APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy.

Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.

First measurements of radon-220 diffusion in mice tumors, towards treatment planning in diffusing alpha-emitters radiation therapy.

BACKGROUND: Diffusing alpha-emitters radiation therapy ("Alpha-DaRT") is a new method for treating solid tumors with alpha particles, relying on the release of the short-lived alpha-emitting daughter atoms of radium-224 from interstitial sources inserted into the tumor. Alpha-DaRT tumor dosimetry is governed by the spread of radium's progeny around the source, as described by an approximate framework called the "diffusion-leakage model". The most important model parameters are the diffusion lengths of radon-220 and lead-212, and their estimation is therefore essential for treatment planning. PURPOSE: Previous works have provided initial estimates for the dominant diffusion length, by measuring the activity spread inside mice-borne tumors several days after the insertion of an Alpha-DaRT source. The measurements, taken when lead-212 was in secular equilibrium with radium-224, were interpreted as representing the lead-212 diffusion length. The aim of this work is to provide first experimental estimates for the diffusion length of radon-220, using a new methodology. METHODS: The diffusion length of radon-220 was estimated from autoradiography measurements of histological sections taken from 24 mice-borne subcutaneous tumors of five different types. Unlike previous studies, the source dwell time inside the tumor was limited to 30 min, to prevent the buildup of lead-212. To investigate the contribution of potential non-diffusive processes, experiments were done in two sets: fourteen in vivo tumors, where during the treatment the tumors were still carried by the mice with active blood supply, and 10 ex-vivo tumors, where the tumors were excised before source insertion and kept in a medium at 37 ∘ C $37^\circ {\text{C}}$ with the source inside. RESULTS: The measured diffusion lengths of radon-220, extracted by fitting the recorded activity pattern up to 1.5 mm from the source, lie in the range 0.25 - 0.6 mm ${0.25-0.6}\nobreakspace {\text{mm}}$ , with no significant difference between the average values measured in in-vivo and ex-vivo tumors: L R n i n - v i v o = 0.40 ± 0.08 mm $L_{Rn}^{in-vivo}=0.40{\pm }0.08\nobreakspace {\text{mm}}$ versus L R n e x - v i v o = 0.39 ± 0.07 mm $L_{Rn}^{ex-vivo}=0.39{\pm }0.07\nobreakspace {\text{mm}}$ . However, in-vivo tumors display an enhanced spread of activity 2-3 mm away from the source. This effect is not explained by the current model and is much less pronounced in ex-vivo tumors. CONCLUSIONS: The average measured radon-220 diffusion lengths in both in-vivo and ex-vivo tumors are consistent with published data on the diffusion length of radon in water and lie close to the upper limit of the previously estimated range of 0.2 - 0.4 mm $0.2-0.4\nobreakspace {\text{mm}}$ . The observation that close to the source there is no apparent difference between in-vivo and ex-vivo tumors, and the good agreement with the theoretical model in this region suggest that the spread of radon-220 is predominantly diffusive in this region. The departure from the model prediction in in-vivo tumors at large radial distances may hint at potential vascular contribution, which will be the subject of future works.

Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Deep inspiratory breath hold assisted by continuous positive airway pressure ventilation for lung stereotactic body radiotherapy.

PURPOSE: Continuous positive airway pressure (CPAP) ventilation hyperinflates the lungs and reduces diaphragmatic motion. We hypothesized that CPAP could be safely combined with deep inspiratory breath hold (CPAP-DIBH) during lung stereotactic radiotherapy (SBRT). MATERIAL AND METHODS: Patients with stage-1 lung cancer or lung metastasis treated with CPAP-DIBH SBRT between 3/2017-5/2021 were analyzed retrospectively. Patient characteristics, treatment parameters, duration of breath holds in all sessions and tolerance to CPAP-DIBH were recorded. Local control (LC) was assessed from CT or PET-CT imaging. The distances between the tumor and mediastinal organs at risk (OAR) in centrally located tumors using either free breathing (FB) or CPAP-DIBH were compared. Toxicity was graded retrospectively. RESULTS: Forty-five patients with 71 lesions were treated with CPAP-DIBH SBRT. Indications for CPAP-DIBH were prior radiation (35/71, 65%), lower lobe location (34/71, 48%), multiple lesions (26/71, 36.6%) and proximity to mediastinal OAR (7/71, 10%). Patient characteristics were: F:M 43%: 57%; mean gross tumor volume 4.5cm3 (SD 7.9), mean planning target volume 20cm3 (SD 27), primary: metastatic lesions (7%:93%). Mean radiation dose was 52.5 Gray (SD3.5). Mean lung volume was 5292cm3 (SD 1106). Mean duration of CPAP-DIBH was 41.3s (IQR 31-46.8). LC at 2 years was 89.5% (95% CI 76-95.5). In patients with central lesions, the distance between the tumor and mediastinal OAR increased from 0.84cm (SD 0.65) with FB to 1.23cm (SD 0.8) with CPAP-DIBH (p=0.002). Most patients tolerated CPAP well and completed all treatments after starting therapy. Three patients did not receive treatment: 2 were unable to tolerate CPAP and 1 had syncope (pre-existing). Toxicity was grade 2 in 4/65 (6%) and grade 3 in 1/65 (1.5%). There was no grade 2 or higher esophageal or tracheal toxicities. CONCLUSION: CPAP-DIBH assisted lung SBRT was tolerated well and was associated with minimal toxicity and favorable LC. This technique may be considered when treating multiple lung lesions, lesions located in the lower lobes or adjacent to mediastinal OAR.

Initial estimates of continuous positive airway pressure (CPAP) on heart volume, position and motion in patients receiving chest radiation.

To evaluate effects of Continuous Positive Airway Pressure (CPAP) on cardiac position, volume, and motion in a cohort of patients receiving thoracic radiation therapy (RT). Patients underwent 3-dimensional (3D) and 4D-computerized tomography (CT) imaging with free-breathing (FB) and CPAP for RT planning. All scans were co-registered on the treatment planning system for contouring, identification of the center of heart volume and comparative measurements of cardiac displacement, volume and motion. Heart volume (HV) was created from 3D-CT contours. Range of heart motion was estimated by creating an internal heart volume (IHV) from 4D-CT contours. Magnitude of cardiac motion (cardiac excursion) was recorded as the difference in volume between IHV and HV. Wilcoxon signed rank test and Spearmen's rank correlation coefficient were used to assess differences between variables and correlations between lung volume and heart parameters. Results from 9 patient data sets were available for this report. Compared to FB, CPAP use was associated with caudal displacement of the HV (1 cm, p < 0.008) and IHV (1.1 cm, p < 0.008). CPAP use decreased HV 6% (p < 0.008) and IHV 13% (p < 0.008). Cardiac excursion was 49% (p < 0.01) less with CPAP than with FB. CPAP use increased mean lung volume by 30% (p < 0.008) which correlated with caudal displacement of the HV (r = 0.83, p < 0.008) and IHV (r = 0.98, p < 0.001). The use of CPAP reduced cardiac motion and volume although the reduction in volume was minimal. The increase in lung volume correlated with caudal displacement of the heart. These results suggest the mechanism for achieving dosimetric benefit was obtained by cardiac displacement and decreased lung and heart motion rather than reduction of HV. Further evaluation of CPAP as a novel technique to reduce heart exposure when offering RT is warranted.

Benefits of Continuous Positive Airway Pressure (CPAP) During Radiation Therapy: A Prospective Trial.

PURPOSE: This study aimed to study the impact of continuous positive airway pressure (CPAP) on chest anatomy and tumor motion in patients receiving radiation therapy. METHODS AND MATERIALS: Patients with primary or secondary lung tumors, left-sided breast cancer, or liver metastases referred for radiation therapy were trained to breathe with a CPAP device using a face mask to a maximal pressure of 15 cm H2O. Three- and 4-dimensional computed tomography simulation was performed twice for each patient: once with free breathing (FB) and again using CPAP. Volumetric and dosimetric parameters of treatment plans were compared. RESULTS: Forty-nine patients were enrolled, of whom 6 withdrew consent before simulation and 3 withdrew because of discomfort. Thus, a total of 40 patients were analyzed. Twenty-seven patients (67.5%) were treated with CPAP based on confirmation of the volumetric or dosimetric benefit of CPAP. Mean lung volume increased by 37% (P < .001). The mean augmentation was 1283 ± 1128 cm3 (CPAP vs FB; P = .0006) in patients with normal lung function tests and 719 ± 341 cm3 (P = .003) in patients with a restrictive pattern. Increased lung volume was independent of age, body mass index, sex, chronic obstructive pulmonary disease, smoking status, and heart disease. Tumor motion in the lung was decreased as reflected in a mean reduction of planning target volume by 19% (P < .001). The greatest reduction of tumor trajectory and planning target volume occurred in tumors in the lower lung, particularly in the range of up to 6 cm above the dome of the diaphragm. The mean lung dose was reduced by 15%, lung V20 by 20%, lung V5 by 11%, and heart V5 by 16% (P < .01). CONCLUSIONS: In this prospective trial, the use of CPAP was associated with significant volumetric and dosimetric benefits compared with FB. CPAP was safe, simple to implement, and well tolerated by most patients, and it should be studied further as a method to reduce the risk of lung and heart toxicity.

Gallium-68 prostate-specific membrane antigen PET-CT and the clinical management of prostate cancer.

OBJECTIVES: The purpose of this study was to evaluate the use of Gallium-68 prostatic-specific membrane antigen (PSMA) PET-computerized tomography (CT) in patients with prostate cancer undergoing imaging for initial staging, biochemical failure or the evaluation of metastatic disease. METHODS: This is a single institution retrospective study of 95 patients with prostate cancer who were referred for PSMA PET-CT scans. The National Comprehensive Cancer Network guidelines were used to generate treatment recommendations. Univariate and multivariate statistical analyses were performed to identify parameters associated with positive findings on a PET-CT PSMA scan. RESULTS: Mean age, Gleason score, and median prostate serum antigen (PSA) were: 72 years, 7.6 and 4 ng/ml, respectively. PSMA PET-CT was positive in 75.5% of the patients. A maximum standardized uptake value was 10.7 ± 8.8. PSMA avidity increased with rising PSA level: PSA ≤ 1 ng/ml: 5/15 patients (33%); PSA 1-5 ng/ml: 18/27 patients (67%), and PSA ≥ 5 ng/ml: 33/34 patients (97%). Following imaging in nine high-risk patients referred for staging, changes in treatment occurred in 6 (67%). Treatment recommendations changed in 27/35 (65%) patients referred due to biochemical failure; these included recurrences suitable for salvage therapy (n = 14), metastatic disease not suitable for salvage therapy (n = 10), and no lesion (n = 17). No changes in treatment occurred in any of the 35 patients referred to evaluate metastatic disease. DISCUSSION: PSMA PET-CT imaging may have a substantial impact on clinical management in prostate cancer patients at the time of initial staging or with biochemical failure; yet this modality does not appear useful in the management of patients with known metastatic disease.

Use of 18F-FDG PET-CT imaging to determine internal mammary lymph node location for radiation therapy treatment planning in breast cancer patients.

PURPOSE: Adjuvant internal mammary lymph node (IMN) radiation is often delivered with 2-dimensional techniques that use anatomic landmarks and predetermined depths for field placement and dose specification. In contrast, 3-dimensional planning uses the internal mammary vessels (IMVs) to localize the IMNs for planning. Our purpose was to determine if localization of the involved IMN (i-IMN) by 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) offers opportunities to improve treatment. METHODS AND MATERIALS: Breast cancer patients (n = 80) who had i-IMNs (n = 112) on PET-CT for initial staging (n = 40) or recurrence (n = 40) were studied. Size, intercostal space (IC), and distance from skin, sternum, and IMVs were recorded. Effects on 2- and 3-dimensional planning were evaluated. RESULTS: Most i-IMNs (94.6%) were in the first to third ICs. Few were in the fourth (4.5%) or fifth (0.9%) IC. Mean i-IMN depth was 3.4 cm (range, 1.1-7.3 cm). Prescriptive depths of 4, 5, and 6 cm would result in undertreatment of 25%, 10.7%, and 5.3% of IMNs, respectively. Most IMNs (86.6%) were lateral or adjacent to the sternal edge. Only 13.4% of IMNs were posterior to the sternum. Use of the ipsilateral or contralateral sternal edge for field placement increases the risk of geographic miss or excess normal tissue exposure. Most i-IMNs were adjacent to (83%) or ≤0.5 cm (14%) from the IMV edge. Three (3%) were >0.5 cm beyond the IMV edge. The clinical target volume (CTV) defined by the first to third ICs encompassed 78% of i-IMNs. IMN-CTV coverage of i-IMNs increased with inclusion of the fourth IC (82%), 0.5 cm medial and lateral margin expansion (93%), or both (96.5%). CONCLUSION: Two-dimensional treatment techniques risk geographic miss of IMNs and exposure of excess normal tissue to radiation. An IMN-CTV defined by the IMVs from the first to third ICs with 0.5-cm medial and lateral margin expansion encompasses almost all i-IMNs identified on PET-CT imaging. Inclusion of the fourth IC offers modest coverage improvement, and its inclusion should be weighed against potential increase in cardiac exposure. SUMMARY: The use of 2-dimensional treatment techniques for adjuvant internal mammary lymph node (IMN) radiation may cause geographic miss of tumor and expose normal tissue to radiation injury. Conformal 3-dimensional planning improves coverage and reduces risk of normal tissue damage by using the internal mammary vessel to define an IMN clinical target volume (CTV). Contouring the IMN-CTV from the first to third intercostal spaces with a 0.5-cm expansion medially and laterally encompasses most IMN. Positron emission tomography-computed tomography may have a role in radiation planning by identifying involved-IMN for dose escalation.