PURPOSE:To determine the benefit, measured as complete removal of a tumor so that no tumor cells are detectable during histopathologic examination of the resection margin (R0 resection rate), of induction chemotherapy plus chemoradiotherapy (CRT) compared with chemotherapy alone for unresectable pancreatic tumors. PATIENTS AND METHODS:CONKO-007, an investigator-initiated open-label, multicentric, phase III randomized clinical trial, enrolled 525 patients with unresectable tumors, and 495 patients received induction chemotherapy (402 with fluorouracil, irinotecan, and oxaliplatin [FOLFIRINOX] and 93 with gemcitabine). Patients without progression after 3 months of induction chemotherapy (n = 336) were randomly assigned for continuation of the same chemotherapy (n = 167) or CRT (n = 169; 50.4Gy concurrently with gemcitabine). Resectability was centrally reassessed by a panel of surgeons. Surgery was recommended if possible. After an interim analysis, the primary end point was changed from overall survival (OS) to overall R0 resection rate because of slow recruitment. The median follow-up was 76 months. Important planned secondary end points were R0 resection rate in the surgically treated population and OS. RESULTS:The primary end point (overall R0 resection rate) was not significantly different between treatment arms with 25% (43 of 169) in the CRT arm versus 18% in the chemotherapy arm (30 of 167; P = .113). Secondary end point analysis showed that surgery was performed equally often (P = .91); R0 resection rate in patients who underwent surgery was higher after CRT, 69.4% (43 of 62) compared with chemotherapy alone: 50.0% (30 of 60 patients, P = .04). Other parameters of resection (ratio of R0/R1/R2/no resection) also favored CRT (P = .02). No difference in OS was seen between treatment arms (hazard ratio [HR], 0.937 [95% CI, 0.747 to 1.174]; P = .57; randomly assigned intention-to-treat patients). Surgery was associated with longer OS (P < .001, HR, 0.525 [95% CI, 0.408 to 0.676]). CONCLUSION:Although not improving overall R0 resection rate or survival, CRT enables a R0 resection in surgically treated patients more often than chemotherapy alone.

Background Even in the area of immune therapies, multimodal treatment of head and neck squamous cell carcinoma (HNSCC) is a big challenge. Small molecule kinase inhibitors (smKI), that target the DNA damage repair (DDR) system, have been described to alter, in addition to their radio-sensitizing effects, the immune phenotype of HNSCC. Thereby, the ATM and ATR kinases are key mediators of the DDR. However, the consequences these changes of the tumor cell phenotype have on immune cells are still poorly understood. Consequently, we here investigated how single and combination treatment of HNSCC cells with an ATM (ATMi) or an ATR inhibitor (ATRi) in combination with hypo-fractionated radiotherapy (RT) differently affects the activation of human cytotoxic CD8 + T cells regarding proliferation, activation marker surface expression and cytokine secretion. Methods Human papillomavirus (HPV)-negative (Cal-33, HSC4) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC tumor cells were treated with hypo-fractionated RT of 2 x 5 Gray (Gy) in combination with AZD0156 (ATMi) or VE-822 (ATRi) and co-cultured with human CD8 + T cells for 96 h. T cell activation was quantified by CFSE-signal detected proliferation rates, activation marker expression on surfaces of the T cells, and by secretion of interferon gamma (IFN-γ) in the supernatants of the co-cultures via ELISA. Results In 2D co-cultivation settings RT-, HPV-status- and inhibitor-dependent influences on Tcell activation were observed. Thereby, a stronger activation of T cells could be achieved after co-cultivation with ATRi-treated HNSCC tumor cells compared to ATMi. However, the addition of immune checkpoint inhibitors did not lead to enhanced T cell activation. In 3D co-cultures, a shift from RT-induced to a more inhibitor-induced effect on human T cells was visible and confirmed the superiority of ATRi, especially in combination with additional RT. Conclusion The combination of RT + ATRi resulted in increased T cell activation compared to the combined treatment with ATMi, respectively. This suggests an advantage of ATRi in comparison to ATMi in combination with RT for induction of beneficial anti-tumor immune responses in HNSCC.

BACKGROUND:Intraoperative cone-beam computed tomography (CBCT) provides a valuable option for accurate three-dimensional applicator positioning in gynecologic brachytherapy, but is associated with radiation exposure and increased intervention time especially in case of repeated CBCT imaging being required for creating a sufficient implant arrangement. PURPOSE:To reduce the need for multiple CBCT scans for corresponding applicator verification, this work proposes two methods for needle path navigation, including corrections of potential bending in situ, by combining infrared tracking with planar x-ray imaging for enabling accurate intraoperative needle guidance. METHODS:An examined 200 mm brachytherapy needle was rigidly mounted on an infrared-reflective tracking tool to enable real time tracking. Two planar x-ray images, acquired from varying distinct angles, were used to determine the exact 3D position of the needle tip region via backprojection. A spline was fitted through the obtained coordinates to reconstruct the full needle path. Based on this, only a single initial CBCT scan was required to visualize the predicted needle path within this scan. Additionally, a second approach for needle prediction was presented focusing on only one planar x-ray image by incorporating prior needle bending information from the initial CBCT scan. Both methods were evaluated in preclinical studies and validated against a corresponding ground-truth obtained from CBCT. RESULTS:The proposed method considering two planar x-ray images successfully reconstructed the needle path with deviations of less than 1 mm from the CBCT reference scan, when using at least 20° offset between the x-ray image acquisitions. The single-scan approach, using prior bending information, yielded promising results with deviations at the tip of below 1.3 mm. CONCLUSIONS:Both described methods demonstrated their feasibility in preclinical studies, showing potential to improve and accelerate clinical implantation workflows by means of needle navigation in the future.

Head and neck squamous cell carcinoma (HNSCC) is a relevant cancer entity with two main risk factors. Human papilloma virus (HPV)-positive ones are induced by virus infection and generally have a good prognosis due to their chemo- and radiosensitivity. In contrast, HPV-negative HNSCCs are primarily caused by tobacco and alcohol abuse; patients have a poor prognosis resulting in the need of innovative targeted and combinatory treatment options. Therefore, we combined the Mre11-Rad50-Nbs1 (MRN) inhibitor Mirin with ionizing radiation (IR). Our hypothesis is that the inhibition of the cancer cells’ DNA damage response (DDR) by Mirin leads to reduced repair capacity and a radiosensitization of the cancer cells. We investigated the effect of Mirin in combination with IR on five HPV-negative and two HPV-positive HNSCC cell lines and one primary fibroblast cell line - serving as healthy control - in several functional assays. We suggest – on the one hand - that Mirin shows a trend towards radiosensitizing effects regarding cell death, cell cycle distribution, colony formation, and deoxyribonucleic acid (DNA) damage in HPV-negative HNSCC cell lines but not in HPV-positive ones. On the other hand, the healthy control was nearly unaffected by the combinatory treatment which indicates low side effects. It is useful to generate a deeper insight into the underlying cellular mechanisms of Mirin response in future studies and further validate Mirin’s potential radiosensitizing effect in HPV-negative HNSCCs.

Low dose radiation therapy (LDRT) is commonly applied for its pain and symptom-relieving effects in the treatment of different benign diseases, such as chronic degenerative and inflammatory, or hyperproliferative disorders. Most clinical trials report a beneficial therapeutic effect of LDRT and further, robust preclinical evidence on the biological modes of action of LDRT is existent. In chronic degenerative and inflammatory diseases such as osteoarthritis, LDRT can ameliorate inflammatory processes and impacts positively on the bone metabolism. A key mechanism is the modulation of the endothelium and the phenotype of macrophages. In the bone, the deposition of new bone matrix is supported, while bone degradation is diminished. In hyperproliferative disorders, the main mode of action is the inhibition of the differentiation and proliferation of fibroblasts and myofibroblasts, along with a modulation of inflammatory mediators, such as cytokines. Even though comprehensive preclinical evidence supports the use of LDRT, biological mechanistic insights from randomized clinical trials is mostly missing for LDRT and indicates a significant translational gap. Apart from preclinical data, the evidence for LDRT is based largely on observational clinical trials, with only limited randomized and placebo-controlled trials available. In the future, rigorously designed randomized disease-specific studies with standardized protocols, translational research programs and objectifiable clinical and biological endpoints are needed to establish LDRT as precise and evidence-based therapy.

Abstract Increased radiosensitivity can cause adverse radiotherapy effects. Heterozygote variants in breast cancer risk genes increase cancer risk and may affect radiosensitivity. This study assessed their impact on individual radiosensitivity to determine the radiation risk for gene carriers. Radiosensitivity was analyzed in 273 patients with breast cancer risk gene variants. Using fluorescence in situ hybridization (FiSH), chromosomal aberrations were quantified as breaks per metaphase (B/M) after ex vivo irradiation of blood lymphocytes. Results were compared with healthy controls and breast cancer cases, both without confirmed non-carrier status, limiting gene-specific conclusions. Gene carriers showed slightly increased radiosensitivity (mean 0.488 B/M ± 0.134) compared with healthy controls (0.411 B/M ± 0.088; p < 0.0001) but similar to breast cancer control group (0.498 B/M ± 0.192; p = 0.563). In BRCA1/2 carriers, radiosensitivity was slightly increased, while single cases in BARD1, RAD51, and MSH variants suggested a possible increase (p < 0.003). Radiosensitivity was influenced by gene locus, variant type, age, and cancer history. 24.5% of carriers exceeded a cutoff of ≥ 0.55 B/M, where dose reduction could be considered. Radiosensitivity of breast cancer risk gene carriers varies and is slightly increased. Individuals with increased radiosensitivity risk should consider testing.

ABSTRACT:Radiotherapy is an established treatment for low-grade primary cutaneous B-cell lymphoma. Recommendations on its use differ internationally, which prompted our group to conduct this analysis. Twenty-two institutions participated in this international study. Patient eligibility required a diagnosis of limited (T1/T2) primary cutaneous marginal zone or follicle center lymphoma treated with radiotherapy between 1995 and 2023. Data were collected retrospectively until February 2024 within the framework of the International Lymphoma Radiation Oncology Group. Overall, 535 patients were analyzed. Predominant locations were the head (40%) and trunk (36%). Radiotherapy had a median dose of 24 Gy in fractions of 2 Gy. Complete responses were observed in 91% at a median time of 3.6 months following radiotherapy. There was no statistically significant difference between treatments ≤4 Gy and >4 Gy for complete or overall response rates (P = .077 and P = .056, respectively). However, there was an inferior duration of local control with ≤4 Gy (5-year local control 73% ± 12% vs 96% ± 2%; P< .001). Radiation dose was the main prognostic factor in the univariate and multivariable Cox analysis; however, higher doses did not translate into an overall survival benefit. Toxicities rarely exceeded grade 2 but were more frequent in the >4 Gy group. Radiotherapy remains an effective treatment option for indolent skin lymphoma with low toxicity. High response rates are observed with low doses of ≤4 Gy. In comparison to conventional doses, these treatments have a shorter duration of local control but a favorable toxicity profile.

Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) remain challenging due to their reduced radiosensitivity. Targeting the DNA damage response (DDR) with kinase inhibitors may enhance tumor susceptibility to radiotherapy (RT). While RT is known to alter the immune phenotype of HNSCC cells, its impact on innate immune responses, particularly on natural killer (NK) cells, remains unclear. We therefore investigated how RT combined with ATM or ATR inhibition—key DDR kinases—affects NK cell-mediated killing and activation. The tumor cell lines HSC4 and Cal33 (both HPV-negative) and UM-SCC-47 and UD-SCC‑2 (both HPV-positive) were treated with the DDR inhibitors VE-822 (ATRi) and AZD0156 (ATMi) and hypofractionated RT (2 × 5 Gy). After co-cultivation with primary human NK cells, tumor cell death was measured using flow cytometry after 24 h. Further, NK cell activation markers and the supernatant of tumor cell–NK cell co-cultures were measured and the effect of immune checkpoint inhibitors (durvalumab, monalizumab) was additionally investigated. Particularly the HPV-negative HSC4 cells pretreated with either ATMi or RT + ATMi showed significantly increased killing by NK cells. Reduced secretion of granulysin by NK cells was mainly found in the co-cultures of HPV-negative HNSCC treated with ATRi. Treatment with the immune checkpoint inhibitor durvalumab (anti-PD-L1) did not result in significant augmentation of NK cell-induced tumor cell killing in this setting. Conversely, treatment with monalizumab (anti-NKG2A) resulted in a modest increase. Natural killer cells showed only a limited contribution to the killing of HNSCC cells pretreated with RT or RT + DDRi. However, a subset of patients with head and neck tumors—such as those represented by the HSC4 model—might still benefit from combining RT with ATMi rather than ATRi to enhance NK cell-mediated tumor killing.

Introduction Salivary gland carcinomas (SGC) are rare tumours. The term SGC is not more than an umbrella for a variety of histogenetically, morphologically and biologically distinct entities. Accordingly, SGCs have not been sufficiently investigated to date. Their rarity makes it difficult to reach high patient numbers for individual entities in clinical studies, leading to pooling patients with different histological subtypes to attain sufficient participants. The different histological subtypes of SGC differ significantly in their clinicopathological features, such as their grading, their occurrence and their outcome. SGCs are usually stratified into low-grade, intermediate-grade or high-grade tumours. In most kinds of SGC, specific targetable molecular markers are lacking. The inclusion of immunotherapy (IT), however, might improve the outcome of patients suffering from high-grade SGCs. In order to integrate IT as a therapeutic option for SGC and to facilitate therapeutic decisions based on tumour (immune) biology, predictive and prognostic immunological biomarkers are indispensable.Methods and analysis In this prospective study, 500 patients will be enrolled, who are distributed in three arms. The observational cohort includes patients with malignant salivary gland tumours, whereas patients with benign tumours of a salivary gland are grouped in the control group 1. In the control cohort, 2 patients do not have a salivary gland tumour but have a planned functional surgery of the nose or ear or a maxillofacial surgery. The local immune status from the tumour tissue and the microbiome will be sampled before treatment. In addition, the systemic immune status from peripheral blood will be analysed before and after surgery and after the adjuvant and definitive chemoradiotherapy, if applicable. Clinical baseline characteristics and outcome parameters will additionally be collected. Data mining and modelling approaches will finally be applied to identify interactions of local and systemic immune parameters and to define predictive and prognostic immune signatures based on the evaluated immune markers.Ethics and dissemination Approval from the institutional review board of the Friedrich-Alexander-Universität Erlangen-Nürnberg was granted in September 2023 (application number 23-292-B). The results will be disseminated to the scientific audience and the general public via presentations at conferences and publication in peer-reviewed journals.Trial registration number NCT06047236.

Background and purpose:Consolidation durvalumab, standard-of-care treatment for patients with unresectable stage III non-small-cell lung cancer (NSCLC) and no disease progression after chemoradiotherapy, may be associated with pneumonitis. We performed exploratory analyses of radiotherapy patterns and potential risk factors for symptomatic pneumonitis (SP) in PACIFIC-R. Materials and methods:PACIFIC-R is an ongoing, international, observational study based on medical chart data for patients in the durvalumab early access program. Patients with no missing data for candidate SP risk factors were included. SP was defined as a pneumonitis event (any cause) of grade ≥ 2 or requiring corticosteroids. Multivariable logistic regression identified variables associated with SP during durvalumab treatment; sensitivity analyses used a Cox proportional hazards model to account for time to SP. Results:Analyses included 268 patients; most received concurrent (86.6%) versus sequential (13.4%) chemoradiotherapy and intensity-modulated (IMRT; 66.8%) versus three-dimensional conformal (25.7%) radiotherapy, with between-country differences. Patients receiving IMRT were older, more frequently had nonsquamous histology, and had larger tumors. Fifty-two patients (19.4%) had SP during durvalumab treatment. Higher mean lung radiotherapy dose (log transformed) and prior chronic obstructive pulmonary disease (COPD) were associated with higher SP risk, with odds ratios (95% confidence interval [CI]) of 4.73 (1.66-15.07) and 2.60 (1.21-5.65), respectively, and hazard ratios (95% CI) of 3.28 (1.54-6.95) and 1.93 (1.04-3.56), respectively. Conclusions:Concurrent chemoradiotherapy and IMRT were the most common radiotherapy approaches. Higher mean lung radiotherapy dose and prior COPD were associated with higher SP risk during consolidation durvalumab for unresectable stage III NSCLC.

IntroductionLarge language models (LLM) have shown great potential in clinical decision support and medical education. GPT-5 is a novel LLM system that has been specifically marketed towards oncology use. This study comprehensively benchmarks GPT-5 for the field of radiation oncology.MethodsPerformance was assessed using two complementary benchmarks: (i) the American College of Radiology Radiation Oncology In-Training Examination (TXIT, 2021), comprising 300 multiple-choice items, and (ii) a curated set of 60 authentic radiation oncologic vignettes representing diverse disease sites and treatment indications. For the vignette evaluation, GPT-5 was instructed to generate structured therapeutic plans and concise two-line summaries. Four board-certified radiation oncologists independently rated outputs for correctness, comprehensiveness, and hallucinations. Inter-rater reliability was quantified using Fleiss’ κ. GPT-5–14 results were compared to published GPT-3.5 and GPT-4 baselines.ResultsOn the TXIT benchmark, GPT-5 achieved a mean accuracy of 92.8%, outperforming GPT-4 (78.8%) and GPT-3.5 (62.1%). Domain-specific gains were most pronounced in dose specification and diagnosis. In the vignette evaluation, GPT-5’s treatment recommendations were rated highly for correctness (mean 3.24/4, 95% CI: 3.11–3.38) and comprehensiveness (3.59/4, 95% CI: 3.49–3.69). Hallucinations were rare, flagged in 10.0% of all individual reviewer assessments (24 of 240), and no patient case reached majority consensus for their presence. Inter-rater agreement was low (Fleiss’ κ 0.083 for correctness), reflecting inherent variability in clinical judgment. Errors clustered in complex scenarios requiring precise trial knowledge or detailed clinical adaptation.DiscussionGPT-5 clearly outperformed prior model variants on the radiation oncology multiple-choice benchmark. Although GPT-5 exhibited favorable performance in generating real-world radiation oncology treatment recommendations, correctness ratings indicate room for further improvement. While hallucinations were infrequent, the presence of substantive errors underscores that GPT-5-generated recommendations require rigorous expert oversight before clinical implementation. In addition, considerable inter-rater variability highlights the challenge of achieving consistent expert evaluation.

Background/Objectives: Soft tissue sarcomas are rare, heterogeneous tumors with limited therapeutic options and suboptimal outcomes in advanced stages. Lurbinectedin is a promising new antineoplastic alkylating agent. This study investigates its cytotoxic effects and its potential as a radiosensitizing agent on soft tissue sarcoma. Methods: Four soft tissue sarcoma cell lines were treated with lurbinectedin alone or in combination with ionizing radiation. Single-dose irradiation in a 4-day protocol was compared with prolonged treatment and an additional fractionated ionizing radiation scheme in a 6-day protocol. Cellular responses were analyzed by flow cytometry for apoptosis (Annexin V)/necrosis (7AAD) and cell cycle (Hoechst), clonogenic cell survival, and scratch assays for cell migration. Results: In the 4-day protocol, lurbinectedin induced G2/M arrest in all cell lines (p = 0.029) and significantly increased apoptosis/necrosis (p = 0.029) in SW-872. Lurbinectedin-treatment resulted in a decrease (p ≤ 0.002) of clonogenic cells in all cell lines. In the scratch assay, cell migration was delayed in two cell lines (p = 0.048) after lurbinectedin-treatment. Additional radiotherapy had no significant effect compared to lurbinectedin-monotherapy in apoptosis/necrosis and G/2M arrest in the 4-day protocol, clonogenic cell assay, and scratch assay. In the 6-day protocol, lurbinectedin induced an increase (p = 0.029) in G2/M arrest in all cell lines and apoptosis/necrosis in three cell lines, while resulting in a decrease (p < 0.001) of clonogenic cells. Additional radiotherapy had a significant effect on the decrease in clonogenic cells (p ≤ 0.048) in two cell lines but did not increase G2/M arrest and apoptosis/necrosis. Conclusions: Lurbinectedin had strong effects on three of the selected cell lines by inducing G2/M arrest, promoting apoptosis/necrosis, and reducing clonogenic survival, suggesting that it may be a promising chemotherapeutic agent in soft tissue sarcoma treatment. The effect on the fourth cell line was limited, as well as the effect on cell migration. Single-dose irradiation occasionally interfered with the effects of Lurbinectedin, whereas adding fractionated irradiation caused an additional decrease in clonogenic survival, indicating that the combination of Lurbinectedin with fractionated ionizing radiation may have promising effects.