High-Flow Oxygen with Capping or Suctioning for Tracheostomy Decannulation.

BACKGROUND: When patients with a tracheostomy tube reach a stage in their care at which decannulation appears to be possible, it is common practice to cap the tracheostomy tube for 24 hours to see whether they can breathe on their own. Whether this approach to establishing patient readiness for decannulation leads to better outcomes than one based on the frequency of airway suctioning is unclear. METHODS: In five intensive care units (ICUs), we enrolled conscious, critically ill adults who had a tracheostomy tube; patients were eligible after weaning from mechanical ventilation. In this unblinded trial, patients were randomly assigned either to undergo a 24-hour capping trial plus intermittent high-flow oxygen therapy (control group) or to receive continuous high-flow oxygen therapy with frequency of suctioning being the indicator of readiness for decannulation (intervention group). The primary outcome was the time to decannulation, compared by means of the log-rank test. Secondary outcomes included decannulation failure, weaning failure, respiratory infections, sepsis, multiorgan failure, durations of stay in the ICU and hospital, and deaths in the ICU and hospital. RESULTS: The trial included 330 patients; the mean (±SD) age of the patients was 58.3±15.1 years, and 68.2% of the patients were men. A total of 161 patients were assigned to the control group and 169 to the intervention group. The time to decannulation was shorter in the intervention group than in the control group (median, 6 days [interquartile range, 5 to 7] vs. 13 days [interquartile range, 11 to 14]; absolute difference, 7 days [95% confidence interval, 5 to 9]). The incidence of pneumonia and tracheobronchitis was lower, and the duration of stay in the hospital shorter, in the intervention group than in the control group. Other secondary outcomes were similar in the two groups. CONCLUSIONS: Basing the decision to decannulate on suctioning frequency plus continuous high-flow oxygen therapy rather than on 24-hour capping trials plus intermittent high-flow oxygen therapy reduced the time to decannulation, with no evidence of a between-group difference in the incidence of decannulation failure. (REDECAP ClinicalTrials.gov number, NCT02512744.).

Development of an antibody cocktail for treatment of Sudan virus infection.

Antibody-based therapies are a promising treatment option for managing ebolavirus infections. Several Ebola virus (EBOV)-specific and, more recently, pan-ebolavirus antibody cocktails have been described. Here, we report the development and assessment of a Sudan virus (SUDV)-specific antibody cocktail. We produced a panel of SUDV glycoprotein (GP)-specific human chimeric monoclonal antibodies (mAbs) using both plant and mammalian expression systems and completed head-to-head in vitro and in vivo evaluations. Neutralizing activity, competitive binding groups, and epitope specificity of SUDV mAbs were defined before assessing protective efficacy of individual mAbs using a mouse model of SUDV infection. Of the mAbs tested, GP base-binding mAbs were more potent neutralizers and more protective than glycan cap- or mucin-like domain-binding mAbs. No significant difference was observed between plant and mammalian mAbs in any of our in vitro or in vivo evaluations. Based on in vitro and rodent testing, a combination of two SUDV-specific mAbs, one base binding (16F6) and one glycan cap binding (X10H2), was down-selected for assessment in a macaque model of SUDV infection. This cocktail, RIID F6-H2, provided protection from SUDV infection in rhesus macaques when administered at 50 mg/kg on days 4 and 6 postinfection. RIID F6-H2 is an effective postexposure SUDV therapy and provides a potential treatment option for managing human SUDV infection.

Impact of an intradialysis virtual-reality-based exercise program on healthcare resources expenditure: a micro-costing analysis.

BACKGROUND: Engagement in exercise by haemodialysis (HD) patients has been shown to generate benefits both in terms of improved functional capacity and in the health-related quality of life. The use of non-immersive virtual reality (VR) games represents a new format for the implementation of intradialysis exercise. Some studies have shown that engaging in exercise for 6 months reduces the consumption of antihypertensive drugs and decreases the time spent admitted to hospital among individuals receiving HD treatments. The objective of this study was to evaluate changes in the consumption of healthcare resources and micro-costing for patients on HD who completed a VR exercise program. MATERIALS AND METHODS: Design: This study is a secondary analysis of a clinical trial. The participants performed an intradialysis exercise program with non-immersive virtual reality for 3 months. The variables were recorded in two periods: 12 months before and 12 months after the start of the exercise program. RESULTS: The micro-costing analysis showed a significant decrease in the mean cost, in euros, for the consumption of laboratory tests - 330 (95% CI:[- 533, - 126];p = 0.003), outpatient visits - 351 ([- 566, - 135];p = 0.003), and radiology tests - 111 ([- 209, - 10];p = 0.03) in the 12 months after the implementation of the exercise program relative to the 12 months prior to its start. CONCLUSION: The implementation of intradialysis exercise programs decreased the expenditure of some healthcare resources. Future studies could help clarify if longer interventions would have a stronger impact on these cost reductions.

Classifying brain metastases by their primary site of origin using a radiomics approach based on texture analysis: a feasibility study.

OBJECTIVE: To examine the capability of MRI texture analysis to differentiate the primary site of origin of brain metastases following a radiomics approach. METHODS: Sixty-seven untreated brain metastases (BM) were found in 3D T1-weighted MRI of 38 patients with cancer: 27 from lung cancer, 23 from melanoma and 17 from breast cancer. These lesions were segmented in 2D and 3D to compare the discriminative power of 2D and 3D texture features. The images were quantized using different number of gray-levels to test the influence of quantization. Forty-three rotation-invariant texture features were examined. Feature selection and random forest classification were implemented within a nested cross-validation structure. Classification was evaluated with the area under receiver operating characteristic curve (AUC) considering two strategies: multiclass and one-versus-one. RESULTS: In the multiclass approach, 3D texture features were more discriminative than 2D features. The best results were achieved for images quantized with 32 gray-levels (AUC = 0.873 ± 0.064) using the top four features provided by the feature selection method based on the p-value. In the one-versus-one approach, high accuracy was obtained when differentiating lung cancer BM from breast cancer BM (four features, AUC = 0.963 ± 0.054) and melanoma BM (eight features, AUC = 0.936 ± 0.070) using the optimal dataset (3D features, 32 gray-levels). Classification of breast cancer and melanoma BM was unsatisfactory (AUC = 0.607 ± 0.180). CONCLUSION: Volumetric MRI texture features can be useful to differentiate brain metastases from different primary cancers after quantizing the images with the proper number of gray-levels. KEY POINTS: • Texture analysis is a promising source of biomarkers for classifying brain neoplasms. • MRI texture features of brain metastases could help identifying the primary cancer. • Volumetric texture features are more discriminative than traditional 2D texture features.

Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease.

Antibody therapies to prevent or limit filovirus infections have received modest interest in recent years, in part because of early negative experimental evidence. We have overcome the limitations of this approach, leveraging the use of antibody from nonhuman primates (NHPs) that survived challenge to filoviruses under controlled conditions. By using concentrated, polyclonal IgG antibody from these survivors, we treated filovirus-infected NHPs with multiple doses administered over the clinical phase of disease. In the first study, Marburg virus (MARV)-infected NHPs were treated 15 to 30 min postexposure with virus-specific IgG, with additional treatments on days 4 and 8 postexposure. The postexposure IgG treatment was completely protective, with no signs of disease or detectable viremia. MARV-specific IgM antibody responses were generated, and all macaques survived rechallenge with MARV, suggesting that they generated an immune response to virus replication. In the next set of studies, NHPs were infected with MARV or Ebola virus (EBOV), and treatments were delayed 48 h, with additional treatments on days 4 and 8 postexposure. The delayed treatments protected both MARV- and EBOV-challenged NHPs. In both studies, two of the three IgG-treated NHPs had no clinical signs of illness, with the third NHP developing mild and delayed signs of disease followed by full recovery. These studies clearly demonstrate that postexposure antibody treatments can protect NHPs and open avenues for filovirus therapies for human use using established Food and Drug Administration-approved polyclonal or monoclonal antibody technologies.

Venezuelan equine encephalitis virus replicon particle vaccine protects nonhuman primates from intramuscular and aerosol challenge with ebolavirus.

There are no vaccines or therapeutics currently approved for the prevention or treatment of ebolavirus infection. Previously, a replicon vaccine based on Venezuelan equine encephalitis virus (VEEV) demonstrated protective efficacy against Marburg virus in nonhuman primates. Here, we report the protective efficacy of Sudan virus (SUDV)- and Ebola virus (EBOV)-specific VEEV replicon particle (VRP) vaccines in nonhuman primates. VRP vaccines were developed to express the glycoprotein (GP) of either SUDV or EBOV. A single intramuscular vaccination of cynomolgus macaques with VRP expressing SUDV GP provided complete protection against intramuscular challenge with SUDV. Vaccination against SUDV and subsequent survival of SUDV challenge did not fully protect cynomolgus macaques against intramuscular EBOV back-challenge. However, a single simultaneous intramuscular vaccination with VRP expressing SUDV GP combined with VRP expressing EBOV GP did provide complete protection against intramuscular challenge with either SUDV or EBOV in cynomolgus macaques. Finally, intramuscular vaccination with VRP expressing SUDV GP completely protected cynomolgus macaques when challenged with aerosolized SUDV, although complete protection against aerosol challenge required two vaccinations with this vaccine.

Embedded ARM system for volcano monitoring in remote areas: application to the active volcano on Deception Island (Antarctica).

This paper describes the development of a multi-parameter system for monitoring volcanic activity. The system permits the remote access and the connection of several modules in a network. An embedded ARM™ processor has been used, allowing a great flexibility in hardware configuration. The use of a complete Linux solution (Debian™) as Operating System permits a quick, easy application development to control sensors and communications. This provides all the capabilities required and great stability with relatively low energy consumption. The cost of the components and applications development is low since they are widely used in different fields. Sensors and commercial modules have been combined with other self-developed modules. The Modular Volcano Monitoring System (MVMS) described has been deployed on the active Deception Island (Antarctica) volcano, within the Spanish Antarctic Program, and has proved successful for monitoring the volcano, with proven reliability and efficient operation under extreme conditions. In another context, i.e., the recent volcanic activity on El Hierro Island (Canary Islands) in 2011, this technology has been used for the seismic equipment and GPS systems deployed, thus showing its efficiency in the monitoring of a volcanic crisis.

Creating uniform cluster dose spread-out Bragg peaks for proton and carbon beams.

BACKGROUND: Preliminary data have shown a close association of the generalized ionization cluster size dose (in short, cluster dose) with cell survival, independent of particle type, and energy, when cluster dose is derived from an ionization detail parameter preferred for its association with cell survival. Such results suggest cluster dose has the potential to replace RBE-weighted dose in proton and ion beam radiotherapy treatment plan optimization, should a uniform cluster dose lead to comparable biological effects. However, further preclinical investigations are warranted to confirm this premise. PURPOSE: To present an analytical approach to create uniform cluster dose spread-out Bragg peaks (SOBP) for evaluation of the potential of cluster dose to result in uniform biological effect. METHODS: We modified the coefficients of the Bortfeld and Schlegel weight formula, an analytical method typically used for the creation of radiation dose SOBP in particle therapy, to produce uniform cluster dose SOBP of different widths (1-5 cm) at relevant clinical proton and carbon beam energies. Optimum parameters were found by minimization of the ratio between the maximum and minimum cluster dose in the SOBP region using the Nelder-Mead method. RESULTS: The coefficients of the Bortfeld and Schlegel weight formula leading to uniform cluster dose SOBPs were determined for each combination of beam energy and SOBP width studied. The uniformity of the resulting cluster dose SOBPs, calculated as the relative difference between the maximum and minimum cluster dose within the SOBP, was within 0.3%-3.5% for the evaluated proton beams and 1.3%-3.4% for the evaluated carbon beams. CONCLUSIONS: The modifications to the analytical approach to create radiation dose SOBPs resulted in uniform cluster dose proton and carbon SOBPs over a wide range of beam energies and SOBP widths. Such SOBPs should prove valuable in preclinical investigations for the selection of nanodosimetric quantities to be used in proton and ion therapy treatment planning.

An interface tool to parametrize treatment plans for the TrueBeam radiotherapy system into TOPAS parameter control files for Monte Carlo simulation.

PURPOSE: The Monte Carlo (MC) method, the gold standard method for radiotherapy dose calculations, is underused in clinical research applications mainly due to computational speed limitations. Another reason is the time-consuming and error prone conversion of treatment plan specifications into MC parameters. To address this issue, we developed an interface tool that creates a set of TOPAS parameter control files (PCF) from information exported from a clinical treatment planning system (TPS) for plans delivered by the TrueBeam radiotherapy system. METHODS: The interface allows the user to input DICOM-RT files, exported from a TPS and containing the plan parameters, and choose different multileaf-collimator models, variance reduction technique parameters, scoring quantities and simulation output formats. Radiation sources are precomputed phase space files obtained from Varian. Based on this information, ready-to-run TOPAS PCF that incorporate the position and angular rotation of the TrueBeam dynamic collimation devices, gantry, couch, and patient according to treatment plan specifications are created. RESULTS: Dose distributions computed using these PCF were compared against predictions from commercial TPS for different clinical treatment plans and techniques (3D-CRT, IMRT step-and-shoot and VMAT) to evaluate the performance of the interface. The agreement between dose distributions from TOPAS and TPS (>98 % pass ratio in the gamma test) confirmed the correct parametrization of treatment plan specifications into MC PCF. CONCLUSIONS: This interface tool is expected to widen the use of MC methods in the clinical medical physics field by facilitating the straightforward transfer of treatment plan parameters from commercial TPS into MC PCF.

Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps.

Spatially fractionated radiation therapy (SFRT) is a therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT activates distinct radiobiological mechanisms which lead to a remarkable increase in normal tissue tolerances. Several decades of clinical use and numerous preclinical experiments suggest that SFRT has the potential to increase the therapeutic index, especially in bulky and radioresistant tumors. To unleash the full potential of SFRT a deeper understanding of the underlying biology and its relationship with the complex dosimetry of SFRT is needed. This review provides a critical analysis of the field, discussing not only the main clinical and preclinical findings but also analyzing the main knowledge gaps in a holistic way.

Lithium inelastic cross-sections and their impact on micro and nano dosimetry of boron neutron capture.

Objective.To present a new set of lithium-ion cross-sections for (i) ionization and excitation processes down to 700 eV, and (ii) charge-exchange processes down to 1 keV u-1. To evaluate the impact of the use of these cross-sections on micro a nano dosimetric quantities in the context of boron neutron capture (BNC) applications/techniques.Approach.The Classical Trajectory Monte Carlo method was used to calculate Li ion charge-exchange cross sections in the energy range of 1 keV u-1to 10 MeV u-1. Partial Li ion charge states ionization and excitation cross-sections were calculated using a detailed charge screening factor. The cross-sections were implemented in Geant4-DNA v10.07 and simulations and verified using TOPAS-nBio by calculating stopping power and continuous slowing down approximation (CSDA) range against data from ICRU and SRIM. Further microdosimetric and nanodosimetric calculations were performed to quantify differences against other simulation approaches for low energy Li ions. These calculations were: lineal energy spectra (yf(y) andyd(y)), frequency mean lineal energyyF-, dose mean lineal energyyD-and ionization cluster size distribution analysis. Microdosimetric calculations were compared against a previous MC study that neglected charge-exchange and excitation processes. Nanodosimetric results were compared against pure ionization scaled cross-sections calculations.Main results.Calculated stopping power differences between ICRU and Geant4-DNA decreased from 33.78% to 6.9%. The CSDA range difference decreased from 621% to 34% when compared against SRIM calculations. Geant4-DNA/TOPAS calculated dose mean lineal energy differed by 128% from the previous Monte Carlo. Ionization cluster size frequency distributions for Li ions differed by 76%-344.11% for 21 keV and 2 MeV respectively. With a decrease in theN1within 9% at 10 keV and agreeing after the 100 keV. With the new set of cross-sections being able to better simulate low energy behaviors of Li ions.Significance.This work shows an increase in detail gained from the use of a more complete set of low energy cross-sections which include charge exchange processes. Significant differences to previous simulation results were found at the microdosimetric and nanodosimetric scales that suggest that Li ions cause less ionizations per path length traveled but with more energy deposits. Microdosimetry results suggest that the BNC's contribution to cellular death may be mainly due to alpha particle production when boron-based drugs are distributed in the cellular membrane and beyond and by Li when it is at the cell cytoplasm regions.

Investigating the biochemical response of proton minibeam radiation therapy by means of synchrotron-based infrared microspectroscopy.

The biology underlying proton minibeam radiation therapy (pMBRT) is not fully understood. Here we aim to elucidate the biological effects of pMBRT using Fourier Transform Infrared Microspectroscopy (FTIRM). In vitro (CTX-TNA2 astrocytes and F98 glioma rat cell lines) and in vivo (healthy and F98-bearing Fischer rats) irradiations were conducted, with conventional proton radiotherapy and pMBRT. FTIRM measurements were performed at ALBA Synchrotron, and multivariate data analysis methods were employed to assess spectral differences between irradiation configurations and doses. For astrocytes, the spectral regions related to proteins and nucleic acids were highly affected by conventional irradiations and the high-dose regions of pMBRT, suggesting important modifications on these biomolecules. For glioma, pMBRT had a great effect on the nucleic acids and carbohydrates. In animals, conventional radiotherapy had a remarkable impact on the proteins and nucleic acids of healthy rats; analysis of tumour regions in glioma-bearing rats suggested major nucleic acid modifications due to pMBRT.

Thoracic Proton Minibeam Radiation Therapy: Tissue Preservation and Survival Advantage Over Conventional Proton Therapy.

PURPOSE: Proton minibeam radiation therapy (pMBRT) is an innovative radiation therapy approach that highly modulates the spatial dimension of the dose delivery using narrow, parallel, and submillimetric proton beamlets. pMBRT has proven its remarkable healthy tissue preservation in the brain and skin. This study assesses the potential advantages of pMBRT for thoracic irradiations compared with conventional radiation therapy in terms of normal tissue toxicity. The challenge here was the influence of respiratory motion on the typical peak and valley dose patterns of pMBRT and its potential biologic effect. METHODS AND MATERIALS: The whole thorax of naïve C57BL/6 mice received one fraction of high dose (18 Gy) pMBRT or conventional proton therapy (CPT) without any respiratory control. The development of radiation-induced pulmonary fibrosis was longitudinally monitored using cone beam computed tomography. Anatomopathologic analysis was carried out at 9 months postirradiation and focused on the reaction of the lungs' parenchyma and the response of cell types involved in the development of radiation-induced fibrosis and lung regeneration as alveolar type II epithelial cells, club cells, and macrophages. RESULTS: pMBRT has milder effects on survival, skin reactions, and lung fibrosis compared with CPT. The pMBRT-induced lung changes were more regional and less severe, with evidence of potential reactive proliferation of alveolar type II epithelial cells and less extensive depletion of club cells and macrophage invasion than the more damaging effects observed in CPT. CONCLUSIONS: pMBRT appears suitable to treat moving targets, holding a significant ability to preserve healthy lung tissue, even without respiratory control or precise targeting.

Activation and disease control of patients on chronic hemodialysis: An observational study.

BACKGROUND AND OBJECTIVE: Patient activation is a concept that refers to the willingness to manage one's health and medical care. To assess it, a patient activation measure (PAM) has been developed and validated. Several studies report low activation in patients with chronic diseases. However, information on activation in hemodialysis patients is scarce. The aim of the present study is to describe the activation level of patients on chronic treatment in an HD unit and its relationship with disease control parameters. MATERIALS AND METHODS: Cross-sectional observational study in patients with advanced chronic kidney disease on chronic HD treatment. Ninety-six patients were included. Activation was measured with the PAM-13 questionnaire. Its relationship with descriptive variables (age, sex, comorbidity, studies, habitat) and disease control variables (vascular access, blood flow, potassaemia, phosphataemia, interdialytic gain) was studied. For this purpose, Spearman's correlation test, multiple linear regression model and logistic model were used as statistical methods. RESULTS: The mean (SD) PAM-13 score was 63.19 (15.21). Activation was significantly associated with vascular access (P = 0.003), blood flow (P = 0.024), and interdialytic gain of patients (P = 0.008). CONCLUSIONS: Activation in patients on chronic hemodialysis treatment is low. Higher activation is related having an arteriovenous fistula, higher blood flow and lower interdialytic gain. Future studies are needed to confirm and apply our results.

Proton minibeam radiation therapy for treating metastases: A treatment plan study.

BACKGROUND: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. Such preclinical results encourage the preparation of clinical trials. PURPOSE: In this study, the potential of pMBRT for treating clinical indications candidates for the first clinical trials (i.e., brain, lung, and liver metastases) was evaluated. METHODS: Four clinical cases, initially treated with stereotactic radiotherapy (SRT), were selected for this study. pMBRT, SRT, and conventional proton therapy (PT) dose distributions were compared by using three main criteria: (i) the tumor coverage, (ii) the mean dose to organs-at-risk, and (iii) the possible adverse effects in normal tissues by considering valley doses as the responsible for tissue sparing. pMBRT plans consisted of one fraction and one-two fields. Dose calculations were computed by means of Monte Carlo simulations. RESULTS: pMBRT treatments provide a similar or superior target coverage than SRT, even using fewer fields. pMBRT also significantly reduces the biologically effective dose (BED) to organs-at-risk. In addition, valley and mean doses to normal tissues remain below tolerance limits when treatments are delivered in a single fraction, contrary to PT treatments. CONCLUSIONS: This work provides a first insight into the possibility of treating metastases with pMBRT. More favorable dose distributions and treatment delivery regimes may be expected from this new approach than SRT. The advantages of pMBRT would need to be confirmed by means of Phase I clinical trials.

Evaluation of the Role of the Immune System Response After Minibeam Radiation Therapy.

PURPOSE: Minibeam radiation therapy (MBRT) is an innovative technique that uses a spatial dose modulation. The dose distribution consists of high doses (peaks) in the path of the minibeam and low doses (valleys). The underlying biological mechanism associated with MBRT efficacy remains currently unclear and thus we investigated the potential role of the immune system after treatment with MBRT. METHODS AND MATERIALS: Rats bearing an orthotopic glioblastoma cell line were treated with 1 fraction of high dose conventional radiation therapy (30 Gy) or 1 fraction of the same mean dose in MBRT. Both immunocompetent (F344) and immunodeficient (Nude) rats were analyzed in survival studies. Systemic and intratumoral immune cell population changes were studied with flow cytometry and immunohistochemistry (IHC) 2 and 7 days after the irradiation. RESULTS: The absence of response of Nude rats after MBRT suggested that T cells were key in the mode of action of MBRT. An inflammatory phenotype was observed in the blood 1 week after irradiation compared with conventional irradiation. Tumor immune cell analysis by flow cytometry showed a substantial infiltration of lymphocytes, specifically of CD8 T cells and B cells in both conventional and MBRT-treated animals. IHC revealed that MBRT induced a faster recruitment of CD8 and CD4 T cells. Animals that were cured by radiation therapy did not suffer tumor growth after reimplantation of tumoral cells, proving the long-term immunity response generated after a high dose of radiation. CONCLUSIONS: Our findings show that MBRT can elicit a robust antitumor immune response in glioblastoma while avoiding the high toxicity of a high dose of conventional radiation therapy.

Ionization detail parameters and cluster dose: a mathematical model for selection of nanodosimetric quantities for use in treatment planning in charged particle radiotherapy.

Objective. To propose a mathematical model for applying ionization detail (ID), the detailed spatial distribution of ionization along a particle track, to proton and ion beam radiotherapy treatment planning (RTP).Approach. Our model provides for selection of preferred ID parameters (Ip) for RTP, that associate closest to biological effects. Cluster dose is proposed to bridge the large gap between nanoscopicIpand macroscopic RTP. Selection ofIpis demonstrated using published cell survival measurements for protons through argon, comparing results for nineteenIp:Nk,k= 2, 3, …, 10, the number of ionizations in clusters ofkor more per particle, andFk,k= 1, 2, …, 10, the number of clusters ofkor more per particle. We then describe application of the model to ID-based RTP and propose a path to clinical translation.Main results. The preferredIpwereN4andF5for aerobic cells,N5andF7for hypoxic cells. Significant differences were found in cell survival for beams having the same LET or the preferredNk. Conversely, there was no significant difference forF5for aerobic cells andF7for hypoxic cells, regardless of ion beam atomic number or energy. Further, cells irradiated with the same cluster dose for theseIphad the same cell survival. Based on these preliminary results and other compelling results in nanodosimetry, it is reasonable to assert thatIpexist that are more closely associated with biological effects than current LET-based approaches and microdosimetric RBE-based models used in particle RTP. However, more biological variables such as cell line and cycle phase, as well as ion beam pulse structure and rate still need investigation.Significance. Our model provides a practical means to select preferredIpfrom radiobiological data, and to convertIpto the macroscopic cluster dose for particle RTP.

Proton Beam Therapy in the Oligometastatic/Oligorecurrent Setting: Is There a Role? A Literature Review.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS) with conventional photon radiotherapy (XRT) are well-established treatment options for selected patients with oligometastatic/oligorecurrent disease. The use of PBT for SABR-SRS is attractive given the property of a lack of exit dose. The aim of this review is to evaluate the role and current utilisation of PBT in the oligometastatic/oligorecurrent setting. METHODS: Using Medline and Embase, a comprehensive literature review was conducted following the PICO (Patients, Intervention, Comparison, and Outcomes) criteria, which returned 83 records. After screening, 16 records were deemed to be relevant and included in the review. RESULTS: Six of the sixteen records analysed originated in Japan, six in the USA, and four in Europe. The focus was oligometastatic disease in 12, oligorecurrence in 3, and both in 1. Most of the studies analysed (12/16) were retrospective cohorts or case reports, two were phase II clinical trials, one was a literature review, and one study discussed the pros and cons of PBT in these settings. The studies presented in this review included a total of 925 patients. The metastatic sites analysed in these articles were the liver (4/16), lungs (3/16), thoracic lymph nodes (2/16), bone (2/16), brain (1/16), pelvis (1/16), and various sites in 2/16. CONCLUSIONS: PBT could represent an option for the treatment of oligometastatic/oligorecurrent disease in patients with a low metastatic burden. Nevertheless, due to its limited availability, PBT has traditionally been funded for selected tumour indications that are defined as curable. The availability of new systemic therapies has widened this definition. This, together with the exponential growth of PBT capacity worldwide, will potentially redefine its commissioning to include selected patients with oligometastatic/oligorecurrent disease. To date, PBT has been used with encouraging results for the treatment of liver metastases. However, PBT could be an option in those cases in which the reduced radiation exposure to normal tissues leads to a clinically significant reduction in treatment-related toxicities.

MRI texture-based radiomics analysis for the identification of altered functional networks in alcoholic patients and animal models.

Alcohol use disorder (AUD) is a complex condition representing a leading risk factor for death, disease and disability. Its high prevalence and severe health consequences make necessary a better understanding of the brain network alterations to improve diagnosis and treatment. The purpose of this study was to evaluate the potential of resting-state fMRI 3D texture features as a novel source of biomarkers to identify AUD brain network alterations following a radiomics approach. A longitudinal study was conducted in Marchigian Sardinian alcohol-preferring msP rats (N = 36) who underwent resting-state functional and structural MRI before and after 30 days of alcohol or water consumption. A cross-sectional human study was also conducted among 33 healthy controls and 35 AUD patients. The preprocessed functional data corresponding to control and alcohol conditions were used to perform a probabilistic independent component analysis, identifying seven independent components as resting-state networks. Forty-three radiomic features extracted from each network were compared using a Wilcoxon signed-rank test with Holm correction to identify the network most affected by alcohol consumption. Features extracted from this network were then used in the machine learning process, evaluating two feature selection methods and six predictive models within a nested cross-validation structure. The classification was evaluated by computing the area under the ROC curve. Images were quantized using different numbers of gray-levels to test their influence on the results. The influence of ageing, data preprocessing, and brain iron accumulation were also analyzed. The methodology was validated using structural scans. The striatal network in alcohol-exposed msP rats presented the most significant number of altered features. The radiomics approach supported this result achieving good classification performance in animals (AUC = 0.915 ± 0.100, with 12 features) and humans (AUC = 0.724 ± 0.117, with 9 features) using a random forest model. Using the structural scans, high accuracy was achieved with a multilayer perceptron in both species (animals: AUC > 0.95 with 2 features, humans: AUC > 0.82 with 18 features). The best results were obtained using a feature selection method based on the p-value. The proposed radiomics approach is able to identify AUD patients and alcohol-exposed rats with good accuracy, employing a subset of 3D features extracted from fMRI. Furthermore, it can help identify relevant networks in drug addiction.

Preclinical dosimetry in proton minibeam radiation therapy: Robustness analysis and guidelines.

PURPOSE: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. The dosimetry of pMBRT is challenging and error prone due to the submillimetric beamlet sizes used. The aim of this study was to perform a robustness analysis on the setup parameters utilized in current preclinical trials and provide guidelines for reproducible dosimetry. The results of this work are intended to guide upcoming implementations of pMBRT worldwide, as well as pave the way for future clinical implementations. METHODS: Monte Carlo simulations and experimental data were used to evaluate the impact of variations in setup parameters and uncertainties in collimator specifications on lateral pMBRT dose distributions. The value of each parameter was modified individually to evaluate their effect on dose distributions. Experimental dosimetry was performed by means of high-resolution detectors, that is, radiochromic films, the IBA Razor and the Microdiamond detector. New guidelines were proposed to optimize the experimental setup in pMBRT studies and perform reproducible dosimetry. RESULTS: The sensitivity of dose distributions to uncertainties and variations in setup parameters was quantified. Quantities that define pMBRT lateral profiles (i.e., the peak-to-valley dose ratio [PVDR], peak and valley doses, and peak width) are significantly influenced by small-scale fluctuations in several of those parameters. The setup implemented at the Orsay proton therapy center for pMBRT irradiation was optimized to increase PVDRs and peak symmetry. In addition, we proposed guidelines to perform accurate and reproducible dosimetry in preclinical studies. CONCLUSIONS: This study revealed the importance of adopting guidelines and protocols tailored to the distinct dose delivery method and dose distributions in pMBRT. This new methodology leads to reproducible dosimetry, which is imperative in preclinical trials. The results and guidelines presented in this manuscript can ease the initiation of pMBRT investigations in other centers.