Nowadays, more than ever before, the treatment of cancer patients requires an interdisciplinary approach more than ever. Radiation therapy (RT) has become an indispensable pillar of cancer treatment early on, offering a local, curative treatment option and symptom control in palliative cases.

Supplementary Figure S3. (Top) Hypoxia-M V2 is associated with decreased OS in the TCGApancancer cohort (p<0.002) (Bottom) Hypoxia-M V2 is an independent prognosticator of OS (HR=1.81, p<0.03) after adjusting for demographic and clinical factors.

Supplementary Figure S2. (Top) Hypoxia-M V2 is prognostic in the DKTK-ROG cohort. Patients predicted to have higher tumor hypoxia by Hypoxia-M V2 had higher rates of death (p=0.0097), local recurrence (p=0.0037), distant metastasis (p=0.027) and disease progression (p=0.00096). (Bottom) Hypoxia-M V2 remains an independent prognosticator of OS, LR and disease progression after adjusting for age, smoking status, GTV and anatomical site. Additionally, there is a trend towards higher rates of distant metastasis (HR=2.33, p=0.13)

We prospectively evaluated the effects of stereotactic body radiotherapy (SBRT) on circulating immune cells. Patients with oligo-metastatic and oligo-progressive pulmonary lesions were treated with SBRT with (cSBRT) or without (SBRT group) concurrent systemic treatment (chemotherapy or immune checkpoint blockade) using different fractionation regimes. Immunoprofiling of peripheral blood cells was performed at baseline, during, at the end of SBRT, and at the first and second follow-ups. The study accrued 100 patients (80 with evaluable samples). The proportion of proliferating CD8+ T-cells significantly increased after treatment. This increase remained significant at follow-up in the SBRT group, but not in the cSBRT group and was not detected with doses of >10Gy per fraction indicating that lower doses are necessary to increase proliferating T-cells' frequency. We detected no favorable impact of concurrent systemic treatment on systemic immune responses. The optimal timing of systemic treatment may be post-SBRT to leverage the immune-modulating effects of SBRT.

Accurate segmentation of prostate tumours from PET images presents a formidable challenge in medical image analysis. Despite considerable work and improvement in delineating organs from CT and MR modalities, the existing standards do not transfer well and produce quality results in PET related tasks. Particularly, contemporary methods fail to accurately consider the intensity-based scaling applied by the physicians during manual annotation of tumour contours. In this paper, we observe that the prostate-localised uptake threshold ranges are beneficial for suppressing outliers. Therefore, we utilize the intensity threshold values, to implement a new custom-feature-clipping normalisation technique. We evaluate multiple, established U-Net variants under different normalisation schemes, using the nnU-Net framework. All models were trained and tested on multiple datasets, obtained with two radioactive tracers: [68-Ga]Ga-PSMA-11 and [18-F]PSMA-1007. Our results show that the U-Net models achieve much better performance when the PET scans are preprocessed with our novel clipping technique.

IntroductionProstate cancer (PCa) is a prevalent malignancy in European men, often treated with radiotherapy (RT) for localized disease. While modern RT achieves high success rates, concerns about late gastrointestinal (GI) toxicities persist. This retrospective study aims to identify predictors for late GI toxicities following definitive conventionally fractionated external beam RT (EBRT) for PCa, specifically exploring the dose to the rectal wall.Materials and methodsA cohort of 96 intermediate- to high-risk PCa patients underwent EBRT between 2008 and 2016. Rectum and rectum wall contours were delineated, and 3D dose matrices were extracted. Volumetric and dosimetric indices were computed, and statistical analyses were performed to identify predictors using the Mann–Whitney U-rank test, logistic regression, and recursive feature elimination.ResultsIn our cohort, 15 out of 96 patients experienced grade II late proctitis. Our analysis reveals distinct optimal predictors for rectum and rectum wall (RW) structures varying with α/β values (3.0 and 2.3 Gy) across prescribed doses of 68 to 76 Gy. Despite variability, RW predictors demonstrate greater consistency, notably V68Gy[%] to V74Gy[%] for α/β 3.0 Gy, and V68Gy[%] to V70Gy[%] for α/β 2.3 Gy. The model with α/β 2.3 Gy, featuring RW volume receiving 70 Gy (V70Gy[%]), stands out with a BIC value of 62.92, indicating its superior predictive effectiveness. Finally, focusing solely on the rectum structure, the V74Gy[%] emerges the best predictor for α/β 3.0 Gy, with a BIC value of 66.73.ConclusionThis investigation highlights the critical role of V70Gy[%] in the rectum wall as a robust predictor for grade II late gastrointestinal (GI) toxicity following external beam radiation therapy (EBRT) for prostate cancer (PCa). Furthermore, our findings suggest that focusing on the rectum wall specifically, rather than the entire rectum, may offer improved accuracy in assessing proctitis development. A V70Gy (in EQD2 with α/β 2.3 Gy) of ≤5% and if possible ≤1% for the rectal wall should be achieved to minimize the risk of late grade II proctitis.

Although grading is defined by the highest histological grade observed in a glioma, most high-grade gliomas retain areas with histology reminiscent of their low-grade counterparts. We sought to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) validate the high mobility group protein B2 (HMGB2) as a key player in tumor progression and as a prognostic/predictive biomarker for diffuse astrocytomas. We performed liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple areas of adult-type astrocytomas and validated our finding in multiplatform-omics studies and high-throughput IHC analysis. LC-MS/MSdetected proteomic signatures characterizing glioma evolution towards higher grades associated with, but not completely dependent, on IDH status. Spatial heterogeneity of diffuse astrocytomas was associated with dysregulation of specific molecular pathways, and HMGB2 was identified as a putative driver of tumor progression, and an early marker of worse overall survival in grades 2 and 3 diffuse gliomas, at least in part regulated by DNA methylation. In grade 4 astrocytomas, HMGB2 expression was strongly associated with proliferative activity and microvascular proliferation. Grounded in proteomic findings, our results showed that HMGB2 expression assessed by IHC detected early signs of tumor progression in grades 2 and 3 astrocytomas, as well as identified GBMs that had a better response to the standard chemoradiation with temozolomide.

Background:The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods:A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results:Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). Conclusions:The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration:NCT05871021.

The purpose of this review is to address the rising incidence of cerebral metastases in breast cancer patients, which is now estimated to affect 30–40

Hintergrund Die ProtecT Studie hat durch PSA-Testung 2664 Patienten mit lokalisiertem Prostatakarzinom (PCa) diagnostiziert und 1643 von Ihnen zwischen aktivem Monitoring (AM) (n = 545), Prostatektomie (RPE) (n = 553) und Strahlentherapie (RT) (

Purpose/Objective Recent studies have shown a potential function of the gut microbiome in the immunological modulation of anti-cancer treatments. However, the role of the oral microbiome in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing radiotherapy in terms of radiation-induced toxicities as well as tumor response is largely unknown. Here, we examined a potential influence of the oral microbiome composition on acute radiation-induced mucositis and locoregional tumor control (LRC). Material/Methods Saliva samples of two independent prospective trials (SALIVA and ZiSStrans trial [DRKS00012947]), in which HNSCC patients undergoing (chemo)radiation were enrolled, were analyzed in terms of their oral microbiome composition. In both trials, unstimulated saliva was collected before the first radiotherapy application and stored at -80°C. Baseline oral microbiome was examined using V3-4 16S rRNA sequencing, and bioinformatic analyses were carried out in R (v4.3.1). Kaplan-Meier analyses were carried out regarding LRC. Results A total of 106 HNSCC patients (53 in the SALIVA trial, 53 in the ZiSStrans trial), who were treated with definitive (chemo)radiation, had stored saliva samples available and could be analyzed. Median age was 60 years (SALIVA) and 61 years (ZiSStrans), most common tumor localization was the oropharynx (n=25 in both trials), and majority of patients had a positive smoking history (n=29 [SALIVA], n=27 [ZiSStrans]). Fourty-four (83%) and 30 (57%) patients in the SALIVA and ZiSStrans trial developed acute grade 3-4 mucositis during treatment, respectively. Grade 3-4 mucositis occurred after a median radiation dose of 34 Gy (SALIVA) and 31.5 Gy (ZiSStrans). 2-year LRC rate was 69% and 72% in the SALIVA and ZiSStrans trial, respectively. No differences in alpha diversity were found in terms of patient age, sex, T stage, N stage, tumor localization and smoking status in both trials (p>0.05), neither did the beta diversity analysis reveal relevant differences between these groups. Furthermore, neither alpha nor beta diversity was associated with development of grade 3-4 mucositis in the two trials (p>0.05). In the ZiSStrans trial, Shannon index was significantly higher in patients with no locoregional recurrence after 2 years (p=.03), which was not validated in the SALIVA trial (p=0.35). Lower Lachnoanaerobaculum abundance (p=0.02 [SALIVA], p=0.03 [ZiSStrans], ALDEx2, Wilcoxon-test) were associated with increased 2-year locoregional recurrence rates in both the SALIVA and ZissTrans trial. 2-year LRC was 96% (SALIVA) and 85% (ZiSStrans) in patients with Lachnoanaerobaculum abundance above the median value versus 35% (SALIVA) and 58% (ZiSStrans) in patients with Lachnoanaerobaculum abundance below the median (p<0.05, log-rank). Conclusion While we could not find an association between the baseline oral microbiome and development of acute grade 3-4 mucositis, we identified higher Lachnoanaerobaculum abundance associated with increased LRC after radiotherapy in both independent prospective trials. In terms of oral mucositis, further in-depth analyses of the oral microbiome composition in both prospective trials are ongoing to examine potential associations between distinct bacterial genera and the onset of grade 3-4 mucositis. Prospective longitudinal analyses of the alterations in patients’ oral microbiome composition are necessary in order to improve the understanding of the complex interactions between the microbiome and the immune system in patients with HNSCC undergoing radiotherapy.

PURPOSE:Mesenchymal stromal cells (MSCs) within the glioblastoma microenvironment have been shown to promote tumor progression. Tumor Treating Fields (TTFields) are alternating electric fields with low intensity and intermediate frequency that exhibit anti-tumorigenic effects. While the effects of TTFields on glioblastoma cells have been studied previously, nothing is known about the influence of TTFields on MSCs. METHODS:Single-cell RNA sequencing and immunofluorescence staining were employed to identify glioblastoma-associated MSCs in patient samples. Proliferation and clonogenic survival of human bone marrow-derived MSCs were assessed after TTFields in vitro. MSC' characteristic surface marker expression was determined using flow cytometry, while multi-lineage differentiation potential was examined with immunohistochemistry. Apoptosis was quantified based on caspase-3 and annexin-V/7-AAD levels in flow cytometry, and senescence was assessed with ß-galactosidase staining. MSCs' migratory potential was evaluated with Boyden chamber assays. RESULTS:Single-cell RNA sequencing and immunofluorescence showed the presence of glioblastoma-associated MSCs in patient samples. TTFields significantly reduced proliferation and clonogenic survival of human bone marrow-derived MSCs by up to 60% and 90%, respectively. While the characteristic surface marker expression and differentiation capacity were intact after TTFields, treatment resulted in increased apoptosis and senescence. Furthermore, TTFields significantly reduced MSCs' migratory capacity. CONCLUSION:We could demonstrate the presence of tumor-associated MSCs in glioblastoma patients, providing a rationale to study the impact of TTFields on MSCs. TTFields considerably increase apoptosis and senescence in MSCs, resulting in impaired survival and migration. The results provide a basis for further analyses on the role of MSCs in glioblastoma patients receiving TTFields.

Abstract Purpose The number of older adults with head and neck squamous cell carcinoma (HNSCC) is continuously increasing. Older HNSCC patients may be more vulnerable to radiotherapy-related toxicities, so that extrapolation of available normal tissue complication probability (NTCP) models to this population may not be appropriate. Hence, we aimed to investigate the correlation between organ at risk (OAR) doses and chronic toxicities in older patients with HNSCC undergoing definitive radiotherapy. Methods Patients treated with definitive radiotherapy, either alone or with concomitant systemic treatment, between 2009 and 2019 in a large tertiary cancer center were eligible for this analysis. OARs were contoured based on international consensus guidelines, and EQD2 doses using α/ß values of 3 Gy for late effects were calculated based on the radiation treatment plans. Treatment-related toxicities were graded according to Common Terminology Criteria for Adverse Events version 5.0. Logistic regression analyses were carried out, and NTCP models were developed and internally validated using the bootstrapping method. Results A total of 180 patients with a median age of 73 years fulfilled the inclusion criteria and were analyzed. Seventy-three patients developed chronic moderate xerostomia (grade 2), 34 moderate dysgeusia (grade 2), and 59 moderate-to-severe (grade 2–3) dysphagia after definitive radiotherapy. The soft palate dose was significantly associated with all analyzed toxicities (xerostomia: OR = 1.028, dysgeusia: OR = 1.022, dysphagia: OR = 1.027) in the multivariable regression. The superior pharyngeal constrictor muscle was also significantly related to chronic dysphagia (OR = 1.030). Consecutively developed and internally validated NTCP models were predictive for the analyzed toxicities (optimism-corrected AUCs after bootstrapping: AUCxerostomia=0.64, AUCdysgeusia=0.60, AUCdysphagia=0.64). Conclusions Our data suggest that the dose to the soft palate is associated with chronic moderate xerostomia, moderate dysgeusia and moderate-to-severe dysphagia in older HNSCC patients undergoing definitive radiotherapy. If validated in external studies, efforts should be undertaken to reduce the soft palate dose in these patients.

Background To assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction. Methods This multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65–92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated. Results Thirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%). Conclusions In our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.

Background and Purpose: In patients requiring prophylactic cranial irradiation (PCI) or whole-brain radiotherapy (WBRT) for brain metastases (BMs), hippocampal avoidance (HA) has been shown to preserve neurocognitive function and quality of life. Here, we aim to estimate the incidence of hippocampal and perihippocampal BMs and the subsequent risk of local undertreatment in patients undergoing hippocampal sparing radiotherapy. Materials and Methods: MEDLINE, Embase, and Scopus were searched with the terms "Hippocampus", "Brain Neoplasms", and related terms. Trials reporting on the incidence of hippocampal and/or perihippocampal BMs or hippocampal failure rate after PCI or WBRT were included. Results: Forty records were included, encompassing a total of 5,374 patients with over 32,570 BMs. Most trials employed a 5 mm margin to define the HA zone. In trials reporting on BM incidence, 4.4 % (range 0 - 27 %) and 9.2 % (3 - 41 %) of patients had hippocampal and perihippocampal BMs, respectively. The most common risk factor for hippocampal BMs was the total number of BMs. The reported failure rate within the HA zone after HAPCI or HA-WBRT was 4.5 % (0 - 13 %), salvageable with radiosurgery in most cases. SCLC histology was not associated with a higher risk of hippocampal failure (OR = 2.49; p = 0.23). In trials comparing with a conventional (non-HA) PCI or WBRT group, HA did not increase the hippocampal failure rate (OR = 1.90; p = 0.17). Conclusion: The overall incidence of hippocampal and perihippocampal BMs is considerably low, with a subsequent low risk of local undertreatment following HA-PCI or HA-WBRT. In patients without involvement, the hippocampus should be spared to preserve neurocognitive function and quality of life.

Background: This study aimed to predict lesion-specific outcomes after stereotactic radiotherapy (SRT) in patients with brain metastases from malignant melanoma (MBM), using clinical, dosimetric, and pretherapeutic MRI data. Methods: In this multicenter retrospective study, 517 MBM from 130 patients treated with single-fraction or hypofractionated SRT at three centers were analyzed. From contrast-enhanced T1-weighted MRI, 1576 radiomic features (RF) were extracted per lesion - 788 from the gross tumor volume (GTV) and 788 from a 3 mm peritumoral margin. Clinical, dosimetric and RF data from one center were used for feature selection and model development via nested cross-validation employing an ensemble learning approach; external validation used data from the other two centers. Results: Local failure occurred in 72/517 lesions (13.9

Background: Hypofractionated radiotherapy (hRT) can induce a T cell -mediated abscopal effect on non -irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). However, clinically, this effect is still rare, and ICB-mediated adverse events are common. Lenalidomide (lena) is an anti-angiogenic and immunomodulatory drug used in the treatment of hematologic malignancies. We here investigated in solid tumor models whether lena can enhance the abscopal effect in double combination with hRT. Methods: In two syngeneic bilateral tumor models (B16-CD133 melanoma and MC38 colon carcinoma), the primary tumor was treated with hRT. Lena was given daily for 3 weeks. Besides tumor size and survival, the dependence of the antitumor effects on CD8+ cells, type -I IFN signaling, and T cell costimulation was determined with depleting or blocking antibodies. Tumor -specific CD8+ T cells were quantified, and their differentiation and effector status were characterized by multicolor flow cytometry using MHC-I tetramers and various antibodies. In addition, dendritic cell (DC) -mediated tumor antigen cross -presentation in vitro and directly ex vivo and the composition of tumor -associated vascular endothelial cells were investigated. Results: In both tumor models, the hRT/lena double combination induced a significant abscopal effect. Control of the non -irradiated secondary tumor and survival were considerably better than with the respective monotherapies. The abscopal effect was strongly dependent on CD8+ cells and associated with an increase in tumor -specific CD8+ T cells in the non -irradiated tumor and its draining lymph nodes. Additionally, we found more tumor -specific T cells with a stem -like (TCF1+ TIM3- PD1+) and a transitory (TCF1-TIM3+CD101-PD1+) exhausted phenotype and more expressing effector molecules such as GzmB, IFN gamma, and TNF alpha. Moreover, in the non -irradiated tumor, hRT/lena treatment also increased DCs cross -presenting a tumor model antigen. Blocking type -I IFN signaling, which is essential for cross -presentation, completely abrogated the abscopal effect. A gene expression analysis of bone marrow -derived DCs revealed that lena augmented the expression of IFN response genes and genes associated with differentiation, maturation (including CD70, CD83, and CD86), migration to lymph nodes, and T cell activation. Flow cytometry confirmed an increase in CD70+ CD83+ CD86+ DCs in both irradiated and abscopal tumors. Moreover, the hRT/lena-induced abscopal effect was diminished when these costimulatory molecules were blocked simultaneously using antibodies. In line with the enhanced infiltration by DCs and tumor -specific CD8+ T cells, including more stem -like cells, hRT/lena also increased tumor -associated high endothelial cells (TA-HECs) in the non -irradiated tumor. Conclusions: We demonstrate that lena can augment the hRT-induced abscopal effect in mouse solid tumor models in a CD8 T cell- and IFN-I-dependent manner, correlating with enhanced anti -tumor CD8 T cell immunity, DC cross -presentation, and TA-HEC numbers. Our findings may be helpful for the planning of clinical trials in (oligo)metastatic patients.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.