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Background: The medical coding of radiology reports is essential for a good quality of care and correct billing, but at the same time a complex and error-prone task., Objective: To assess the performance of natural language processing (NLP) for ICD-10 coding of German radiology reports using fine tuning of suitable language models., Material and Methods: This retrospective study included all magnetic resonance imaging (MRI) radiology reports acquired at our institution between 2010 and 2020. The codes on discharge ICD-10 were matched to the corresponding reports to construct a dataset for multiclass classification. Fine tuning of GermanBERT and flanT5 was carried out on the total dataset (ds total ) containing 1035 different ICD-10 codes and 2 reduced subsets containing the 100 (ds 100 ) and 50 (ds 50 ) most frequent codes. The performance of the model was assessed using top‑k accuracy for k = 1, 3 and 5. In an ablation study both models were trained on the accompanying metadata and the radiology report alone., Results: The total dataset consisted of 100,672 radiology reports, the reduced subsets ds 100 of 68,103 and ds 50 of 52,293 reports. The performance of the model increased when several of the best predictions of the model were taken into consideration, when the number of target classes was reduced and the metadata were combined with the report. The flanT5 outperformed GermanBERT across all datasets and metrics and was is suited as a medical coding assistant, achieving a top 3 accuracy of nearly 70% in the real-world dataset ds total ., Conclusion: Finely tuned language models can reliably predict ICD-10 codes of German magnetic resonance imaging (MRI) radiology reports across various settings. As a coding assistant flanT5 can guide medical coders to make informed decisions and potentially reduce the workload., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Point-of-care (POC) manufacturing of chimeric antigen receptor (CAR) modified T cell has expanded rapidly over the last decade. In addition to the use of CD19 CAR T cells for hematological diseases, there is a growing interest in targeting a variety of tumor-associated epitopes., Methods: Here, we report the manufacturing and characterization of autologous anti-CD20 CAR T cells from melanoma patients within phase I clinical trial (NCT03893019). Using a second-generation lentiviral vector for the production of the CD20 CAR T cells on the CliniMACS Prodigy®., Results: We demonstrated consistency in cell composition and functionality of the products manufactured at two different production sites. The T cell purity was >98.5%, a CD4/CD8 ratio between 2.5 and 5.5 and transduction rate between 34% and 61% on day 12 (harvest). Median expansion rate was 53-fold (range, 42-65-fold) with 1.7-3.8×10 9 CAR T cells at harvest, a sufficient number for the planned dose escalation steps (1×10 5 /kg, 1×10 6 /kg, 1×10 7 /kg BW). Complementary research of some of the products pointed out that the CAR+ cells expressed mainly central memory T-cell phenotype. All tested CAR T cell products were capable to translate into T cell activation upon engagement of CAR target cells, indicated by the increase in pro-inflammatory cytokine release and by the increase in CAR T cell amplification. Notably, there were some interindividual, cell-intrinsic differences at the level of cytokine release and amplification. CAR-mediated T cell activation depended on the level of CAR cognate antigen., Discussion: In conclusion, the CliniMACS Prodigy® platform is well suited for decentralized POC manufacturing of anti-CD20 CAR T cells and may be likewise applicable for the rapid and automated manufacturing of CAR T cells directed against other targets., Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03893019?cond=Melanoma&term=NCT03893019&rank=1, identifier NCT03893019., Competing Interests: UK: Consultant and/or speaker fees: AstraZeneca, Affimed, Glycostem, GammaDelta, Zelluna, Miltenyi Biotec and Novartis Pharma GmbH, Bristol-Myers Squibb GmbH & Co. KGaA; MAk, MAp, MAs, IB, AR, PA und CS are employees of Miltenyi Biotec and Miltenyi Biomedicine. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Aleksandrova, Leise, Priesner, Aktas, Apel, Assenmacher, Bürger, Richter, Altefrohne, Schubert, Holzinger, Barden, Bezler, von Bergwelt-Baildon, Borchmann, Goudeva, Glienke, Arseniev, Esser, Abken and Koehl.)

Objectives: This randomized clinical trial focused on patients with thin peri-implant soft-tissue height (STH) (≤ 2.5 mm) and investigated the impact of an allogenic collagen scaffold (aCS) on supracrestal tissue height and marginal bone loss (MBL)., Material & Methods: Forty patients received bone level implants and were randomly assigned to the test group with simultaneous tissue thickening with aCS or the control group. After three months, prosthetic restoration occurred. STH measurements were taken at baseline (T0) and reopening surgery (TR), with MBL assessed at 12 months (T1). Descriptive statistics were calculated for continuous variables, and counts for categorical variables (significance level, p = 0.05)., Results: At T1, 37 patients were available. At T0, control and test groups had mean STH values of 2.3 ± 0.3 mm and 2.1 ± 0.4 mm. TR revealed mean STH values of 2.3 ± 0.2 mm (control) and 2.6 ± 0.7 mm (test), with a significant tissue thickening of 0.5 ± 0.6 mm in the test group (p < 0.03). At T1, control and test groups showed MBL mean values of 1.1 ± 0.8 mm and 1.0 ± 0.6 mm, with a moderate but significant correlation with STH thickening (-0.34), implant position (0.43), history of periodontitis (0.39), and smoking status (0.27)., Conclusion: The use of an aCS protocol resulted in soft tissue thickening but did not reach a threshold to reliably reduce MBL compared to the control group within the study's limitations., Clinical Relevance: Peri-implant STH is crucial for maintaining peri-implant marginal bone stability. Marginal bone stability represents a crucial factor in prevention of peri-implantitis development. German register of clinical trial registration number DRKS00033290., (© 2024. The Author(s).)

This study evaluated the brushing efficacy of different interdental brushes around a multibracket appliance in vitro. In four models displaying misaligned and aligned teeth with and without attachment loss, the brushing capacities of three interdental brushes (IDB) were tested: A waist-shaped IDB with a diameter of 9 mm at both ends and 5 mm in the middle (B1), a cylindrical brush with a diameter of 9 mm (B2) and one with 5 mm (B3). Before cleaning, the black teeth in the respective models were stained white with titanium (IV) oxide and the percentage of cleaned surface was planimetrically assessed. In addition, the forces applied to the IDB were also recorded. The effect of brush and model on expected cleaning performance was examined using an analysis of variance (ANOVA). The cleaning performance of the brushes in decreasing order was B2>B3>B1; no significant differences between the different tooth areas and models were found. With regard to force measurements, significant differences were found with the highest and lowest forces IDB (2) and (1), respectively. There was a significant correlation between force and cleaning performance: The higher the force needed the higher was the cleaning performance. In summary, this study showed that cylindrical interdental brushes achieved a better cleaning performance than the waist-shaped IDB. Given some shortcomings of this first laboratory study, more research is still needed, but IDB may represent a valuable yet still clinically underused tools.

Due to the paucity of targetable antigens, triple-negative breast cancer (TNBC) remains a challenging subtype of breast cancer to treat. In this study, we developed and evaluated a chimeric antigen receptor (CAR) T cell-based treatment modality for TNBC by targeting stage-specific embryonic antigen 4 (SSEA-4), a glycolipid whose overexpression in TNBC has been correlated with metastasis and chemoresistance. To delineate the optimal CAR configuration, a panel of SSEA-4-specific CARs containing alternative extracellular spacer domains was constructed. The different CAR constructs mediated antigen-specific T cell activation characterized by degranulation of T cells, secretion of inflammatory cytokines, and killing of SSEA-4-expressing target cells, but the extent of this activation differed depending on the length of the spacer region. Adoptive transfer of the CAR-engineered T cells into mice with subcutaneous TNBC xenografts mediated a limited antitumor effect but induced severe toxicity symptoms in the cohort receiving the most bioactive CAR variant. We found that progenitor cells in the lung and bone marrow express SSEA-4 and are likely co-targeted by the CAR T cells. Thus, this study has revealed serious adverse effects that raise safety concerns for SSEA-4-directed CAR therapies because of the risk of eliminating vital cells with stem cell properties.

Solid tumors consist of malignant and nonmalignant cells that together create the local tumor microenvironment (TME). Additionally, the TME is characterized by the expression of numerous soluble factors such as TGF-β. TGF-β plays an important role in the TME by suppressing T cell effector function and promoting tumor invasiveness. Up to now CAR T cells exclusively target tumor-associated antigens (TAA) located on the cell membrane. Thus, strategies to exploit soluble antigens as CAR targets within the TME are needed. This study demonstrates a novel approach using Adapter CAR (AdCAR) T cells for the detection of soluble latent TGF-β within the TME of a pancreatic tumor model. We show that AdCARs in combination with the respective adapter can be used to sense soluble tumor-derived latent TGF-β, both in vitro and in vivo . Sensing of the soluble antigen induced cellular activation and effector cytokine production in AdCAR T cells. Moreover, we evaluated AdCAR T cells for the combined targeting of soluble latent TGF-β and tumor cell killing by targeting CD66c as TAA in vivo . In sum, our study broadens the spectrum of targetable moieties for AdCAR T cells by soluble latent TGF-β., Competing Interests: Niels Werchau, Bettina Kotter, Elvira Criado-Moronati, Andre Gosselink, Nicole Cordes, Dominik Lock, Simon Lennartz, Carolin Kolbe, Nora Winter, Karin Teppert, Fabian Engert, Brian Webster, Joerg Mittelstaet, Daniel Schaefer, Mario Assenmacher, Thomas Schaser, Pierre Abramowski, Andrew D. Kaiser were employees of Miltenyi Biotec B.V. & Co. KG at the time the study was conducted. Niels Werchau, Bettina Kotter, Joerg Mittelstaet, and Andrew D. Kaiser are coinventors of a patent application focusing on sensing of soluble antigens with adapter CAR technology. Joerg Mittelstaet and Andrew D. Kaiser are coinventors of a patent application focusing on adapter CAR technology. Michael von Bergwelt-Baildon: Astellas Pharma, Bristol-Myers Squibb, Kite Gilead, Miltenyi Biotec, MOLOGEN, MSD, Novartis, Roche (Honoraria, Speakers’ Bureau, Research Funding, Travel, Accomodations, Expenses)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Selective gene delivery to a cell type of interest utilizing targeted lentiviral vectors (LVs) is an efficient and safe strategy for cell and gene therapy applications, including chimeric antigen receptor (CAR)-T cell therapy. LVs pseudotyped with measles virus envelope proteins (MV-LVs) have been retargeted by ablating binding to natural receptors while fusing to a single-chain antibody specific for the antigen of choice. However, the broad application of MV-LVs is hampered by the laborious LV engineering required for every new target. Here, we report the first versatile targeting system for MV-LVs that solely requires mixing with biotinylated adapter molecules to enable selective gene transfer. The analysis of the selectivity in mixed cell populations revealed transduction efficiencies below the detection limit in the absence of an adapter and up to 5000-fold on-to-off-target ratios. Flexibility was confirmed by transducing cell lines and primary cells applying seven different adapter specificities in total. Furthermore, adapter mixtures were applied to generate CAR-T cells with varying CD4/CD8-ratios in a single transduction step. In summary, a selective and flexible targeting system was established that may serve to improve the safety and efficacy of cellular therapies. Compatibility with a wide range of readily available biotinylated molecules provides an ideal technology for a variety of applications.

Background: There is an increasing demand for chimeric antigen receptor (CAR) T cell products from patients and care givers. Here, we established an automated manufacturing process for CAR T cells on the CliniMACS Prodigy platform that is scaled to provide therapeutic doses and achieves gene-transfer with virus-free Sleeping Beauty (SB) transposition., Methods: We used an advanced CliniMACS Prodigy that is connected to an electroporator unit and performed a series of small-scale development and large-scale confirmation runs with primary human T cells. Transposition was accomplished with minicircle (MC) DNA-encoded SB100X transposase and pT2 transposon encoding a CD19 CAR., Results: We defined a bi-pulse electroporation shock with bi-directional and unidirectional electric field, respectively, that permitted efficient MC insertion and maintained a high frequency of viable T cells. In three large scale runs, 2E8 T cells were enriched from leukapheresis product, activated, gene-engineered and expanded to yield up to 3.5E9 total T cells/1.4E9 CAR-modified T cells within 12 days (CAR-modified T cells: 28.8%±12.3%). The resulting cell product contained highly pure T cells (97.3±1.6%) with balanced CD4/CD8 ratio and a high frequency of T cells with central memory phenotype (87.5%±10.4%). The transposon copy number was 7.0, 9.4 and 6.8 in runs #1-3, respectively, and gene analyses showed a balanced expression of activation/exhaustion markers. The CD19 CAR T cell product conferred potent anti-lymphoma reactivity in pre-clinical models. Notably, the operator hands-on-time was substantially reduced compared with conventional non-automated CAR T cell manufacturing campaigns., Conclusions: We report on the first automated transposon-based manufacturing process for CAR T cells that is ready for formal validation and use in clinical manufacturing campaigns. This process and platform have the potential to facilitate access of patients to CAR T cell therapy and to accelerate scaled, multiplexed manufacturing both in the academic and industry setting., Competing Interests: Competing interests: DL, CB, SL, KT, NW, MA, AK and TS are employees of Miltenyi Biotec. MH is listed as an inventor on patent applications and granted patents that have been filed by the Fred Hutchinson Cancer Research Center, Seattle, WA and the University of Würzburg that are related to CAR technologies and the use of MC DNA for genetransfer into lymphocytes and that have been licensed—in part—to industry. MH is a cofounder and equity owner of T-CURX. MSchm and MSchl are listed as inventors on granted patents of PlasmidFactory that cover the use of transposons in combination with Minicircle technology for cell transfection. No competing financial interests exist for the remaining authors., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)