Guido Hildebrandt

Background: This study sought to evaluate 30- and 60-day mortality following palliative whole-brain radiotherapy (WBRT) in patients with metastatic non-small cell lung cancer (NSCLC), and to identify readily accessible clinical predictors to guide therapeutic decisions. Methods: This retrospective single-centre study analyzed 392 patients treated with WBRT. Pretreatment factors were assessed using multivariable Cox regression and translated into the six-point Bedside Early Mortality Score (BEMS). The score’s ability to predict mortality within 30 and 60 days of WBRT completion was evaluated using receiver operating characteristic (ROC) analysis and compared with Lung-specific Graded Prognostic Assessment (Lung GPA) and Recursive Partitioning Analysis (RPA). Results: Overall, 115 patients (29.3%) died within 30 days and 178 (45.4%) within 60 days. The score included four parameters readily available during bedside consultation: age ≥65 years, direct inpatient transfer, and abnormal mental status at initiation of WBRT each contributed one point, while impaired mobility contributed three points. Each additional point increased the risk of mortality by 55% (HR 1.55, 95% CI 1.46–1.64). Thirty- and sixty-day mortality according to score were, respectively, 2.2% and 8.5% (0–1 points), 10% and 36.7% (2–3 points), 57.8% and 85.7% (4–5 points), and 85.8% and 90.5% (6 points). Areas under the ROC curve for 30- and 60- day mortality were 0.855 and 0.881, compared with 0.685 and 0.740 for Lung GPA and 0.833 and 0.899 for RPA. Conclusions: The Bedside Early Mortality Score may complement clinical evaluation and support shared decision making in WBRT. Independent validation is required.

The closer a cancer model simulates the natural tumour environment, the more likely is a new therapeutic approach tested in this environment to succeed in clinical trials. A three-dimensional (3D) cell culture model provides several advantages over a simple, single-layer 2D cell culture: it can more closely simulate the cancer cell interactions occurring in a spontaneous tumour invading a living organism. The 3D cultures may be used to simulate a larger cancer cell load, thereby presenting a higher challenge for destruction by therapeutic intervention. In such a model, the nutritional support in the centre of the 3D structure would decrease with increasing diameter, similar to the situation found in a fast-growing tumour. For the purpose of experimental radiotherapy, we have designed a 3D cancer cell model in a two-layered agar matrix. Although this model does not represent a complex tumour microenvironment, we were able to visualise the three-dimensional growth utilising synchrotron-based microCT imaging of cancer cells loaded with gold nanoparticles (GNP) injected and proliferated in an agar matrix. We have also irradiated 3D cell cultures with microbeams, then embedded, sectioned and stained the agar matrices similarly to organic tissue samples. Thus, we have demonstrated the suitability of our in-vitro model for experimental radiotherapy.

Durvalumab consolidation after definitive chemoradiotherapy (CRT) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC) but real-world data comparing PD-L1-defined subgroups are limited. This retrospective single-centre study analyzed overall survival (OS) and progression-free survival (PFS) in 142 patients with inoperable stage III NSCLC with definitive CRT between 2015 and 2022. All tumours were assessed for PD-L1 expression, including retrospective testing, where required. Patients were assigned into three cohorts: PD-L1-positive with (PD-L1+mD; n = 57) and without (PD-L1+oD; n = 44) durvalumab maintenance and PD-L1-negative without durvalumab (PD-L1−oD; n = 41). Mean follow-up was 44.0 months. Median OS was 27.3, 15.1 and 23.4 months for PD-L1+mD, PD-L1+oD, and PD-L1−oD, respectively. Median PFS was 18.4, 10.5 and 13.4 months for PD-L1+mD, PD-L1+oD, and PD-L1−oD, respectively. OS and PFS were significantly improved with durvalumab in PD-L1-positive patients (p = 0.043 and p = 0.027). PD-L1-negative patients showed no significant OS or PFS differences versus PD-L1+oD. Immunotherapy-related pneumonitis ≥grade 1 was documented in 15.7% patients. In real-world practice, durvalumab improves OS and PFS in PD-L1-positive unresectable stage III NSCLC and its omission appears particularly unfavourable.

Background: This study sought to evaluate overall survival (OS) following palliative radiotherapy in glioblastoma and to identify clinically applicable predictors supporting patient-centred treatment decisions, with exploration of early mortality. Methods: This retrospective single-centre study analysed 169 glioblastoma patients treated with palliative radiotherapy between 2010 and 2025. Baseline clinical and treatment variables were assessed. OS calculated from the last day of radiotherapy was estimated using Kaplan–Meier analysis; predictors were analysed using Cox regression. Early mortality (≤30 and ≤60 days) was evaluated using logistic regression. Results: Median age at diagnosis was 75 years, median Karnofsky Performance Status (KPS) was 60%, with 63% of patients < 70%. Impaired mental status, sensorimotor deficits, and steroid use were observed in 47%, 68%, and 86% of patients, respectively. Median OS was 3.5 months. Impaired mental status (HR 2.25), sensorimotor deficits (HR 1.77), steroid use (HR 1.39), multilobar involvement (HR 1.44), and age (HR 1.03) were independently associated with OS, whereas KPS was not. The rate of early mortality at 30 and 60 days was 18% and 31%. Early mortality analysis indicated impaired mental status and steroid use as indicators of very limited survival. Conclusions: Impaired mental status and steroid use identify patients with limited survival, whereas KPS lacks independent prognostic value in this setting.

Background: For the application of mesenchymal stem cells (MSCs) in regenerative medicine, xeno‐free ex vivo cultivation is necessary. Therefore, this study aimed to investigate whether adipose‐derived stem cells (ADSCs) from human breast tissue could be cultivated with human platelet lysate (hPL)—a promising alternative derived from human platelets—instead of fetal bovine serum (FBS). Methods: The influence of hPL within the culture medium of ADSCs from the female breast was analyzed regarding immunophenotype, adipogenic differentiation capacity, growth kinetics, and cell cycle distribution of ADSCs. Subsequently, the formation of spheres in hPL‐supplemented medium was characterized in detail. Results: In comparison to FBS, the supplementation of medium with hPL resulted in a change in morphology, but the immunophenotype remained unchanged. Furthermore, supplementation of the medium with hPL caused an improved adipogenic differentiation capacity, increased growth, and shortened population doubling time (PDT) in ADSCs. Additionally, the cultivation of ADSCs with hPL led to spontaneous formation of spheres. Conclusion: hPL is not only a replacement for the ethically controversial cell culture additive FBS but also offers a xeno‐free method for the cultivation of breast tissue‐derived ADSCs and thus represents an important step from bench to bedside.

Spatially fractionated radiotherapy (SFRT) is emerging as a powerful tool in cancer therapy for patients who are ineligible for treatment with clinically established irradiation techniques. Microbeam radiotherapy (MRT) is characterized by spatial dose fractionation in the micrometre range. This presents challenges in both treatment planning and dosimetry. While a dosimetry system with a spatial resolution of 10 µm and an option for real-time readout already exists, this system can only record dose in a very small volume. Thus, we are exploring dosimetry in an N-isopropylacrylamide (NIPAM) gel as an option for 3D dose visualization and, potentially, also three-dimensional dosimetry in larger volumes. In the current study, we have recorded the geometric patterns of single- and multiport irradiation with microbeam arrays in NIPAM gel. Data for 3D dose distribution was acquired in a 7T small animal MRI scanner. We found that the resolution of the gel is well suited for a detailed 3D visualization of microbeam patterns even in complex multiport geometries, similar to that of radiochromic film, which is well established for recording 2D dose distribution in MRT. The results suggest that a dose–response calibration is required for reliable quantitative dosimetry.

The results of radiotherapy in patients with primary malignant brain tumors are extremely dissatisfactory: the overall survival after a diagnosis of glioblastoma is typically less than three years. The development of spatially fractionated radiotherapy techniques could help to improve this bleak prognosis. In order to develop technical equipment and organ-specific therapy plans, dosimetry studies as well as radiobiology studies are conducted. Although perfect spheres are considered optimal phantoms by physicists, this does not reflect the wide variety of head sizes and shapes in our patient community. Depth from surface and X-ray dose absorption by tissue between dose entry point and target, two key parameters in medical physics planning, are largely determined by the shape and thickness of the skull bone. We have, therefore, designed and produced a biomimetic tool to correlate measured technical dose and biological response in human cancer cells: a brain phantom, produced from tissue-equivalent materials. In a first pilot study, utilizing our phantom to correlate technical dose measurements and metabolic response to radiation in human cancer cell lines, we demonstrate why an anthropomorphic phantom is preferable over a simple spheroid phantom.

To enhance the treatment of tumors that are resistant to radio- and chemotherapy while minimizing the side effects of radiochemotherapy, researchers are continuously seeking new active compounds for use in combination with radiotherapy. Therefore, the aim of our study was to examine the cytotoxic and radiosensitizing effects of an extract from St. John’s Wort (Hypericum perforatum), referred to as HP01, on human epithelial tumor cells in vitro. The growth of MCF-7 (breast carcinoma) and HT-29 (colon carcinoma) cells was examined under the influence of HP01. In combination with radiation, the effects of HP01 on cytotoxicity and long-term survival were assessed using a colony formation assay. The number of DNA double-strand breaks was analyzed using the γH2AX assay, while cell cycle distribution was examined via flow cytometry. A growth-inhibiting and cytotoxic effect was observed for both tumor cell lines starting at a concentration of 10 µg/mL HP01. Treatment with HP01 resulted in an inhibition of clonogenic survival of tumor cells after ionizing radiation (6 Gy). The number of DNA double-strand breaks (DSBs) in tumor cells increased with HP01 treatment, but the repair of radiation-induced DNA DSBs was not affected. Cell cycle analysis revealed that HP01, in addition to radiation, enhanced G2/M arrest in MCF-7 and HT-29 cells. Overall, HP01 not only showed a growth-inhibiting effect but also demonstrated a radiosensitizing effect on human tumor cells for the first time. We conclude that the HP01-induced G2/M accumulation of cells may be the main rationale for the drug-induced radiosensitivity. It is therefore a promising candidate for combined therapy in tumor diseases and warrants further investigation.

A three-dimensional (3D) understanding of muscle attachment footprints became increasingly relevant for musculoskeletal modeling. The established method to project attachments as points ignores patient-specific individuality. Research focuses on investigating certain muscle groups rather than comprehensively studying all muscles spanning a joint. Therefore, we present a reliable method to study several muscle attachments in order to reconstruct the attachment sites in 3D based on CT imaging for future applications in musculoskeletal modeling. For the present feasibility study, 23 knee-related muscle attachments were CT-scanned postmortem from four nonadipose male specimens. For this, the specific muscle attachments were dissected and marked with a barium sulfate containing paint (60 g BaSO₄ in 30 mL water and 10 mL acrylic paint). Subsequently, bone geometries and muscle attachments were reconstructed and evaluated from CT datasets. Bone morphology and footprint variations were studied. Exemplarily, variations were high for pes anserinus insertions (mean 56%) and the origins of M. biceps femoris (mean 54%). In contrast, the origins of the vastus muscles as well as the insertion of the Achilles tendon showed low variation (mean 9% and 13%, respectively). Most attachment sites showed variation exceeding the individuality of bone morphology. In summary, the present data were consistent with the few published studies of specific muscle footprints. Our data shed light on the high variability of muscle attachments, which need to be addressed when studying muscle forces and movements through musculoskeletal modeling. This is the first step to achieving a more profound understanding of muscle morphology to be utilized in numerical simulations.