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BackgroundSalvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure. ObjectiveThis study aims to evaluate prostate-specific membrane antigen–positron emission tomography (PSMA-PET)–based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model’s performance, aiming to improve clinical management of recurrent prostate cancer. MethodsThis multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET–based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions. ResultsBaseline characteristics of 1029 patients undergoing sRT PSMA-PET–based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (

IntroductionSince the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines.Materials and methodsTo longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses.ResultsA total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate.ConclusionWhile the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

[This corrects the article DOI: 10.1371/journal.pone.0221502.].

PurposeThe concept of dysphagia/aspiration-related structures (DARS) was developed against the background of severe late side effects of radiotherapy (RT) for head and neck cancer (HNC). DARS can be delineated on CT scans, but with a better morphological discrimination on magnetic resonance imaging (MRI). Swallowing function was analyzed by use of patient charts and prospective investigations and questionnaires.MethodSeventeen HNC patients treated with intensity-modulated radiotherapy (IMRT) ± chemotherapy between 5/2012 - 8/2015 were included. Planning CT (computed tomography) scans and MRIs (magnetic resonance imaging) prior, during 40 Gray (Gy) radiotherapy and posttreatment were available and co-registered to delineate DARS. The RT dose of each DARS was calculated. Five patients were investigated posttreatment for swallowing function and assessed by means of various questionnaires for quality of life (QoL), swallowing, and voice function.ResultsBy retrospective comparison of DARS volume, a significant change in four of eight DARS was detected over time. Three increased and one diminished. The risk of posttreatment dysphagia rose by every 1Gy above the mean dose (D mean) of RT to DARS. 7.5 was the risk factor for dysphagia in the first 6 months, reducing to 4.7 for months 6-12 posttreatment. For all five patients of the prospective part of swallowing investigations, a function disturbance was detected. These results were in contrast to the self-assessment of patients by questionnaires. There was neither a dose dependency of D mean DARS volume changes over time nor of dysphonia and no correlation between volume changes, dysphagia or dysphonia.ConclusionDelineation of DARS on MRI co-registered to planning CT gave the opportunity to differentiate morphology better than by CT alone. Due to the small number of patients with complete MRI scans over time, we failed to detect a dose dependency of DARS and swallowing and voice disorder posttreatment.

Side effects caused by radiation are a limiting factor to the amount of dose that can be applied to a tumor volume. A novel method to reduce side effects in radiotherapy is the use of spatial fractionation, in which a pattern of sub-millimeter beams (minibeams) is applied to spare healthy tissue. In order to determine the skin reactions in dependence of single beam sizes, which are relevant for spatially fractionated radiotherapy approaches, single pencil beams of submillimeter to 6 millimeter size were applied in BALB/c mice ears at a Small Animal Radiation Research Platform (SARRP) with a plateau dose of 60 Gy. Radiation toxicities in the ears were observed for 25 days after irradiation. Severe radiation responses were found for beams ≥ 3 mm diameter. The larger the beam diameter the stronger the observed reactions. No ear swelling and barely reddening or desquamation were found for the smallest beam sizes (0.5 and 1 mm). The findings were confirmed by histological sections. Submillimeter beams are preferred in minibeam therapy to obtain optimized tissue sparing. The gradual increase of radiation toxicity with beam size shows that also larger beams are capable of healthy tissue sparing in spatial fractionation.

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.

IntroductionThe major stress-inducible heat shock protein 70 (Hsp70) is induced after different stress stimuli. In tumors, elevated intracellular Hsp70 levels were associated on the one hand with radio- and chemotherapy resistance and on the other hand with a favorable outcome for patients. This study was undertaken to investigate cytosolic Hsp70 (cHsp70) as a potential biomarker for progression free (PFS) and overall survival (OS) in patients with primary glioblastomas (GBM).MethodsThe cHsp70 expression in tumor tissue of 60 patients diagnosed with primary GBM was analyzed by immunohistochemistry. The cHsp70 expression was correlated to the PFS and OS of the patients.ResultsA high cHsp70 expression was associated with a prolonged PFS (hazard ratio = 0.374, p = 0.001) and OS (hazard ratio = 0.416, p = 0.014) in GBM patients treated according to the standard Stupp protocol with surgery, radiotherapy and temozolomide.ConclusionsThese data suggest that the intracellular Hsp70 expression might serve as a prognostic marker in patients with primary GBM.

X-ray microbeam radiotherapy can potentially widen the therapeutic window due to a geometrical redistribution of the dose. However, high requirements on photon flux, beam collimation, and system stability restrict its application mainly to large-scale, cost-intensive synchrotron facilities. With a unique laser-based Compact Light Source using inverse Compton scattering, we investigated the translation of this promising radiotherapy technique to a machine of future clinical relevance. We performed in vitro colony-forming assays and chromosome aberration tests in normal tissue cells after microbeam irradiation compared to homogeneous irradiation at the same mean dose using 25 keV X-rays. The microplanar pattern was achieved with a tungsten slit array of 50 μm slit size and a spacing of 350 μm. Applying microbeams significantly increased cell survival for a mean dose above 2 Gy, which indicates fewer normal tissue complications. The observation of significantly less chromosome aberrations suggests a lower risk of second cancer development. Our findings provide valuable insight into the mechanisms of microbeam radiotherapy and prove its applicability at a compact synchrotron, which contributes to its future clinical translation.

For about 30 years, researchers developed prognostic scores and searched for prognostic factors to predict outcomes for cancer patients. The "Combs Prognostic Score" for re-irradiation in recurrent glioma was recently validated and results showed that the score is a significant (p < .001) and reliable predictor for patients undergoing re-irradiation (re-RT). We sought to enhance the score and generated a novel scoring approach, taking into account the information on resection of recurrent tumors, KPS, and tumor volume.The prognostic score was generated based on 209 patients treated between 2002 and 2016 for recurrent glioma at the department of radiation oncology at the Klinikum rechts der Isar, Munich. To further enhance the previously validated Combs Prognostic Score, which uses the prognostic factors primary histology, time between primary RT and re-RT, and age, we added KPS, tumor volume (PTV) and re-resection into the scoring scheme.The median follow-up time was 3.5 months. 67.5% were WHO IV gliomas with a median OS after re-RT of 7.9 months, 17.7% were WHO III gliomas with an OS of 11.3 months and 14.8% were WHO I/II gliomas with an OS of 14.7 months. Multivariate analyses confirmed the prognostic factors KPS (p < .001) and showed a tendency to significance for tumor volume (p = .067) and re-resection (p = .064). The new prognostic score demonstrated a high significance (p < .001).The "New Combs Prognostics Score" is a significant and useful tool to predict the overall effect of re-RT in patients with recurrence gliomas. This modified score offers an even better way to classify patients in clinical routine and prospective clinical trials investigating re-irradiation.

Sulforaphane (SFN), an herbal isothiocyanate enriched in cruciferous vegetables like broccoli and cauliflower, has gained popularity for its antitumor effects in cell lines such as pancreatic cancer. Antiproliferative as well as radiosensitizing properties were reported for head and neck cancer but little is known about its effects in pancreatic cancer cells in combination with irradiation (RT).In four established pancreatic cancer cell lines we investigated clonogenic survival, analyzed cell cycle distribution and compared DNA damage via flow cytometry and western blot after treatment with SFN and RT.Both SFN and RT show a strong and dose dependent survival reduction in clonogenic assays, an induction of a G2/M cell cycle arrest and an increase in γH2AX protein level indicating DNA damage. Effects were more pronounced in combined treatment and both cell cycle perturbation and DNA damage persisted for a longer period than after SFN or RT alone. Moreover, SFN induced a loss of DNA repair proteins Ku 70, Ku 80 and XRCC4.Our results suggest that combination of SFN and RT exerts a more distinct DNA damage and growth inhibition than each treatment alone. SFN seems to be a viable option to improve treatment efficacy of chemoradiation with hopefully higher rates of secondary resectability after neoadjuvant treatment for pancreatic cancer.

Recently, information availability has become more elaborate and wide spread, and treatment decisions are based on a multitude of factors including imaging, molecular or pathological markers, surgical results and patient’s preference. In this context the term Big Data evolved also in health care. The hype is heavily discussed in literature. In interdisciplinary medical specialties, such as radiation oncology, not only a heterogeneous and voluminous amount of data must be evaluated, it is also spread in different styles across various information systems. Exactly this problem is also referred to in many ongoing discussions about Big Data - the three V’s: volume, velocity, and variety. We reviewed 895 articles extracted from the NCBI databases about current developments in electronic clinical data management systems and their further analysis or post-processing procedures. Few articles show first ideas and ways to immediately make use of collected data, particularly imaging data. Many developments can be noticed in the field of clinical trial or analysis documentation, mobile devices for documentation and genomics research. Using Big Data to advance medical research is definitely on the rise. Health care is perhaps the most comprehensive, important and economically viable field of application.

The aim of the thesis is to improve treatment plans of carbon ion irradiation by integrating the tissues' specific [Formula: see text]-values for patients with locally advanced pancreatic cancer (LAPC).Five patients with LAPC were included in this study. By the use of the treatment planning system Syngo RT Planning (Siemens, Erlangen, Germany) treatment plans with carbon ion beams have been created. Dose calculation was based on [Formula: see text]-values for both organs at risk (OAR) and the tumor. Twenty-five treatment plans and thirty-five forward calculations were created. With reference to the anatomy five field configurations were included. Single Beam Optimization (SBO) and Intensity Modulated Particle Therapy (IMPT) were used for optimization. The plans were analyzed with respect to both dose distributions and individual anatomy. The plans were evaluated using a customized index.With regard to the target, a field setup with one single posterior field achieves the highest score in our index. Field setups made up of three fields achieve good results in OAR sparing. Nevertheless, the field setup with one field is superior in complex topographic conditions. But, allocating an [Formula: see text]-value of 2 Gy to the spinal cord leads to critical high maximum doses in the spinal cord. The evaluation of dose profiles showed significant dose peaks at borders of the [Formula: see text]-gradient, especially in case of a single posterior field.Optimization with specific [Formula: see text]-values allows a more accurate view on dose distribution than previously. A field setup with one single posterior field achieves good results in case of difficult topographic conditions, but leads to high maximum doses to the spinal cord. So, field setups with multiple fields seem to be more adequate in case of LAPC, being surrounded by highly radiosensitive normal tissues.

Proton therapy is actively and repeatedly discussed within the framework of particle therapy for the treatment of prostate cancer. The argument in favor of treating the prostate with protons is partly financial: given that small volumes are treated, treat-ment times are low, resulting in a hypothetical high patient throughput. However, such considerations should not form the basis of medical decision-making. There are also physical and biological arguments which further support the use of particle therapy for prostate cancer.The only relevant randomized data currently available is the study by Zietman and colleagues, comparing a high to a low proton boost, resulting in a significant increase in PSA-free survival in the experimental (high-dose) arm. 1 With modern photon treatments and image guided radiotherapy (IGRT) equally high doses can be applied with photons, and thus a randomized trial comparing high-end photons to protons is warranted.For high-linear energy transfer (LET) particles, such as carbon ions, the increase in relative biological effectiveness (RBE) could potentially convert into an improvement in outcome. Additionally, through the physical differences of protons and carbon ions, the steeper dose gradient with carbon ions and the lack of beam broadening in the proton beam lead to a superior dose

INTRODUCTION:To understand if and which patients would be open-minded to Complementary and Alternative Medicine (CAM) use parallel to their oncological treatment. Moreover, we sought to determine which methods are most accepted and which are the primary motivators to use CAM. METHODS:We developed and anonymously conducted a questionnaire for patients in the oncology center (TU Munich). Questions focus on different CAM methods, previous experiences, and willingness to apply or use CAM when offered in a university-based setting. RESULTS:A total of 171 of 376 patients (37.4% women, 62.0% men, 0.6% unknown) participated. This corresponds to a return rate of 45%. Median age was 64 years (17-87 years). Of all participants, 15.2% used CAM during their oncological therapy; 32.7% have used it in the past. The majority (81.9%) was not using CAM during therapy; 55.5% have not used CAM in the past respectively. The analysis revealed a significant correlation between education and CAM use during therapy (r = 0.18; p = 0.02), and CAM use in the past (r = 0.17; p = 0.04). Of all patients using CAM during therapy, favored methods were food supplements (42.3%), vitamins/minerals (42.3%), massage (34.6%). Motivations are especially the reduction of side effect and stress, the positive effect of certain CAM-treatments on the immune system and tumor therapy. Results showed no difference between women and men. Most patients not having had any experience with CAM complain about the deficiency of information by their treating oncologist (31.4%) as well as missing treatment possibilities (54.3%). CONCLUSION:Since many patients believe in study results demonstrating the efficacy of CAM, it stresses our task to develop innovative study protocols to investigate the outcomes of certain CAM on symptom reduction or other endpoints. Thus, prospective trials and innovative evidence-based treatment concepts to include CAM into high-end oncology is what patients demand and what a modern oncology center should offer.

Heat shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor, on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D and natural cytotoxicity receptors (NCRs; NKp44, NKp46, NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after RCT at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume (GTV) was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69+/CD94+ NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that the innate immune system might get activated by soluble Hsp70 in squamous cell but not adeno NSCLC.

While neutron therapy was a highly topical subject in the 70’s and 80’s, today there are only a few remaining facilities offering fast neutron therapy. Nevertheless, up to today more than 30,000 patients were treated with neutron therapy. For some indications like salivary gland tumors and malignant melanoma there is clinical evidence that the addition of Fast Neutron Therapy (FNT) leads to superior local control compared to photon treatment alone. FNT was available in Munich from 1985 until 2000 at the RENT facility (Reactor Neutron Therapy). Patient treatment continued at the new research reactor FRM II in 2007 under improved treatment conditions and today it can still be offered to selected patients as an individual treatment option. As there is a growing interest in high-linear energy transfer (LET) therapy with new hadron therapy centers emerging around the globe, the clinical data generated by neutron therapy might help to develop biologically driven treatment planning algorithms. Also FNT might experience its resurgence as a combinational partner of modern immunotherapies.

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and NSCLC in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2015. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum based radiochemotherapy with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with radiochemotherapy alone. As secondary endpoints overall survival, toxicity, quality-of-life and biological responses will be determined in both study groups.

BACKGROUND: Aim of this study was to evaluate the relative biological effectiveness (RBE) of carbon (12C) and oxygen ion (16O)-irradiation applied in the raster-scanning technique at the Heidelberg Ion beam Therapy center (HIT) based on clonogenic survival in hepatocellular carcinoma cell lines compared to photon irradiation. METHODS: Four human HCC lines Hep3B, PLC, HepG2 and HUH7 were irradiated with photons, 12C and 16O using a customized experimental setting at HIT for in-vitro trials. Cells were irradiated with increasing physical photon single doses of 0, 2, 4 and 6 Gy and heavy ion-single doses of 0, 0.125, 0.5, 1, 2, 3 Gy (12C and 16O). SOBP-penetration depth and extension was 35 mm +/-4 mm and 36 mm +/-5 mm for carbon ions and oxygen ions respectively. Mean energy level and mean linear energy transfer (LET) were 130 MeV/u and 112 keV/um for 12C, and 154 MeV/u and 146 keV/um for 16O. Clonogenic survival was computated and relative biological effectiveness (RBE) values were defined. RESULTS: For all cell lines and both particle modalities α- and β-values were determined. As expected, α-values were significantly higher for 12C and 16O than for photons, reflecting a steeper decline of the initial slope of the survival curves for high-LET beams. RBE-values were in the range of 2.1-3.3 and 1.9-3.1 for 12C and 16O, respectively. CONCLUSION: Both irradiation with 12C and 16O using the raster-scanning technique leads to an enhanced RBE in HCC cell lines. No relevant differences between achieved RBE-values for 12C and 16O were found. Results of this work will further influence biological-adapted treatment planning for HCC patients that will undergo particle therapy with 12C or 16O.