Pancreatic cancer remains one of the most treatment-refractory malignancies, displaying profound resistance to chemotherapy and radiotherapy. While the benefit of photon radiotherapy remains debated, heavy-ion modalities such as carbon ions show promise in overcoming radioresistance. Here, we extend this paradigm by evaluating oxygen-ion beam irradiation in pancreatic cancer cells and directly comparing its efficacy with carbon ions and photons. Oxygen ions induce higher clonogenic cell killing in human pancreatic cancer cells, with a relative biological effectiveness (RBE) around two times higher for oxygen ions than for carbon ions. Moreover, their growth-inhibitory effects are substantially less dependent on gemcitabine-mediated radiosensitization than those of carbon ions or photons. Mechanistically, oxygen-ion irradiation induces greater direct and complex DNA damage, slows down DNA repair kinetics, and augments apoptosis following combined gemcitabine treatment, accompanied by sustained activation of DNA damage response pathways. These findings delineate the distinct radiobiological advantages of oxygen ion beam irradiation in pancreatic cancer and highlight their potential as a powerful modality to overcome radioresistance, providing a compelling rationale for further translational and clinical exploration.

Background/Aim: Adjuvant radiotherapy is a key part of the overall treatment plan for local advanced breast cancer. In this study, we investigated the long-term clinical outcomes of helical tomotherapy (hT) following mastectomy. Patients and Methods: Female patients (n=38) with locally advanced or lymph node-positive breast cancer who had undergone mastectomy, sentinel-node biopsy, and/or axillary lymph node dissection were included in this singlecenter analysis. Postmastectomy radiation therapy (PMRT) to involved chest wall was applied by using hT with cumulative dose of 50.4 Gy. Lymphatic drainage pathways were included when they contained tumor cells. Generally, additional mastectomy scar boost irradiation (10 Gy) was applied up to a cumulative dose of 60.4 Gy. Local control (LC), metastasis, survival, toxicity, and secondary malignancy rates were analyzed retrospectively. Results: The mean follow-up duration was 80 months. LC rates at 5 and 8 years were 97.2%, while metastasis-free survival (MFS) rates were 61.6% and 58%, respectively. Overall survival (OS) rates at 5 and 8 years were 83.9% and 66%, respectively. The occurrence of acute erythema was recorded in 60.5% (grades 1-2) and 23.7% (grade 3) of patients. 18.4% of treated patients developed grade 1 ipsilateral arm lymphedema and 5.3% grade 2. Serious adverse events, higher than grade 3, were not seen. Only one patient showed secondary malignancy 24 months after PMRT. Conclusion: Excellent long-term results and low toxicity rates can be achieved in patients with locally advanced breast cancer by applying PMRT using hT. We are the first to report on the very low late toxicity rates and incidence of secondary malignancies. Our data suggests that broader clinical implementation of hT could benefit these patients.

Radiotherapy triggers chemokine release and leukocyte infiltration in preclinical models through activation of the senescence-associated secretory phenotype (SASP). However, effects of irradiation on senescence and SASP in human tissue and in the context of particle radiotherapy remain unclear. Here, we analyzed chemokine patterns after radiotherapy of human pancreatic tumors and cancer cell lines. We show that irradiated tumor cells coexpressed SASP chemokines in defined modules. These chemokine modules correlated with infiltration of distinct leukocyte subtypes expressing cognate receptors. We developed a patient-derived pancreatic tumor explant system, which verified our identified radiation-induced chemokine modules. Chemokine modules were partially conserved in cancer cells in response to photon and particle irradiation, showing a dose-dependent plateau effect, and induced subsequent migration of NK and T cell populations. Hence, our work reveals redundant interactions of cancer cells and immune cells in human tissue, suggesting that targeting multiple chemokines is required to efficiently perturb leukocyte infiltration after photon or particle radiotherapy.

BACKGROUND/AIM:Adjuvant radiotherapy is an integral component of the interdisciplinary curative treatment of lymph node-positive breast cancer. We investigated long-term clinical outcomes of helical tomotherapy following breast-conserving surgery. PATIENTS AND METHODS:This single-center analysis included 80 female patients with breast cancer stages T1-T4 and lymph node metastasis (N1-N3) who underwent breast-conserving surgery, sentinel node biopsy, and/or axillary lymph node dissection. Patients received adjuvant fractionated radiation therapy to the whole breast and regional lymph node areas using helical tomotherapy. Boost irradiation was delivered sequentially or through the simultaneous integrated boost technique. Local control (LC), metastasis, survival, toxicity, and secondary malignancy rates were retrospectively analyzed. RESULTS:The mean follow-up duration was 75 months. The 5- and 8-year overall survival rates were 89.4% and 87.0%, respectively. LC rates at 5- and 8-year were 98.7%, and metastasis-free survival rates were 91.2% and 85.2%, respectively. Acute erythema occurred in 70% (Grades 1-2) and 26% (Grade 3) of patients. Ipsilateral arm lymphedema of Grade 1 and Grade 2 developed in 10% and 1.3% of the treated patients, respectively. Acute or late toxicities exceeding Grade 3 were not observed. CONCLUSION:Helical tomotherapy showed excellent long-term results and low toxicity rates as adjuvant radiotherapy in patients with lymph node-positive breast cancer. The incidence of secondary malignancies was relatively low and corresponded to the preexisting records on radiation therapy. Broader clinical implementation of helical tomotherapy could benefit patients.

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radiotherapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cytotoxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types.

Purpose: The Ethos (Varian Medical Systems) radiotherapy device combines semi-automated anatomy detection and plan generation for cone beam computer tomography (CBCT)-based daily online adaptive radiotherapy (oART). However, CBCT offers less soft tissue contrast than magnetic resonance imaging (MRI). This work aims to present the clinical workflow of CBCT-based oART with shuttle-based offline MR guidance. Methods: From February to November 2023, 31 patients underwent radiotherapy on the Ethos (Varian, Palo Alto, CA, USA) system with machine learning (ML)-supported daily oART. Moreover, patients received weekly MRI in treatment position, which was utilized for daily plan adaptation, via a shuttle-based system. Initial and adapted treatment plans were generated using the Ethos treatment planning system. Patient clinical data, fractional session times (MRI + shuttle transport + positioning, adaptation, QA, RT delivery) and plan selection were assessed for all fractions in all patients. Results: In total, 737 oART fractions were applied and 118 MRIs for offline MR guidance were acquired. Primary sites of tumors were prostate (n = 16), lung (n = 7), cervix (n = 5), bladder (n = 1) and endometrium (n = 2). The treatment was completed in all patients. The median MRI acquisition time including shuttle transport and positioning to initiation of the Ethos adaptive session was 53.6 min (IQR 46.5–63.4). The median total treatment time without MRI was 30.7 min (IQR 24.7–39.2). Separately, median adaptation, plan QA and RT times were 24.3 min (IQR 18.6–32.2), 0.4 min (IQR 0.3–1,0) and 5.3 min (IQR 4.5–6.7), respectively. The adapted plan was chosen over the scheduled plan in 97.7% of cases. Conclusion: This study describes the first workflow to date of a CBCT-based oART combined with a shuttle-based offline approach for MR guidance. The oART duration times reported resemble the range shown by previous publications for first clinical experiences with the Ethos system.

Reactive oxygen species (ROS)-mediated immunogenic cell death (ICD) is crucial in radioimmunotherapy by boosting innate antitumor immunity. However, the hypoxic tumor microenvironment (TME) often impedes ROS production, limiting the efficacy of radiotherapy. To tackle this challenge, a combination therapy involving radiotherapy and immune checkpoint blockade (ICB) with anti-programmed death-ligand 1 (PD-L1) has been explored to enhance antitumor effects and reprogram the immunosuppressive TME. Here, we introduce a novel PD-L1 aptamer-functionalized nanoradiosensitizer designed to augment radiotherapy by increasing X-ray deposition specifically at the tumor site. This innovative X-ray-activated nanoradiosensitizer, comprising gold-MnO2 nanoflowers, efficiently enhances ROS generation under single low-dose radiation and repolarizes M2-like macrophages, thereby boosting antitumor immunity. Additionally, the ICB inhibitor BMS-202 synergizes with the PD-L1 aptamer-assisted nanoradiosensitizer to block the PD-L1 receptor, promoting T cell activation. Furthermore, this nanoradiosensitizer exhibits exceptional photothermal conversion efficiency, amplifying the ICD effect. The PD-L1-targeted nanoradiosensitizer effectively inhibits primary tumor growth and eliminates distant tumors, underscoring the potential of this strategy in optimizing both radioimmunotherapy and photothermal therapy.

A new experimental method for creating void-free complex (``dusty'') plasmas under microgravity conditions is presented. The method is based on a pulsed operation mode of a four-channel radio-frequency generator for plasma sustainment. A dust cloud of micrometer-sized particles can be immersed in the bulk of a low temperature plasma under microgravity conditions. It typically contains a central volume depleted of particles - the void - that prevents the generation of large, continuous clouds. Experiments performed at different neutral gas pressures and discharge volumes during the microgravity phase of a parabolic flight show that the central void is closed completely once the pulsed operation mode is applied. The particle cloud shape, and the density distribution within the cloud, are practically independent on the pulse period within the investigated parameter range, and mainly depend on the overall discharge parameters neutral gas pressure and discharge volume. This indicates that the pulsed operation of the plasma source does not introduce new physical effects on the particles aside from the void closure. The proposed method has great potential for future application in experimental facilities dedicated to fundamental studies of large three-dimensional, homogeneous complex plasma systems in microgravity.

Over the last decade, the annual Immunorad Conference, held under the joint auspicies of Gustave Roussy (Villejuif, France) and the Weill Cornell Medical College (New-York, USA) has aimed at exploring the latest advancements in the fields of tumor immunology and radiotherapy-immunotherapy combinations for the treatment of cancer. Gathering medical oncologists, radiation oncologists, physicians and researchers with esteemed expertise in these fields, the Immunorad Conference bridges the gap between preclinical outcomes and clinical opportunities. Thus, it paves a promising way toward optimizing radiotherapy-immunotherapy combinations and, from a broader perspective, improving therapeutic strategies for patients with cancer. Herein, we report on the topics developed by key-opinion leaders during the 7th Immunorad Conference held in Paris-Les Cordeliers (France) from September 27th to 29th 2023, and set the stage for the 8th edition of Immunorad which will be held at Weill Cornell Medical College (New-York, USA) in October 2024.

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.

Background: This retrospective study aimed to investigate the outcomes and adverse events (AEs) associated with adjuvant radiotherapy with helical tomotherapy (hT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS). Methods: Twenty-eight patients with DCIS underwent postoperative hT between 2011 and 2020. hT was chosen since it provided optimal target coverage and tolerable organ-at-risk doses to the lungs and heart when tangential 3-dimensional conformal radiotherapy (3D-CRT) was presumed to provide unfavorable dosimetry. The median total (single) dose was 50.4 Gy (1.8 Gy). The median time between BCS and the start of hT was 5 weeks (range, 4-38 weeks). Statistical analysis included local recurrence-free survival, overall survival (OS), and secondary cancer-free survival. AEs were classified according to the Common Toxicity Criteria for Adverse Events, version 5. Results: The patients’ median age was 58 years. The median follow-up period was 61 months (range, 3-123 months). The 1-, 3-, and 5-year OS rates were 100% each. None of the patients developed secondary cancer, local recurrence, or invasive breast cancer during follow-up. The most common acute AEs were dermatitis (n = 27), fatigue (n = 4), hyperpigmentation (n = 3), and thrombocytopenia (n = 4). The late AE primarily included surgical scars (n = 7) and hyperpigmentation (n = 5). None of the patients experienced acute or late AEs > grade 3. The mean conformity and homogeneity indices were 0.9 (range, 0.86-0.96) and 0.056 (range, 0.05-0.06), respectively. Conclusion: hT after BCS for DCIS is a feasible and safe form of adjuvant radiotherapy for patients in whom 3D-CRT is contraindicated due to unfavorable dosimetry. During follow-up, there were no recurrences, invasive breast cancer diagnoses, or secondary cancers, while the adverse effects were mild.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45–50.4 Gy in 25–28 fractions with 55.0–58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

BACKGROUND:To retrospectively access outcome, adverse events and prognostic factors in oropharyngeal carcinoma (OPC) patients treated with intensity-modulated radiotherapy (IMRT). METHODS:Ninety-eight OPC patients were treated between 2000 and 2015. Thirty-three patients received definitive and 65 adjuvant radiotherapy. Seventy-one percent had simultaneous chemotherapy. Patients were systematically followed up (mean 114 months, range 19-197 months). Statistical analysis used Kaplan-Meier method, Cox regression analysis, and log-rank test. Adverse events were classified according to common toxicity criteria version (CTCAE) 4.03. RESULTS:The 1-, 5-, and 10-year overall survival rates in the adjuvant vs. definitive cohort were 90.8% vs. 66.7%, 67.4% vs. 33.1%, and 57.7% vs. 16.5%. Survival in the adjuvant cohort was significantly longer than in the definitive cohort (P < 0.00005). Patients <65 years had a significantly longer survival than older patients. Locoregional tumor control rates after 1-, 5-, and 10 years in the adjuvant vs. definitive cohort were 90.2% vs. 66.7%, 82.2% vs 45.4%, and 72.1% vs. 30.3%. Locoregional tumor control in the adjuvant cohort was significantly longer than in the definite cohort (P < 0.005). Distant metastases were diagnosed in 20.4% of all patients. Most patients had mild CTCAE grade 1 and 2 adverse events and mild late adverse events including xerostomia, dysphagia, and lymphedema. CONCLUSION:Intensity-modulated radiotherapy for OPC is an important part of the treatment algorithm alone and in particular after surgery while the additional benefits of chemotherapy might be age dependent. Despite advanced tumor stages, nearly half of our patients were alive in the long term. The majority of patients had relatively mild chronic adverse events.

We aimed to demonstrate the effects of tumor treating fields (TTFields) in head and neck squamous cell carcinoma (HNSCC) cells when combined with radiotherapy (RT) and chemotherapy.

Properties of self-excited dust acoustic waves under the influence of active compression of the dust particle system were experimentally studied in the laboratory and under microgravity conditions (parabolic flight). Ground based laboratory experiments clearly show that wave properties can be manipulated by changing the discharge volume, its aspect ratio, and thus the dust particle density. Complementary experiments under microgravity conditions, performed to exclude the effects of gravity inflicted sedimentation and anisotropic behavior, were less conclusive due to residual fluctuations in the planes acceleration indicating the need for a better microgravity environment. A theoretical model, using plasma parameters obtained from particle-in-cell simulations as input, supports the experimental findings. It shows that the waves can be described as a new observation of the dust acoustic mode, which demonstrates their generic character.

PDF file, 37KB, Regulated GO-terms and Genes.

Supplementary Table 1 from Analysis of Gene Expression Profiles of Microdissected Cell Populations Indicates that Testicular Carcinoma In situ Is an Arrested Gonocyte