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.

Thermal fluctuation and conformational effects on NMR parameters in ß-O-4 lignin dimers from QM/MM and machine-learning approaches.

Advanced solid-state and liquid-state nuclear magnetic resonance (NMR) approaches have enabled high throughput information about functional groups and types of bonding in a variety of lignin fragments from degradation processes and laboratory synthesis. The use of quantum chemical (QM) methods may provide detailed insight into the relationships between NMR parameters and specific lignin conformations and their dynamics, whereas a rapid prediction of NMR properties could be achieved by combining QM with machine-learning (ML) approaches. In this study, we present the effect of conformations of ß-O-4 linked lignin guaiacyl dimers on 13C and 1H chemical shifts while considering the thermal fluctuations of the guaiacyl dimers in water, ethanol and acetonitrile, as well as their binary 75 wt% aqueous solutions. Molecular dynamics and QM/MM simulations were used to describe the dynamics of guaiacyl dimers. The isotropic shielding of the majority of the carbon nuclei was found to be less sensitive toward a specific conformation than that of the hydrogen nuclei. The largest 1H downfield shifts of 4-6 ppm were established in the hydroxy groups and the rings in the presence of organic solvent components. The Gradient Boosting Regressor model has been trained on 60% of the chemical environments in the dynamics trajectories with the NMR isotropic shielding (σiso), computed with density-functional theory, for lignin atoms. The high efficiency of this machine-learning model in predicting the remaining 40% σiso(13C) and σiso(1H) values was established.

Diagnostic accuracy of pigmented labial macules by in vivo reflectance confocal microscopy and correlation among techniques.

BACKGROUND: Pigmented labial macules (PLMs) are clinical, dermoscopic, and histopathologic challenges. OBJECTIVE: To describe and evaluate the utility of reflectance confocal microscopy (RCM) in PLMs and to establish a correlation between dermoscopy, RCM, histopathology, and immunohistochemistry. METHODS: Prospective study of PLMs from 4 tertiary referral dermatology centers. The study included 51 biopsy specimen-proven PLMs. Dermoscopic, RCM images, and histopathologic preparations were evaluated for malignant criteria. Diagnostic accuracy of RCM for melanoma diagnosis, RCM Lip Score previously reported, and κ values between techniques were calculated. RESULTS: Included were 5 melanomas and 46 benign PLMs. Dermoscopically, melanomas exhibited more frequently ≥3 colors and ≥3 structures. With RCM, pagetoid spreading, epithelial disarray, continuous proliferation of atypical cells around papillae, nonhomogeneously distributed papillae, marked cellular atypia, and a higher number of dendritic cells per papillae were more frequent in melanomas. The RCM Lip Score was significantly higher in malignant lesions. Good κ values were observed in most of the evaluated features. A perfect sensitivity and specificity was obtained combining dermoscopy and RCM. LIMITATIONS: A low number of melanomas were obtained. CONCLUSIONS: RCM improves lip melanoma diagnosis, and the RCM Lip Score represents a useful tool for the evaluation of a PLM.

Oral submucous fibrosis presenting with histopathological lichenoid changes as predominant feature: Report of five cases and review of the literature.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity associated with habitual chewing of quid, with a high incidence among populations of the Indian subcontinent and Southeast Asia. Clinically, its initial manifestation may mimic oral lichen planus or lichen sclerosus. If the habit is not halted, the mucosa gets leathery and thickened, and fibrous bands form causing significant morbidity. Microscopically, it is characterized by atrophic epithelium, loss of rete ridges, and hyalinization of lamina propria. Of note, these hallmark histopathological features may be overlooked in the unusual presence of lichenoid interface changes, which may lead to the wrong diagnosis. We present herein five cases in which the rare joint appearance of OSF and lichenoid reaction features posed a diagnostic challenge. Due to its progressive nature and malignant potential, the presence of oral lichenoid changes overlying submucous hyalinization, in the right clinical and demographic setting, should raise suspicion of OSF and prompt actions directed at quid-chewing discontinuation.

Molecular Insight into the Cosolvent Effect on Lignin-Cellulose Adhesion.

Understanding and controlling the physical adsorption of lignin compounds on cellulose pulp are key parameters in the successful optimization of organosolv processes. The effect of binary organic-aqueous solvents on the coordination of lignin to cellulose was studied with molecular dynamics simulations, considering ethanol and acetonitrile to be organic cosolvents in aqueous solutions in comparison to their monocomponent counterparts. The structures of the solvation shells around cellulose and lignin and the energetics of lignin-cellulose adhesion indicate a more effective disruption of lignin-cellulose binding by binary solvents. The synergic effect between solvent components is explained by their preferential interactions with lignin-cellulose complexes. In the presence of pure water, long-lasting H-bonds in the lignin-cellulose complex are observed, promoted by the nonfavorable interactions of lignin with water. Ethanol and acetonitrile compete with water and lignin for cellulose oxygen binding sites, causing a nonlinear decrease in the lignin-cellulose interactions with the amount of the organic component. This effect is modulated by the water exclusion from the cellulose solvation shell by the organic solvent component. The amount and rate of water exclusion depend on the type of organic cosolvent and its concentration.

Diagnostic Accuracy of Non-melanocytic Pink Flat Skin Lesions on the Legs: Dermoscopic and Reflectance Confocal Microscopy Evaluation.

Pink flat skin lesions on the legs in elderly people represent a diagnostic challenge due to the paucity of clinical and dermoscopic evidence. A prospective study of 114 pink flat lesions on the legs of 85 elderly patients was performed to describe the utility of reflectance confocal microscopy in this clinical context. Evaluation of clinical, dermoscopic and confocal parameters and calculation of diagnostic accuracy/sensitivity/specificity for non-melanoma skin cancer diagnosis of each technique were carried out. Thirty-four benign and 80 malignant neoplasms were analysed. A correct clinical diagnosis was established in 49.1% of cases (sensitivity 68.7%, specificity 73.5%). Dermoscopy achieved 59.6% correct diagnosis (sensitivity 85%, specificity 67.6%) and confocal microscopy evaluation after clinical and dermoscopic evaluation rendered a correct diagnosis in 85.1% of cases (sensitivity 97.5%, specificity 88.2%). Confocal microscopy may improve diagnostic accuracy, sensitivity and specificity as a secondary evaluation after dermoscopy. A diagnostic confocal algorithm for pink flat lesions on the legs is proposed.

Dermoscopic features of idiopathic facial aseptic granuloma.

Idiopathic facial aseptic granuloma is a recently described condition with defined clinical features, natural history, and underlying histopathologic findings. Several reports have recently described the potential diagnostic usefulness of ultrasound findings in idiopathic facial aseptic granuloma. We describe herein the dermoscopic features of idiopathic facial aseptic granuloma.

Dermoscopy Improves the Diagnostic Accuracy of Melanomas Clinically Resembling Seborrheic Keratosis: Cross-Sectional Study of the Ability to Detect Seborrheic Keratosis-Like Melanomas by a Group of Dermatologists with Varying Degrees of Experience.

BACKGROUND: Malignant melanomas mimicking seborrheic keratosis (SK-like MMs) carry the risk of delayed diagnosis and inadequate treatment. The value of dermoscopy to improve the correct detection of these mimickers has not been previously studied. OBJECTIVE: To evaluate the diagnostic accuracy of clinically SK-like MMs with and without dermoscopy. METHODS: Clinical and dermoscopic images of histopathologically proven SK-like MMs (n = 134) intermingled with other melanomas and benign tumors were randomly presented to clinicians with different levels of experience, blinded to the diagnosis and goal of the study. Each participant classified each lesion as melanoma or benign tumor. The clinical and clinical-dermoscopic diagnostic accuracies were measured separately. RESULTS: Overall, 54 participants with a mean clinical experience of 15.8 years (SD 11.8) evaluated 231 tumors. Almost 40% of SK-like melanomas were clinically misclassified as benign tumor. Dermoscopy improved diagnostic accuracy for all participants, independently of experience, from 60.9 to 68.1% (p < 0.001), mostly due to a significant increase in the sensitivity (clinical 61.9% vs. dermoscopic 74.5%) (p < 0.001). Dermoscopy did not significantly affect specificity among the experienced participants (≥6 years of experience) compared to clinical examination (61.1 vs. 59.6%, respectively); in contrast, dermoscopy was associated with a decrease in specificity compared to clinical diagnosis among novice participants (< 6 years) (45.6 vs. 61.1%, respectively; p = 0.02). CONCLUSION: Melanomas can be clinically indistinguishable from SKs despite being evaluated by expert dermatologists. Dermoscopy, even in nonexpert hands, significantly improves their recognition.

Verruciform xanthoma developing in recessive dystrophic epidermolysis bullosa: A sheep in wolf's clothing.

A 23-year-old male affected of recessive dystrophic epidermolysis bullosa presented with a 2-month history of a growing verrucous plaque on the right flank. The clinical features and evolution suggested the diagnosis of cutaneous squamous cell carcinoma. Histopathological examination showed hyperkeratosis, parakeratossis, and verrucous acanthosis and numerous large xanthoma cells in the papillary dermis. Reflectance confocal microscopy disclosed the absence of epidermal atypia and the presence of aggregates of reflecting cells at dermal-epidermal junction and upper dermis. These cells were ultrastructurally characterized and corresponded to foamy histiocytes. Verruciform xanthoma is a benign reactive lesion that has occasionally been reported to develop in chronically eroded areas in patients with recessive dystrophic epidermolysis bullosa. In this group of patients, verruciform xanthoma may clinically mimic cutaneous squamous cell carcinoma and a correct diagnosis is crucial to avoid inappropriate aggressive therapeutic approaches. In vivo noninvasive image technologies such as reflectance confocal microscopy may be helpful diagnostic tools in this clinical setting.

Loss of dyskerin facilitates the acquisition of metastatic traits by altering the mevalonate pathway.

The initial dissemination of cancer cells from many primary tumors implies intravasation to lymphatic nodes or blood vessels. To investigate the mechanisms involved, we analyzed the expression of small non-coding RNAs in cutaneous squamous cell carcinoma (cSCC), a prevalent tumor that mainly spreads to lymph nodes. We report the reduced expression of small nucleolar RNAs in primary cSCCs that metastasized when compared to non-metastasizing cSCCs, and the progressive loss of DKC1 (dyskerin, which stabilizes the small nucleolar RNAs) along the metastasis. DKC1 depletion in cSCC cells triggered lipid metabolism by altering the mevalonate pathway and the acquisition of metastatic traits. Treatment of DKC1-depleted cells with simvastatin, an inhibitor of the mevalonate pathway, blocked the expression of proteins involved in the epithelial-to-mesenchymal transition. Consistently, the expression of the enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1 was associated with pathological features of high metastatic risk in cSCC patients. Our data underpin the relevance of the mevalonate metabolism in metastatic dissemination and pave the possible incorporation of therapeutic approaches among the antineoplastic drugs used in routine patient care.

Cyclin-Dependent Kinase 4/6 Inhibitors and Dermatologic Adverse Events: Results from the EADV Task Force "Dermatology for Cancer Patients" International Study.

BACKGROUND: The introduction of cyclin-dependent kinase inhibitors (CDK4/6i) was a great advance in therapeutics for patients with estrogen receptor+/human epidermal growth factor receptor (HER2) locally advanced and metastatic breast cancer. Despite the increasing use of these agents, their adverse drug-related events have not yet been fully characterized. We describe the spectrum of cutaneous adverse reactions occurring in advanced breast cancer patients treated with cyclin-dependent kinase inhibitors, analyzing types, severity, time to onset, and possible treatment outcomes. METHODS: We performed a multicentric retrospective study including patients with advanced breast cancer who developed cutaneous lesions during treatment with CDK4/6i in the period from June 2020 to June 2021. Patients > 18 years were recruited at eleven onco-dermatology units located in Albania (1), Argentina (1), France (1), Greece (3), Italy (3), and Spain (2). We evaluated patients' epidemiological and clinical characteristics, types of cutaneous adverse events, their time to onset, and treatment outcomes. The severity of the skin reactions was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 score. RESULTS: Seventy-nine patients (median age: 62.3 years; range 39-83 years) were included in the study, and, collectively, we recorded a total of 165 cutaneous adverse events during follow-up visits. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and eczematous lesions (24/79). Cutaneous toxicities were usually mild in severity (>65%) and occurred after a median of 6.5 months. Only four patients (5%) required treatment discontinuation due to the severity of the skin lesions. The majority of the skin reactions were managed with topical treatments. CONCLUSIONS: To the best of our knowledge, we present the largest case series of cutaneous adverse events developing in advanced breast cancer patients treated with CDK4/6i. We showed that cutaneous toxicities are usually mild in severity, and manageable with standard supportive care; however, in selected cases, they can lead to treatment discontinuation with possible implications for patients' clinical outcomes.

Melanoma-specific survival is worse in the elderly: a multicentric cohort study.

We aimed to characterise cutaneous melanoma in the elderly and determine its association with poorer prognosis. We studied a prospective cohort of the melanoma population in Catalonia between 2012 and 2016. We compared young patient group (<75 years old) with elderly patient group (≥75 years old). We included 3009 patients (52.5% women) from 14 centres, with a mean age at diagnosis of 61.1 years. In the ≥75-year-old group there was a predominance of men (53.9% vs. 45.5%, P  < 0.001), melanoma was more frequently located in the head and neck area (37.7% vs. 15.5%, P  < 0.001) and lentigo maligna melanoma subtype was significantly more frequent (31.4% vs. 11.6%, P  < 0.001), as were nodular melanoma and acral lentiginous melanoma ( P  < 0.001). In older people, Breslow index, the presence of ulceration and mitotic rate were higher than in younger people. Kaplan-Meier survival curves showed longer melanoma-specific survival (MSS) and melanoma-free survival (MFS) in <75-year-old group compared to the elderly group. Cox regression models demonstrated reduced MSS in patients ≥75 years regardless of gender, location, IB, ulceration and lymph node status at diagnosis (HR 1.54, P  = 0.013) whereas MFS was not independently associated with elderly when head and neck location was considered. Age appears to be an independent risk factor for MSS but not for MFS. Worse melanoma prognosis in elderly could be explained by factors unrelated to the tumour, such as age-related frailty and comorbidities that limit the access to systemic treatments and, eventually, age-related immune dysfunction.

Incidence of human papillomavirus infection in male sexual partners of women diagnosed with CIN II-III.

INTRODUCTION: Human papillomavirus (HPV) infection is a very common sexually transmitted disease which has been strongly related to cervical cancer and cervical intraepithelial neoplasia (CIN), penile cancer and intraepithelial and infiltrating anal squamous cell carcinoma. OBJECTIVES: To describe the HPV status of male sexual partners of women diagnosed with CIN II/III and to evaluate the practical usefulness of the HPV detection in urine as a reliable marker of genital high-risk HPV infection in men. METHODS: Ninety-one heterosexual male partners (mean age 32.7) were included in the study. A panel of epidemiological data was recorded. Peniscopy was performed at the first visit and after 6 months. Urine samples and anal and penile scrapings were obtained and Hybrid Capture II test for high-risk HPV was performed. Physical examination disclosed clinically or peniscopic lesions in only 5.4% patients. HPV was isolated in 12.9% and 6.2% of penile and anal scrapings respectively whereas HPV detection was positive in 28% of urine samples. Overall, 41% of the evaluated patients presented at least one finding diagnostic of HPV infection. CONCLUSION: HPV detection in male partners of women with CIN is a frequent event, and urine HPV detection by Hybrid Capture test is a sensitive method for its detection. The determination of HPV in urine samples seems to be a simple method to investigate the subrogated genital HPV infection in men.

Molecular diagnosis of dermatofibrosarcoma protuberans: a comparison between reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization methodologies.

Dermatofibrosarcoma protuberans (DFSP) is characterized by the presence of the t(17;22)(q22;q13) that leads to the fusion of the COL1A1 and PDGFB genes. This translocation can be detected by multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH) techniques. We have evaluated the usefulness of a dual color dual fusion FISH probe strategy for COL1A1/PDGFB detection in a series of 103 archival DFSPs and compared the obtained results with RT-PCR analyses. FISH and RT-PCR were carried out on paraffin embedded tissue samples. Regarding the RT-PCR approach, all COL1A1 exons and exon 2 of PDGFB were evaluated. Sensitivity, specificity, positive and negative predictive values were assessed considering the histological diagnosis as the gold standard. We also analyzed the relationship between the genetic findings and the clinicopathological variables of the tumors. The COL1A1/PDGFB translocation was detected in 93% of DFSP. Both techniques showed a similar specificity (100%), but FISH was more sensitive than RT-PCR (90% vs. 72%). Regarding, clinicopathological features, a higher percentage of positive cells detected by FISH was significantly associated with the fibrosarcomatous DFSP variant (P < 0.001). Interestingly, all CD34 negative DFSP (n = 5) were positive for COL1A1/PDGFB translocation by both techniques. In conclusion, the majority of DFSP harbor the COL1A1/PDGFB translocation and FISH technique should be recommended as a routine diagnostic tool, especially in cases showing unusual histopathological subtypes and/or immunohistochemical features.