Anthracycline-induced cardiotoxicity is dose-dependent, yet guidelines provide inconsistent cumulative dose thresholds and few standards for converting doses when multiple agents are used. Moreover, no formal guideline exists to unify these practices and responsibilities. Therefore, we evaluated anthracycline dosing and cardiotoxicity monitoring across Dutch hospitals to identify variability. A national cross-sectional survey was conducted among hospital pharmacists in the first quarter of 2024 in the Netherlands. Hospitals completed a 16‑item questionnaire assessing cumulative dose thresholds, equivalence factors for converting to doxorubicin‑equivalent doses, cardiac monitoring protocols and circumstances under which thresholds are exceeded. Responses were received from 43 of 69 hospitals (62
To compare patient characteristics, treatment patterns, and survival between de novo and metachronous metastatic breast cancer (MBC) using nationwide data. A total of 2,366 MBC patients (900 de novo, 1,466 metachronous) diagnosed in 2019 were selected from the Netherlands Cancer Registry. Patient- and tumor characteristics and systemic treatment patterns were compared using chi-squared or Fisher’s exact tests. Overall survival (OS) was compared using Kaplan-Meier curves and Cox proportional hazard analyses. All analyses were stratified by clinical subtype (HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-). For patients with HR+/HER2 − tumors, a sub-analysis examined OS in de novo versus metachronous MBC, stratifying the latter by receipt of prior (neo)adjuvant systemic treatment. De novo MBC patients were younger, had more HER2-positive (22
BCMA- or GPRC5D-directed T-cell immunotherapies have substantially improved the survival of patients with relapsed/refractory multiple myeloma (MM). Despite these advances, a subset of patients does not respond, and most patients will eventually relapse. Tumor heterogeneity, resulting in rapid selection of both antigen-negative and antigen-low cells, is a critical issue affecting response to T-cell immunotherapies targeting single tumor-associated antigens. In addition, antigen escape (due to deletions, mutations, or epigenetic alterations) is frequently observed in patients who experience disease progression after CAR T-cell infusion or during BsAb treatment. Simultaneous targeting of two tumor-associated antigens may improve efficacy by addressing heterogeneous target expression and preventing antigen escape. Various dual-targeting strategies are currently evaluated in MM, including the combination of two single-antigen targeting BsAbs. Notably, the efficacy of the combination of teclistamab and talquetamab appears to have enhanced anti-MM activity, compared to the corresponding conventional BsAbs alone in similar patient populations. Furthermore, dual-antigen targeting with T-cell redirecting trispecific antibodies (e.g., ramantamig [BCMAxGPRC5D] and ISB2001 [BCMAxCD38]) has already demonstrated promising results in heavily pretreated MM with several studies ongoing in earlier stages of the disease. Studies with limited numbers of patients have demonstrated that CAR T-cell products with specificity for more than one antigen are also effective in advanced MM, but at this time none of the dual-targeting CAR T-cell products is clearly superior to targeting BCMA alone with ciltacabtagene autoleucel (cilta-cel). Dual-targeting should eventually be compared in large phase 3 trials with the classical approach of serial treatment with mono-targeting agents with target switch.
Cholangiocarcinoma (CCA) is a deadly cancer, characterized by abundant stroma. The tumor microenvironment (TME) plays an important role in its aggressive behavior and poor response to therapeutics; however, the underlying pathways are unknown. To fill this gap, we used multiplexed immunohistochemistry, high-dimensional cytometry, and single cell transcriptomics. Our findings confirm an abundance of regulatory T cells (Tregs) and a lack of effector memory T cells within the tumor. Tumor-infiltrating T cells show signs of exhaustion. Using our transcriptomic data, we revealed cellular crosstalk in poor prognosis patients. This crosstalk is driven by stromal cells and macrophages. Among the responsible receptor-ligand pairs are GAS6-AXL, VCAN-TLR2, and EGFR-TGF-β. The multiple mechanisms leading to the exclusion of relevant immune cells needed for an anti-cancer response and mechanisms leading to active immune suppression are part of complex cell-cell crosstalk. This study provides a deeper insight into the immune exhausted phenotype in CCA.
Objective.Probabilistic evaluation improves the trade-off between target coverage and OAR sparing in IMPT but remains computationally demanding. This study proposes sparse probabilistic evaluation (SPE), a computationally efficient approach integrated into a clinical treatment planning system.Approach.Clinical plans of 20 IMPT head and neck cancer patients treated in 2024 were included. SPE used a predefined setup and range error grid with Monte Carlo (MC) computed dose distributions. Two grid settings were evaluated: the maximum errorEmax(3σor 4σ), withσ=(σrandomerror)2+(σsystematicerror)2, and the number of setup error pointsnsetup(7, 33, 123). Accuracy and duration of SPE with each grid were evaluated in the calibration group (5 patients). A total of 1000 treatments with normally distributed random (σ= 1 mm) and systematic (σ= 0.92 mm) setup and range (σ= 1.5%) errors were simulated. The dose distribution of the nearest error point in the grid was assigned to each fraction. Probability distributions derived from SPE were compared with those from a reference based on 35 000 MC calculations. Agreement was quantified using the mean percentile error (MPE), the mean absolute difference across percentiles 0.01, 0.02, …, 1. The found optimal grid (Emax= 3σ, nsetup= 33) was applied to the validation group (15 patients).Main results.The median MPE in the calibration group decreased significantly as the number of error points increased from 7 (tavg= 2 min) to 33 (tavg= 9 min), with no further improvement between 33 and 123 (tavg= 27 min) error points. IncreasingEmaxfrom 3σto 4σonly improved accuracy for values above the 98th percentile. Applying SPE to the validation group resulted in median errors of 0.02 Gy RBE (range: -0.11-0.07) for the 10th percentile of theD99.8%, CTVdistribution and 0.0 Gy RBE (range: -0.14-0.23) for the 95th percentile of theD0.03cc,SpinalCord Coredistribution.Significance.SPE achieves sufficient accuracy while requiring clinically acceptable computation times, paving the way for probabilistic evaluation in clinical practice.
