Involvement of an IgE/Mast cell/B cell amplification loop in abdominal aortic aneurysm progression

by Alexia Loste, Marc Clément, Sandrine Delbosc, Kevin Guedj, Jean Sénémaud, Anh-Thu Gaston, Marion Morvan, Guillaume Even, Grégory Gautier, Alexander Eggel, Michel Arock, Emanuele Procopio, Catherine Deschildre, Liliane Louedec, Jean-Baptiste Michel, Lydia Deschamps, Yves Castier, Raphaël Coscas, Jean-Marc Alsac, Pierre Launay, Giuseppina Caligiuri, Antonino Nicoletti, Marie Le Borgne

IgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression.

Through histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably, in vitro the IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysed in vivo in ApoE^-/- mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression.

Our data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.

Prediction models of incontinence and sexual function one year after radical prostatectomy based on data from 20 164 prostate cancer patients

by Nora Tabea Sibert, Tobias Kurth, Clara Breidenbach, Simone Wesselmann, Günther Feick, Ernst-Günter Carl, Sebastian Dieng, Mohamad Hatem Albarghouth, Atiqullah Aziz, Stefan Baltes, Elisabeth Bartolf, Jens Bedke, Andreas Blana, Marko Brock, Stefan Conrad, Christopher Darr, Florian Distler, Konstantinos Drosos, Gregor Duwe, Amr Gaber, Markus Giessing, Nina Natascha Harke, Axel Heidenreich, Sameh Hijazi, Andreas Hinkel, Björn Theodor Kaftan, Shatlyk Kheiderov, Thomas Knoll, Gerd Lümmen, Inga Peters, Bülent Polat, Valentin Schrodi, Jens-Uwe Stolzenburg, Zoltan Varga, Julius von Süßkind-Schwendi, Vahudin Zugor, Christoph Kowalski

Incontinence and sexual dysfunction are long-lasting side effects after surgical treatment (radical prostatectomy, RP) of prostate cancer (PC). For an informed treatment decision, physicians and patients should discuss expected impairments. Therefore, this paper firstly aims to develop and validate prognostic models that predict incontinence and sexual function of PC patients one year after RP and secondly to provide an online decision making tool.

Observational cohorts of PC patients treated between July 2016 and March 2021 in Germany were used. Models to predict functional outcomes one year after RP measured by the EPIC-26 questionnaire were developed using lasso regression, 80–20 splitting of the data set and 10-fold cross validation. To assess performance, R², RMSE, analysis of residuals and calibration-in-the-large were applied. Final models were externally temporally validated. Additionally, percentages of functional impairment (pad use for incontinence and firmness of erection for sexual score) per score decile were calculated to be used together with the prediction models.

For model development and internal as well as external validation, samples of 11 355 and 8 809 patients were analysed. Results from the internal validation (incontinence: R² = 0.12, RMSE = 25.40, sexual function: R² = 0.23, RMSE = 21.44) were comparable with those of the external validation. Residual analysis and calibration-in-the-large showed good results. The prediction tool is freely accessible: https://nora-tabea.shinyapps.io/EPIC-26-Prediction/.

The final models showed appropriate predictive properties and can be used together with the calculated risks for specific functional impairments. Main strengths are the large study sample (> 20 000) and the inclusion of an external validation. The models incorporate meaningful and clinically available predictors ensuring an easy implementation. All predictions are displayed together with risks of frequent impairments such as pad use or erectile dysfunction such that the developed online tool provides a detailed and informative overview for clinicians as well as patients.