Tomasz Skóra

Background Central nervous system (CNS) tumors, including gliomas, are among the most aggressive cancers, with glioblastoma multiforme (GBM) being the most common and lethal. This study explores the potential of multidrug repositioning as a modern chemotherapy strategy for GBM cell lines. It combines the standard GBM chemotherapeutic temozolomide (TMZ) with olaparib (OLA) and oxaliplatin (OXA), both repurposed from other cancer types. Most experimental drug therapy studies focus on just one or two selected high-grade GBM cell lines, but in this study, four such cell lines were used. Methods Glioblastoma (GBM) cell lines U118 MG, H4, U251 MG and U87 MG were treated for 72 h with oxaliplatin (OXA, 50–200 µM), olaparib (OLA, 1–100 µM), or temozolomide (TMZ, 10–100 µM). Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay. Half-maximal inhibitory concentration (IC₅₀) values were calculated using GraphPad Prism 8. A human fibroblast line (hFib) from a healthy donor was used as a control. The type of cell death following the above treatments was analysed using a fluorescence-based Apoptotic, Necrotic & Healthy Cells Quantification Kit. Results The combination of OLA, OXA, and TMZ significantly reduced cell viability and survival, inducing apoptosis/necrosis more effectively than TMZ alone. These synergistic effects alter glioblastoma metabolism, promote apoptosis, and enhance antitumor activity in vitro. Conclusions The proposed multidrug repositioning chemotherapy produced a therapeutic effect at lower doses, suggesting that it is potentially a safer and more effective treatment option.

This study presents Fast paRticle thErapy Dose optimizer (FREDopt), a newly developed GPU-accelerated open-source optimization software for simultaneous proton dose and dose-averaged linear energy transfer (LET_d) optimization in intensity-modulated proton therapy treatment planning. FREDopt was implemented entirely in Python, leveraging CuPy for GPU acceleration and incorporating fast Monte Carlo simulations from the FRED code. The treatment plan optimization workflow includes pre-optimization and optimization, the latter equipped with a novel superiorization of feasibility-seeking algorithms. Feasibility-seeking requires finding a point that satisfies prescribed constraints. Superiorization interlaces computational perturbations into iterative feasibility-seeking steps to steer them toward a superior feasible point, replacing the need for costly full-fledged constrained optimization. The method was validated on two treatment plans of patients treated in a clinical proton therapy center, with dose and LET_d distributions compared before and after reoptimization. Simultaneous dose and LET_d optimization using FREDopt led to a substantial reduction of LET_d and (dose) × (LET_d) in organs at risk while preserving target dose conformity. Computational performance evaluation showed execution times of 14–50 min, depending on the algorithm and target volume size—satisfactory for clinical and research applications while enabling further development of the well-tested, documented open-source software.

Objective. Cyclotron Centre Bronowice Krakow proton therapy center is establishing a methodology for dosimetric evaluation to support treatments of moving targets, particularly in the mediastinal area. We propose a robust 4D Monte Carlo (MC) dose evaluation approach for proton treatment plans, integrating temporal information on both pencil beam delivery and organ motion in the context of free-breathing treatments. Approach. A specialized tool combining the GPU-accelerated FRED MC code and temporal patient and treatment delivery data was developed. The methodology includes standard 3D dose evaluation for setup and CT calibration uncertainties, plan recalculation across respiratory phases, and robust 4D dose evaluation (4DDE). The 4DDE approach accumulates dose over deformable respiratory phases using log file time information to assess treatment plans at various respiratory cycle starting points. Validation used anonymized 4D computed tomography scans from a Hodgkin lymphoma patient, with deformable image registration extracting motion vector fields. For reference, proton plans were also recalculated on the median tumor position phase image and results were analyzed for dose–volume histograms parameters variability, 3D gamma index (GI) analysis (3%/3 mm) and voxel-wise worst case scenario, relative to the reference treatment planning system calculation. Main results. Exemplary robust 4DDE revealed that considering time provides insight into the worst-case scenarios, resulting in wider dose ranges (GI 55.05% to 88.36% vs 48.26% to 92.92% for 3D and 4D analysis, respectively). The voxel-wise worst-case dose distribution showed reduced target coverage by 47.4% and 20.8% (for 95% and 90% isodose) when accounting for respiratory motion. Significance. The study introduces a fast tool for 4DDE, demonstrating versatility ensures robustness in 3D and 4D evaluations, underscoring the significance of dynamic anatomical considerations in 4D proton radiotherapy.

Background: This work presents the procedures and application of the deep inspiration breath-hold (DIBH) technique for mediastinal lymphoma patients at a proton therapy (PT) center. It also discusses the implementation and validation of the surface-guided radiotherapy (SGRT) protocol in terms of positioning accuracy. Methods: This study included six lymphoma patients. Dedicated computed tomography (CT) protocols and a treatment workflow based on international guidelines were developed. Clinical data from the treatment planning system (TPS) were used to assess the difference between DIBH and free-breathing irradiation. Additionally, data from an optical patient positioning system and kilovoltage (kV) imaging system were used to estimate positioning shifts. The new CT protocol reduced the volume CT dose index by over six times compared with the standard protocol. Results: The DIBH method decreased the mean dose to the heart and lungs by up to 7.02 Gy(RBE) and 0.83 Gy(RBE), respectively. The median magnitude of patient setup errors and repeatability in DIBH positioning was 0.4 cm and 0.18 cm (mean for males and females) for the SGRT protocol. The kV imaging showed a setup error of over 0.3 cm for both groups. Conclusions: Despite the small size of the patient cohort, the relatively large number of individual positioning sessions enabled the detection of statistically significant differences (p < 0.05) in certain areas between male and female patients; however, no significant difference in the displacement vector magnitude was observed. DIBH treatment with SGRT offers high reproducibility for patient positioning.

Background: Chordoma is a rare and aggressive primary bone sarcoma. En-block resection remains the primary treatment, but some patients are unable to undergo it due to the location and potential complications. Currently, there is no direct comparison of the effects of radiotherapy (RTH) and surgical treatment. However, retrospective analyses indicate the potential benefits of using RTH. Methods: A retrospective analysis was conducted on 48 patients with sacral chordoma who were treated with surgery and/or radiotherapy between 2001-2020. Among those, 22 were initially treated with surgery, 19 with definitive radiotherapy, and 7 received combined treatment. The outcomes of the treatment of recurrence in 16 patients were considered. The resection margins were defined according to R classification, and the Kaplan-Meier method was employed to calculate disease-free survival (DFS) and overall survival (OS). Results: The median (mOS) for the entire cohort was 80.6 months (95% CI: 62.3-NA), and the median (mDFS) was 40.4 months (95% CI: 35-69.5). Patients who underwent radical surgery of the primary tumor did not achieve the mOS (mean 68), while patients treated only with RTH for the primary tumor achieved an mOS of 62.3 months (95% CI: 52.1-NA). This resulted in a significant advantage of surgery over RTH in terms of OS ( P = 0.01). This was not observed for DFS. The 3-year DFS rates were 65% in the surgical treatment group and 53.3% in the RTH group. The 3-year OS rates were 96% in the surgery group and 88.9% in the RTH group. In the treatment of recurrence, there were no statistically significant differences between RTH and surgery, for OS ( P = 0.76). Conclusions: Radical surgery remains the optimal treatment for sacral chordoma. For patients who are not candidates for surgical intervention, RTH offers excellent long-term outcomes. The treatment of recurrence remains a significant challenge. Comparing modern RTH techniques and surgical procedures could provide further insights.

Introduction: CRP, together with albumin, has been included in the risk scoringmodel of both the traditional Glasgow prognostic index (GPS) and its modifiedversion (mGPS), both of which have shown independent prognostic value inpatients with various cancers. However, the utility of the mGPS has not beeninvestigated in patients with muscle invasive bladder cancer (MIBC) eligiblefor radical conservative or palliative treatment.Aim: The aim of this study was to determine the associations between 3 differentmodified Glasgow prognostic indices and progression-free survival (PFS) and overall survival (OS). For the analysis, authors of this study used the standard modified mGPS, and twoof their own modified GPS that they created: the new nGPS index, whose scales were calculated using a CRPconcentration of 5 mg/l (nGPS), and the calculated cGPS index based on optimal CRP and albumin cut-offvalues calculated from ROC curve analysis.Material and methods: A retrospective observational study was conducted in a group of 136 patients withMIBC eligible for radical conservative or palliative treatment. CRP and albumin concentrations were measuredin all patients prior to treatment. The Kaplan-Meier method was used to assess the association between theGPS studied and overall survival (OS) and cancer progression-free time (PFS). The log-rank test was used todetermine differences between groups.Results: Analysis of the probability of PFS in patients treated with radical conservative treatment for mGPS,nGPS and cGPS showed a significant difference only for authors of this article proposed cGPS based on CRPand albumin levels calculated from ROC curve analysis, patients with cGPS 1 or 2 had a significantly shorterprogression-free time compared to the group with cGPS 0 (p = 0.0349). Kaplan-Meier analysis showed a significantdifference in patients' OS between scales (“0”, “1”, “2”) of all GPS assessed, but the differences betweenscales “0” and “1” for our proposed cGPS and nGPS were highly statistically significant (<0.001) compared tomGPS (p = 0.02). Furthermore, OS of patients with scale “0” were highest in the group with our calculated cGPS(79.3%), slightly lower in the group with authors of this study second proposed nGPS (75.6%) and lowest inthe group with standard mGPS (70.1%). Authors of this article also found that palliatively treated patients hadsignificantly shorter 2-year survival with scale “2” compared to the group with scale “0” or “1” in both of authorsproposed GPS: cGPS: 22.6% vs. 64.0% (p = 0.0005), nGPS: 20.8% vs. 56.3% (p = 0.0026).Conclusions: • The cGPS proposed by the authors of this article, based on optimal cut-off values of CRP andalbumin concentrations determined by ROC curves, showed to be a better prognostic factor for PFS in patientswith MIBC treated with radical conservative therapy compared to nGPS and mGPS.• Both nGPS and cGPS, authors modified indices, showed to be negative prognostic factors for OS in patientstreated with radical conservative treatment with disease progression.• nGPS and cGPS appear to be better markers for predicting disease progression, overall survival compared tothe standard mGPS based on CRP concentration = 10 mg/l.