Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- ("Triple") wild type melanomas.

BACKGROUND: Melanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as "triple wild-type" (tWT) melanomas. They constitute 5-10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. METHODS: Targeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. RESULTS: 184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4-9) and mOS was 24.8 months (95 % CI: 14.2-53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9-8.5) and mOS was 29.18 months (95 % CI: 17.5-46.2). CONCLUSIONS: While known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.

Clinical and genetic characteristics of BAP1-mutated non-uveal and uveal melanoma.

Background: Screening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. BAP1 gene mutations have been identified in various tumor types and acknowledged as a critical event in metastatic uveal melanoma, but their role in non-uveal melanoma remains inadequately characterized. Methods: A retrospective analysis of all melanomas sequenced in our department from 2014-2022 (n=2650) was conducted to identify BAP1 mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome. Results: BAP1 mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating BAP1 mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal BAP1 mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. GNAQ and GNA11 mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with NF1, BRAF V600 and NRAS Q61 mutations occurring in decreasing frequency, consistent with a strong UV association. Survival outcomes did not differ among non-uveal melanoma patients based on whether they received targeted or immune checkpoint therapy, or if their tumors harbored inactivating BAP1 mutations. Conclusion: In contrast to uveal melanomas, where BAP1 mutations serve as a significant prognostic indicator of an unfavorable outcome, BAP1 mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective.

Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events.

Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable. Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57). Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively). Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.

[Cutaneous adverse events to systemic anticancer therapies : Hand-foot syndrome and nail changes]. / Kutane Nebenwirkungen onkologischer Systemtherapien : Hand-Fuß-Syndrom und Nagelveränderungen.

BACKGROUND: Hand-foot syndrome (HFS) and nail changes are frequent adverse events of anticancer therapies. OBJECTIVES: To provide a review of current evidence in HFS and nail disorders associated with medical tumor treatment. MATERIALS AND METHODS: Basis is the current German S3 guideline "Supportive therapy in oncologic patients" and literature on this topic published since the guideline was finalized. RESULTS: Two variants of HFS are distinguished: a chemotherapy-associated and a kinase-inhibitor-associated variant. In the first form, painful erythema, blisters and ulceration can occur, also in other areas with a high number of sweat glands such as axillary and inguinal regions. Thus, the secretion of toxic substances through sweat glands is a proposed pathogenetic mechanism. For the second form, which results in callus-like painful thickening of the horny layer on areas of mechanic pressure, a vascular mechanism is proposed. For prophylaxis of HFS, avoidance of mechanical stress, regular cleaning of predisposed areas, and also urea- and diclofenac-containing ointments are recommended; in case of infusions (taxanes, doxorubicine), cooling of hands and feet during infusion is recommended. In case of manifest HFS, dose reduction or prolongation of intervals of the associated treatment are recommended. Nail changes often develop under therapy with chemotherapeutic agents but also under treatment with agents such as checkpoint inhibitors or under targeted therapy. Different components of the nail unit may be involved such as the nail matrix, nail bed, nail plate, hyponychium, lunula and proximal and lateral nail folds. CONCLUSION: This work gives insight into the pathophysiology of HFS and nail disorders that develop under systemic oncologic treatments and gives recommendations for prophylaxis and treatment.

S1-Guideline Sebaceous Carcinoma.

Sebaceous gland carcinomas are rare malignant cutaneous adnexal tumors with sebocytic differentiation. The typical predilection area is the head and neck region, where sebaceous gland carcinomas are the most common malignant adnexal tumors of the skin. According to their localization a distinction is made between periocular and extraocular sebaceous gland carcinomas. Muir-Torre syndrome (MTS) should always be ruled out if it is suspected. In terms of prognosis, sebaceous gland carcinomas are potentially aggressive tumors with a clear tendency to recur and metastasize. Only small extraocular sebaceous gland carcinomas that have been completely resected have a very good prognosis. Sebaceous gland carcinomas most frequently metastasize lymphogenously to regional or distant lymph nodes; organ metastasis occurs less frequently. Periocular sebaceous gland carcinomas have a higher metastasis rate (up to 15%) than extraocular sebaceous gland carcinomas (up to 2%). Complete micrographically controlled surgery (MCS) of the primary tumor is the therapy of first choice, regardless of periocular or extraocular localization. Adjuvant or therapeutic radiotherapy may be considered. There is currently no established standard therapy for advanced, inoperable, or metastatic sebaceous gland carcinomas. Local procedures and systemic therapies such as chemotherapy or immunotherapy can be considered. The procedure should be determined individually by an interdisciplinary tumor board. Close follow-up care is recommended for these potentially aggressive carcinomas.

The side effect registry immuno-oncology (SERIO) - A tool for systematic analysis of immunotherapy-induced side effects.

BACKGROUND: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes. METHODS: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered. RESULTS: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy. CONCLUSIONS: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy.

Effects of an immunosuppressive therapy on the efficacy of immune checkpoint inhibition in metastatic melanoma - An analysis of the prospective skin cancer registry ADOREG.

BACKGROUND: The impact of immunosuppressive therapy (IST) on immune-checkpoint inhibition (ICI) is unclear. METHODS: Patients with unresectable advanced melanoma (MM) treated with ICI in the years 2011-2020 were identified from the prospective multicenter German skin cancer registry ADOREG. Patients with IST within 60 days before, or within 30 days after start of ICI were compared to patients without IST. End points were disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) determined by Kaplan-Meier method. Prognostic factors were evaluated in a Cox regression model. RESULTS: Of 814 patients treated with ICI, 73 (9%) received concomitant IST, mainly steroids. Patients with brain metastases (BM) received IST more frequently (n = 34/130 patients; 26%), than patients without BM (39/684 patients; 6%). In patients without BM, IST initiated before, but not IST initiated after start of ICI was significantly associated with worse PFS (univariate hazard ratio (HR) 2.59, 95% confidence interval (95%-CI) 1.07-6.28, p = 0.035; multivariate HR 3.48, 95%-CI 1.26-9.6, p = 0.016). There was no association between IST and OS or DCR. In patients with BM, IST initiated before, but not after start of ICI was significantly associated with worse OS (univariate HR 2.06, 95%-CI 1.07-3.95, p = 0.031; multivariate HR 5.91, 95%-CI 1.74-20.14, p = 0.004). There was no association between IST and PFS or DCR. CONCLUSION: Patients receiving IST 60 days before start of ICI showed a tendency to an impaired therapy outcome. IST initiated within 30 days after start of ICI, mainly due to early side effects, did not affect the efficacy of ICI therapy.

Fatal and Near-Fatal Anaphylaxis: Data From the European Anaphylaxis Registry and National Health Statistics.

BACKGROUND: Anaphylaxis is a serious systemic reaction-data on fatal and near-fatal reactions are limited. OBJECTIVE: To better understand clinical patterns and risks factors of severe anaphylaxis by a deep analysis of data from fatal and near-fatal anaphylaxis. METHODS: Data from the European Anaphylaxis Registry on fatal/near-fatal anaphylactic reactions and national data on anaphylaxis fatalities were investigated. RESULTS: A total of 305 fatal/near-fatal reactions among children and adults including 35 fatalities from the European Anaphylaxis Registry were identified. The most frequent elicitors were drugs, insects, and food. Male patients (66%/60%) were more frequently affected. Male sex, higher age, concomitant mastocytosis, and cardiovascular disease were associated with a more severe outcome. With increasing reaction severity, skin symptoms were less frequently observed (45% of fatal reactions). In parallel, anaphylaxis mortality rates were studied. The data show that anaphylaxis mortality rates increased in Germany from 0.48 (2009) to 0.59 per 1,000,000 population per year (2020). This increase was apparent only in the female population. In this data set, drugs were the most frequent elicitor of anaphylaxis fatalities, and the rate for this increased over time. CONCLUSIONS: We identified not only elicitors but also individual factors to be associated with an increased risk of fatal anaphylaxis. Such patients should be recognized and managed with great caution. The increase in drug-induced fatalities points to the need for a better allergological care of patients suffering from drug hypersensitivity.

Contact allergies to dental materials in patients.

BACKGROUND: Concerns regarding contact allergies and intolerance reactions to dental materials are widespread among patients. Development of novel dental materials and less frequent amalgam use may alter sensitization profiles in patients with possible contact allergy. OBJECTIVES: To analyse current sensitization patterns to dental materials in patients with suspected contact allergy. METHODS: This retrospective, multicentre analysis from the Information Network of Departments of Dermatology (IVDK) selected participants from 169 834 people tested in 2005-2019 and registered with (i) an affected area of 'mouth' (and 'lips'/'perioral'), (ii) with the dental material in question belonging to one of three groups (dental filling materials, oral implants or dentures or equivalents) and (iii) with patch-testing done in parallel with the German baseline series, (dental) metal series and dental technician series. RESULTS: A total of 2730 of 169 834 tested patients met the inclusion criteria. The patients were predominantly women (81.2%) aged ≥ 40 years (92.8%). The sensitization rates with confirmed allergic contact stomatitis in women (n = 444) were highest for metals (nickel 28.6%, palladium 21.4%, amalgam 10.9%), (meth)acrylates [2-hydroxyethyl methacrylate (HEMA) 4.8%] and the substances propolis (6.8%) and 'balsam of Peru' (11.4%). The most relevant acrylates were HEMA, 2-hydroxypropyl methacrylate, methyl methacrylate, ethylene glycol dimethacrylate and pentaerythritol triacrylate. Few men were diagnosed with allergic contact stomatitis (n = 68); sensitization rates in men were highest for propolis (14.9%) and amalgam (13.6%). CONCLUSIONS: Allergic contact stomatitis to dental materials is rare. Patch testing should not only focus on metals such as nickel, palladium, amalgam and gold, but also (meth)acrylates and the natural substances propolis and 'balsam of Peru'.

Correlation of tumor PD-L1 expression in different tissue types and outcome of PD-1-based immunotherapy in metastatic melanoma - analysis of the DeCOG prospective multicenter cohort study ADOREG/TRIM.

BACKGROUND: PD-1-based immune checkpoint inhibition (ICI) is the major backbone of current melanoma therapy. Tumor PD-L1 expression represents one of few biomarkers predicting ICI therapy outcome. The objective of the present study was to systematically investigate whether the type of tumor tissue examined for PD-L1 expression has an impact on the correlation with ICI therapy outcome. METHODS: Pre-treatment tumor tissue was collected within the prospective DeCOG cohort study ADOREG/TRIM (CA209-578; NCT05750511) between February 2014 and May 2020 from 448 consecutive patients who received PD-1-based ICI for non-resectable metastatic melanoma. The primary study endpoint was best overall response (BOR), secondary endpoints were progression-free (PFS) and overall survival (OS). All endpoints were correlated with tumor PD-L1 expression (quantified with clone 28-8; cutoff ≥5%) and stratified by tissue type. FINDINGS: Tumor PD-L1 was determined in 95 primary tumors (PT; 36.8% positivity), 153 skin/subcutaneous (34.0% positivity), 115 lymph node (LN; 50.4% positivity), and 85 organ (40.8% positivity) metastases. Tumor PD-L1 correlated with BOR if determined in LN (OR = 0.319; 95% CI = 0.138-0.762; P = 0.010), but not in skin/subcutaneous metastases (OR = 0.656; 95% CI = 0.311-1.341; P = 0.26). PD-L1 positivity determined on LN metastases was associated with favorable survival (PFS, HR = 0.490; 95% CI = 0.310-0.775; P = 0.002; OS, HR = 0.519; 95% CI = 0.307-0.880; P = 0.014). PD-L1 positivity determined in PT (PFS, HR = 0.757; 95% CI = 0.467-1.226; P = 0.27; OS; HR = 0.528; 95% CI = 0.305-0.913; P = 0.032) was correlated with survival to a lesser extent. No relevant survival differences were detected by PD-L1 determined in skin/subcutaneous metastases (PFS, HR = 0.825; 95% CI = 0.555-1.226; P = 0.35; OS, HR = 1.083; 95% CI = 0.698-1.681; P = 0.72). INTERPRETATION: For PD-1-based immunotherapy in melanoma, tumor PD-L1 determined in LN metastases was stronger correlated with therapy outcome than that assessed in PT or organ metastases. PD-L1 determined in skin/subcutaneous metastases showed no outcome correlation and therefore should be used with caution for clinical decision making. FUNDING: Bristol-Myers Squibb (ADOREG/TRIM, NCT05750511); German Research Foundation (DFG; Clinician Scientist Program UMEA); Else Kröner-Fresenius-Stiftung (EKFS; Medical Scientist Academy UMESciA).

Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial.

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

Immune checkpoint inhibition in patients with NRAS mutated and NRAS wild type melanoma: a multicenter Dermatologic Cooperative Oncology Group study on 637 patients from the prospective skin cancer registry ADOREG.

BACKGROUND: Melanomas frequently harbour somatic mutations in BRAF (40%) or NRAS (20%). Impact of NRAS mutations on the therapeutic outcome of immune checkpoint inhibitors (ICI) remains controversial. Potential correlation of the NRAS mutational status and programmed cell death ligand-1 (PD-L1) expression in melanoma is unknown. PATIENTS AND METHODS: Advanced, non-resectable melanoma patients with known NRAS mutation status treated with first-line ICI between 06/2014 and 05/2020 in the prospective multicenter skin cancer registry ADOREG were included. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to NRAS status were analysed. A multivariate Cox model was used to analyse factors associated with PFS and OS; survival was analysed using the Kaplan-Meier approach. RESULTS: Among 637 BRAF wild-type patients, 310 (49%) had an NRAS mutation with Q61R (41%) and Q61K (32%). NRAS-mutated (NRASmut) melanomas were significantly more often located on the lower extremities and trunk (p = 0.001); nodular melanoma was the most common subtype (p < 0.0001). No significant differences were found for PFS and OS for anti-PD1 monotherapy (2-year PFS 39%, [95% confidence interval (CI), 33-47] in NRASmut patients and 41% [95% CI, 35-48] in NRAS-wild type (NRASwt) patients; 2-year OS was 54% [95% CI, 48-61] in NRASmut patients and 57% [95% CI, 50-64] in NRASwt patients) and anti-PD1 plus anti-CTLA4 therapy between both cohorts (2-year PFS was 54% [95% CI, 44-66] in NRASmut patients and 53% [95% CI, 41-67] in NRASwt patients; 2-year OS was 58% [95% CI, 49-70] in NRASmut patients and 62% [95% CI, 51-75] in NRASwt patients). The ORR to anti-PD1 was 35% for NRASwt patients and 26% for NRASmut patients and 34% compared to 32% for combinational therapy. Data on PD-L1 expression was available in 82 patients (13%). PD-L1 expression (>5%) was not correlated to NRAS mutational status. In multivariate analysis, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance status ≥ 1, and brain metastases were significantly associated with a higher risk of death in all patients. CONCLUSIONS: The PFS and OS were not affected by NRAS mutational status in patients treated with anti-PD1-based ICI. Similar ORR was seen in NRASwt and NRASmut patients. Tumour PD-L1 expression did not correlate with NRAS mutational status.

[Hand eczema or psoriasis: update on the FB 323 study occupational dermatology cohort]. / Handekzem oder Psoriasis: Aktuelles aus der berufsdermatologischen Kohorte der FB323-Studie.

In daily dermatological practice, the distinction between eczema and psoriasis in dermatoses of the hands can be difficult. However, a clear diagnosis is necessary to initiate optimal therapy and management. In recent years, the so-called molecular classifier has been developed for optimized differentiation of eczema and psoriasis. An occupational dermatological cohort has been established at Heidelberg University Hospital since 2020. It is funded by the German Statutory Accident Insurance. The aim is to follow-up patients over 3 years where this new diagnostic method is used and to compare the results with a retrospective occupational dermatological cohort. Recruitment ended in December 2022. The current analysis reports participants' occupational activity, insurance status, disease progression, and number of sick days. A total of 287 patients were included; mean age was 50.4 years and 63.5% (n = 181) were undergoing treatment at the expense of the liable statutory accident insurance at the start of the study. About 50% of the patients worked in health professions, metal industry, or construction. The average duration of occupational dermatosis was 6.5 years. In 38.9% of the patients, the clinical diagnosis had been classified as unclear by the treating dermatologist. By using the molecular classifier, the diagnosis could be clarified in 98% of the cases (eczema vs. psoriasis). The first analyses demonstrate that the molecular classifier contributes to improving therapy by optimizing the diagnosis.

S2k Guideline - Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) - Update 2022.

Merkel cell carcinoma (MCC, ICD-O M8247/3) is a rare, malignant, primary skin tumor with epithelial and neuroendocrine differentiation. The tumor cells share many morphologic, immunohistochemical, and ultrastructural features with cutaneous Merkel cells. Nevertheless, the cell of origin of MCC is unclear. MCC appears clinically as a reddish to purple spherical tumor with a smooth, shiny surface and a soft to turgid, elastic consistency, usually showing rapid growth. Spontaneous and often complete regressions of the tumor are observed. These likely immunologically-mediated regressions explain the cases in which only lymph node or distant metastases are found at the time of initial diagnosis and why the tumor responds very well to immunomodulatory therapies even at advanced stages. Due to its aggressiveness, the usually given indication for sentinel lymph node biopsy, the indication of adjuvant therapies to be evaluated, as well as the complexity of the necessary diagnostics, clinical management should already be determined by an interdisciplinary tumor board at the time of initial diagnosis.

Food-Induced Anaphylaxis: Data From the European Anaphylaxis Registry.

BACKGROUND: Food is one of the most common elicitors of anaphylaxis, with an increasing incidence over recent years. OBJECTIVES: To characterize elicitor-specific phenotypes and identify factors enhancing the risk or severity of food-induced anaphylaxis (FIA). METHODS: We analyzed data from the European Anaphylaxis Registry applying an age- and sex-matched analysis of associations (Cramer's V) for single food triggers and calculated odds ratios (ORs) for severe FIA. RESULTS: We identified 3,427 cases of confirmed FIA showing an age-dependent elicitor ranking (for children: peanut, cow's milk, cashew, and hen's egg; and for adults: wheat flour, shellfish, hazelnut, and soy). The age- and sex-matched analysis revealed defined symptom patterns for wheat and cashew. Wheat-induced anaphylaxis was more frequently associated with cardiovascular symptoms (75.7%; Cramer's V = 0.28) and cashew-induced anaphylaxis with gastrointestinal symptoms (73.9%; Cramer's V = 0.20). Furthermore, concomitant atopic dermatitis was slightly associated with anaphylaxis to hen's egg (Cramer's V = 0.19) and exercise was strongly associated with anaphylaxis to wheat (Cramer's V = 0.56). Additional factors influencing the severity were alcohol intake in wheat anaphylaxis (OR = 3.23; CI, 1.31-8.83) and exercise in peanut anaphylaxis (OR = 1.78; CI, 1.09-2.95). CONCLUSIONS: Our data show that FIA is age-dependent. In adults, the range of elicitors inducing FIA is broader. For some elicitors, the severity of FIA seems to be related to the elicitor. These data require confirmation in future studies considering a clear differentiation between augmentation and risk factors in FIA.

Characterisation and outcome of RAC1 mutated melanoma.

BACKGROUND: Activating hot spot R29S mutations in RAC1, a small GTPase influencing several cellular processes including cell proliferation and cytoskeleton rearrangement, have been reported in up to 9% of sun-exposed melanomas. Clinical characteristics and treatment implications of RAC1 mutations in melanoma remain unclear. METHODS: We investigated the largest set (n = 64) of RAC1 mutated melanoma patients reported to date, including a retrospective single institution cohort (n = 34) from the University Hospital Essen and a prospective multicentre cohort (n = 30) from the translational study Tissue Registry in Melanoma (TRIM; CA209-578), for patient and tumour characteristics as well as therapy outcomes. RESULTS: From 3037 sequenced melanoma samples screened RAC1 mutations occurred in ∼2% of samples (64/3037). The most common RAC1 mutation was P29S (95%, 61/64). The majority of tumours had co-occuring MAP kinase mutations (88%, 56/64); mostly activating NRAS (47%, 30/64) mutations, followed by activating BRAF (28%, 18/64) and NF1 (25%, 16/64) mutations. RAC1 mutated melanomas were almost exclusively of cutaneous origin (84%, 54/64) or of unknown primary (MUP, 14%, 9/64). C > T alterations were the most frequent mutation type identified demonstrating a UV-signature for RAC1 mutated melanoma. Most patients with unresectable disease (39) received immune checkpoint inhibitors (ICI) (77%, 30/39). Objective response rate of first-line treatment in patients with stage III/IV disease was 21%; median overall survival was 47.8 months. CONCLUSIONS: RAC1 mutated melanomas are rare, mostly of cutaneous origin and frequently harbour concomitant MAP kinase mutations, particularly in NRAS. Patients with advanced disease benefit from systemic treatment with ICI.

Etanercept leads to a rapid recovery of a Dabrafenib-/Trametinib-associated toxic epidermal necrolysis-like severe skin reaction.

Targeted therapy with BRAF- and MEK-Inhibitors (BRAFi, MEKi) provides an excellent therapeutic option for patients with malignant melanomas with a BRAF-Mutation. Mild cutaneous adverse events have been common under the BRAF- and MEK-Inhibitor therapy, on the contrary, severe cutaneous adverse reactions to drugs (SCARs) are rarely reported. We present the case of a 59- year-old female patient who after the resection of cutaneous in-transit metastases of a malignant melanoma received one adjuvant cycle of Nivolumab followed by a switch of the therapy to an oral BRAFi/MEKi therapy. 3-4 Weeks after the therapy switch she developed high fever, chills, progredient general weakness, headaches, abdominal complaints, generalised rash as well as thrombocytopaenia, eosinophilia, elevated liver enzymes, declining kidney, and pulmonary function as well as a maculopapular exanthema. She was diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS) and quickly started recovery after initiation of a high steroid substitution. Under steroid dose reduction, the exanthema worsened and toxic epidermal necrolysis (TEN) was histologically diagnosed. After a series of unsuccessful therapeutic approaches (high dose steroid, human immunoglobulins and ciclosporin) the patient received a single dose of the TNF-alpha inhibitor etanercept, which led to a quick recovery. This case demonstrates that DRESS and TEN can present a spectrum of possibly transitioning SCARs providing a diagnostic and therapeutic challenge. Nevertheless, in a such complicated therapeutic setting, etanercept may be lifesaving even after multiple previous unsuccessful therapies. This effective approach provides evidence SCARs due to BRAF/MEK targeted therapy may be driven by TNF-alpha.

Injection Site Reaction to Various Insulins as Type III Allergy With Urticarial Vasculitis in a Patient With Type I Diabetes Mellitus.

ABSTRACT: Injection site reactions are defined as skin reactions at the injection site to drugs administered subcutaneously. Pathophysiologically, these reactions are based on different immunological mechanisms. We report the case of a 49-year-old patient with type 1 diabetes mellitus (first diagnosis in 1994 at the age of 23 years). Continuous subcutaneous insulin infusion using an insulin pump has been used for many years. The patient presented to the department of dermatology with progressive symptoms in the area of the insulin injection sites on the lower abdomen, accompanied by pain, burning, erythema, tenderness, and the formation of subcutaneous nodules. Previous attempts to use different insulins and to change the injection sites did not improve his symptoms. Furthermore, the symptoms appeared within hours after the insulin pump was attached, so that the injection site has to be changed as soon as every 48 hours. No anaphylactic shock was reported at any time. Multiple histological specimens were obtained from an older lesion on the abdomen as well as from test sites after standard allergological tests (prick and intradermal tests) of various insulins. Histologically, these biopsies showed the image of an extensive deep-reaching small vessel vasculitis with the aspect of an urticarial vasculitis and confirmed the diagnosis of an injection-site reaction that can be characterized as a type III hypersensitivity reaction.

Characterization of the skin microbiota in bullous pemphigoid patients and controls reveals novel microbial indicators of disease.

INTRODUCTION: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It predominately afflicts the elderly and is significantly associated with increased mortality. The observation of age-dependent changes in the skin microbiota as well as its involvement in other inflammatory skin disorders suggests that skin microbiota may play a role in the emergence of BP blistering. We hypothesize that changes in microbial diversity associated with BP might occur before the emergence of disease lesions, and thus could represent an early indicator of blistering risk. OBJECTIVES: The present study aims to investigate potential relationships between skin microbiota and BP and elaborate on important changes in microbial diversity associated with blistering in BP. METHODS: The study consisted of an extensive sampling effort of the skin microbiota in patients with BP and age- and sex-matched controls to analyze whether intra-individual, body site, and/or geographical variation correlate with changes in skin microbial composition in BP and/or blistering status. RESULTS: We find significant differences in the skin microbiota of patients with BP compared to that of controls, and moreover that disease status rather than skin biogeography (body site) governs skin microbiota composition in patients with BP. Our data reveal a discernible transition between normal skin and the skin surrounding BP lesions, which is characterized by a loss of protective microbiota and an increase in sequences matching Staphylococcus aureus, a known inflammation-promoting species. Notably, Staphylococcus aureus is ubiquitously associated with BP disease status, regardless of the presence of blisters. CONCLUSION: The present study suggests Staphylococcus aureus may be a key taxon associated with BP disease status. Importantly, we however find contrasting patterns in the relative abundances of Staphylococcus hominis and Staphylococcus aureus reliably discriminate between patients with BP and matched controls. This may serve as valuable information for assessing blistering risk and treatment outcomes in a clinical setting.