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Cutaneous squamous cell carcinoma (cSCC) is the most common tumour entity that grows secondarily into the orbital area, while basal cell carcinoma (BCC) is the most common periocular and eyelid tumour. Diagnostic delays are common and may increase post‐treatment complications. The therapy is challenging and must be discussed at an interdisciplinary tumour board. We discuss four cases of cSCC with orbital invasion treated with immune‐checkpoint inhibitors with variable responses. [ABSTRACT FROM AUTHOR]

Avibactam (AVI) is a diazabicyclooctane (DBO) β-lactamase inhibitor used clinically in combination with ceftazidime. At concentrations higher than those typically achieved in vivo , it also has broad-spectrum direct antibacterial activity against Enterobacterales strains, including metallo-β-lactamase-producing isolates, mediated by inhibition of penicillin-binding protein 2 (PBP2). This activity is mechanistically similar to that of more potent novel DBOs (zidebactam, nacubactam) in late clinical development. We found that resistance to AVI emerged readily, with a mutation frequency of 2×10 -6 to 8×10 -5 . Whole genome sequencing of resistant isolates revealed a heterogeneous mutational target that permitted bacterial survival and replication despite PBP2 inhibition, in line with prior studies of PBP2-targeting drugs. While such mutations are believed to act by upregulating the bacterial stringent response, we found a similarly high mutation frequency in bacteria deficient in components of the stringent response, although we observed a different set of mutations in these strains. Although avibactam-resistant strains had increased lag time, suggesting a fitness cost that might render them less problematic in clinical infections, there was no statistically significant difference in growth rates between susceptible and resistant strains. The finding of rapid emergence of resistance to avibactam as the result of a large mutational target has important implications for novel DBOs with potent direct antibacterial activity, which are being developed with the goal of expanding cell wall-active treatment options for multidrug-resistant gram-negative infections but may be vulnerable to treatment-emergent resistance.

Background: Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non-responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment., Methods: We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed-up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment., Results: Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD-RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months)., Conclusion: In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long-term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long-term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re-transplantation., (© 2024 The Author(s). Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Introduction: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors., Methods: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases., Results: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%)., Conclusions: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis., Competing Interests: Conflicts of interest This study was partly sponsored by the European Academy of Dermatology and Venerology (EADV), however this did not affect the content of the manuscript. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment., Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS., Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022., Main Outcomes/measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1., Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup., Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

Primary infection with the Omicron variant of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) can be serologically identified with distinct profiles of neutralizing antibodies (nAbs), as indicated by high titers against the Omicron variant and low titers against the ancestral wild-type (WT). Here, we evaluated whether a novel surrogate virus neutralization assay (sVNT) that simultaneously quantifies the binding inhibition of angiotensin-converting enzyme 2 (ACE2) to the proteins of the WT- and Omicron-specific receptor-binding domains (RBDs) can identify nAb profiles after primary Omicron infection with accuracy similar to that of variant-specific live-virus neutralization tests (NTs). Therefore, we comparatively tested 205 samples from individuals after primary infection with the Omicron variant and the WT, and vaccinated subjects with or without Omicron breakthrough infections. Indeed, variant-specific RBD-ACE2 binding inhibition levels significantly correlated with respective NT titers ( p < 0.0001, Spearman's r = 0.92 and r = 0.80 for WT and Omicron, respectively). In addition, samples from individuals after primary Omicron infection were securely identified with the sVNT according to their distinctive nAb profiles (area under the curve = 0.99; sensitivity: 97.2%; specificity: 97.84%). Thus, when laborious live-virus NTs are not feasible, the novel sVNT we evaluated in this study may serve as an acceptable substitute for the serological identification of individuals with primary Omicron infection.

Objective: The main goal of this study was to assess the potential clinical impact of an outpatient administration of available antivirals including SOT, N/R, and MOL to COVID-19 patients at high risk for disease progression., Methods: We conducted a retrospective analysis on 2606 outpatient individuals with mild to moderate COVID-19 at risk for disease progression, hospitalization, or death. After receiving either SOT (420/2606), MOL (1788/2606), or N/R (398/2606), patients were followed-up with regarding primary (hospitalization rate) and secondary (treatment and side effects) outcomes by phone., Result: A total of 2606 patients were treated at the outpatient clinic (SOT: 420; N/R: 398; MOL: 1788). 3.2% of the SOT patients (1 ICU admission), 0.8% of the MOL patients (2 ICU admissions), and none of the N/R patients were hospitalized. 14.3% of the N/R patients reported strong to severe side effects, exceeding SOT (2.6%) and MOL (5%) patients. A reduction in COVID symptoms after the treatment was experienced by 43% of patients in both the SOT and MOL groups and by 67% of patients in the N/R group, respectively. Women had a higher chance of symptom improvement with MOL (OR 1.2, 95%CI 1.0-1.5)., Conclusion: All antiviral treatment options effectively prevented hospitalization in high-risk COVID-19 patients and were well tolerated. Side effects were pronounced in patients with N/R.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but potentially life-threatening cutaneous adverse reactions. There is still no consensus on adjuvant treatments, and little is known about their effects on systemic inflammation in SJS/TEN. Our aim was to characterize the systemic and cutaneous immune profiles of SJS/TEN patients and to investigate whether/how intravenous immunoglobulins (IVIG), cyclosporine A (CSA), and best supportive care only (BSCO) affected the systemic immune signature and clinical outcome (6 week-mortality, complications, hospitalization stay)., Methods: We included 16 patients with SJS/TEN, treated with high-dose IVIG (n = 8), CSA (n = 4) or BSCO (n = 4). Serial serum samples were obtained prior-, 5-7 days, and 21 days after treatment onset. Serum levels of inflammation-/immune response-associated proteins were measured by high-throughput proteomics assay (OLINK) and cytotoxic molecules by ELISA. RNA extracted from skin biopsies collected prior treatment was analyzed by Nanostring., Results: Serum inflammatory profiles in SJS/TEN patients were notably characterized by massive upregulation of type 1 immune response and proinflammatory markers. Surprisingly, there was limited overlap between cutaneous and serum immune profiles. Serial serological measurements of immune response markers showed very diverse dynamics between the different treatment groups. IVIG-treated patients showed completely different dynamics and most significant proteomic changes in an early phase (Day 5-7). In all treatment groups, type 1-/inflammatory response markers were dampened at day 21. Clinically, there were no outcome differences., Conclusion: Our study demonstrates that BSCO, CSA, and IVIG have very diverse biological effects on the systemic inflammatory response in SJS/TEN, which may not correlate with clinical outcome differences., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Chronic prurigo (CPG) presents with pruriginous lesions and reduced quality of life (QoL). Established treatment options are often unsatisfying. Little is known about the efficacy of topical occlusive treatments. Patients often report rapid relief of symptoms when using topical occlusive zinc oxide patches (ZOP). We, therefore, aimed to assess the efficacy of ZOP., Methods: In this randomized controlled split-body crossover study, 22 participants were analyzed, receiving three treatments sequentially: ZOP, topical betamethasone 17-valerate (topical glucocorticosteroids [TGCs]), and both ZOP and TGC combined (ZOP + TGC). Each intervention was applied to either the right or left side of the body for seven consecutive days. Outcomes were a count of active excoriated pruriginous lesions (APLs), itch, recurrence of APL, QoL, and treatment comfort. They were assessed through photographs and questionnaires: modified Prurigo Activity and Severity Score, modified Itchy Quality of Life Questionnaire, and Therapy Comfort Score., Results: We observed a significant reduction of 46% in APL count for ZOP (95% CI from 30% to 58%, p value: &lt;0.0001). Similar reduction was seen for ZOP + TGC, and a lower reduction was seen for TGC alone (48% [95% CI from 33% to 60%, p value: &lt;0.0001] vs. 26% [95% CI from 4% to 43%, p value: 0.02]). APL counts on the non-treated side remained stable. Significant reduction in itch was observed after all treatments, with the largest improvement for ZOP + TGC, followed by TGC and, lastly, ZOP alone (-2.3 units [95% CI from -3.5 to -1.1, p value: 0.00015] vs. -1.5 units [95% CI from -2.8 to -0.3, p value: 0.01 vs. -1.4 units [95% CI from -2.6 to -0.2, p value: 0.02]). QoL increased significantly after ZOP + TGC as well as after TGC (-8.3 units [95% CI from -13.6 to -3.1, p value: 0.0018] vs. -5.7 units [95% CI from -10.9 to -0.5, p value: 0.03]). A good subjective response concerning treatment comfort was observed., Conclusion: ZOP are effective in reducing APL after 1 week of treatment. Adding TGC to ZOP did not add considerable benefit in reducing APL. All three treatments reduced itch and improved QoL, with the largest improvement shown by ZOP combined with TGC. Patients tolerated ZOP well and reported no adverse events. We therefore suggest ZOP combined with TGC as an effective, fast-acting, low-cost treatment for reducing APL and itch in patients with CPG., (© 2023 S. Karger AG, Basel.)

Background: Chronic prurigo (CPG) is a pruritic skin disease, characterized by an itch-scratch cycle and scarring. It reduces patients' quality of life (QoL). Dupilumab is a monoclonal human IgG antibody that inhibits signaling of the interleukin 4 (IL-4) and interleukin 13 (IL-13) pathways through blockade of the IL-4 receptor. Patients with CPG who receive dupilumab often report great improvement in itch and overall QoL. We therefore reviewed our experience in order to follow up on QoL, safety, and treatment response in patients with CPG who received dupilumab., Methods: We conducted a real-world retrospective single-center case series. Outcomes were assessed by phone interviews and photographs using validated questionnaires and scores. Demographic data were obtained from the hospital files. Follow-up was up to 2 years. We assessed QoL with the Dermatology Life Quality Index (DLQI) and the Itchy quality of life questionnaire (ItchyQoL). Numerical Rating Scale (NRS) was used to assess itch. Prurigo lesions were documented with the Prurigo activity and severity score (PAS)., Results: Ten patients were included in this study. Results were reported up to 2 years after treatment with dupilumab. The response variables for DLQI, ItchyQoL, NRS, and PAS analyses showed a statistically significant decrease over time (DLQI: p ≤ 0.0001 [-0.84; -1.27], ItchyQoL: p ≤ 0.0001 [-9.89; -18.69], NRS maximum and average: p ≤ 0.0001 [-0.52; -0.86] and p ≤ 0.0001 [-0.55; -0.94], and PAS number of lesions: p = 0.0005 [-1.70; -5.28]). The percent decrease after 1 year of treatment (this estimate is based on model estimates) ranges from -42% to -82%. Four (40%) patients reported mild side effects. No serious side effects were reported., Conclusion: Dupilumab treatment of CGP for up to 2 years is associated with improved QoL and less itching., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Abstract: A 78-year-old man with multiple squamous cell carcinomas of the skin underwent 18F-FDG-PET/CT for restaging after 4 cycles of cemiplimab. The scan showed new disseminated FDG-avid skin lesions. Dermatologic examination and biopsy revealed bullous pemphigoid. Discontinuation of cemiplimab and treatment with corticosteroids led to clinical improvement, after which treatment with cemiplimab was resumed. A broad spectrum of inflammatory adverse events can occur in patients treated with immune checkpoint inhibitors, and FDG avidity of these lesions may mimic metastases. Knowledge of such imaging pitfalls is essential for interpreting 18F-FDG-PET/CT, particularly if they occur in the same organ as the primary tumor., Competing Interests: Conflicts of interest and sources of funding: M.W.H. is a recipient of grants and speaker’s fees from GE Healthcare, grants for translational and clinical cardiac and oncological research from the Alfred and Annemarie von Sick Grant legacy, and grants from the Artificial Intelligence in Oncological Imaging Network by the University of Zurich. S.M.S. received research grants from the Palatin Foundation. The other authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The joint effects of interacting environmental factors on key demographic parameters can exacerbate or mitigate the separate factors' effects on population dynamics. Given ongoing changes in climate and land use, assessing interactions between weather and food availability on reproductive performance is crucial to understand and forecast population dynamics. By conducting a feeding experiment in 4 years with different weather conditions, we were able to disentangle the effects of weather, food availability and their interactions on reproductive parameters in an expanding population of the red kite (Milvus milvus), a conservation-relevant raptor known to be supported by anthropogenic feeding. Brood loss occurred mainly during the incubation phase, and was associated with rainfall and low food availability. In contrast, brood loss during the nestling phase occurred mostly due to low temperatures. Survival of last-hatched nestlings and nestling development was enhanced by food supplementation and reduced by adverse weather conditions. However, we found no support for interactive effects of weather and food availability, suggesting that these factors affect reproduction of red kites additively. The results not only suggest that food-weather interactions are prevented by parental life-history trade-offs, but that food availability and weather conditions are crucial separate determinants of reproductive output, and thus population productivity. Overall, our results suggest that the observed increase in spring temperatures and enhanced anthropogenic food resources have contributed to the elevational expansion and the growth of the study population during the last decades., (© 2021. The Author(s).)