Real-World Data on Clinical Outcomes and Treatment Management of Advanced Melanoma Patients: Single-Center Study of a Tertiary Cancer Center in Switzerland.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. METHODS: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). RESULTS: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. CONCLUSION: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.

Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

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.

Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus.

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.

Zinc Oxide Patches Are a Highly Effective Treatment for Chronic Prurigo: A Randomized Split-Body Study.

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: <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: <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.

Dupilumab for Chronic Prurigo: Case Series on Effectiveness, Safety, and Quality of Life.

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.

Immune Checkpoint Inhibitors in Solid Organ Transplant Recipients With Advanced Skin Cancers-Emerging Strategies for Clinical Management.

Use of immune checkpoint inhibitors (ICIs) in solid organ transplant recipients (SOTRs) with advanced skin cancers presents a significant clinical management dilemma. SOTRs and other immunosuppressed patients have been routinely excluded from ICI clinical trials with good reason: immune checkpoints play an important role in self- and allograft-tolerance and risk of acute allograft rejection reported in retrospective studies affects 10% to 65% of cases. These reports also confirm that cutaneous squamous cell carcinoma and melanoma respond to ICI therapy, although response rates are generally lower than those observed in immunocompetent populations. Prospective trials are now of critical importance in further establishing ICI efficacy and safety. However, based on current knowledge, we recommend that ICIs should be offered to kidney transplant recipients with advanced cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma if surgery and/or radiotherapy have failed. For kidney transplant recipients, this should be first line ahead of chemotherapy and targeted therapies. In SOTRs, the use of ICIs should be carefully considered with the benefits of ICIs versus risks of allograft rejection weighed up on a case-by-case basis as part of shared decision-making with patients. In all cases, parallel management of immunosuppression may be key to ICI responsiveness. We recommend maintaining immunosuppression before ICI initiation with a dual immunosuppressive regimen combining mammalian target of rapamycin inhibitors and either corticosteroids or calcineurin inhibitors. Such modification of immunosuppression must be considered in the context of allograft risk (both rejection and also its subsequent treatment) and risk of tumor progression. Ultimately, a multidisciplinary approach should underpin all clinical decision-making in this challenging scenario.

Intravenous immunoglobulins, cyclosporine, and best supportive care in epidermal necrolysis: Diverse effects on systemic inflammation.

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.

Swiss Recommendations for Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer in Switzerland and worldwide. Most BCCs can be treated in a curative setting. However, patients can develop locally destructive and, rarely, metastatic tumors that require a different treatment approach. The clinical subtype of individual lesions provides prognostic information and influences management decisions. Surgical excision, topical therapies, and radiotherapy are highly effective in the majority of subtypes as well as in low- and high-risk diseases. For patients with low-risk diseases and superficial tumors not amenable to surgery, several nonsurgical alternatives are available. Systemic therapy is indicated for high-risk BCCs, which are not amenable to either surgery or radiotherapy. Hedgehog pathway inhibitors (HHI) are currently approved. Other therapeutic options such as immune checkpoint inhibitors show promising results in clinical trials. This first version of Swiss recommendations for diagnosis and management of BCC was prepared through extensive literature review and an advisory board consensus of expert dermatologists and oncologists in Switzerland. The present guidelines recommend therapies based on a multidisciplinary team approach and rate of recurrence for individual lesions. Based on the risk of recurrence, two distinct groups have been identified: low-risk (easy-to-treat) and high-risk (difficult-to-treat) tumors. Based on these classifications, evidence-based recommendations of available therapies are presented herein.

Severe Toxic Epidermal Necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms Overlap Syndrome Treated with Benralizumab: A Case Report.

TEN/DRESS overlap syndrome can be difficult to diagnose, especially if it is masked by comorbidities in critically ill patients in intensive care units. The existing therapy for the two conditions is also a major challenge for the treating team. A possible alternative, especially for refractory cases, is benralizumab as an IL-5-receptor alpha-chain-specific humanized monoclonal antibody (IgG1k). We are able to show a successful treatment in this case report.

Eight Years of Real-Life Experience with Smoothened Inhibitors in a Swiss Tertiary Skin Referral Center.

BACKGROUND: The hedgehog inhibitors vismodegib and sonidegib are approved for the treatment of advanced basal cell carcinoma. This study reports the experiences with these therapies in a tertiary skin referral center in daily practice. METHODS: A retrospective, observational, single-center study analyzing medical records of patients with aBCC treated with a smoothened (SMO) inhibitor outside a clinical trial for at least one month between 2013 and 2021. RESULTS: In total, 33 patients were included: 21 (64%) patients were treated with vismodegib, 3 (9%) patients with sonidegib and 9 (27%) patients with both treatments subsequently. With vismodegib, the best overall response was complete response (CR) in 33% cases, and partial response (PR) in 33% cases. Under sonidegib, 42% patients achieved CR and 17% PR. Mean duration to next treatment was 33 and 14 months for vismodegib and sonidegib, respectively. Adverse events varied in frequency between continuous and intermittent dosing and they were the most common reason for therapy discontinuation. CONCLUSIONS: Our real-world data illustrate the pitfalls and benefits of HhIs as well as the impact of different dosing regimens on adverse events, patient adherence and response. Treatment duration remains limited by adverse events and resistance. Additional treatment options, including immunotherapy and drug combinations, are needed.

Immunotherapy (Cemiplimab)-Induced Bullous Pemphigoid: A Possible Pitfall in 18F-FDG PET/CT.

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.

Assessment of Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Insights From a Pan-European Multicenter Study.

IMPORTANCE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions associated with a high rate of mortality and morbidity. There is no consensus on the treatment strategy. OBJECTIVE: To explore treatment approaches across Europe and outcomes associated with the SJS/TEN disease course, as well as risk factors and culprit drugs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective pan-European multicenter cohort study including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted. A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31, 2019, and data were collected from a follow-up period of 6 weeks. MAIN OUTCOMES AND MEASURES: Risk factors for severe acute-phase complications (acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks following admission were evaluated using a multivariable-adjusted logistic regression model. One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis (SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity. RESULTS: Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the most common suspected agents. Treatment approaches ranged from best supportive care only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%), cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%) developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal body surface area detachment (≥30%) was found to be independently associated with severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12; P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality (fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with a higher frequency of greater than or equal to 20% increase in body surface area detachment in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and intravenous immunoglobulins were associated with a decreased risk of infections (adjusted OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was found between treatment groups. CONCLUSIONS AND RELEVANCE: This cohort study noted differences in treatment strategies for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies to be conducted and registries to be developed.

Enhancement of antibody-dependent cellular cytotoxicity is associated with treatment response to extracorporeal photopheresis in Sézary syndrome.

Sézary syndrome (SS) is a rare, leukemic type of cutaneous T-cell lymphoma (CTCL), for which extracorporeal photopheresis (ECP) is a first-line therapy. Reliable biomarkers to objectively monitor the response to ECP in patients with SS are missing. We examined the quantitative and qualitative impact of ECP on natural killer (NK) cell activity in SS patients, and especially their functional ability for antibody-dependent cell-mediated cytotoxicity (ADCC). Further, we addressed the question whether the magnitude of the effect on ADCC can be associated with the anti-cancer efficacy of ECP in SS patients. We assessed numbers of NK cells, ADCC activity, and treatment response based on blood tumor staging in a cohort of 13 SS patients (8 women, 5 men) treated with ECP as a first-line therapy. Blood samples were collected before treatment start and after an average of 9 months of uninterrupted ECP treatment. NK cell numbers were reduced in SS patients compared to healthy individuals and showed a tendency of recovery after long-term ECP treatment, independent of the clinical response to treatment. Patients with marginal increase (≤1.5 AU-fold) or lack of increase in ADCC activity failed to respond clinically to treatment, while patients with an increased ADCC activity showed a reduction in blood tumor burden. NK-mediated ADCC is selectively enhanced and might be a mechanism underlying the effect of ECP while in addition it can possibly serve as a reliable biomarker to objectively monitor response to ECP in patients with SS.

ECP as additional immunomodulation in idiopathic hyperammonemia and recurrent hypercapnic respiratory failure early post lung transplantation.

Extra-corporeal photopheresis (ECP) is known as safe ultimate treatment option for chronic lung allograft dysfunction (CLAD). Here, we report the first case of ECP as "second-line" immunomodulatory therapy early post-transplant in an adult patient undergoing lung transplantation for severe chronic thromboembolic pulmonary hypertension, complicated by impaired consciousness due to idiopathic hyperammonemia resulting in recurrent hypercapnic respiratory failure. ECP was initiated twice weekly on post-transplant day 25 and standard triple immunosuppression reduced. Within 2 weeks, the clinical status improved. ECP has been continued every 4 weeks after discharge. At 1 year post-transplant, ECP was stopped as maintenance immunosuppression was reached. We recommend to consider the immunomodulatory effect of ECP as "second line" immunomodulatory therapy in cases where standard immunosuppression causes severe collateral damage. ECP is able to assist prevention of allograft rejection in conjunction with reduced levels of standard immunosuppression, even in the early period following lung transplantation.

Skin Cancer Development in Solid Organ Transplant Recipients in Switzerland (Swiss Transplant Cohort Study).

IMPORTANCE: Skin cancer, in particular squamous cell carcinoma, is the most frequent malignancy among solid organ transplant recipients with a higher incidence compared to the general population. OBJECTIVE: To determine the skin cancer incidence in organ transplant recipients in Switzerland and to assess the impact of immunosuppressants and other risk factors. DESIGN: Prospective cohort study of solid organ transplant recipients in Switzerland enrolled in the Swiss Transplant Cohort Study from 2008 to 2013. PARTICIPANTS: 2,192 solid organ transplant recipients. MATERIALS AND METHODS: Occurrence of first and subsequent squamous cell carcinoma, basal cell carcinoma, melanoma and other skin cancers after transplantation extracted from the Swiss Transplant Cohort Study database and validated by medical record review. Incidence rates were calculated for skin cancer overall and subgroups. The effect of risk factors on the occurrence of first skin cancer and recurrent skin cancer was calculated by the Cox proportional hazard model. RESULTS: In 2,192 organ transplant recipients, 136 (6.2%) developed 335 cases of skin cancer during a median follow-up of 32.4 months, with squamous cell carcinoma as the most frequent one. 79.4% of skin cancer patients were male. Risk factors for first and recurrent skin cancer were age at transplantation, male sex, skin cancer before transplantation and previous transplantation. For a first skin cancer, the number of immunosuppressive drugs was a risk factor as well. CONCLUSIONS AND RELEVANCE: Skin cancer following solid organ transplantation in Switzerland is greatly increased with risk factors: age at transplantation, male sex, skin cancer before transplantation, previous transplantation and number of immunosuppressive drugs.

Blockade of programmed cell death protein 1 (PD-1) in Sézary syndrome reduces Th2 phenotype of non-tumoral T lymphocytes but may enhance tumor proliferation.

Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (L-CTCL) that arises from malignant clonally derived skin-homing CD4+ T cells. Based on advancements in our understanding of the mechanisms underlying L-CTCL, boosting the suppressed immune response emerges as a promising strategy in SS management. Immune checkpoint inhibitory molecules have already demonstrated efficacy in a wide spectrum of malignancies. Currently, agents targeting the programmed death-1 (PD-1) axis are under evaluation in L-CTCL. Here we investigated the expression of PD-1 and its ligands, PD-L1 and PD-L2 in blood and skin from patients with L-CTCL. We demonstrate that PD-1 expression is markedly increased on tumor T cells compared to non-tumor CD4+ T cells from SS patients and to CD4+ cells from healthy individuals. In contrast, PD-L1 shows decreased expression on tumor T cells, while PD-L2 expression is low without significant differences between these groups. Functional PD-1 blockade in vitro resulted in reduced Th2 phenotype of non-tumor T lymphocytes, but enhanced the proliferation of tumor T cells from SS patients. Our study sheds some light on the PD-1 axis in both peripheral blood and skin compartments in SS patients, which may be relevant for the treatment of L-CTCL with immune checkpoint inhibitor.

Sequential somatic mutations upon secondary anti-HER2 treatment resistance in metastatic ERBB2S310F mutated extramammary Paget's disease.

Metastatic extramammary Paget's disease is a rare adenocarcinoma with poor prognosis. Several reports of human epidermal growth factor receptor 2 alterations point to its pathogenic role in the disease. However, the occurrence of treatment resistance to anti-HER2 therapy demand the need for further knowledge. We report of a patient with metastatic penoscrotal extramammary Paget's disease, with an ERBB2S310F mutation, in which near complete response was achieved upon treatment with trastuzumab and carboplatin. However, after 10 cycles of trastuzumab and carboplatin, widespread metastasis re-occurred. Analysis of a newly developing metastasis revealed additional genomic alterations including ERBB3A232V and PIK3CAG106V point mutations as well as MET and CDK6 amplification, providing a potential mechanism of acquired treatment resistance. Therefore, ERBB family inhibitor afatinib was initiated. Unfortunately, the patient succumbed to disease-related complications shortly after treatment initiation. This is the first report of ERBB2S310F mutated, metastatic extramammary Paget's disease with secondary resistance to trastuzumab / carboplatin, potentially due to additional acquired genomic alterations. This case contributes to the growing evidence of HER2 in the pathogenesis of metastatic extramammary Paget's disease and emphasizes the importance of repetitive, genomic analysis in rare diseases.

Short- and long-term effects of two emollients on itching and skin restoration in xerotic eczema.

Pruritus is associated with various skin diseases, dry skin, and with it an impaired skin barrier function. The study objective was to investigate short-term and long-term effects of two emollients on symptoms and skin barrier functions in xerotic eczema. Randomized, double-blind, study enrolling females/males, with bilateral itching. Two emollients, containing lactic acid and refined almond oil with/without polidocanol were administered on left versus right body sides. Itching severity, skin moisture, lipid content, and pH were assessed on Day 1, within 30-120 min after first administration, and on Days 7 and 14, and compared with baseline assessments. Severity of itching decreased 30 min after first administration of both emollients compared with baseline (p < .0001) and reached a maximum reduction of 63% (p < .0001) and 69% (p < .0001) on Day 14. Skin moisture and lipid content increased after first application, and further ameliorated within 14 days of treatment (p < .0001). Both emollients were tolerated well, and only a few adverse events were reported. This study confirmed the clinical efficacy of the two study emollients to substantially reduce itching already after first administration, and restore skin barrier integrity and thus should be considered as therapeutic approach for xerotic eczema.

Liver Allograft Failure After Nivolumab Treatment-A Case Report With Systematic Literature Research.

BACKGROUND: Orthotopic liver transplantation (OLT) is a potential curative treatment in patients with hepatocellular carcinoma (HCC); however, treatment options for recurrent HCC after OLT are limited. Immune checkpoint inhibitors, such as nivolumab, an inhibitor of programmed cell death protein 1, have been successfully used for metastatic HCC but data on safety of nivolumab following solid organ transplantation are limited. METHODS: We report a 53-year-old woman with HCC who was treated with OLT. After 2 years, HCC recurred. Initial treatment with sorafenib was discontinued due to side effects and disease progression. Progressive HCC in the lung and lymph nodes was subsequently treated with nivolumab. One week after the first nivolumab dose, rapid progressive liver dysfunction was noted. Liver biopsy revealed severe cellular graft rejection prompting treatment with intravenous steroids and tacrolimus. Liver function continued to decline, leading to severe coagulopathy. The patient succumbed to intracranial hemorrhage. RESULTS: A systematic PubMed search revealed 29 cases treated with a checkpoint inhibitor following solid organ transplantation. Loss of graft was described in 4 (36%) of 11 cases with OLT and in 7 (54%) of 13 cases after kidney transplantation. However, cases with favorable outcome were also described. Eighteen cases with adverse events were identified upon searching the World Health Organization database VigiBase, including 2 cases with fatal outcome in liver transplant recipients due to graft loss. CONCLUSION: Experience with checkpoint inhibitors in solid organ transplant recipients is limited. Published cases so far suggest severe risks for graft loss as high as 36% to 54%.

Phase I, open-label study of pasireotide in patients with BRAF-wild type and NRAS-wild type, unresectable and/or metastatic melanoma.

INTRODUCTION: Somatostatin analogues exert antitumour activity via direct and indirect mechanisms. The present study was designed to assess the safety and efficacy of pasireotide in patients with BRAF-wild type (WT) and NRAS-WT metastatic melanoma. PATIENTS AND METHODS: Patients with unresectable and/or metastatic melanoma or Merkel cell carcinoma were eligible. Pasireotide was administered at different doses for ≤8 weeks in dose-escalation phase, followed by long-acting pasireotide 80 mg or lower dose in case of toxicity in follow-up phase up to six additional months. Primary endpoint was safety in the first 8 weeks of dose-escalation phase. RESULTS: The study was terminated early due to slow recruitment. Of the 10 patients with metastatic melanoma enrolled, only four reached the high dose level: two patients reached 3600 µg in dose-escalation and follow-up phases and two patients reached 3600 µg in dose-escalation and long-acting pasireotide 80 mg in follow-up phases and were stable for >5 months. Most common adverse events (AEs) during dose-escalation phase in ≥2 patients (20%) were: diarrhoea (50%), nausea (50%), fatigue (20%), hyperglycaemia (20%), hypophosphatemia (20%), chills (20%) and tumour pain (20%). Grade 3 or 4 study drug-related AEs were diarrhoea and nausea, reported in one patient. Partial response was documented in one patient and stable disease in another. CONCLUSIONS: Pasireotide was well tolerated, and safety results were similar to those previously reported in other indications. Further studies are needed to evaluate its antitumour activity alone and in combination with other drugs in melanoma.