore and received travel grants and speaker fees from Philogen, Pierre Fabre, BMS, MSD, Sun Pharma, Sanofi Aventis, Novartis, Medac and has received research support from Novartis. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Lunaphore, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi and travel support from Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. MS declares no conflicts of interest. KP reports grants and personal fees from Sanofi, Novartis, Abbvie, Almirall, Philogen, Leo Pharma, Lilly, Janssen, Pierre Fabre, Sun Pharma, Biogen, Galderma. KP received speaker fees from Lilly, Sanofi, Sun Pharma. GMPP has conflicts of interest with Sun Pharma, Almirall and La Roche-Posay. RFdM has/had a consultant/advisory role for Takeda, Kyowa Kirin, Recordati, Sun Pharma and received travel support from Kyowa Kirin, Sun Pharma, Janssen, UCB. RBE and REH have no conflicts of interest to state. AH reports grants and personal fees from Agenus, Almirall, Amgen, BMS, CureVac, Dermagnostix, Eisai, Highlight Therapeutics, Huya Biosciences, IO Biotech, Immunocore, Incyte, Iovance, Kyowa Kirin, MerckPfizer, MSD/Merck, NeraCare, Novartis Pharma, Philogen, Pierre Fabre, Replimune, Regeneron, Roche, Sanofi-Genzyme, Seagen, Xenthera, and from Sun Pharma outside the submitted work. SM, NG, and RA are employees of Sun Pharmaceuticals Industries and SUN Pharmaceuticals Germany GmbH., (© 2024. The Author(s).)

Objective: Patients with nonmelanoma skin cancer (NMSC)-ie, basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)-have an increased risk of developing a second skin cancer. The aim of this study was to describe the frequency, incidence per 1000 person-years, and predictors of a second skin cancer in a cohort of patients with NMSC treated with Mohs micrographic surgery (MMS)., Material and Methods: Prospective study of a national cohort of patients with NMSC who underwent MMS at 22 Spanish hospitals between July 2013 and February 2020; case data were recorded in the REGESMOHS registry. The study variables included demographic characteristics, frequency and incidence per 1000 person-years of second skin cancers diagnosed during the study period, and risk factors identified using mixed-effects logistic regression., Results: We analyzed data for 4768 patients who underwent MMS; 4397 (92%) had BCC and 371 (8%) had SCC. Mean follow-up was 2.4 years. Overall, 1201 patients (25%) developed a second skin cancer during follow-up; 1013 of the tumors were BCCs (21%), 154 were SCCs (3%), and 20 were melanomas (0.4%). The incidence was 107 per 1000 person-years (95% CI, 101-113) for any cancer, 90 per 1000 person-years (95% CI, 85-96) for BCC, 14 (95% CI, 12-16) per 1000 person-years for SCC, and 2 (95% CI, 1-3) per 1000 person-years for melanoma. More men than women developed a subsequent skin cancer (738 [61%] vs 463 [39%]). The main risk factors were a history of multiple tumors before diagnosis (relative risk [RR], 4.6; 95% CI, 2.9-7.1), immunosuppression (RR, 2.1; 95% CI, 1.4-3.1), and male sex (RR, 1.6; 95% CI, 1.4-1.9)., Conclusion: Patients have an increased risk of developing a second tumor after MMS treatment of NMSC. Risk factors are a history of multiple tumors at diagnosis, immunosuppression, and male sex., (Copyright © 2022. Publicado por Elsevier España, S.L.U.)

Randomized studies to assess the efficacy of Mohs micrographic surgery in basal cell and squamous cell carcinomas are limited by methodological and ethical issues and a lack of long follow-up periods. This study presents the "real-life" results of a nationwide 7-years cohort on basal cell carcinoma and squamous cell carcinoma treated with Mohs micrographic surgery. A prospective cohort was conducted in 22 Spanish centres (from July 2013 to February 2020) and a multivariate analysis, including characteristics of patients, tumours, surgeries and follow-up, was performed. A total of 4,402 patients followed up for 12,111 patient-years for basal cell carcinoma, and 371 patients with 915 patient-years of follow-up for squamous cell carcinoma were recruited. Risk factors for recurrence included age, non-primary tumours and more stages or unfinished surgeries for both tumours, and immunosuppression for squamous cell carcinoma. Incidence rates of recurrence were 1.3 per 100 person-years for basal cell carcinoma (95% confidence interval 1.1-1.5) and 4.5 for squamous cell carcinoma (95% confidence interval 3.3-6.1), being constant over time (0-5 years). In conclusion, follow-up strategies should be equally intense for at least the first 5 years, with special attention paid to squamous cell carcinoma (especially in immunosuppressed patients), elderly patients, non-primary tumours, and those procedures requiring more stages, or unfinished surgeries.

Sonidegib is an antagonist of the transmembrane protein Smoothened in the Hedgehog signaling pathway. It is indicated for the treatment of locally advanced basal cell carcinoma (BCC) that is not amenable to curative surgery or radiotherapy. Sonidegib's efficacy and safety were demonstrated in the phase 2 BOLT trial, where 61% (95% CI, 48-72%) of patients with locally advanced BCC treated with sonidegib 200 mg achieved an objective response to treatment with a mean time to response of 4 months. The median duration of response was 26.1 months and the median progression-free survival was 22.1 months. The most common adverse events were muscle spasms (54.4%), hair loss (49.4%), and loss of taste (44.3%); most events were grade 1 or 2. In this review, we summarize the main findings on the efficacy, safety, and tolerability of sonidegib and discuss the management of locally advanced BCC with this drug., (Copyright © 2020 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: There is debate in the literature regarding the management of basal cell carcinoma following excision with positive surgical margins. While in some cases recurrence is not observed even after many years of follow-up, those in which recurrence does occur are at an increased risk of complications. Factors may exist that help to choose the best therapeutic approach for basal cell carcinomas on the head in which positive margins are observed following excision., Material and Methods: A total of 46 patients were selected who had been treated by Mohs micrographic surgery as a result of positive surgical margins being present following previous tumor excision. The factors associated with the absence of tumor nests and the occurrence of negative margins following a single Mohs stage were analyzed., Results: No associations were observed with sex, tumor size, affected margin (lateral, deep, or both), time since diagnosis, number of previous treatments, histological type, or tumor site. There was a certain trend towards more frequent identification of tumor nests when both surgical margins were affected and towards a requirement for a single Mohs stage in tumors less than 1.2 cm and in which less than 5 years had elapsed since diagnosis., Conclusions: Conclusive data are unavailable with which to define cases in which repeat excision is necessary or those in which conventional excision could be sufficient. The best option for the treatment of these tumors is Mohs micrographic surgery, although conventional excision could be reasonable in small tumors located at low-risk sites and in which long periods have not elapsed since diagnosis., (Copyright © 2010 Elsevier España, S.L. y AEDV. All rights reserved.)

In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.

To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.

Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.

Background: Location of the tumour is a well-known prognostic factor for recurrence of basal cell carcinoma (BCC). We have observed that tumours located in the nasolabial fold may deserve a particular attention., Objective: The aim of this study is to evaluate the behaviour of BCC located on the nasolabial fold in comparison to a control group of patients with BCC in lower risk sites, and to detect characteristics which may imply a more complicated treatment or the consideration of adjuvant treatment., Methods: A series of 24 patients with BCC located on the nasolabial fold were retrospectively recruited from our database of Mohs surgery from January 1997 to December 2000. A control group of 37 patients with BCC located on the cheek or forehead were selected from the same database. The differences between both groups in clinical, surgical and histological terms were evaluated., Results: BCC on the nasolabial fold presented with shorter evolution time from first symptom, had a smaller size, had been less frequently treated before and showed mostly non-aggressive histologic subtype, but needed more surgical stages and more complex reconstruction., Conclusion: We have observed that BCC on the nasolabial fold, despite presenting with better clinical and histological features, needed more complicated surgery. In our opinion, this location warrants a particular attention and further prospective studies should be made to corroborate our findings.

Xeroderma pigmentosum (XP) is an autosomal recessive disease in which patients have a 1000-fold increased risk of developing cutaneous neoplasms. Management of patients with XP is a difficult therapeutic challenge as they usually present with many cutaneous malignancies and continue to form skin tumours at a high rate. We describe a 19-year-old woman with XP who had been previously treated with many different therapeutic approaches. She had an excellent clinical response of her multiple small pigmented basal cell carcinomas and pigmentary changes using imiquimod 5% cream with only minor side-effects.