We review the current status of proton FLASH experimental systems, including preclinical physical and biological results. Technological limitations on preclinical investigation of FLASH biological ...mechanisms and determination of clinically relevant parameters are discussed. A review of the biological data reveals no reproduced proton FLASH effect in vitro and a significant in vivo FLASH sparing effect of normal tissue toxicity observed with multiple proton FLASH irradiation systems. Importantly, multiple studies suggest little or no difference in tumor growth delay for proton FLASH when compared to conventional dose rate proton radiation. A discussion follows on future areas of development with a focus on the determination of the optimal parameters for maximizing the therapeutic ratio between tumor and normal tissue response and ultimately clinical translation of proton FLASH radiation.
Recent studies suggest that ultrahigh-dose-rate, “FLASH,” electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. ...Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection.
Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation.
The double scattering and collimation apparatus was dosimetrically validated with dose rates of 78 ± 9 Gy per second and 0.9 ± 0.08 Gy per second for the FLASH and standard PRT. Whole abdominal FLASH PRT at 15 Gy significantly reduced the loss of proliferating cells in intestinal crypts compared with standard PRT. Studies with local intestinal irradiation at 18 Gy revealed a reduction to near baseline levels of intestinal fibrosis for FLASH-PRT compared with standard PRT. Despite this difference, FLASH-PRT did not demonstrate tumor radioprotection in MH641905 pancreatic cancer flank tumors after 12 or 18 Gy irradiation.
We have designed and dosimetrically validated a FLASH-PRT system with accurate control of beam flux on a millisecond time scale and online monitoring of the integral and dose delivery time structure. Using this system, we found that FLASH-PRT decreases acute cell loss and late fibrosis after whole-abdomen and focal intestinal RT, whereas tumor growth inhibition is preserved between the 2 modalities.
•Among an extensive set of 32 clinical and dosimetric features, Lung V20, mean lung dose, lung V10 and lung V5 are the best individual predictors of radiation pneumonitis in stage II–III ...LA-NSCLC.•The combined predictive performance of radiation pneumonitis predictors such as maximum esophagus dose, lung V20, mean lung dose, pack-year, lung V5 and lung V10 improves the performance of individual predictors up to a 24.6% improvement rate using random forest.•Lung V20, maximum esophagus dose and mean lung dose are consistently selected as the most important predictors of radiation pneumonitis by the machine learning algorithms, random forest, RUSBoost and CART.
Radiation pneumonitis (RP) is a radiotherapy dose-limiting toxicity for locally advanced non-small cell lung cancer (LA-NSCLC). Prior studies have proposed relevant dosimetric constraints to limit this toxicity. Using machine learning algorithms, we performed analyses of contributing factors in the development of RP to uncover previously unidentified criteria and elucidate the relative importance of individual factors.
We evaluated 32 clinical features per patient in a cohort of 203 stage II–III LA-NSCLC patients treated with definitive chemoradiation to a median dose of 66.6 Gy in 1.8 Gy daily fractions at our institution from 2008 to 2016. Of this cohort, 17.7% of patients developed grade ≥2 RP. Univariate analysis was performed using trained decision stumps to individually analyze statistically significant predictors of RP and perform feature selection. Applying Random Forest, we performed multivariate analysis to assess the combined performance of important predictors of RP.
On univariate analysis, lung V20, lung mean, lung V10 and lung V5 were found to be significant RP predictors with the greatest balance of specificity and sensitivity. On multivariate analysis, Random Forest (AUC = 0.66, p = 0.0005) identified esophagus max (20.5%), lung V20 (16.4%), lung mean (15.7%) and pack-year (14.9%) as the most common primary differentiators of RP.
We highlight Random Forest as an accurate machine learning method to identify known and new predictors of symptomatic RP. Furthermore, this analysis confirms the importance of lung V20, lung mean and pack-year as predictors of RP while also introducing esophagus max as an important RP predictor.
The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LETd) while keeping the radiobiologically weighted ...dose (DRBE) to the target the same.
The target is painted with LETd by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning STP). As the LETd within the target increases with increasing number of fields, D decreases to maintain the DRBE the same as the conventional treatment planning method by using beams treating the full target (full target planning FTP).
The LETd increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LETd led to a decrease of D with 5.3 ± 0.6 Gy for 2STP, 4.4 ± 0.7 Gy for 4STP, and 5.3 ± 1.1 Gy for 7STP, keeping the Drbe at 90% of the volume (Drbe, 90) constant to FTP.
LETd painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment.
3D patient-derived organoids (PDOs) have been utilized to evaluate potential therapies for patients with different cancers. However, the use of PDOs created from treatment-naive patient biopsies for ...prediction of clinical outcomes in patients with esophageal cancer has not yet been reported. Herein we describe a pilot prospective observational study with the goal of determining whether esophageal cancer PDOs created from treatment naive patients can model or predict clinical outcomes. Endoscopic biopsies of treatment-naive patients at a single tertiary care center were used to generate esophageal cancer PDOs, which were treated with standard-of-care chemotherapy, gamma-irradiation, and newer non-standard approaches, such as proton beam therapy or two small molecule inhibitors. Clinical outcomes of patients following neoadjuvant treatment were compared to their in vitro PDO responses, demonstrating the PDO's ability to mirror clinical response, suggesting the value of PDOs in prediction of clinical response to new therapeutic approaches. Future prospective clinical trials should test the use of pre-treatment PDOs to identify specific, targeted therapies for individual patients with esophageal adenocarcinoma.
The expansion of machine learning to high-stakes application domains such as medicine, finance, and criminal justice, where making informed decisions requires clear understanding of the model, has ...increased the interest in interpretable machine learning. The widely used Classification and Regression Trees (CART) have played a major role in health sciences, due to their simple and intuitive explanation of predictions. Ensemble methods like gradient boosting can improve the accuracy of decision trees, but at the expense of the interpretability of the generated model. Additive models, such as those produced by gradient boosting, and full interaction models, such as CART, have been investigated largely in isolation. We show that these models exist along a spectrum, revealing previously unseen connections between these approaches. This paper introduces a rigorous formalization for the additive tree, an empirically validated learning technique for creating a single decision tree, and shows that this method can produce models equivalent to CART or gradient boosted stumps at the extremes by varying a single parameter. Although the additive tree is designed primarily to provide both the model interpretability and predictive performance needed for high-stakes applications like medicine, it also can produce decision trees represented by hybrid models between CART and boosted stumps that can outperform either of these approaches.
FLASH is an emerging treatment paradigm in radiotherapy (RT) that utilizes ultra-high dose rates (UHDR; >40 Gy)/s) of radiation delivery. Developing advances in technology support the delivery of ...UHDR using electron and proton systems, as well as some ion beam units (eg, carbon ions), while methods to achieve UHDR with photons are under investigation. The major advantage of FLASH RT is its ability to increase the therapeutic index for RT by shifting the dose response curve for normal tissue toxicity to higher doses. Numerous preclinical studies have been conducted to date on FLASH RT for murine sarcomas, alongside the investigation of its effects on relevant normal tissues of skin, muscle, and bone. The tumor control achieved by FLASH RT of sarcoma models is indistinguishable from that attained by treatment with standard RT to the same total dose. FLASH's high dose rates are able to mitigate the severity or incidence of RT side effects on normal tissues as evaluated by endpoints ranging from functional sparing to histological damage. Large animal studies and clinical trials of canine patients show evidence of skin sparing by FLASH vs. standard RT, but also caution against delivery of high single doses with FLASH that exceed those safely applied with standard RT. Also, a human clinical trial has shown that FLASH RT can be delivered safely to bone metastasis. Thus, data to date support continued investigations of clinical translation of FLASH RT for the treatment of patients with sarcoma. Toward this purpose, hypofractionated irradiation schemes are being investigated for FLASH effects on sarcoma and relevant normal tissues.
•FLASH proton PBS has strong potential to be implemented for patient treatment.•Clinical proton PBS delivery parameters were extrapolated to high cyclotron current.•It is challenging to achieve ...>40Gy/s FLASH dose rate for field size >4x4 cm2.•Scanning magnet slew and energy switching times appear to be the limiting factors.•Portion of the local dose can be delivered at FLASH dose rate.
Proton Pencil Beam Scanning (PBS) is an attractive solution to realize the advantageous normal tissue sparing elucidated from FLASH high dose rates. The mechanics of PBS spot delivery will impose limitations on the effective field dose rate for PBS.
This study incorporates measurements from clinical and FLASH research beams on uniform single energy and the spread-out Bragg Peak PBS fields to extrapolate the PBS dose rate to high cyclotron beam currents 350, 500, and 800 nA. The impact of the effective field dose rate from cyclotron current, spot spacing, slew time and field size were studied.
When scanning magnet slew time and energy switching time are not considered, single energy effective field FLASH dose rate (≥40 Gy/s) can only be achieved with less than 4 × 4 cm2 fields when the cyclotron output current is above 500 nA. Slew time and energy switching time remain the limiting factors for achieving high effective dose rate of the field. The dose rate-time structures were obtained. The amount of the total dose delivered at the FLASH dose rate in single energy layer and volumetric field was also studied.
It is demonstrated that while it is difficult to achieve FLASH dose rate for a large field or in a volume, local FLASH delivery to certain percentage of the total dose is possible. With further understanding of the FLASH radiobiological mechanism, this study could provide guidance to adapt current clinical multi-field proton PBS delivery practice for FLASH proton radiotherapy.
The environmental conditions that could lead to an increased risk for the development of an infection during prolonged space flight include: microgravity, stress, radiation, disturbance of circadian ...rhythms, and altered nutritional intake. A large body of literature exists on the impairment of the immune system by space flight. With the advent of missions outside the Earth's magnetic field, the increased risk of adverse effects due to exposure to radiation from a solar particle event (SPE) needs to be considered. Using models of reduced gravity and SPE radiation, we identify that either 2 Gy of radiation or hindlimb suspension alone leads to activation of the innate immune system and the two together are synergistic. The mechanism for the transient systemic immune activation is a reduced ability of the GI tract to contain bacterial products. The identification of mechanisms responsible for immune dysfunction during extended space missions will allow the development of specific countermeasures.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) represents a challenge in oncology, with limited treatment options for advanced-stage patients. Chimeric antigen receptor T cell (CAR T) therapy targeting ...mesothelin (MSLN) shows promise, but challenges such as the hostile immunosuppressive tumor microenvironment (TME) hinder its efficacy. This study explores the synergistic potential of combining proton radiation therapy (RT) with MSLN-targeting CAR T therapy in a syngeneic PDAC model. Proton RT significantly increased MSLN expression in tumor cells and caused a significant increase in CAR T cell infiltration into tumors. The combination therapy reshaped the immunosuppressive TME, promoting antitumorigenic M1 polarized macrophages and reducing myeloid-derived suppressor cells (MDSC). In a flank PDAC model, the combination therapy demonstrated superior attenuation of tumor growth and improved survival compared to individual treatments alone. In an orthotopic PDAC model treated with image-guided proton RT, tumor growth was significantly reduced in the combination group compared to the RT treatment alone. Further, the combination therapy induced an abscopal effect in a dual-flank tumor model, with increased serum interferon-γ levels and enhanced proliferation of extratumoral CAR T cells. In conclusion, combining proton RT with MSLN-targeting CAR T therapy proves effective in modulating the TME, enhancing CAR T cell trafficking, and exerting systemic antitumor effects. Thus, this combinatorial approach could present a promising strategy for improving outcomes in unresectable PDAC.
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