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Simple Summary: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM). We performed a retrospective, multicenter study to analyze the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% of patients, which was managed with antipyretic drugs (66.1%), intravenous fluids (28.6%) and systemic corticosteroids or tocilizumab (5.4%), and skin toxicity in 53.8%, which was managed with topical corticosteroids (38.1%) or antihistamines (45.2%). Background: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. Patients and Methods: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Results: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. Conclusions: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence. [ABSTRACT FROM AUTHOR]

Simple Summary: With the common use of immune checkpoint inhibitors (ICIs) as a standard therapy for many tumor entities, the number of immune-related adverse events (irAEs) has increased. Side effect management for irAEs includes the administration of corticosteroids which are mostly very effective. However, a subgroup of patients with checkpoint inhibitor-induced side effects do not adequately respond to steroids with so-called steroid-refractory side effects (sr-irAEs) or cannot be tapered off steroids without the recurrence of side effects, the so-called steroid-dependent side effects (sd-irAEs). Since little is known about the incidence and management of sr/sd-irAEs, we investigated the occurrence and management of these difficult-to-treat side effects. This is the first study to report on the incidence rate of steroid-refractory or steroid-dependent irAEs in patients with skin cancer. The occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. From a total of 1330 cases, 217 patients (16.3%) received 249 second‐line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed. • Steroid-refractory immune-related adverse events pose a clinical challenge. • Analysis of the SERIO-registry: 19 different second-line therapies were used. • Therapy choice was determined by the type of immune-related adverse event. • Similar onset of steroid-responsive and steroid-refractory irAEs. • Similar tumor responses in second-line treated and steroid-only treated patients. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Growing number of challenging immune-related adverse events (irAE) • Real-world international database - Side Effect Registry Immuno-Oncology (SERIO) • 1330 rare, complex, and therapy-refractory irAE cases from 58 centers worldwide • 44 original publications ranging from irMyocarditis to life-threatening irAEs • To optimize irAE management and reduce immunotherapy-induced morbidity and mortality [ABSTRACT FROM AUTHOR]

Previous studies have underlined the substantial role of nuclear factor of activated T cells (NFAT) in hypertension-induced myocardial hypertrophy ultimately leading to heart failure. Here, we aimed at neutralizing four members of the NFAT family of transcription factors as a therapeutic strategy for myocardial hypertrophy transiting to heart failure through AAV-mediated cardiac expression of a RNA-based decoy oligonucleotide (dON) targeting NFATc1-c4. AAV-mediated dON expression markedly decreased endothelin-1 induced cardiomyocyte hypertrophy in vitro and resulted in efficient expression of these dONs in the heart of adult mice as evidenced by fluorescent in situ hybridization. Cardiomyocyte-specific dON expression both before and after induction of transverse aortic constriction protected mice from development of cardiac hypertrophy, cardiac remodeling, and heart failure. Singular systemic administration of AAVs enabling a cell-specific expression of dONs for selective neutralization of a given transcription factor may thus represent a novel and powerful therapeutic approach. [ABSTRACT FROM AUTHOR]

Blastocystis is a parasite with a worldwide distribution and a varying prevalence in different countries. The pleomorphic nature of the protozoon and the lack of understanding a possible pathogenesis have led to confusion regarding its clinical significance. The aim of the study was to shed light on clinical characteristics of pediatric patients in Swiss children with a positive stool sample for Blastocystis, in order to provide recommendations for a practical approach for the clinician to know whom, when, and how to test. This is a retrospective study of pediatric patients, whose stool has been tested positive for Blastocystis in the last 10 years in northern Switzerland. A total of 4047 stool samples, belonging to 1887 different patients, were analyzed; 240 stool samples (of 160 patients) were tested positive for Blastocystis. On average, 2.2 (CI 1.98-2.35) stool samples per patient were analyzed, of which 1.48 (CI 1.36-1.61) were positive for Blastocystis. In 63% abdominal pain was the leading symptom, while in 17.5% it was an accidental finding without symptoms. There was a high significance in correlation of abdominal pain and chronicity (p < 0.0001) but none in diarrhea (p = 0.082) nor nausea/vomiting or other symptoms and chronicity. Followed by Entamoeba coli (8%), 26.3% of the patients with Blastocystis had a co-infection with another parasite, mostly Endolimax nana (13%).Conclusion: Carriage of Blastocystis is common; therefore, only children/teenagers at risk for a symptomatic Blastocystis infection should be tested. There is a good correlation between Blastocystis and chronic abdominal pain. Children with abdominal symptoms persisting over 4 weeks should have two different stool samples analyzed. No screening after travels/immigration is recommended.What is Known:• Blastocystis has a worldwide distribution.• The clinical significance is unclear.What is New:• Based on retrospective data, we recommend to only test children/teenagers with chronic abdominal pain for Blastocystis.• Two different stool samples should be examined by microscopy; serological investigations are not warranted. [ABSTRACT FROM AUTHOR]