Interleukin-23 (IL23) has been reported to drive androgen receptor (AR) and JAK2-STAT3 signaling, promoting treatment resistance and disease progression in advanced prostate cancer (PC). We evaluated the safety, tolerability, and antitumor activity of the anti-IL23 monoclonal antibody tildrakizumab in combination with the AR pathway inhibitor (ARPI) abiraterone acetate (AA) in men with ARPI-resistant metastatic castration-resistant PC (mCRPC). mCRPC patients of ECOG performance status (PS) ≤ 2, who had previously progressed on first-line ARPI therapy, were treated with tildrakizumab (100 mg, 300 mg, 600 mg; 4-weekly) in combination with AA (YonsaTM, 500 mg daily). The primary objective was to determine the recommended phase 2 dose. Secondary endpoints were elucidation of pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. No dose limiting toxicities (DLTs) were observed, nor any grade ≥ 3 adverse effects (AEs). The most common treatment-related AEs attributable to tildrakizumab were grade 1—2 fatigue (n = 3/12; 25.0
No multicenter study has validated cochlear dose constraints for hearing preservation in pediatric brain tumor patients in a real-world setting. Although the PENTEC review proposed a 35 Gy mean cochlear dose threshold, supporting evidence from heterogeneous, multicenter pediatric cohorts remains scarce. To evaluate dosimetric, therapeutic, and clinical risk factors for sensorineural hearing loss (SNHL) after pediatric cranial radiotherapy in a national multicenter cohort, with a specific focus on validating the clinical relevance of the 35 Gy mean cochlear dose threshold. We retrospectively analyzed 88 children treated with cranial radiotherapy between 2014 and 2024 across four French pediatric radiotherapy centers participating in the national PediaRT registry. All patients had baseline and at least two post-radiotherapy audiograms graded according to the Chang Ototoxicity Scale, with SNHL defined as Chang grade ≥ 1a. Mean (Dmean) and minimum (Dmin) cochlear doses were extracted and analyzed using Kaplan–Meier estimates and Cox proportional hazards models. Over a median follow-up of 37 months, 17 patients (19.3
Background: Accurate biodosimetry is essential for effective radiological triage, precise clinical monitoring, and assessment of risks from diagnostic exposures. Immunofluorescent detection of phosphorylated histone H2AX (γH2AX) and p53-binding protein 1 (53BP1) DNA double-strand break repair foci provides high sensitivity for radiation dose assessment within the first hours after exposure. However, inter-laboratory reproducibility of γH2AX/53BP1-based biodosimetry remains limited, and the contribution of pharmacological modifiers is unresolved. Methods: Here, we conducted an inter-laboratory comparison of in vitro radiation dose–response relationships of foci yields measured in cryopreserved umbilical cord blood lymphocytes (UCBLs) and freshly isolated peripheral blood lymphocytes (PBLs) from healthy donors using fluorescent microscopy with emphasis on workflow harmonization and reproducibility across laboratories. Results: Under low-dose γ irradiation, both UCBLs and PBLs exhibited a strong linear, dose-dependent induction of γH2AX, 53BP1, and co-localized foci, with co-localization emerging as the most sensitive endpoint. γH2AX pan-nuclear staining was observed exclusively in UCBLs and functioned as a distinct endpoint under the examined conditions. Under harmonized low-dose conditions, calyculin A at a non-toxic concentration of 1 nM did not provide measurable stabilization or enhancement of ionizing radiation-induced foci (IRIF) yields. Although IRIF yields differed between the two laboratories, dose–response slopes were highly concordant, demonstrating reproducibility under harmonized experimental conditions. Conclusions: These findings demonstrate that inter-laboratory reproducibility of γH2AX/53BP1-based biodosimetry is achieved primarily through disciplined workflow harmonization rather than through pharmacological enhancement. By reinforcing assay reproducibility and biological consistency, this work supports the translational applicability of IRIF-based biodosimetry for broader application in radiation exposure assessment.
Intravoxel incoherent motion (IVIM) MRI allows for simultaneous assessment of tissue microcirculation (perfusion) and diffusion of water. In single-center studies, IVIM has shown great potential for diagnosis, treatment outcome prediction, and treatment monitoring for many different diseases and organs. However, heterogeneity in data acquisition protocols, pre-processing pipelines, and post-processing routines yields differences in reported IVIM parameters, which has constrained large-scale deployment of IVIM. Moreover, deploying IVIM protocols and analysis typically requires technical expertise, further challenging wider use, especially for clinicians. In this consensus paper, to accelerate the deployment of IVIM, we provide recommendations and harmonize protocols for brain, breast, kidney, liver, muscle, and pancreas IVIM studies. For this goal we organized multiple questionnaires and held a dedicated workshop. To ensure a level of standardized, reproducible results, without restricting innovation, we suggest a small subset of b-values to always be measured and analyzed separately, and to which more extensive b-value sampling can be added for advanced investigations. We further introduce detailed recommendations on acquisition protocols and analysis pipelines. To increase consistency, repeatability, and reproducibility, we highly recommend that these protocols and pipelines be deployed by scientists and clinicians for IVIM studies. For advanced users who desire different protocols or analysis approaches, we suggest adding results from our suggested protocols and analysis pipeline in the supplemental part of their paper to enable retrospective studies.
