Real-world study: Impact of multidisciplinary management of apalutamide-associated adverse events in prostate cancer.

OBJECTIVE: To analyse the adverse events (AEs) associated with apalutamide and the impact of a multidisciplinary team (MDT) protocol on its management at a tertiary care hospital in a real-world setting. METHODS: This was an observational, prospective, cohort study based on real-world evidence at the Hospital Clínic de Barcelona. Includes patients diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) and who started treatment with apalutamide between May 2019 and March 2023 in a real-world clinical setting. RESULTS: Of the 121 patients treated with apalutamide, 52.1% experienced an AE, 19.8% experienced temporarily interruption or a reduction in the dose of apalutamide, and 13.2% discontinued treatment due to AEs. Without MDT protocol (49 patients), 24.5% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 10.1 months, and 24.5% discontinued apalutamide due to AEs, with a median time from the start of treatment of 3.1 months. Meanwhile, whit MDT protocol (72 patients), 16.7% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 1.6 months, and 5.6% discontinued apalutamide due to AEs, with a median time from the start of treatment of 4 months. The risk reduction associated with treatment discontinuation was statistically significant (p-value = 0.003). CONCLUSIONS: This study highlights the importance of MDT management of AEs associated with apalutamide to reduce treatment discontinuation.

Restrospective reappraisal of the prognostic classification of spitzoid melanocytic neoplasms after BRAF and NRAS mutation characterisation: a single institution experience.

AIMS: The current WHO classification of melanocytic tumours excludes neoplasms showing BRAF or NRAS mutations from the Spitz category. This study aimed to review and reclassify atypical melanocytic tumours with spitzoid morphological features diagnosed between 2009 and 2021 in our hospital after expanding the molecular profile, including BRAF and NRAS mutations in all cases. METHODS AND RESULTS: A total of 71 neoplasms showing spitzoid features (Spitz-like) and atypia were included. The risk of progression of tumours was first studied by integrating the morphology, immunohistochemistry (p16, Ki67, HMB45 and PRAME) and fluorescence in-situ hybridisation (FISH) results (melanoma multiprobe and 9p21). In a second step, after expanding the molecular study, including BRAF and NRAS mutational status, the neoplasms were finally classified into four subgroups: atypical Spitz tumour (AST, n = 45); BRAF-mutated naevus/low-grade melanocytoma with spitzoid morphology (BAMS, n = 2); Spitz melanoma (SM, n = 14); and BRAF or NRAS mutated melanoma with spitzoid features (MSF, n = 10). Follow-up of patients revealed uneventful results for AST and BAMS. Only one SM presented lymph node metastasis after 134 months. Conversely, patients with MSF showed an unfavourable outcome: three developed lymph node metastases after a mean time of 22 months, with one patient presenting distant metastasis and dying of the disease 64 months from diagnosis. The progression-free survival showed significant differences between the four groups of spitzoid tumours (P < 0.001) and between both melanoma subtypes (P = 0.012). CONCLUSIONS: The classification and prognostication of atypical neoplasms with spitzoid features requires the integration of histomorphology with the molecular investigation of tumours, which should include BRAF and NRAS mutational status.

Prognostic Value of the Neutrophil-to-lymphocyte Ratio, Platelet-to- lymphocyte Ratio and Monocyte-to-lymphocyte Ratio in Melanoma Patients: A Cohort Study.

The prognostic value of the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio in patients with melanoma has yielded controversial results in the literature. A retrospective single-centre cohort study was conducted from 1998 to 2020, including patients diagnosed with invasive melanoma. A total of 2,721 patients were included in the study. The median follow-up was 8.23 years (IQR 4.41-13.25). The median baseline neutrophil- lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio values increased significantly (p < 0.001) with the increasing American Joint Committee on Cancer stage. The optimal cut-off values for neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were determined as 2.1, 184 and 0.2, respectively. In the multivariate analysis, high levels of neutrophil-lymphocyte ratio (≥ 2.1), platelet-lymphocyte ratio (≥ 184) and monocyte-lymphocyte ratio (≥ 0.2) were independently associated with significantly shorter melanoma-specific survival (neutrophil-lymphocyte ratio: HR 1.30, 95% CI 1.06-1.60, p = 0.013; platelet-lymphocyte ratio: HR 1.37, 95% CI 1.06-1.76, p = 0.014; monocyte- lymphocyte ratio: HR 1.29, 95% CI 1.05-1.58, p = 0.015) and overall survival (neutrophil-lymphocyte ratio: HR 1.39, 95% CI 1.19-1.64, p < 0.001; platelet- lymphocyte ratio: HR 1.44, 95% CI 1.19-1.74, p < 0.001; monocyte-lymphocyte ratio: HR 1.42, 95% CI 1.21-1.66, p < 0.001). High levels of neutrophil- lymphocyte ratio and monocyte-lymphocyte ratio were also associated with poor relapse-free survival, while platelet-lymphocyte ratio was not. In conclusion, baseline neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were identified as independent predictors for the prognosis of melanoma.

The MC1R r allele does not increase melanoma risk in MITF E318K carriers.

BACKGROUND: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. OBJECTIVES: To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals. MATERIALS AND METHODS: Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). RESULTS: The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals. CONCLUSIONS: RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.

Prognostic role of microsatellites in melanoma and implications in the American Joint Committee on Cancer classification system: A cohort study.

BACKGROUND: There is limited information on microsatellite survival outcomes in patients with melanoma. OBJECTIVE: To evaluate survival outcomes in patients with microsatellites, assess their role within stage III stratification of the American Joint Committee on Cancer classification, and assess the results of sentinel lymph node biopsies in patients with microsatellites. METHODS: A retrospective bicenter cohort study from 1998 to 2019 included patients with a diagnosis of invasive cutaneous melanoma. RESULTS: Of a total of 5216 patients, 108 (2.1%) had microsatellites at initial staging. Survival analysis showed that microsatellites were an independent risk factor with decreased overall survival (OS), melanoma-specific survival (MSS), and disease-free survival, with hazard ratios of 1.57, 1.76, and 1.76, respectively. Stratified analysis in patients with stage III melanoma showed a 5-year OS of 35% (95% CI, 17.3%-73.4%) and a MSS of 45% (95% CI, 23.1-87.5) for patients with stage IIIB melanoma with microsatellites. LIMITATIONS: Retrospective design of the study. CONCLUSION: Microsatellites were associated with other adverse melanoma prognostic factors. A multivariate Cox regression analysis showed that they are an independent risk factor for worse OS, MSS, and disease-free survival. Patients with stage IIIB melanoma with microsatellites had worse OS and MSS, whereas patients with stage IIIC melanoma had worse OS but not MSS.

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

Analysis of dermoscopic changes of blue nevi on digital follow-up: A 21-year retrospective cohort study.

BACKGROUND: Blue nevi are benign dermal melanocytic proliferations that are often easy to recognize clinically. Rarely, these lesions can display atypical features, suggesting the presence of a malignant blue nevus or mimicking cutaneous metastases of melanoma. OBJECTIVE: To describe the clinical evolution of blue nevi over time and to assess the need for monitoring these lesions. METHODS: We conducted a retrospective cohort study of 103 patients who were followed between December 1998 and November 2019. An artificial intelligence algorithm was used to identify blue nevi from the databases of two digital epiluminescence devices. Changes in the area of each lesion were calculated with a segmentation neural network. RESULTS: We included 123 blue nevi from 103 patients. Most of the lesions segmented, 99 (91.7%), were considered stable. Of the 9 (8.3%) growing blue nevi identified, 2 (1.85%) showed significant growth. The studied growing blue nevi turned out to be cellular blue nevi, presented with a low tumour mutation burden and GNAQ c.626A>T alteration was identified in both lesions. LIMITATIONS: Some clinical variants of blue nevi might not be included. CONCLUSIONS: Most blue nevi remain stable during their evolution. Rarely, they can show progressive growth, although histopathological or molecular signs of malignancy have not been identified.

Common genetic variants associated with melanoma risk or naevus count in patients with wildtype MC1R melanoma.

BACKGROUND: Hypomorphic MC1R variants are the most prevalent genetic determinants of melanoma risk in the white population. However, the genetic background of patients with wildtype (WT) MC1R melanoma is poorly studied. OBJECTIVES: To analyse the role of candidate common genetic variants on the melanoma risk and naevus count in Spanish patients with WT MC1R melanoma. METHODS: We examined 753 individuals with WT MC1R from Spain (497 patients and 256 controls). We used OpenArray reverse-transcriptase polymerase chain reaction to genotype a panel of 221 common genetic variants involved in melanoma, naevogenesis, hormonal pathways and proinflammatory pathways. Genetic models were tested using multivariate logistic regression models. Nonparametric multifactor dimensionality reduction (MDR) was used to detect gene-gene interactions within each biological subgroup of variants. RESULTS: We found that variant rs12913832 in the HERC2 gene, which is associated with blue eye colour, increased melanoma risk in individuals with WT MC1R [odds ratio (OR) 1·97, 95% confidence interval (CI) 1·48-2·63; adjusted P < 0·001; corrected P < 0·001]. We also observed a trend between the rs3798577 variant in the oestrogen receptor alpha gene (ESR1) and a lower naevus count, which was restricted to female patients with WT MC1R (OR 0·51, 95% CI 0·33-0·79; adjusted P = 0·002; corrected P = 0·11). This sex-dependent association was statistically significant in a larger cohort of patients with melanoma regardless of their MC1R status (n = 1497; OR 0·71, 95% CI 0·57-0·88; adjusted P = 0·002), reinforcing the hypothesis of an association between hormonal pathways and susceptibility to melanocytic proliferation. Last, the MDR analysis revealed four genetic combinations associated with melanoma risk or naevus count in patients with WT MC1R. CONCLUSIONS: Our data suggest that epistatic interaction among common variants related to melanocyte biology or proinflammatory pathways might influence melanocytic proliferation in individuals with WT MC1R. What is already known about this topic? Genetic variants in the MC1R gene are the most prevalent melanoma genetic risk factor in the white population. Still, 20-40% of cases of melanoma occur in individuals with wildtype MC1R. Multiple genetic variants have a pleiotropic effect in melanoma and naevogenesis. Additional variants in unexplored pathways might also have a role in melanocytic proliferation in these patients. Epidemiological evidence suggests an association of melanocytic proliferation with hormonal pathways and proinflammatory pathways. What does this study add? Variant rs12913832 in the HERC2 gene, which is associated with blue eye colour, increases the melanoma risk in individuals with wildtype MC1R. Variant rs3798577 in the oestrogen receptor gene is associated with naevus count regardless of the MC1R status in female patients with melanoma. We report epistatic interactions among common genetic variants with a role in modulating the risk of melanoma or the number of naevi in individuals with wildtype MC1R. What is the translational message? We report a potential role of hormonal signalling pathways in melanocytic proliferation, providing a basis for better understanding of sex-based differences observed at the epidemiological level. We show that gene-gene interactions among common genetic variants might be responsible for an increased risk for melanoma development in individuals with a low-risk phenotype, such as darkly pigmented hair and skin.

Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: a multicentre study from the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients.

BACKGROUND: Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). OBJECTIVES: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. METHODS: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. RESULTS: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01-0·76] and vitiligo (OR 0·07, 95% CI 0·006-0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02-0·31), lichenoid reactions (OR 0·15, 95% CI 0·03-0·77) and eczematous reactions (OR 0·24, 95% CI 0·07-0·78), all compared with pruritic rash. CONCLUSIONS: Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic? Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work? In this multicentre cohort study we showed that ICI-related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy. Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non-small cell lung cancer. The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus. Clinical awareness and specialized dermatological consultation should be advocated.

Reflectance Confocal Microscopy and Electrical Impedance Spectroscopy in the Early Detection of Melanoma in Changing Lesions during Long-term Follow-up of Very High-risk Patients.

Electrical impedance spectroscopy has clinical relevance in diagnosing malignancy in melanocytic lesions. Sixty-eight lesions with changes during digital follow-up of patients at very high risk of developing melanoma were prospectively included in this study from February to December 2016. Electrical impedance spectroscopy and reflectance confocal microscopy were performed to evaluate their performance in this subset of difficult lesions. Forty-six lesions were considered suspicious on reflectance confocal microscopy and were excised, of these, 19 were diagnosed as melanoma. Fifteen melanomas were detected by electrical impedance spectroscopy, while 4 received a score lower than 4, which suggested no malignancy. The addition of reflectance confocal microscopy improves accuracy while maintaining the same sensitivity. In the case of electrical impedance spectroscopy scores <4, lesions exhibiting changes in follow-up may need short-term monitoring or excision if dermoscopy shows criteria for melanoma. Results of electrical impedance spectroscopy in this subset of very early lesions should be carefully considered due to the risk of false negatives.

Diagnostic Accuracy of Image-guided Biopsies for Diagnosis of Metastatic Melanoma in a Real-life Setting.

Early detection of melanoma metastasis is essential in order to initiate treatment and improve patient prognosis. The aim of this study was to determine the diagnostic accuracy of different image-guided biopsy techniques in patients with melanoma. A cohort study of patients diagnosed with melanoma who had undergone image-guided biopsies (ultrasound-guided fine-needle aspiration cytology, ultrasound-guided core-needle biopsy, computerized tomography--guided fine-needle aspiration cytology and computerized tomography-guided core-needle biopsy) to detect melanoma metastasis between 2004 and 2021 was conducted. The reference standard was histological confirmation and/or clinical-radiological follow-up. Sensitivity, specificity, positive and negative predictive values were calculated. A total of 600 image--guided biopsies performed on 460 patients were included for analysis. Locoregional lesions represented 459 (76.5%) biopsies, and 141 (23.5%) were distant lesions. Of the included biopsies, 49 (8.2%) were insufficient for diagnosis. Overall, sensitivity and specificity were 92% (95% confidence interval 89-94) and 96% (95% confidence interval 91-99), respectively. Sensitivity sub-analyses revealed lower diagnostic accuracy values in the lung, inguinal lymph nodes, and computerized tomography-guided lesions under 1 cm. Limitations include spontaneous metastasis regression and arbitrary minimum follow-up period. Image-guided biopsies in patients with melanoma have high sensitivity and specificity for detection of regional or distant metastasis. Tissue type, location and tumour burden may influence the diagnostic accuracy of the test.

Immunophenotype of tumor-infiltrating lymphocytes in atypical Spitzoid tumors according to the risk of progression.

The aims of the study were to investigate and compare the immunophenotype of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in a series of benign, intermediate and malignant Spitzoid lesions showing marked inflammatory lymphoid component, to find out its possible relation with the prognosis of these lesions. Six out of 97 Spitz nevus (SN) (6 %), five out of 26 atypical Spitz tumors (AST) (16 %) and seven out of 37 Spitzoid melanomas (SM) (19 %) showed diffuse, intense inflammatory component and were included in the study. The biological risk of the tumors was assessed in all AST through the melanoma 4 probe-FISH assay and the 9p21 locus exploration. TILs were quantitatively immunophenotyped using CD3, CD4, CD8, CD20, TIA1, FOXP3 and PD1 antibodies. PD-L1 was assessed in tumoral cells and inflammatory cells adjacent to the tumor. No significant differences of TILs immunophenotype were found between SN, AST and SM. However, the classification of tumors according to the biological risk showed that grouped SN plus low-risk AST had a significantly higher number of T-cells CD8+ and TIA-1+, as well as a lower CD4/CD8 relation and B- lymphocyte number than high-risk of progression tumors (grouped high-risk AST plus SM). Immunoregulatory T-cell markers PD1 and FOXP3 only correlated with each other and with PD-L1 expression. In conclusion, The TILs immunoprofile differences between low-risk and high-risk of progression Spitzoid tumors, especially regarding CD8 and the cytotoxic immune response, can add prognostic information about these challenging tumors and impact the clinical management of patients.

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.

PURPOSE: Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach. METHODS: Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays. RESULTS: We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70. CONCLUSION: This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.

Immune checkpoint-mediated psoriasis: A multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs (ENCADO) group.

BACKGROUND: Immune checkpoint inhibitor (ICI)-mediated psoriasis poses significant diagnostic and therapeutic challenges. OBJECTIVE: To report data on ICI-mediated psoriasis, emerging from the largest cohort to date, to our knowledge, and to propose a step-by-step management algorithm. METHODS: The medical records of all patients with ICI-mediated psoriasis were retrospectively reviewed across 9 institutions. RESULTS: We included a cohort of 115 individuals. Grade 1, 2, and 3 disease severity was reported in 60 of 105 (57.1%, 10 missing data), 34 of 105 (32.4%), and 11 of 105 (10.5%), respectively. The ratio between exacerbation and de novo cases was 1:4.3. The most common systemic therapy was acitretin (23 patients, 20.1%), followed by systemic steroids (8 patients, 7%), apremilast (7 patients, 6.1%), methotrexate (5 patients, 4.3%) and biologics (4 patients, 3.6%). Overall, 29 of 112 patients (25.9%) interrupted and 20 of 111 (18%) permanently discontinued ICIs because of psoriasis. Body surface area of greater than 10% at baseline had a 3.6 increased risk for ICI treatment modification (odds ratio, 3.64; 95% confidence interval, 1.27-10.45; P = .03) and a 6.4 increased risk for permanent discontinuation (odds ratio, 6.41; 95% confidence interval, 2.40-17.11; P < .001). Guttate psoriasis and grade 2 or 3 disease were significant positive predictors for antitumor response of ICI, whereas pruritus was a negative predictor. LIMITATIONS: Retrospective design. CONCLUSION: Acitretin, apremilast, and methotrexate are safe and effective modalities for ICI-mediated psoriasis. In most cases, ICI can be completed unhindered. A therapeutic algorithm is proposed.

An international 3-center training and reading study to assess basal cell carcinoma surgical margins with ex vivo fluorescence confocal microscopy.

BACKGROUND: Novel solutions are needed for expediting margin assessment to guide basal cell carcinoma (BCC) surgeries. Ex vivo fluorescence confocal microscopy (FCM) is starting to be used in freshly excised surgical specimens to examine BCC margins in real time. Training and educational process are needed for this novel technology to be implemented into clinic. OBJECTIVE: To test a training and reading process, and measure diagnostic accuracy of clinicians with varying expertise level in reading ex vivo FCM images. METHODS: An international three-center study was designed for training and reading to assess BCC surgical margins and residual subtypes. Each center included a lead dermatologic/Mohs surgeon (clinical developer of FCM) and three additional readers (dermatologist, dermatopathologist, dermatologic/Mohs surgeon), who use confocal in clinical practice. Testing was conducted on 30 samples. RESULTS: Overall, the readers achieved 90% average sensitivity, 78% average specificity in detecting residual BCC margins, showing high and consistent diagnostic reading accuracy. Those with expertise in dermatologic surgery and dermatopathology showed the strongest potential for learning to assess FCM images. LIMITATIONS: Small dataset, variability in mosaic quality between centers. CONCLUSION: Suggested process is feasible and effective. This process is proposed for wider implementation to facilitate wider adoption of FCM to potentially expedite BCC margin assessment to guide surgery in real time.

Initial Stage of Cutaneous Primary Melanoma Plays a Key Role in the Pattern and Timing of Disease Recurrence.

Given recent developments in the treatment of metastatic melanoma, early detection of disease recurrence is crucial. The aim of this single-centre retrospective cohort study was to investigate the impact of the initial stage of primary melanoma on the pattern and timing of disease recurrence and post-recurrence survival. Patients diagnosed with cutaneous melanoma with initial stage IA-IIID, between January 1996 and December 2018 and who developed disease recurrence until May 2019 were included (n = 784). Earlier stage at diagnosis was associated with a higher proportion of locoregional and a lower proportion of distant metastasis (p = 0.01). The median time to first metastasis decreased with the more advanced stages at initial diagnosis: 3.32 years (interquartile range (IQR) 1.72-6.14 years) for stage I, 1.85 years (IQR 0.99-3.78 years) for stage II and 1.19 years (IQR 0.70-2.42 years) for stage III disease (p < 0.001). These findings add evidence that American Joint Committee on Cancer stages at initial diagnosis of melanoma play a key role in the pattern and timing of disease recurrence and may be helpful to improve surveillance strategies in the follow-up of patients with melanoma.

Clinicopathological, Genetic and Survival Advantages of Naevus-associated Melanomas: A Cohort Study.

Several studies have suggested that naevus-associated melanomas differ from de novo melanomas, being thinner and with less ulceration; however, the prognostic implication is unclear. The objective of this study was to describe clinicopathological, genetic and survival characteristics of de novo and naevus-associated melanomas in a cohort of primary invasive cutaneous melanomas over a 20-year period. Of the 2,227 patients included in the study, 509 (22.86%) had naevus-associated melanomas. Compared with patients with de novo melanoma, they were younger, with a fairer phototype and a higher naevus count, tumours were predominantly the superficial spreading subtype, American Joint Committee on Cancer stage I, located on the trunk, and there were fewer signs of invasiveness (thinner Breslow index, less ulceration, lower mitotic index and less satellitosis). Germline mutation-al status did not show any significant association. As determined through univariate analysis, overall surviv-al was significantly better in patients with naevus- associated melanoma (hazard ratio 0.64; 95% confidence interval 0.51-0.80, p < 0.001), but multivariate analysis did not support this prognostic indication (hazard ratio 0.94; 95% confidence interval 0.75-1.18, p < 0.606). Despite this, we conclude that naevus- associated and de novo melanomas should be considered as different subtypes of melanoma.

Visual Impact of Large and Giant Congenital Naevi: Comparison of Surgical Scars with Naevi Before Surgery.

Surgical attempts to remove large/giant congenital melanocytic naevi (LGCMN) are supported mainly by the theoretical improvement in patients' self-image; however such surgery can result in unaesthetic scarring. We hypothesize that difference in appearance itself has an impact, and hence surgery cannot negate this impact. The aim of this cross-sectional study was to explore how LGCMN and scarring are perceived by non-affected people. We surveyed the visual impact on 1,015 health and non-health professionals working in a university hospital. Participants were assigned to 1 of 3 surveys, which, based on photographs of children: (i) assessed the visual impact of LGCMN; (ii) the visual impact of scarring; (iii) compared the impact of LGCMN and scarring. Feelings and perceptions evoked by images of children, either with LGCMN or with scarring, were remarkably similar. However, when the images of the same child (with LGCMN or scarring) were shown together, respondents showed significantly increased preference for scarring.

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations.

BACKGROUND: Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. METHODS: CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. RESULTS: Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). CONCLUSION: Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.

Serotonin involvement in okadaic acid-induced diarrhoea in vivo.

The consumption of contaminated shellfish with okadaic acid (OA) group of toxins leads to diarrhoeic shellfish poisoning (DSP) characterized by a set of symptoms including nausea, vomiting and diarrhoea. These phycotoxins are Ser/Thr phosphatase inhibitors, which produce hyperphosphorylation in cellular proteins. However, this inhibition does not fully explain the symptomatology reported and other targets could be relevant to the toxicity. Previous studies have indicated a feasible involvement of the nervous system. We performed a set of in vivo approaches to elucidate whether neuropeptide Y (NPY), Peptide YY (PYY) or serotonin (5-HT) was implicated in the early OA-induced diarrhoea. Fasted Swiss female mice were administered NPY, PYY(3-36) or cyproheptadine intraperitoneal prior to oral OA treatment (250 µg/kg). A non-significant delay in diarrhoea onset was observed for NPY (107 µg/kg) and PYY(3-36) (1 mg/kg) pre-treatment. On the contrary, the serotonin antagonist cyproheptadine was able to block (10 mg/kg) or delay (0.1 and 1 mg/kg) diarrhoea onset suggesting a role of 5-HT. This is the first report of the possible involvement of serotonin in OA-induced poisoning.