OBJECTIVE: We report on a case of locally advanced hepatocellular carcinoma (HCC) accompanied by an inferior vena cava tumor thrombus (IVCTT), treated successfully with proton-beam therapy (PBT).
METHODS: A 63-year-old male presented with a primary, single HCC with IVCTT, without metastasis to the intrahepatic region, lymph nodes, or distant organs. The clinical staging was identified as T4N0M0 Stage IIIB. The patient\'s liver function was classified as Child-Pugh class A (score: 6), with a modified albumin-bilirubin (mALBI) grade of 2a. The patient had liver cirrhosis due to non-alcoholic steatohepatitis. Magnetic resonance imaging revealed a nodular tumor measuring 13.2×8.9×9.8 cm across segments 1, 6, 7, and 8, along with IVCTT. The patient received PBT, with a total dose of 72.6 Gy (relative biological effectiveness) delivered in 22 fractions. Throughout the PBT treatment, the patient experienced no acute toxicities and completed the therapy as planned. Twelve months following PBT, the patient was alive without evidence of local recurrence, lymph node involvement, or distant organ metastasis. The only late toxicity observed was a mild worsening of the mALBI grade.
CONCLUSIONS: We observed a favorable local response with manageable toxicities in a patient with locally advanced HCC and IVCTT treated with PBT. While this is a single case report, our findings suggest that PBT could be considered a viable treatment option for HCC with IVCTT.

The use of charged particle radiotherapy is currently increasing, but combination therapy with DNA repair inhibitors remains to be exploited in the clinic. The high-linear energy transfer (LET) radiation delivered by charged particles causes clustered DNA damage, which is particularly effective in destroying cancer cells. Whether the DNA damage response to this type of damage is different from that elicited in response to low-LET radiation, and if and how it can be targeted to increase treatment efficacy, is not fully understood. Although several preclinical studies have reported radiosensitizing effects when proton or carbon ion irradiation is combined with inhibitors of, e.g., PARP, ATR, ATM, or DNA-PKcs, further exploration is required to determine the most effective treatments. Here, we examine what is known about repair pathway choice in response to high- versus low-LET irradiation, and we discuss the effects of inhibitors of these pathways when combined with protons and carbon ions. Additionally, we explore the potential effects of DNA repair inhibitors on antitumor immune signaling upon proton and carbon ion irradiation. Due to the reduced effect on healthy tissue and better immune preservation, particle therapy may be particularly well suited for combination with DNA repair inhibitors.

OBJECTIVE: This study aims to develop an ensemble machine learning-based (EML-based) risk prediction model for radiation dermatitis (RD) in patients with head and neck cancer undergoing proton radiotherapy, with the goal of achieving superior predictive performance compared to traditional models.
METHODS: Data from 57 head and neck cancer patients treated with intensity-modulated proton therapy at Kaohsiung Chang Gung Memorial Hospital were analyzed. The study incorporated 11 clinical and 9 dosimetric parameters. Pearson\'s correlation was used to eliminate highly correlated variables, followed by feature selection via LASSO to focus on potential RD predictors. Model training involved traditional logistic regression (LR) and advanced ensemble methods such as Random Forest and XGBoost, which were optimized through hyperparameter tuning.
RESULTS: Feature selection identified six key predictors, including smoking history and specific dosimetric parameters. Ensemble machine learning models, particularly XGBoost, demonstrated superior performance, achieving the highest AUC of 0.890. Feature importance was assessed using SHAP (SHapley Additive exPlanations) values, which underscored the relevance of various clinical and dosimetric factors in predicting RD.
CONCLUSIONS: The study confirms that EML methods, especially XGBoost with its boosting algorithm, provide superior predictive accuracy, enhanced feature selection, and improved data handling compared to traditional LR. While LR offers greater interpretability, the precision and broader applicability of EML make it more suitable for complex medical prediction tasks, such as predicting radiation dermatitis. Given these advantages, EML is highly recommended for further research and application in clinical settings.

Beam position uncertainties along the beam trajectory arise from the accelerator, beamline, and scanning magnets (SMs). They can be monitored in real time, e.g., through strip ionization chambers (ICs), and treatments can be paused if needed. Delivery is more reliable and accurate if the beam position is projected from monitored nozzle parameters to the isocenter, allowing for accurate online corrections to be performed. Beam position projection algorithms are also used in post-delivery log file analyses. In this paper, we investigate the four potential algorithms that can be applied to all pencil beam scanning (PBS) nozzles. For some combinations of nozzle configurations and algorithms, however, the projection uses beam properties determined offline (e.g., through beam tuning or technical commissioning). The best algorithm minimizes either the total uncertainty (i.e., offline and online) or the total offline uncertainty in the projection. Four beam position algorithms are analyzed (A1-A4). Two nozzle lengths are used as examples: a large nozzle (1.5 m length) and a small nozzle (0.4 m length). Three nozzle configurations are considered: IC after SM, IC before SM, and ICs on both sides. Default uncertainties are selected for ion chamber measurements, nozzle entrance beam position and angle, and scanning magnet angle. The results for other uncertainties can be determined by scaling these results or repeating the error propagation. We show the propagation of errors from two locations and the SM angle to the isocenter for all the algorithms. The best choice of algorithm depends on the nozzle length and is A1 and A3 for the large and small nozzles, respectively. If the total offline uncertainty is to be minimized (a better choice if the offline uncertainty is not stable), the best choice of algorithm changes to A1 for the small nozzle for some hardware configurations. Reducing the nozzle length can help to reduce the gantry size and make proton therapy more accessible. This work is important for designing smaller nozzles and, consequently, smaller gantries. This work is also important for log file analyses.

The growing interest in proton therapy (PT) in recent decades is justified by the evidence that protons dose distribution allows maximal dose release at the tumor depth followed by sharp distal dose fall-off. But, in the holistic management of head and neck cancer (HNC), limiting the potential of PT to a mere dosimetric advantage appears reductive. Indeed, the precise targeting of PT may help evaluate the effectiveness of de-escalation strategies, especially for patients with human papillomavirus associated-oropharyngeal cancer (OPC) and nasopharyngeal cancer (NPC). Furthermore, PT could have potentially greater immunogenic effects than conventional photon therapy, possibly enhancing both the radiotherapy (RT) capability to activate anti-tumor immune response and the effectiveness of immunotherapy drugs. Based on these premises, the aim of the present paper is to conduct a narrative review reporting the safety and efficacy of PT compared to photon RT focusing on NPC and OPC. We also provide a snapshot of ongoing clinical trials comparing PT with photon RT for these two clinical scenarios. Finally, we discuss new insights that may further develop clinical research on PT for HNC.

(1) Background: to analyze the impact of the COVID-19 pandemic on the characteristics and management of uveal melanoma (UM) in the National Referral Center in Poland. (2) Materials and Methods: the retrospective analysis of 1336 patients who were newly diagnosed with UM at the Department of Ophthalmology and Ophthalmic Oncology, Jagiellonian University Collegium Medicum Krakow, Poland between 1 January 2018 and 31 December 2021. The demographic and clinical data were compiled, including localization, size, and treatment methods of tumors. (3) Results: In total, 728 patients with UM were included before the COVID-19 pandemic, in the years 2018-2019, and 608 were included during the COVID-19 pandemic, in the years 2020-2021. Fixed-base dynamics indicators for the incidence of uveal melanoma (base year 2018) in the National Referral Center in Poland were 80.22% and 86.81% in the years 2020 and 2021, respectively. UMs were statistically significantly larger and more frequently localized anterior to the equator of the eye globe in the year 2021 than in the year 2018 (Chi-square Pearson test p = 0.0001 and p = 0.0077, respectively). The rate of patients treated with enucleation increased from 15.94% in the year 2018 to 26.90% in the year 2021 (Chi-square Pearson test p = 0.0005). (4) Conclusions: Statistically significant differences were found in the management of uveal melanoma in the National Referral Center in Poland during the COVID-19 pandemic with tumors being larger, more frequently localized anterior to the equator of the eye globe, and more often enucleated.

Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications.

Photon-based radiotherapy (XRT) is one of the most frequently used treatment modalities for HPV-negative and HPV-positive locally advanced head and neck squamous cell carcinoma (HNSCC). However, locoregional recurrences and normal RT-associated toxicity remain major problems for these patients. Proton therapy (PT), with its dosimetric advantages, can present a solution to the normal toxicity problem. However, issues concerning physical delivery and the lack of insights into the underlying biology of PT hamper the full exploitation of PT. Here, we assessed the radiobiological processes involved in PT in HPV-negative and HPV-positive HNSCC cells. We show that PT and XRT activate the DNA damage-repair and stress response in both HPV-negative and HPV-positive cells to a similar extent. The activation of these major radiobiological mechanisms resulted in equal levels of clonogenic survival and mitotic cell death. Altogether, PT resulted in similar biological effectiveness when compared to XRT. These results emphasize the importance of dosimetric parameters when exploiting the potential of increased clinical effectiveness and reduced normal tissue toxicity in PT treatment.

Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary malignancies, and neurocognitive dysfunction. Despite its benefits in dose distribution and biological effectiveness, the application of proton therapy is challenged by uncertainties in its relative biological effectiveness (RBE). Overcoming the challenges related to RBE is key to fully realizing proton therapy\'s potential, which extends beyond its physical dosimetric properties when compared with photon-based therapies. In this paper, we discuss the clinical significance of RBE within treatment volumes and adjacent serial organs at risk in the management of head and neck and skull-base tumors. We review proton RBE uncertainties and its modeling and explore clinical outcomes. Additionally, we highlight technological advancements and innovations in plan optimization and treatment delivery, including linear energy transfer/RBE optimizations and the development of spot-scanning proton arc therapy. These advancements show promise in harnessing the full capabilities of proton therapy from an academic standpoint, further technological innovations and clinical outcome studies, however, are needed for their integration into routine clinical practice.

BACKGROUND: Nasopharyngeal adenoid cystic carcinoma (NACC) is a relatively rare salivary gland tumor that is generally associated with poor outcomes. High-dose radiotherapy is a key treatment for patients with NACC. This study reported the long-term efficacy and safety of particle beam radiation therapy (PBRT) for NACC.
METHODS: Twenty-six patients with nonmetastatic NACC who received definitive PBRT alone were included in this retrospective study. The majority of patients (92.3%) had locally advanced disease. Twenty-five (96.15%) patients received intensity-modulated proton radiotherapy (IMPT) followed by a carbon ion radiotherapy (CIRT) boost, and one patient received CIRT alone. Overall survival (OS), local control (LC), regional control (RC), and distant metastasis control (DMC) rates were calculated via the Kaplan-Meier method.
RESULTS: The median follow-up time was 46.95 months for the entire cohort. Seven patients experienced local recurrence, and one patient experience neck lymph node recurrence. The 3- and 4-year OS, LC, RC, and DMC rates were 100% and 91.7%, 92.3% and 84.6%, 95.8% and 87.8%, and 90.2% and 71.3%, respectively. A total of 91.3% of the patients achieved complete remission of gross tumors at 1 year after PBRT. Severe acute toxicity was observed in only two patients. A grade 4 decrease in visual acuity was observed in one patient with orbital apex invasion. No late grade 3 or 5 toxicity was observed.
CONCLUSIONS: Definitive PBRT provided a satisfactory 4-year OS for patients with locally advanced NACC. The toxicity was acceptable and mild. Further follow-up is necessary to confirm the efficacy and safety of definitive PBRT for patients with NACC.