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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.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris–Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities. Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.

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.

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.

Immune checkpoint inhibitor-induced immune-related adverse events (irAEs) can be steroid-refractory (sr) or steroid-dependent (sd), requiring second-line therapy. Evidence guiding optimal management of sr/sd-irAEs while preserving antitumor efficacy is scarce. This study compared extracorporeal photopheresis (ECP) with systemic immunosuppressants (IS) for treatment of sr/sd-irAEs. This prospective two-arm study included 46 patients (23 ECP, 23 IS) with 12 distinct types of irAEs across 6 tumor entities, all classified as steroid-refractory or steroid-dependent. Toxicities affected the gastrointestinal tract, skin, lung, musculoskeletal system, and serosal membranes, with up to seven prior irAE treatment lines. Patients received six cycles of ECP or investigator's choice IS over 12 weeks. Longitudinal assessments included clinical irAE outcomes, quality of life (QoL), and tumor response. ECP was more frequently used in patients with multi-toxicity (39% vs 9%; p=0.02) and multi-resistance to prior second-line immunosuppression (39% vs 17%; p=0.19). At week 12, ECP showed a lower cumulative corticosteroid exposure (395 mg vs 1,260 mg prednisolone equivalent; p=0.03), significantly improved QoL (p=0.01), and a numerically higher irAE response rate without statistical significance compared with IS (94% vs 81%; p=0.85). In advanced cutaneous melanoma, ECP was associated with superior overall survival (15 vs 10 months; p=0.02), and longer progression-free survival (9 vs 3 months; p=0.01). No significant safety concerns were observed with ECP; one fatality in the IS group was infection-related. ECP demonstrated clinical outcomes comparable to IS in sr/sd-irAEs, with significantly lower cumulative corticosteroid exposure and improved QoL. Furthermore, ECP was associated with a favorable safety profile and showed no evidence of compromised antitumor activity. A multicenter trial is planned for further investigation. NCT05700565.

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.

Despite the rise in mass timber buildings globally, challenges remain with timber’s limitations in low-frequency sound and vibration. This is due to timber’s lower density compared to concrete and steel, leading to natural frequencies more susceptible to disturbances from footfall vibrations. This study identifies areas for further research in floor sound and vibration through a combined analysis of practitioner consultations and systematic review. A total of 112 discussions across 13 countries captured varying perspectives from producers of mass timber products through to designers of mass timber structures, as well as researchers of these different approaches. Of those consulted, 75% of producers noted increased mass timber product demand alongside a need for more design data, with 61% of designers and builders facing challenges related to sound and vibration. In addition, 17% of builders reported receiving tenant complaints over sound and vibration-related concerns, with 44% of practitioners noting concerns over sound and vibration performance. Several standards/design guides were analysed and ranked through the systematic review and practitioner consultation finding FprEN 1995-1-1, CCIP-016, and BS 6472-1 to be highly ranked from both analysis approaches. However, there were several cases, where standards ranked highly through the literature analysis approach were not highly ranked through the analysis of practitioner responses. Three under-researched areas were identified: (1) long-span floor systems, (2) the influence of mass timber product material properties, and (3) the undefined relationship between lab and in-situ performance. Furthermore, 71% of practitioners highlighted that the perception of comfort by occupants is under-represented in current research.

Fibrinolysis influences the mobilization of hematopoietic stem cells from their bone marrow microenvironment (BMM). Here we show that activation of plasmin, a key fibrinolytic agent, by annexin A2 (ANXA2) distinctly impacts progression of BCR-ABL1 + B-cell acute lymphoblastic leukemia (B-ALL) via modulation of the extracellular matrix (ECM) in the BMM. The dense ECM in a BMM with decreased plasmin activity entraps insulin-like growth factor (IGF) 1 and reduces mTORC2-dependent signaling and proliferation of B-ALL cells. Conversely, B-ALL conditions the BMM to induce hepatic generation of plasminogen, the plasmin precursor. Treatment with ε-aminocaproic acid (EACA), which inhibits plasmin activation, reduces tumor burden and prolongs survival, including in xenogeneic models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated. Our studies suggest that fibrinolysis-mediated ECM remodeling and subsequent growth factor release influence B-ALL progression and inhibition of this process by EACA may be beneficial as adjunct therapy. The fibrinolytic system promotes the progression of solid tumors. Here, the authors show that the fibrinolytic agent plasmin supports B-cell acute lymphoblastic leukemia (B-ALL) progression via remodeling of the extracellular matrix, and the inhibition of plasmin activation with ε-aminocaproic acid prolongs survival in B-ALL mouse models.