Radiotherapy concepts for spinal metastases-results from an online survey among radiation oncologists of the German Society for Radiation Oncology.

PURPOSE: Spinal metastases (SM) are a common radiotherapy (RT) indication. There is limited level I data to drive decision making regarding dose regimen (DR) and target volume definition (TVD). We aim to depict the patterns of care for RT of SM among German Society for Radiation Oncology (DEGRO) members. METHODS: An online survey on conventional RT and Stereotactic Body Radiation Therapy (SBRT) for SM, distributed via e­mail to all DEGRO members, was completed by 80 radiation oncologists between February 24 and April 29, 2022. Participation was voluntary and anonymous. RESULTS: A variety of DR was frequently used for conventional RT (primary: n = 15, adjuvant: n = 14). 30 Gy/10 fractions was reported most frequently. TVD in adjuvant RT was heterogenous, with a trend towards larger volumes. SBRT was offered in 65% (primary) and 21% (adjuvant) of participants' institutions. A variety of DR was reported (primary: n = 40, adjuvant: n = 27), most commonly 27 Gy/3 fractions and 30 Gy/5 fractions. 59% followed International Consensus Guidelines (ICG) for TVD. CONCLUSION: We provide a representative depiction of RT practice for SM among DEGRO members. DR and TVD are heterogeneous. SBRT is not comprehensively practiced, especially in the adjuvant setting. Further research is needed to provide a solid data basis for detailed recommendations.

Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer.

BACKGROUND AND PURPOSE: Due to the high intrinsic radioresistance of pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) is only beneficial in 30% of patients. Therefore, this study aimed to identify targets to improve the efficacy of RT in PDAC. MATERIALS AND METHODS: Alamar Blue proliferation and colony formation assay (CFA) were used to determine the radioresponse of a cohort of 38 murine PDAC cell lines. A gene set enrichment analysis was performed to reveal differentially expressed pathways. CFA, cell cycle distribution, γH2AX FACS analysis, and Caspase 3/7 SYTOX assay were used to examine the effect of a combination treatment using KIRA8 as an IRE1α-inhibitor and Ceapin-A7 as an inhibitor against ATF6. RESULTS: The unfolded protein response (UPR) was identified as a pathway highly expressed in radioresistant cell lines. Using the IRE1α-inhibitor KIRA8 or the ATF6-inhibitor Ceapin-A7 in combination with radiation, a radiosensitizing effect was observed in radioresistant cell lines, but no substantial alteration of the radioresponse in radiosensitive cell lines. Mechanistically, increased apoptosis by KIRA8 in combination with radiation and a cell cycle arrest in the G1 phase after ATF6 inhibition and radiation have been observed in radioresistant cell lines. CONCLUSION: So, our data show evidence that the UPR is involved in radioresistance of PDAC. Increased apoptosis and a G1 cell cycle arrest seem to be responsible for the radiosensitizing effect of UPR inhibition. These findings are supportive for developing novel combination treatment concepts in PDAC to overcome radioresistance.

Establishment of a 3D Model to Characterize the Radioresponse of Patient-Derived Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite modern, multimodal therapeutic options of surgery, chemotherapy, tumor-treating fields (TTF), and radiotherapy, the 5-year survival is below 10%. In order to develop new therapies, better preclinical models are needed that mimic the complexity of a tumor. In this work, we established a novel three-dimensional (3D) model for patient-derived GBM cell lines. To analyze the volume and growth pattern of primary GBM cells in 3D culture, a CoSeedisTM culture system was used, and radiation sensitivity in comparison to conventional 2D colony formation assay (CFA) was analyzed. Both culture systems revealed a dose-dependent reduction in survival, but the high variance in colony size and shape prevented reliable evaluation of the 2D cultures. In contrast, the size of 3D spheroids could be measured accurately. Immunostaining of spheroids grown in the 3D culture system showed an increase in the DNA double-strand-break marker γH2AX one hour after irradiation. After 24 h, a decrease in DNA damage was observed, indicating active repair mechanisms. In summary, this new translational 3D model may better reflect the tumor complexity and be useful for analyzing the growth, radiosensitivity, and DNA repair of patient-derived GBM cells.

Development of a PTV margin for preclinical irradiation of orthotopic pancreatic tumors derived from a well-known recipe for humans.

In human radiotherapy a safety margin (PTV margin) is essential for successful irradiation and is usually part of clinical treatment planning. In preclinical radiotherapy research with small animals, most uncertainties and inaccuracies are present as well, but according to the literature a margin is used only scarcely. In addition, there is only little experience about the appropriate size of the margin, which should carefully be investigated and considered, since sparing of organs at risk or normal tissue is affected. Here we estimate the needed margin for preclinical irradiation by adapting a well-known human margin recipe from van Herck et al. to the dimensions and requirements of the specimen on a small animal radiation research platform (SARRP). We adjusted the factors of the described formula to the specific challenges in an orthotopic pancreatic tumor mouse model to establish an appropriate margin concept. The SARRP was used with its image-guidance irradiation possibility for arc irradiation with a field size of 10 × 10 mm2 for 5 fractions. Our goal was to irradiate the clinical target volume (CTV) of at least 90% of our mice with at least 95% of the prescribed dose. By carefully analyzing all relevant factors we gain a CTV to planning target volume (PTV) margin of 1.5 mm for our preclinical setup. The stated safety margin is strongly dependent on the exact setting of the experiment and has to be adjusted for other experimental settings. The few stated values in literature correspond well to our result. Even if using margins in the preclinical setting might be an additional challenge, we think it is crucial to use them to produce reliable results and improve the efficacy of radiotherapy.

Outcome of patients with soft tissue sarcomas of the extremities and trunk treated by (neo)adjuvant intensity modulated radiation therapy with curative intent.

BACKGROUND: Soft tissue sarcomas (STS) are a relatively rare group of malignant tumors. Currently, there is very little published clinical data, especially in the context of curative multimodal therapy with image-guided, conformal, intensity-modulated radiotherapy. METHODS: Patients who received preoperative or postoperative intensity-modulated radiotherapy for STS of the extremities or trunk with curative intent were included in this single centre retrospective analysis. A Kaplan-Meier analysis was performed to evaluate survival endpoints. Multivariable proportional hazard models were used to investigate the association between survival endpoints and tumour-, patient-, and treatment-specific characteristics. RESULTS: 86 patients were included in the analysis. The most common histological subtypes were undifferentiated pleomorphic high-grade sarcoma (UPS) (27) and liposarcoma (22). More than two third of the patients received preoperative radiation therapy (72%). During the follow-up period, 39 patients (45%) suffered from some type of relapse, mainly remote (31%). The two-years overall survival rate was 88%. The median DFS was 48 months and the median DMFS was 51 months. Female gender (HR 0.460 (0.217; 0.973)) and histology of liposarcomas compared to UPS proved to be significantly more favorable in terms of DFS (HR 0.327 (0.126; 0.852)). CONCLUSION: Conformal, intensity-modulated radiotherapy is an effective treatment modality in the preoperative or postoperative management of STS. Especially for the prevention of distant metastases, the establishment of modern systemic therapies or multimodal therapy approaches is necessary.

Roadmap for precision preclinical x-ray radiation studies.

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.

Dose-escalated re-irradiation improves outcome in locally recurrent head and neck cancer - Results of a large multicenter analysis.

To determine efficacy and prognostic parameters of definitive re-irradiation of locoregionally recurrent squamous cell carcinoma of the head and neck (HNSCC). MATERIALS AND METHODS: Patients with locoregionally recurrent or second primary HNSCC undergoing re-irradiation with modern radiotherapy technique were eligible for this multicentric retrospective analysis. Main endpoints were overall survival (OS), progression-free survival (PFS) and locoregional control (LC). Univariate analyses were performed using the Kaplan Meier Method (log-rank). For multivariable analysis, Cox regression was used. RESULTS: A total of 253 patients treated between 2009 and 2020 at 16 university hospitals in Germany were included. The median follow up was 27.4 months (range 0.5-130). The median OS and PFS were 13.2 (CI: 10.7 - 15.7) months and 7.9 (CI: 6.7 - 9.1) months, respectively, corresponding to two-year OS and PFS rates of 29 % and 19 %. Rates of locoregional progression and "in-field-failure" were 62 % and 51 % after two years. Multivariable Cox regression analysis identified good ECOG performance status and high radiation dose as independent prognostic parameters for OS. Doses above 50 Gy (EQD2) achieved longer median OS of 17.8 months (vs 11.7 months, p < 0.01) and longer PFS of 9.6 months (vs 6.8 months, p < 0.01). In addition, there was a trend for worse survival in patients with tracheostomy (multivariable, p = 0.061). Concomitant systemic therapy did not significantly impact PFS or OS. CONCLUSION: Re-irradiation of locally recurrent or second primary HNSCC is efficient, especially if doses above 50 Gy (EQD2) are delivered. ECOG performance score was the strongest prognostic parameter for OS and PFS.

Comparison of 3 Positioning Techniques for Fractionated High-precision Radiotherapy in an Orthotopic Mouse Model of Pancreatic Cancer.

Small-animal irradiators are widely used in oncologic research, and many experiments use mice to mimic radiation treatments in humans. To improve fractionated high-precision irradiation in mice with orthotopic pancreatic tumors, we evaluated 3 positioning methods: no positioning aid, skin marker, and immobilization devices (immobilization masks). We retrospectively evaluated the translation vector needed for optimal tumor alignment (by shifting the mouse in left-right, in cranio-caudal, and in anterior-posterior direction) on cone-beam CT from our small-animal radiotherapy system. Of the 3 methods, the skin marker method yielded the smallest mean translation vector (3.8 mm) and was the most precise method overall for most of the mice. In addition, the skin marker method required supplemental rotation (that is, roll, pitch, and yaw) for optimal tumor alignment only half as often as positioning without a positioning aid. Finally, the skin marker method had the highest scores for the quality of the fusion results. Overall, we preferred the skin marker method over the other 2 positioning methods with regard to optimal treatment planning and radiotherapy in an orthotopic mouse model of pancreatic cancer.

Mass spectrometry-based draft of the mouse proteome.

The laboratory mouse ranks among the most important experimental systems for biomedical research and molecular reference maps of such models are essential informational tools. Here, we present a quantitative draft of the mouse proteome and phosphoproteome constructed from 41 healthy tissues and several lines of analyses exemplify which insights can be gleaned from the data. For instance, tissue- and cell-type resolved profiles provide protein evidence for the expression of 17,000 genes, thousands of isoforms and 50,000 phosphorylation sites in vivo. Proteogenomic comparison of mouse, human and Arabidopsis reveal common and distinct mechanisms of gene expression regulation and, despite many similarities, numerous differentially abundant orthologs that likely serve species-specific functions. We leverage the mouse proteome by integrating phenotypic drug (n > 400) and radiation response data with the proteomes of 66 pancreatic ductal adenocarcinoma (PDAC) cell lines to reveal molecular markers for sensitivity and resistance. This unique atlas complements other molecular resources for the mouse and can be explored online via ProteomicsDB and PACiFIC.

Dual energy CT for a small animal radiation research platform using an empirical dual energy calibration.

Objective.Dual energy computed tomography (DECT) has been shown to provide additional image information compared to conventional CT and has been used in clinical routine for several years. The objective of this work is to present a DECT implementation for a Small Animal Radiation Research Platform (SARRP) and to verify it with a quantitative analysis of a material phantom and a qualitative analysis with anex-vivomouse measurement.Approach.For dual energy imaging, two different spectra are required, but commercial small animal irradiators are usually not optimized for DECT. We present a method that enables dual energy imaging on a SARRP with sequential scanning and an Empirical Dual Energy Calibration (EDEC). EDEC does not require the exact knowledge of spectra and attenuation coefficients; instead, it is based on a calibration. Due to the SARRP geometry and reconstruction algorithm, the calibration is done using an artificial CT image based on measured values. The calibration yields coefficients to convert the measured images into material decomposed images.Main results.To analyze the method quantitatively, the electron density and the effective atomic number of a material phantom were calculated and compared with theoretical values. The electron density showed a maximum deviation from the theoretical values of less than 5% and the atomic number of slightly more than 6%. For use in mice, DECT is particularly useful in distinguishing iodine contrast agent from bone. A material decomposition of anex-vivomouse with iodine contrast agent was material decomposed to show that bone and iodine can be distinguished and iodine-corrected images can be calculated.Significance.DECT is capable of calculating electron density images and effective atomic number images, which are appropriate parameters for quantitative analysis. Furthermore, virtual monochromatic images can be obtained for a better differentiation of materials, especially bone and iodine contrast agent.

A comprehensive and efficient quality assurance program for an image-guided small animal irradiation system.

In the field of preclinical radiotherapy, many new developments were driven by technical innovations. To make research of different groups comparable in that context and reliable, high quality has to be maintained. Therefore, standardized protocols and programs should be used. Here we present a guideline for a comprehensive and efficient quality assurance program for an image-guided small animal irradiation system, which is meant to test all the involved subsystems (imaging, treatment planning, and the irradiation system in terms of geometric accuracy and dosimetric aspects) as well as the complete procedure (end-to-end test) in a time efficient way. The suggestions are developed on a Small Animal Radiation Research Platform (SARRP) from Xstrahl (Xstrahl Ltd., Camberley, UK) and are presented together with proposed frequencies (from monthly to yearly) and experiences on the duration of each test. All output and energy related measurements showed stable results within small variation. Also, the motorized parts (couch, gantry) and other geometrical alignments were very stable. For the checks of the imaging system, the results are highly dependent on the chosen protocol and differ according to the settings. We received nevertheless stable and comparably good results for our mainly used protocol. All investigated aspects of treatment planning were exactly fulfilled and also the end-to-end test showed satisfying values. The mean overall time we needed for our checks to have a well monitored machine is less than two hours per month.

Histopathological Tumor and Normal Tissue Responses after 3D-Planned Arc Radiotherapy in an Orthotopic Xenograft Mouse Model of Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. Innovative treatment concepts may enhance oncological outcome. Clinically relevant tumor models are essential in developing new therapeutic strategies. In the present study, we used two human PDAC cell lines for an orthotopic xenograft mouse model and compared treatment characteristics between this in vivo tumor model and PDAC patients. Tumor-bearing mice received stereotactic high-precision irradiation using arc technique after 3D-treatment planning. Induction of DNA damage in tumors and organs at risk (OARs) was histopathologically analyzed by the DNA damage marker γH2AX and compared with results after unprecise whole-abdomen irradiation. Our mouse model and preclinical setup reflect the characteristics of PDAC patients and clinical RT. It was feasible to perform stereotactic high-precision RT after defining tumor and OARs by CT imaging. After stereotactic RT, a high rate of DNA damage was mainly observed in the tumor but not in OARs. The calculated dose distributions and the extent of the irradiation field correlate with histopathological staining and the clinical example. We established and validated 3D-planned stereotactic RT in an orthotopic PDAC mouse model, which reflects the human RT. The efficacy of the whole workflow of imaging, treatment planning, and high-precision RT was proven by longitudinal analysis showing a significant improved survival. Importantly, this model can be used to analyze tumor regression and therapy-related toxicity in one model and will allow drawing clinically relevant conclusions.

In-vivo X-ray dark-field computed tomography for the detection of radiation-induced lung damage in mice.

BACKGROUND AND PURPOSE: Radiotherapy of thoracic tumours can lead to side effects in the lung, which may benefit from early diagnosis. We investigated the potential of X-ray dark-field computed tomography by a proof-of-principle murine study in a clinically relevant radiotherapeutic setting aiming at the detection of radiation-induced lung damage. MATERIAL AND METHODS: Six mice were irradiated with 20 Gy to the entire right lung. Together with five unirradiated control mice, they were imaged using computed tomography with absorption and dark-field contrast before and 16 weeks post irradiation. Mean pixel values for the right and left lung were calculated for both contrasts, and the right-to-left-ratio R of these means was compared. Radiologists also assessed the tomograms acquired 16 weeks post irradiation. Sensitivity, specificity, inter- and intra-reader accuracy were evaluated. RESULTS: In absorption contrast the group-average of R showed no increase in the control group and increased by 7% (p = 0.005) in the irradiated group. In dark-field contrast, it increased by 2% in the control group and by 14% (p = 0.005) in the irradiated group. Specificity was 100% for both contrasts but sensitivity was almost four times higher using dark-field tomography. Two cases were missed by absorption tomography but were detected by dark-field tomography. CONCLUSIONS: The applicability of X-ray dark-field computed tomography for the detection of radiation-induced lung damage was demonstrated in a pre-clinical mouse model. The presented results illustrate the differences between dark-field and absorption contrast and show that dark-field tomography could be advantageous in future clinical settings.

Impact of DNA repair and reactive oxygen species levels on radioresistance in pancreatic cancer.

PURPOSE: Radioresistance in pancreatic cancer patients remains a critical obstacle to overcome. Understanding the molecular mechanisms underlying radioresistance may achieve better response to radiotherapy and thereby improving the poor treatment outcome. The aim of the present study was to elucidate the mechanisms leading to radioresistance by detailed characterization of isogenic radioresistant and radiosensitive cell lines. METHODS: The human pancreatic cancer cell lines, Panc-1 and MIA PaCa-2 were repeatedly exposed to radiation to generate radioresistant (RR) isogenic cell lines. The surviving cells were expanded, and their radiosensitivity was measured using colony formation assay. Tumor growth delay after irradiation was determined in a mouse pancreatic cancer xenograft model. Gene and protein expression were analyzed using RNA sequencing and Western blot, respectively. Cell cycle distribution and apoptosis (Caspase 3/7) were measured by FACS analysis. Reactive oxygen species generation and DNA damage were analyzed by detection of CM-H2DCFDA and γH2AX staining, respectively. Transwell chamber assays were used to investigate cell migration and invasion. RESULTS: The acquired radioresistance of RR cell lines was demonstrated in vitro and validated in vivo. Ingenuity pathway analysis of RNA sequencing data predicted activation of cell viability in both RR cell lines. RR cancer cell lines demonstrated greater DNA repair efficiency and lower basal and radiation-induced reactive oxygen species levels. Migration and invasion were differentially affected in RR cell lines. CONCLUSIONS: Our data indicate that repeated exposure to irradiation increases the expression of genes involved in cell viability and thereby leads to radioresistance. Mechanistically, increased DNA repair capacity and reduced oxidative stress might contribute to the radioresistant phenotype.

The Emerging Role of miRNAs for the Radiation Treatment of Pancreatic Cancer.

Today, pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide with a five-year overall survival rate of less than 7%. Only 15-20% of patients are eligible for curative intent surgery at the time of diagnosis. Therefore, neoadjuvant treatment regimens have been introduced in order to downsize the tumor by chemotherapy and radiotherapy. To further increase the efficacy of radiotherapy, novel molecular biomarkers are urgently needed to define the subgroup of pancreatic cancer patients who would benefit most from radiotherapy. MicroRNAs (miRNAs) could have the potential to serve as novel predictive and prognostic biomarkers in patients with pancreatic cancer. In the present article, the role of miRNAs as blood biomarkers, which are associated with either radioresistance or radiation-induced changes of miRNAs in pancreatic cancer, is discussed. Furthermore, the manuscript provides own data of miRNAs identified in a pancreatic cancer mouse model as well as radiation-induced miRNA changes in the plasma of tumor-bearing mice.

Radiosensitization by Kinase Inhibition Revealed by Phosphoproteomic Analysis of Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and known for its extensive genetic heterogeneity, high therapeutic resistance, and strong variation in intrinsic radiosensitivity. To understand the molecular mechanisms underlying radioresistance, we screened the phenotypic response of 38 PDAC cell lines to ionizing radiation. Subsequent phosphoproteomic analysis of two representative sensitive and resistant lines led to the reproducible identification of 7,800 proteins and 13,000 phosphorylation sites (p-sites). Approximately 700 p-sites on 400 proteins showed abundance changes after radiation in all cell lines regardless of their phenotypic sensitivity. Apart from recapitulating known radiation response phosphorylation markers such as on proteins involved in DNA damage repair, the analysis uncovered many novel members of a radiation-responsive signaling network that was apparent only at the level of protein phosphorylation. These regulated p-sites were enriched in potential ATM substrates and in vitro kinase assays corroborated 10 of these. Comparing the proteomes and phosphoproteomes of radiosensitive and -resistant cells pointed to additional tractable radioresistance mechanisms involving apoptotic proteins. For instance, elevated NADPH quinine oxidoreductase 1 (NQO1) expression in radioresistant cells may aid in clearing harmful reactive oxygen species. Resistant cells also showed elevated phosphorylation levels of proteins involved in cytoskeleton organization including actin dynamics and focal adhesion kinase (FAK) activity and one resistant cell line showed a strong migration phenotype. Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies.

Modification of radiosensitivity by Curcumin in human pancreatic cancer cell lines.

Pancreatic cancer is one of the most aggressive malignancies and is characterized by a low 5-year survival rate, a broad genetic diversity and a high resistance to conventional therapies. As a result, novel therapeutic agents to improve the current situation are needed urgently. Curcumin, a polyphenolic colorant derived from Curcuma longa root, showed pleiotropic influences on cellular pathways in vitro and amongst others anti-cancer properties including sensitization of tumor cells to chemo- and radiation-therapy. In this study, we evaluated the impact of Curcumin on the radiosensitivity of the established human pancreatic cancer cell lines Panc-1 and MiaPaCa-2 in vitro. In contrast to MiaPaCa-2 cells, we found a significant radiosensitization by Curcumin in the more radioresistant Panc-1 cells, possibly caused by cell cycle arrest in the most radiation-sensitive G2/M-phase at the time of irradiation. Furthermore, a significant enhancement of radiation-induced apoptosis, DNA-double-strand breaks and G2/M-arrest after curcumin treatment was observed in both cell lines. These in vitro findings suggest that especially patients with more radioresistant tumors could benefit from a radiation-concomitant, phytotherapeutic therapy with Curcumin.

Proton pencil minibeam irradiation of an in-vivo mouse ear model spares healthy tissue dependent on beam size.

Proton radiotherapy using minibeams of sub-millimeter dimensions reduces side effects in comparison to conventional proton therapy due to spatial fractionation. Since the proton minibeams widen with depth, the homogeneous irradiation of a tumor can be ensured by adjusting the beam distances to tumor size and depth to maintain tumor control as in conventional proton therapy. The inherent advantages of protons in comparison to photons like a limited range that prevents a dosage of distal tissues are maintained by proton minibeams and can even be exploited for interlacing from different beam directions. A first animal study was conducted to systematically investigate and quantify the tissue-sparing effects of proton pencil minibeams as a function of beam size and dose distributions, using beam widths between σ = 95, 199, 306, 411, 561 and 883 µm (standard deviation) at a defined center-to-center beam distance (ctc) of 1.8 mm. The average dose of 60 Gy was distributed in 4x4 minibeams using 20 MeV protons (LET ~ 2.7 keV/µm). The induced radiation toxicities were measured by visible skin reactions and ear swelling for 90 days after irradiation. The largest applied beam size to ctc ratio (σ/ctc = 0.49) is similar to a homogeneous irradiation and leads to a significant 3-fold ear thickness increase compared to the control group. Erythema and desquamation was also increased significantly 3-4 weeks after irradiation. With decreasing beam sizes and thus decreasing σ/ctc, the maximum skin reactions are strongly reduced until no ear swelling or other visible skin reactions should occur for σ/ctc < 0.032 (extrapolated from data). These results demonstrate that proton pencil minibeam radiotherapy has better tissue-sparing for smaller σ/ctc, corresponding to larger peak-to-valley dose ratios PVDR, with the best effect for σ/ctc < 0.032. However, even quite large σ/ctc (e.g. σ/ctc = 0.23 or 0.31, i.e. PVDR = 10 or 2.7) show less acute side effects than a homogeneous dose distribution. This suggests that proton minibeam therapy spares healthy tissue not only in the skin but even for dose distributions appearing in deeper layers close to the tumor enhancing its benefits for clinical proton therapy.

Mobile App Delivery of the EORTC QLQ-C30 Questionnaire to Assess Health-Related Quality of Life in Oncological Patients: Usability Study.

BACKGROUND: Mobile apps are evolving in the medical field. However, ongoing discussions have questioned whether such apps are really valuable and whether patients will accept their use in day-to-day clinical life. Therefore, we initiated a usability study in our department. OBJECTIVE: We present our results of the first app prototype and patient testing of health-related quality of life (HRQoL) assessment in oncological patients. METHODS: We developed an app prototype for the iOS operating system within eight months in three phases: conception, initial development, and pilot testing. For the HRQoL assessment, we chose to implement only the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30; German version 3). Usability testing was conducted for three months. Participation was voluntary and pseudonymized. After completion of the QLQ-C30 questionnaire using iPads provided by our department, we performed a short survey with 10 questions. This survey inquired about patients' opinions regarding general aspects, including technical advances in medicine, mobile and app assistance during cancer treatment, and the app-specific functions (eg, interface and navigation). RESULTS: After logging into the app, the user can choose between starting a questionnaire, reviewing answers (administrators only), and logging out. The questionnaire is displayed with the same information, questions, and answers as on the original QLQ-C30 sheet. No alterations in wording were made. Usability was tested with 81 patients; median age was 55 years. The median time for completing the HRQoL questionnaire on the iPad was 4.0 minutes. Of all participants, 84% (68/81) owned a mobile device. Similarly, 84% (68/81) of participants would prefer a mobile version of the HRQoL questionnaire instead of a paper-based version. Using the app in daily life during and after cancer treatment would be supported by 83% (67/81) of participants. In the prototype version of the app, data were stored on the device; in the future, 79% (64/81) of the patients would agree to transfer data via the Internet. CONCLUSIONS: Our usability test showed good results regarding attractiveness, operability, and understandability. Moreover, our results demonstrate a high overall acceptance of mobile apps and telemedicine in oncology. The HRQoL assessment via the app was accepted thoroughly by patients, and individuals are keen to use it in clinical routines, while data privacy and security must be ensured.

Preoperative Serum Thymidine Kinase Activity as Novel Monitoring, Prognostic, and Predictive Biomarker in Pancreatic Cancer.

OBJECTIVE: The aim of the study was to investigate serum thymidine kinase 1 (S-TK) activity as a diagnostic and prognostic marker for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using the sensitive TK activity assay DiviTum, preoperative serum samples from 404 PDAC, 28 chronic pancreatitis, and 25 autoimmune pancreatitis patients and 83 healthy volunteers were analyzed. The preoperative S-TK activities of 54 PDAC patients who received neoadjuvant therapy (nTx) were also compared with those of 258 PDAC patients who did not receive nTx. RESULTS: The preoperative S-TK activities of PDAC patients were significantly higher and discriminatory from autoimmune and chronic pancreatitis patients and control groups. The S-TK activity in PDAC patients was associated with overall survival. Patients with S-TK activity of less than 80 Du (DiviTum units)/L demonstrated median survival of 20.3 months with an estimated 18.0% 5-year survival rate; for S-TK activity of 80 Du/L or greater, median survival was 15.1 months with a 6.8% 5-year survival rate. For early-stage PDAC, these differences were even more pronounced. The S-TK activity in the nTx group was significantly higher than that in the group not receiving nTx. CONCLUSIONS: Pancreatic ductal adenocarcinomas reveal a significant increase in S-TK activity, which is associated with overall survival, especially in early tumor stages. Serum thymidine kinase 1 activity may be a useful parameter for monitoring nTx efficacy.