Felipe A. Calvo

Background/Objectives: Radiation-induced lymphopenia is consistently associated with adverse outcomes across solid tumours, yet the vascular compartment that carries the irradiated lymphocyte pool is not routinely delineated during treatment planning. The VASA project makes blood vessels an explicit, measurable structure in that process. Phase II aimed primarily to establish the feasibility of that delineation and secondarily to explore how dose–volume metrics computed on MRI-segmented vessels relate to serial immunophenotyping in patients treated with protons or photons. Methods: Thirty-nine patients treated between March 2021 and May 2022 were studied prospectively (30 proton, 9 photon). Flow-contrast three-dimensional MRI with three velocity-encoding directions was added to simulation; vessel masks segmented semi-automatically from the sum-of-magnitude reconstruction were imported into the treatment-planning system to generate dose–volume histograms. The effective dose to circulating immune cells (EDIC), the integral dose to vessels (IDVe) and the integral dose to target were computed. Blood was sampled at the start and at the end of irradiation for lymphocyte counts and B, T and NK immunophenotyping. Groups were compared with Welch’s t-test for continuous variables and Fisher’s exact test for categorical variables, without correction for multiple comparisons; the photon subgroup was not matched. Results: EDIC was higher with photons than protons (5.60 vs. 1.25 Gy; p = 0.005) and in patients who became lymphopenic (4.84 vs. 1.47 Gy; p = 0.027); IDVe differed in the same direction without reaching significance (3.60 vs. 0.53 Gy·L, p = 0.091; 3.08 vs. 0.67 Gy·L, p = 0.180). Within the proton cohort, EDIC and IDVe increased from brain to head-and-neck to thorax–abdomen targets (0.81, 1.11 and 2.17 Gy; 0.13, 0.26 and 1.63 Gy·L), and the IDVe ordering persisted after adjustment for target volume (p < 0.001). Lymphocyte counts fell from 1.92 to 1.43 × 10³/µL in the proton cohort (p < 0.001), with the lowest end-of-treatment values in thorax–abdomen targets (1.31 × 10³/µL). B, T and NK subpopulations all declined in the proton cohort; among regions, only head-and-neck targets showed significant T and NK losses. Conclusions: Patient-specific vascular delineation and dosimetry are feasible in a clinical planning workflow, and the resulting metrics track irradiation modality and the magnitude of lymphocyte depletion. These associations are exploratory; immune-sparing plan optimisation using vascular constraints remains a future application requiring prospective validation.

Background/Objectives: Radiation-induced lymphopenia is consistently associated with adverse outcomes across solid tumours, yet the vascular compartment that carries the irradiated lym-phocyte pool is not common delineated during treatment planning. The VASA project makes blood vessels an explicit, measurable structure in that process. We report Phase II, relating dose–volume metrics computed on MRI-segmented vessels to serial immunophenotyping in patients treated with protons or photons. Methods: Forty-three patients treated between March 2021, and May 2022 were studied prospectively (35 proton, 8 photon). Flow-contrast three-dimensional MRI with three velocity-encoding directions was added to simulation; the sum-of-magnitude recon-struction was used for semi-automated vessel segmentation, and vessel masks were imported into the treatment planning system to generate dose–volume histograms. The effective dose to circu-lating immune cells (EDIC), the integral dose to vessels (IDVe) and the integral dose to target were computed. Blood was sampled at the start, middle and end of irradiation for lymphocyte counts and B, T and NK immunophenotyping. Results: EDIC and IDVe were higher with photons than protons (6.10 vs. 1.22 Gy; 3.6 vs. 0.5 Gy·L) and higher in patients who became lymphopenic than in those who did not (4.2 vs. 1.1 Gy; 2.7 vs. 0.37 Gy·L). Within the proton cohort, EDIC and IDVe increased from brain to head-and-neck to thorax–abdomen targets (0.80, 1.11 and 1.89 Gy; 0.15, 0.26 and 1.31 Gy·L; p < 0.05). Lymphocyte counts fell from 1.81 to 1.42 × 10³/µL overall (p < 0.05), with the lowest nadir in thorax–abdomen targets (0.90 × 10³/µL). B, T and NK subpopula-tions all declined; T and NK losses were greatest in head-and-neck targets. Conclusions: Vascular dose can be measured patient by patient and tracks both irradiation modality and the magnitude of lymphocyte depletion. Treating vessels and circulating blood as an organ at risk is feasible and offers a route to immune-sparing radiotherapy plan optimisation.

Background/Objectives: Photon re-irradiation in previously treated head and neck cancer (HNC) is constrained by cumulative normal-tissue toxicity. Pencil-beam scanning intensity-modulated proton therapy (PBS-IMPT) allows for a sharper dose conformation than conventional photon techniques, which may widen the therapeutic window in previously irradiated tissue. Methods: Sixty-five patients with recurrent or second primary HNC were enrolled in a prospective single-institution registry and re-irradiated with PBS-IMPT between January 2020 and December 2025. Forty-five were treated with radical intent (69.2%), and 20 were treated postoperatively (30.8%), with a median prescribed dose of 66 Gy (RBE) in 30 fractions. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Locoregional control (LRC), adverse events and the prognostic impact of anatomical extent were secondary endpoints. Results: The median follow-up was 9.3 months. The median OS was 17.2 months (95% CI 13.9–NR), with a 12-month rate of 67.1%. The median PFS was 10.1 months and the median LRC was 28.1 months. Central/skull-base involvement was associated with a non-significant trend toward worse OS (14.3 vs. 35.2 months; p = 0.062) and with significantly worse PFS (9.1 vs. 14.7 months; p = 0.037) than peripheral disease, but LRC did not differ between the groups (p = 0.240). Grade ≥ 3 oral mucositis occurred in 7.7%, with no grade 4–5 acute events. Within a median follow-up of 9.3 months, late osteoradionecrosis affected 6.2%, but late toxicity data remain preliminary given the short follow-up. Ninety-two percent of patients completed treatment. Conclusions: PBS-IMPT re-irradiation provided adequate survival with low acute toxicity. T3–T4 stage at re-irradiation was the only variable retaining significance for PFS on multivariable analysis (HR 4.32, 95% CI 1.24–15.13; p = 0.022). The poor survival observed for central/skull-base disease on Kaplan–Meier curves disappeared after T-stage adjustment, indicating the higher concentration of advanced disease in that compartment. Multicentre prospective data and longer follow-up are needed.

Purpose: Due to the labor intensity demanded by proton beam therapy (PBT) in pediatric patients, information on operational procedures related to efficiency is crucial to optimize quality and safety. We aimed to identify patient factors that affect the duration of the pediatric PBT session and to develop an easy-to-use predictive score of extended duration. Methods/patients: This is an observational retrospective cohort study in an academic medical centre, between May 2020 and February 2024. Seventy seven ASA III pediatric patients treated with PBT were recruited. Results: The mean age was 4.8 years [standard deviation (SD): 2.1] and 52% were women. The mean duration of the PBT session was 50 min (SD: 17). Extended duration of the PBT session (> 45 min) occurred in 39 patients (51%). Five predictors of extended duration were selected for the final prediction model. In the multivariable model, an age > 45 months showed a near eightfold increased odds of extended duration [Odds ratio (OR): 7.76, 95% confidence interval (95% CI) 1.63–36.99, P = 0.010]. The OR (95% CI) for long-term venous access, no recurrent tumors, hydrocephalus, and craniospinal location were 5.91 (1.47 to 23.79), 3.81 (0.67 to 21.69), 3.79 (0.90 to 15.97), and 2.59 (0.69 to 9.76), respectively. This five-variable model was used to build a nomogram-based score with an area under the receiver operating characteristic curve of 0.84 (95% CI 0.76–0.93). Conclusions: A simple nomogram based on readily available pretreatment data has potential for planning pediatric PBT standard clinical expert practice.

Purpose. To provide a novel and personalized method (FLIP, FLow and Irradiation Personalized) using patient-specific circulating blood flows and individualized time-dependent irradiation distributions, to quantify the dose delivered to blood in large vessels during proton or photon external beam radiotherapy. Methods. Patient-specific data were obtained from ten cancer patients undergoing radiotherapy, including the blood velocity field in large vessels and the temporal irradiation scheme using photons or protons. The large vessels and the corresponding blood flow velocities are obtained from phase-contrast MRI sequences. The blood dose is obtained discretizing the fluid into individual blood particles (BPs). A Lagrangian approach was applied to simulate the BPs trajectories along the vascular velocity field flowlines. Beam delivery dynamics was obtained from beam delivery machine measurements. The whole IS is split into a sequence of successive IEs, each one with its constant dose rate, as well as its corresponding initial and final time. Calculating the dose rate and knowing the spatiotemporal distribution of BPs, the dose is computed by accumulating the energy received by each BP as the time-dependent irradiation beams take place during the treatment. Results. Blood dose volume histograms from proton therapy and photon radiotherapy patients were assessed. The irradiation times distribution is obtained for BPs in both modalities. Two dosimetric parameters are presented: (i) D _3%, representing the minimum dose received by the 3% of BPs receiving the highest doses, and (ii) V _{0.5 Gy}, denoting the blood volume percentage that has received at least 0.5 Gy. Conclusion. A novel methodology is proposed for quantifying the circulating blood dose along large vessels. This methodology involves the use of patient-specific vasculature, blood flow velocity field, and dose delivery dynamics recovered from the irradiation machine. Relevant parameters that affect the dose received, as the distance between large vessels and CTV, are identified.

Background: The purpose of this study was to evaluate the long-term oncological progression pattern of locally advanced rectal cancer patients with post-neoadjuvant nodal metastatic disease (ypN+) and correlate potential prognostic features associated with proven radiochemoresistant nodal biology. Methods: Individual patient data (100 variables) from a 20-year consecutive single-institution multidisciplinary experience (1995–2015), delivering multimodal therapy to rectal cancer patient candidates for radical treatment, including a neoadjuvant component and surgical resection with or without intraoperative radiotherapy followed by optional adjuvant chemotherapy. The ypN+ disease data was registered in the context of initial staging categories post-neoadjuvant T status (ypT). Results: Data on 487 patients showed histologically confirmed diagnoses of metastatic nodal disease in 108 specimens (ypN+, 22.1). There was a significant age difference (p = 0.009) between the ypN groups: age ≥ 65 was 57.6% in pN0 and 43.5% in ypN+ and patients aged < 65 constituted 42.4% of pN0 and 56.5% of ypN+. According to the clinical stage there were statistically significant differences (p = 0.001) in the categories’ distribution: ypN+ patients 10.8% were stage II and 89.2% were stage III. Univariant analysis on outcome variables showed statistically significant differences in overall survival at 7 years (63.8% vs. 55.7%, p = 0.016) disease-free survival (DFS) (78% vs. 53.8%, p = 0.000) and local recurrence-free survival (LRFS) (93.6% vs. 84%, p = 0.002). Conclusions: The presence of nodal metastases (ypN+) after neoadjuvant therapy containing long-course pelvic irradiation severely impacts the long-term outcome for patients with locally advanced rectal cancer and correlates with multiple clinical and therapeutic variable metrics. Implementation of local and systemic therapies should be adapted and intensified in relation to the finding of ypN+ category in surgical specimens.