Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG.

BACKGROUND: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy. METHODS: For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments. RESULTS: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004). CONCLUSIONS: BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.

Food allergy - New risks through vegan diet? Overview of new allergen sources and current data on the potential risk of anaphylaxis.

A vegan diet is increasingly en vogue, i.e., a diet based on plants, in which animal products are completely avoided, often for health and environmental reasons. The menu is supplemented with pulses (e.g., soy, lentils, peas), nuts (e.g., cashew, macadamia, almond, pecan, para, walnut) and seeds (e.g., chia, flaxseed) or pseudo-grains (quinoa, buckwheat). Indeed, the product range is expanding to include vegan foods such as milk alternatives (e.g., oat, almond, soy drinks) and cheese or meat substitutes (e.g., soy-based). Food allergies are also on the rise, with an increasing prevalence worldwide. It is worthy of note that the main allergens of anaphylactic reactions to food in adults are predominantly of plant origin, mainly pulses and nuts - the very foods that form the main source of protein in the vegan diet. In this context, allergies to storage proteins (e.g., Gly m 5 and Gly m 6 from soya beans) can lead to severe anaphylactic reactions, while highly processed substitute products containing plant protein isolates (e.g., pea flour) in concentrated form continue to be of particular concern and may therefore be allergologically problematic. In this article, we aim to provide an overview of allergens and emerging allergen sources in vegan foods and highlight the anaphylaxis risk of the vegan diet.

Developments and perspectives in allergology.

Allergology is a key part of dermatological care. This paper reviews current pathophysiological, diagnostic and therapeutic developments in immediate-type allergies. Type-2 inflammation is involved in several allergological diseases such as allergic rhinitis and asthma. Allergen immunotherapy as an important therapeutic procedure is regulated in Germany by an official legal directive (Therapieallergene-Verordnung). Therapeutically, several biologics are already available that target interleukin (IL)-4, -5, -13, -33, or TSLP (thymic stromal lymphopoietin). Collateral efficacy may result in simultaneous treatment of allergological comorbidities. In mast cell mediated diseases (urticaria, anaphylaxis), there is increasing understanding of mast cell activation pathways. Several mast cell receptors such as MRGPRX2 (mas-related G protein coupled receptor X2) and Siglec-8 (sialinic acid binding Ig like lectin-8) as well as intracellular signaling pathways have recently been identified. Clinical trials are underway with drugs acting on mast cell receptors and intracellular signaling, i.e., Bruton's tyrosine kinase inhibitors. Further perspectives on biomarkers, novel therapeutics and unmet needs for future research activities are presented.

Atypical fibroxanthoma and pleomorphic dermal sarcoma - gene expression analysis compared with undifferentiated cutaneous squamous cell carcinoma.

BACKGROUND: The histogenetic origin of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) has not been definitively elucidated. In addition to a fibroblastic origin, a keratinocytic differentiation is discussed due to strong clinical, histomorphological and molecular genetic similarities with undifferentiated cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS: 56 cases (36 AFXs, 8 PDSs, 12 undifferentiated cSCCs) were evaluated for their clinical, histomorphological, and immunohistochemical characteristics. RNA transcriptome analysis was performed on 18 cases (6 AFXs/PDSs, 6 undifferentiated cSCCs, 6 differentiated cSCCs). RESULTS: Clinically, the strong similarities in age, gender and tumor location were confirmed. Without further immunohistochemical staining, histomorphological differentiation between AFX/PDS and undifferentiated cSCC is often impossible. Principal component analysis of the RNA transcriptome analysis showed that AFX/PDS and differentiated cSCC each formed their own cluster, while the undifferentiated cSCCs fall in between these two groups, but without forming a cluster of their own. When examining differentially expressed genes (DEGs), the heat maps showed that there were cases within the undifferentiated cSCC that were more likely to be AFX/PDS than differentiated cSCC based on their expression profile. CONCLUSIONS: The results provide evidence of molecular similarities between AFX/PDS and undifferentiated cSCC and suggest a common histogenetic origin.

Treatment of severe cow's milk allergy with omalizumab in an adult.

BACKGROUND: The therapy of severe food allergy so far consists mainly of allergen abstinence and emergency treatment. The use of anti-IgE antibodies represents a promising therapy. CASE REPORT: We report on a 22-year-old male with severe cow's milk allergy with multiple anaphylactic reactions, known since infancy and persisting into adulthood with sometimes severe immediate-type reactions on accidental ingestion. The prick test for native whole milk was positive, the CAP-FEIA was also positive for milk protein, mare's milk, whey, sheep's milk whey as well as Bos d4, Bos d5, and Bos d8 and blue cheese; total IgE was 1,265 kU/L. The patient's history included well-controlled bronchial asthma. An off-label therapy with omalizumab (3 × 150 mg/month SC) and cetirizine 10 mg once daily was initiated. Under this therapy, we performed a double-blind oral exposure test to cow's milk in the patient after long term. Thereby 14 mL could be tolerated. After consumption of 30 mL of cow's milk, urticaria, dyspnea, and angioedema occurred. CONCLUSION: Under therapy with omalizumab, an increase of the tolerance to cow's milk was shown in our patient. As a consequence, reactions during accidental consumption could be prevented.

Invasive Growth of Ailanthus altissima Trees is Associated with a High Rate of Sensitization in Atopic Patients.

Purpose: Ailanthus altissima is one of the world's most invasive species with a globally problematic spread. Pollen is dispersed locally and partially airborne. We aimed at investigating if (i) A. altissima pollen can be detected in relevant quantity in the air and if (ii) sensitization to A. altissima can be detected in patients with seasonal exacerbation of atopic diseases. Patients and Methods: We recorded distribution of A. altissima in Leipzig, Germany. In 2019 and 2020, pollen was collected with a Hirst-type pollen trap placed on the roof of the University Hospital. Specific IgE investigations were performed in children and adults with history of atopic diseases with deterioration between May and July. We analysed specific IgE for A. altissima, Alternaria sp., birch, grasses, profilins, polcalcins and crossreacting carbohydrates. Results: We found abundant growth of A. altissima and pollen was detected from early June to mid-July with a maximum pollen concentration of 31 pollen/m3. Out of 138 patients (63 female, 69 children/adolescents), 95 (69%) had seasonal allergic rhinitis, 84 (61%) asthma, and 43 (31%) atopic dermatitis. Sensitization to A. altissima was shown in 59 (42%). There were no significant differences between age groups. In 59% of patients sensitized (35/59), there was no sensitization to possibly cross-reacting structures. Conclusion: Sensitization to A. altissima pollen could be detected in 42% of our patients with atopic diseases, suggesting allergenic potential of this neophyte. In the context of further spread with climate change, eradication strategies and population-based sensitization studies are needed.

Covering of large scalp defects prior to postoperative irradiation.

BACKGROUND AND OBJECTIVE: After R0 resection of extensive cutaneous squamous cell carcinoma of the scalp with indication for postoperative radiotherapy, closure techniques should be chosen that allow rapid initiation of radiotherapy. The aim of this retrospective analysis is to evaluate defect coverage by transverse transposition flap and split skin grafting of the donor site in such a scenario with regard to oncologic safety (recurrence rate) and permanence of wound closure. PATIENTS AND METHODS: Eleven patients were identified who had histologic cutaneous squamous cell carcinoma treated by microscopically controlled excision and defect coverage using a transverse transposition flap and split skin grafting of the donor site and who received postoperative radiotherapy. Patients were evaluated for recurrence, wound healing disorders and side effects of radiotherapy. RESULTS: The mean age was 81 years. Follow-up time averaged 1.4 years after the last radiotherapy session. Wound healing disorders of the transposition flap or graft necrosis were not detected. All therapy-associated side effects had resolved at follow-up. Local recurrence or metastasis did not occur. CONCLUSIONS: Combined transverse transposition flap plasty with split-skin grafting of the donor site is a safe treatment concept with few side effects for large scalp defects with exposed calvaria requiring postoperative radiotherapy.

Mesenchymal Stem Cells From Mouse Hair Follicles Reduce Hypertrophic Scarring in a Murine Wound Healing Model.

Wound healing of acute full-thickness injuries and chronic non-healing ulcers leads to delayed wound closure, prolonged recovery period and hypertrophic scarring, generating a demand for an autologous cell therapy and a relevant pre-clinical research models for wound healing. In this study, an immunocompetent model for wound healing was employed using a syngeneic murine cell line of mesenchymal stem cells cultured from the mouse whisker hair follicle outer root sheath (named moMSCORS). moMSCORS were isolated using an air-liquid interface method, expanded in vitro and characterized according to the MSC definition criteria - cell viability, in vitro proliferation, MSC phenotype and multi-lineage differentiations. Moreover, upon applying moMSCORS in an in vivo full-thickness wound model in the syngeneic C57BL/6 mice, the treated wounds displayed different morphology to that of the untreated wound beds. Quantitative evaluation of angiogenesis, granulation and wound closure involving clinical scoring and software-based quantification indicated a lower degree of inflammation in the treated wounds. Histological staining of treated wounds by the means of H&E, Alcian Blue, PicroSirius Red and αSMA immune labelling showed lower cellularity, less collagen filaments as well as thinner dermal and epidermal layers compared with the untreated wounds, indicating a general reduction of hypertrophic scars. The decreased inflammation, accelerated wound closure and non-hypertrophic scarring, which were facilitated by moMSCORS, hereby address a common problem of hypertrophic scars and non-physiological tissue properties upon wound closure, and additionally offer an in vivo model for the autologous cell-based wound healing.

Update on Type-1 Allergy Diagnostics.

Diagnostics in type-1 allergy rely on medical history and clinical examination. Extent and severity of signs and symptoms can be documented by standardized scores and questionnaires. Both skin prick test and intradermal test are useful for search of immunoglobulin E-mediated sensitizations but the availability of commercially available diagnostic extracts has been markedly reduced during the last years. Investigation of total and of specific serum IgE is the most important in vitro diagnostic analyte in type-1 allergy. Identification of the individual molecules to which patients are sensitized, known as molecular or component-resolved diagnostics (CRD), has recently markedly improved management of type-1 allergy to pollen, food and hymenoptera venoms. Main features of CRD are increased analytic sensitivity, detection of cross-reactivity and determination of individual sensitization profiles which allow for risk assessment and facilitate decisions for or against allergen immunotherapy. Basophil activation test as well as determination of selected biomarkers (e.g. tryptase) may also be helpful in some cases. If any allergy test is positive, one will have to distinguish reactions, which are clinically relevant, from those, which are not. In vivo provocation tests (e.g. nasal provocation, oral drug or food challenge) may help to clarify the relevance of a sensitization.

Depression, Anxiety, and Suicidal Ideation in Patients with Atopic Eczema in a Prospective Study in Leipzig, Germany.

BACKGROUND: Atopic eczema (AE) is known to be associated with depression and anxiety. We aimed at investigating the occurrence of selected psychological comorbidities in patients with AE under treatment in our university dermatological department. METHODS: Monocentric prospective examination of adult AE patients using PO-SCORAD (Patient-Oriented Severity Scoring of AD), EASI (Eczema Area and Severity Index), POEM (Patient-Oriented Eczema Measure), DLQI (Dermatologic Life Quality Index), LSNS-6 (Lubben Social Network Scale 6), CES-D (Center for Epidemiologic Studies Depression Scale), HADS-D and -A (Hospital Anxiety and Depression Scale), and GAD-7 (Generalized Anxiety Disorder Scale-7) was carried out. We looked for correlations between AE severity and psychosocial comorbidities. Data were compared with age- and sex-matched controls from nonatopic subjects. STATISTICS: Mann-Whitney U test and Spearman's rank correlation were used. RESULTS: Eighty-four patients (44 women, median age 35.0 years, range: 19.4-92.8 years) were included. PO-SCORAD was 40.4 [23.4-55.4] (median [interquartile range]), EASI 9.3 [3.4-18.9], POEM 16 [8-24], and DLQI 10 [4-18]. Compared with 161 from the healthy LIFE-Adult cohort controls, our patients with AE had significantly higher scores for HADS, GAD-7, and CES-D (p < 0.001, respectively), but there was no increase in the LSNS score (18 vs. 19; p = 0.067). Within the group of AE patients, there was a significant correlation of the subjective skin severity and the depression and anxiety values: POEM significantly correlated with GAD-7, CES-D, and HADS-A and -D (p < 0.001). PO-SCORAD significantly correlated with GAD-7 and CES-D (p < 0.05). EASI correlated neither with HADS-A or -D nor with CES-D. Patients with suicidal thoughts, plans, or attempts in the last 12 months had significantly more severe AE than those without (POEM 25 [15.3-26] vs. 15 [7-23]; p = 0.013, and PO-SCORAD 51.6 [40.2-63] vs. 20.5 [20.7-52]; p = 0.014). CONCLUSION: Patients with AE being currently under treatment in our department had significantly increased scores indicating depression and anxiety. Suicidal tendency was increased in patients with severe AE. KEY MESSAGE: AE patients may develop depression, anxiety, and suicidal ideation. Patient-oriented scores may help identifying high-risk patients.

Identification of New Potential Allergens from Green-lipped Mussel (Perna Canaliculus).

The green-lipped mussel (Perna canaliculus) originates from New Zealand. To preserve the health benefits of green-lipped mussel meat, it is freeze-dried to make a long-lasting powder. The powder is used to treat arthritis because of its potential anti-inflammatory properties. The report describes a 54-year-old woman who developed immediate rhinoconjunctival and respiratory symptoms after inhaling green-lipped mussel powder she gave to her dog for arthritis. A skin prick test with green-lipped mussel powder was performed. Protein extracts from P canaliculus were separated by sodium dodecyl-sulfate polyacrylamide (SDS) gel electrophoresis and probed with serum from patients and serum preincubated with green-lipped mussel extract. Bound immunoglobulin E (IgE) was detected by specific anti-human-IgE antibodies, and IgE-binding proteins were subsequently identified by liquid chromatography and mass spectrometry. The skin prick test was positive for green-lipped mussel. Specific IgE against green-lipped mussel extract was detected using Western immunoblotting. These potential allergenic proteins were identified by mass spectrometry as actin, tropomyosin, and paramyosin. All three allergens are reported for the first time for P canaliculus. Actin is a major allergen in Paphia textile, paramyosin in Sarcoptes scarbiei, and tropomyosin in Haliotis discus. For all IgE-binding proteins, the software AllCatPro predicted high allergenicity, supporting our conclusion that these proteins from P canaliculus may also be allergenic. The identification of allergens from P canaliculus provides the opportunity for specific tests to assess the frequency of allergic reactions to P canaliculus.