Search Results (82)

While the Blood–Brain Barrier (BBB) is essential for the protection and function of the Central Nervous System (CNS), it also represents a challenge for drug delivery in the treatment of CNS disorders due to its limited permeability and high expression of efflux transporters. Crossing the BBB becomes even more difficult when dealing with biomolecular therapeutics (e.g., monoclonal antibodies and Antisense Oligonucleotides) due to their hydrophilic nature and high molecular weight. Over the years, different strategies have been developed in order to maximize the ability of biopharmaceuticals to cross the BBB and be delivered to the CNS. Both non-invasive techniques, mainly consisting of developing innovative vectors or using non-conventional routes of administration (e.g., intranasal delivery), and invasive methods, such as intracerebroventricular/intrathecal administration, have been tested individually and in combination. Given the improvements achieved nowadays with both approaches, here, we plan to compare the advances in invasive techniques, such as those based on the use of device-assisted strategies, and the employment of the intranasal route of administration. We are also interested in reporting the applicability of both strategies in the treatment of aggressive forms of cancer, such as glioblastoma, as well as neurodegenerative diseases, in order to determine which technique can be considered a better choice in each specific case. Full article

Ultra-high dose-rate (FLASH) irradiation can transiently deplete oxygen and modulate radical-mediated chemistry in irradiated cells. Cellular antioxidants also contribute to mitigating oxidative damage in a manner dependent on linear energy transfer (LET), as suggested by recent experimental studies. In this work, we employed our multi-track Monte Carlo simulation framework (IONLYS-IRT) to investigate how LET influences transient radiation-induced oxygen depletion (ROD) in a cell-like aqueous environment under FLASH irradiation conditions. FLASH exposures were modeled as single, instantaneous pulses of protons with energies from 300 MeV to 150 keV, corresponding to LET values of ~0.3 to 71 keV/μm. Our simulations revealed a marked decline in oxygen depletion with increasing LET, in agreement with experimental observations. For an intracellular O₂ concentration of 30 μM, the oxygen consumption yield, G(–O₂), decreased from ~4.0 molecules/100 eV at low LET (~0.3 keV/μm) to ~1.6 molecules/100 eV at high LET (~71 keV/μm), representing a ~60% reduction. To assess whether ROD depends solely on LET or is also governed by ion track structure, we systematically compared multiple ion species (protons, ⁴He²⁺, ¹⁰B⁵⁺, ¹²C⁶⁺, ¹⁶O⁸⁺, ²⁰Ne¹⁰⁺, ²⁸Si¹⁴⁺, ³²S¹⁶⁺, and ⁴⁰Ar¹⁸⁺) at comparable LET values. At ~70 keV/μm, heavier ions produced significantly higher G(−O₂) values than protons—though still below those at low LET—suggesting that track structure plays a key role beyond LET alone. These findings highlight the dual importance of LET and ion-specific track structure in modulating ROD under FLASH conditions. Notably, enhanced ROD in surrounding normal tissues (low-LET plateau regions) may contribute to radioprotective effects, whereas reduced ROD in tumor tissues (high-LET Bragg peak regions) would be expected to preserve tumoricidal efficacy. Together, these results provide a mechanistic framework for optimizing proton and heavy-ion approaches in FLASH radiotherapy. Full article

This study investigates whether dedicated tumor segmentation for radiomics (TRAD) offers any advantage over gross tumor volume (GTV) in CT radiomics for predicting adenoid cystic carcinoma (ACC) progression after proton therapy (PT). Fifty-six patients with histologically proven salivary gland ACC were included, and 107 original features were extracted using PyRadiomics v3.1.0. Signatures were selected (n = 3) with sequential backward elimination using multiple classifiers, all optimized for improving cross-validated area under the ROC curve (AUC). Signature similarity was quantified using the Spearman correlation coefficient. Random forest (RF) yielded the best discriminative performance, with no statistical difference in AUCs between contour choices (GTV: 0.87 vs. TRAD: 0.80; ΔAUC_median = 0.0, p = 0.589). Time-to-event analysis confirmed both signatures stratified patients into distinct progression-free survival risk groups (Log-rank p < 0.0001) and demonstrated robust prognostic accuracy (GTV: C-index = 0.74, HR = 11.63; TRAD: C-index = 0.72, HR = 7.01). Biologically, GTV and TRAD signatures were borderline associated with perineural spread (p = 0.056) and solid tumor patterns (p = 0.053), respectively. Overall, CT-based radiomics models performed comparably across both segmentation strategies, supporting GTV as a practical and efficient alternative to TRAD for predicting ACC progression after PT. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor that controls the antioxidant response to oxidative stress, especially after exposure to ionizing radiation (IR). This review examines NRF2’s emerging role as a complementary biomarker in radiobiological dosimetry for assessing radiation exposure and its potential health effects. When cells encounter IR, the resulting reactive oxygen species (ROS) interfere with the NRF2 repressor KEAP1, leading to NRF2 activation and the expression of cytoprotective genes such as HO-1, NQO1, and GCLC. Evidence suggests that NRF2 levels increase in a dose- and time-dependent manner, primarily at low to moderate radiation doses, highlighting its potential for early detection of radiation exposure. However, at high doses (>8 Gy), NRF2 activation may be suppressed due to apoptosis or irreversible damage, which limits its reliability in those situations. The review also compares NRF2 with other biomarkers used in biodosimetry, discussing its advantages, such as sensitivity and early response, along with its limitations, including variability in activation at high doses and expression influenced by other oxidative factors. The authors introduce a comprehensive radiobiological model that illustrates how low-dose IR exposure affects NRF2 expression patterns, thereby improving the understanding of dose-dependent oxidative stress mechanisms. Additionally, the role of NRF2 in inflammation and general health risk assessment is emphasized, suggesting broader applications beyond biodosimetry. Overall, NRF2 holds significant promise for use in evaluating radiation exposure, developing radioprotection strategies, and informing future radiobiological research frameworks. Full article

Among existing radiobiological models, the MKM and its extensions (SMK and OSMK) have demonstrated strong predictive capabilities but remain computationally demanding. To address this, we present pyMKM v0.1.0, an open-source Python package for the generation of microdosimetric tables and radiobiological quantities based on these models. The package includes modules for track structure integration, saturation and stochastic corrections, oxygen modulation, and survival fraction computation. Validation was conducted against multiple published datasets across various ion species, LET values, and cell lines under both normoxic and hypoxic conditions. Quantitative comparisons showed high agreement with reference data, with average log errors typically below 0.06 and symmetric mean absolute percentage errors under 2%. The software achieved full unit test coverage and successful execution across multiple Python versions through continuous integration workflows. These results confirm the numerical accuracy, structural robustness, and reproducibility of pyMKM. The package provides a transparent, modular, and extensible tool for microdosimetric modeling in support of radiobiological studies, Monte Carlo-based dose calculation, and biologically guided treatment planning. Full article

Proton therapy enables precise dose delivery to tumors while sparing healthy tissues, offering significant advantages over conventional radiotherapy. Accurate prediction of biological doses requires detailed knowledge of radiation interactions with biological targets, especially DNA, a key site of radiation-induced damage. While most biophysical models (LEM, mMKM, NanOx) rely on water as a surrogate, this simplification neglects the complexity of real biomolecules. In this work, we calculate the stopping power and range of protons in liquid water, dry DNA, and hydrated DNA using semi-empirical cross sections for ionization, electronic excitation, electron capture, and electron loss by protons and neutral hydrogen in the 10 keV–100 MeV energy range. Additionally, ionization cross sections for uracil are computed to explore potential differences between DNA and RNA damage. Our results show excellent agreement with experimental and ab initio data, highlighting significant deviations in stopping power and range between water and DNA. Notably, the stopping power of DNA exceeds that of water at most energies, reducing proton ranges in dry and hydrated DNA by up to 20% and 26%, respectively. These findings provide improved input for Monte Carlo simulations and biophysical models, enhancing RBE predictions and dose accuracy in hadrontherapy. Full article

Background: Spinal solitary fibrous tumors (SFTs) are a rare oncological entity, almost anecdotal in the pediatric population. They have a high relapse rate and represent an ongoing oncological challenge. Methods: In this article, we conducted a systematic review starting from a case report to highlight the current state of the art in managing these tumors. Results: Spinal solitary fibrous tumors (SFTs) are rare, slow-growing neoplasms that can be either intra- or extramedullary. Only a limited number of studies focus on primary pediatric spinal cord localization. Five pediatric cases of spinal SFT have been documented in the literature. On MRI, they typically present as highly vascularized, contrast-enhancing masses. Histologically, they are composed of spindle-shaped cells within a collagenous stroma featuring staghorn-shaped blood vessels. More aggressive subtypes, such as dedifferentiated SFTs, resemble high-grade sarcomas. The NAB2–STAT6 fusion is a key marker, driving EGFR signaling, collagen production, and fibrosis. Additional diagnostic markers include CD34, CD99, and Bcl-2. Surgical resection remains the primary treatment. In metastatic cases, chemotherapy—mainly with anthracyclines, dacarbazine, or temozolomide—is employed, although no standardized pediatric protocols exist. Anti-angiogenic agents, including tyrosine kinase inhibitors, have shown promise. Radiotherapy is used postoperatively for local disease control, but its impact on survival is still under investigation. Conclusions: Surgery remains the cornerstone of treatment, significantly impacting the natural history of the disease and symptom control. While clinical trials exploring radiotherapy and chemotherapy are ongoing in adults, no specific treatment protocol has been established for pediatric patients. Full article

Intra-fractional respiratory management represents one of the greatest challenges of modern cancer radiotherapy (RT), as significant breathing-induced lesion motion might affect target coverage and organs at risk (OARs) sparing, jeopardizing oncological and toxicity outcomes. The detrimental effects on dosage of uncompensated organ motion are exacerbated in RT with charged particles (e.g., protons and carbon ions), due to their higher ballistic selectivity. The simplest strategies to counteract this phenomenon are the use of larger treatment margins and reductions in or control of respiration (e.g., by means of compression belts, breath hold). Gating and tracking, which synchronize beam delivery with the respiratory signal, also represent widely adopted solutions. When tracking the tumor itself or surrogates, invasive procedures (e.g., marker implantation), an unnecessary imaging dose (e.g., in X-ray-based fluoroscopy), or expensive equipment (e.g., magnetic resonance imaging, MRI) is usually required. When chest and abdomen excursions are measured to infer internal tumor displacement, the additional devices needed to perform this task, such as pressure sensors or surface cameras, present inherent limitations that can impair the procedure itself. In this context, radars have intrigued the radiation oncology community, being inexpensive, non-invasive, contactless, and insensitive to obstacles. Even if real-world clinical implementation is still lagging behind, there is a growing body of research unraveling the potential of these devices in this field. The purpose of this narrative review is to provide an overview of the studies that have delved into the potential of radar-based technologies for motion-adaptive photon and particle RT applications. Full article

Introduction: Acute appendicitis (AA) is a common cause of abdominal pain that can lead to complications like perforation and intra-abdominal abscesses, increasing morbidity and mortality, often requiring emergency surgery. Nevertheless, appendectomy is performed in up to 95% of uncomplicated cases, while complications like perforation and intra-abdominal abscesses increase morbidity and mortality. The current study compares the accuracy of GPT-4.5, DeepSeek R1, and machine learning in assisting with surgical decision-making for patients presenting with lower abdominal pain at the Emergency Department. Methods: In this multicenter retrospective study, 63 histopathologically confirmed appendicitis patients and 50 control patients with right abdominal pain presenting at the Emergency Department at two German hospitals between October 2022 and October 2023 were included. Using each patient’s clinical, laboratory, and radiological findings, DeepSeek (with and without Retrieval-Augmented Generation using 2020 Jerusalem guidelines) was compared in terms of accuracy with GPT-4.5 and a random forest-based machine-learning model, with a board-certified surgeon (reference standard) to determine the optimal treatment approach (laparoscopic exploration/appendectomy versus conservative antibiotic therapy). Results: Accuracy of agreement with board-certified surgeons in the decision-making of appendectomy versus conservative therapy increased non-significantly from 80.5% to 83.2% with DeepSeek and from 70.8 to 76.1% when GPT-4.5 was provided with the World Journal of Emergency Surgery 2020 Jerusalem guidelines on the diagnosis and treatment of acute appendicitis. The estimated machine-learning model training accuracy was 84.3%, while the validation accuracy for the model was 85.0%. Discussion: GPT-4.5 and DeepSeek R1, as well as the machine-learning model, demonstrate promise in aiding surgical decision-making for appendicitis, particularly in resource-constrained settings. Ongoing training and validation are required to optimize the performance of such models. Full article

Background. The use of zygomatic implants (ZIs) provides a highly predictable treatment option for rehabilitation in patients with severe atrophic maxillae. However, these long implants can potentially cause a number of more serious complications than those seen with conventional dental implants. The aim of this study is to report a case of peri-zygomatic cutaneous fistula following placement of monolateral double zygomatic implants and to analyse the available literature on this complication. Methods. The 55-year-old patient was treated with placement of 3 ZIs, two on the left side. Left periorbital swelling with pain appeared 10 days after surgery with progressive worsening of symptoms. After antibiotic treatment, she developed a left cutaneous fistula with purulent discharge. CT showed two ZIs on the left side with the apical portions in close contact with a 1 cm-wide portion of resorbed zygomatic external cortex and a layer of granulation tissue. Results: Due to the limited amount of bone involved by the fixation tip, the left ZIs were removed and the skin fistula repaired. The patient healed without complications but required prosthesis replacement. Conclusions. After conducting a literature review, peri-zygomatic fistulas seem to be more common in patients with two ZIs placed on the same zygoma. In this case, the amount of available zygomatic bone is relatively limited; the bone drill holes can often be too close together and cause overheating, leading to inter-implant bone resorption and infection, with further orbito-zygomatic fistula development. The authors identified the lack of distance between ZI fixtures as one of the main causes of extraoral ZI infection. Full article

Ionizing radiation (IR) as a stress inducer has a significant impact on various normal stem cells differentiation through activation of various signaling pathways. Low levels of oxidative stress of IR may preserve or even enhance cell differentiation. In response to IR, reactive oxygen species (ROS) can activate various signaling pathways that promote cell differentiation, notably through the involvement of nuclear factor erythroid 2–related factor 2 (NRF2). NRF2 interacts with multiple pathways, including Wnt/β-catenin (osteogenesis), PPARγ (adipogenesis), and BDNF/TrkB (neurogenesis). This response is dose-dependent: low doses of IR activate NRF2 and support differentiation, while high doses can overwhelm the antioxidant system, resulting in cell death. However, the quality of various types of IR, such as proton and carbon ion radiation, may have a varied impact on stem cells (SCs) differentiation compared to X-rays. Hence, activation of the NRF2 signaling pathway in SCs and cell differentiation depends on the level of stress and the quality and quantity of IR. This review is an update to explore how IR modulates SCs fate toward osteogenic, adipogenic, and neurogenic lineages through the NRF2 signaling pathway. We highlight mechanistic insights, dose-dependent effects, and therapeutic implications, bridging gaps between experimental models and clinical translation. Full article

Radiation therapy is a medical treatment that uses high doses of radiation to kill or damage cancer cells. It works by damaging the DNA within the cancer cells, ultimately causing cell death. Radiotherapy can be used as a primary treatment, adjuvant treatment in combination with surgery or chemotherapy or palliative treatment to relieve symptoms in advanced cancer stages. Radiation therapy is constantly improving in order to enhance the effect on cancer cells and reduce the side effects on healthy tissues. Our results clearly demonstrate that proton therapy and, even more, carbon ion therapy appear as promising alternatives to overcome the radioresistance of various tumors thanks to less dependency on oxygen and a better ability to kill cancer stem cells. Interestingly, hadrons also retain the advantages of radiosensitization approaches. These data confirm the great ability of hadrons to spare healthy tissue near the tumor via various mechanisms (reduced lymphopenia, bystander effect, etc.). Technology and machine improvements such as image-guided radiotherapy or particle therapies can improve treatment quality and efficacy (dose deposition and biological effect) in tumors while increasingly sparing healthy tissues. Radiation biology can help to understand how cancer cells resist radiation (hypoxia, DNA repair mechanisms, stem cell status, cell cycle position, etc.), how normal tissues may display sensitivity to radiation and how radiation effects can be increased with either radiosensitizers or accelerated particles. All these research topics are under investigation within the ARCHADE research community in France. By focusing on these areas, radiotherapy can become more effective, targeted and safe, enhancing the overall treatment experience and outcomes for cancer patients. Our goal is to provide biological evidence of the therapeutic advantages of hadrontherapy, according to the tumor characteristics. This article aims to give an updated view of our research in radiation biology within the frame of the French “ARCHADE association” and new perspectives on research and treatment with the C400 multi-ions accelerator prototype. Full article

Introduction: Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies, calling for enhanced research. Pancreatic ductal adenocarcinoma (PDAC) represents 70–80% of all cases and is known for its resistance to conventional therapies. Carbon-ion radiotherapy (CIRT) has emerged as a promising approach due to its ability to deliver highly localized doses and unique radiobiological properties compared to X-rays. In vitro radiobiology has relied on two-dimensional (2D) cell culture models so far; however, these are not sufficient to replicate the complexity of the in vivo tumor architecture. Three-dimensional (3D) models become a paradigm shift, surpassing the constraints of traditional models by accurately re-creating morphological, histological, and genetic characteristics as well as the interaction of tumour cells with the microenvironment. Materials and Methods: This study investigates the survival of pancreatic cancer cells in both 2D and spheroids, a 3D model, following photon, proton, and carbon-ion irradiation by means of clonogenic, MTT, spheroid growth, and vitality assays. Results: Our results demonstrate that carbon ions are more efficient in reducing cancer cell survival compared to photons and protons. In 2D cultures, carbon-ion irradiation reduced cell survival to approximately 15%, compared to 45% with photons and 30% with protons. In the 3D culture model, spheroid growth was similarly inhibited by carbon-ion irradiation; however, the overall survival rates were higher across all irradiation modalities compared to the 2D cultures. Carbon ions consistently showed the highest efficacy in reducing cell viability in both models. Conclusions: Our research highlights the pivotal role of 3D models in unraveling the complexities of pancreatic cancer radiobiology, offering new avenues for designing more effective and precise treatment protocols. Full article

Background/Objectives: Primary gynecological melanomas are rare malignancies with lower survival rates compared to cutaneous melanomas. Both preclinical and clinical data support the evidence that mucosal melanomas are photon-radioresistant but responsive to carbon ion radiotherapy (CIRT). The aim of this study is to assess, in a real-world cohort, the effectiveness and tolerability of radical CIRT in patients with inoperable gynecological mucosal melanoma. Methods: This is a real-world study aimed to assess the effectiveness and the safety of CIRT in this setting. We defined as the primary endpoints the objective response rate (ORR) and the clinical benefit (CB). The secondary endpoints included the actuarial local control rate (LC) assessed after 1 year and 2 years and the toxicity scored according to CTCAE v.5. Actuarial outcomes were analyzed using the Kaplan–Meier method, while potential predictors were investigated through the Log-rank test. Results: Between 2017 and 2023, eleven Caucasian patients underwent pelvic CIRT (total dose 68.8 GyRBE) for mucosal malignant melanoma of the vulva or the vagina. With a median follow-up of 18 months, we observed an ORR of 82% and a CB of 100%. LC at 1 and 2 years was 100% and 86%, respectively, and among the factors analyzed for their potential impact on LC, age < 60 years seems to be a potential predictor (p = 0.014). The treatment was well tolerated, with only one case of acute grade 3 erythema and, in the late phase, one case of grade 3 erythema and grade 3 urethral toxicity. Conclusions: CIRT was effective and safe for gynecological melanomas. Larger collaborative cohort studies and longer follow-ups are needed to take a step forward in comprehending the correct management of this disease. Full article

Image-guided treatment adaptation is a game changer in oncological particle therapy (PT), especially for younger patients. The purpose of this study is to present a cycle generative adversarial network (CycleGAN)-based method for synthetic computed tomography (sCT) generation from cone beam CT (CBCT) towards adaptive PT (APT) of paediatric patients. Firstly, 44 CBCTs of 15 young pelvic patients were pre-processed to reduce ring artefacts and rigidly registered on same-day CT scans (i.e., verification CT scans, vCT scans) and then inputted to the CycleGAN network (employing either Res-Net and U-Net generators) to synthesise sCT. In particular, 36 and 8 volumes were used for training and testing, respectively. Image quality was evaluated qualitatively and quantitatively using the structural similarity index metric (SSIM) and the peak signal-to-noise ratio (PSNR) between registered CBCT (rCBCT) and vCT and between sCT and vCT to evaluate the improvements brought by CycleGAN. Despite limitations due to the sub-optimal input image quality and the small field of view (FOV), the quality of sCT was found to be overall satisfactory from a quantitative and qualitative perspective. Our findings indicate that CycleGAN is promising to produce sCT scans with acceptable CT-like image texture in paediatric settings, even when CBCT with narrow fields of view (FOV) are employed. Full article