ResearchPad - therapeutic https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Long-term outcomes of monascin – a novel dual peroxisome proliferator-activated receptor γ/nuclear factor-erythroid 2 related factor-2 agonist in experimental intracerebral hemorrhage]]> https://www.researchpad.co/article/elastic_article_14156 Hematoma is the chief culprit in brain injury following intracranial cerebral hemorrhage (ICH). Noninvasive hematoma clearance could be an option to prevent and alleviate early brain injury after ICH. Peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor-erythroid 2 related factor-2 (Nrf2) facilitate removal of hematoma in ICH. Monascin acts as the natural Nrf2 activator with PPAR-γ agonist, and the long-term effects of monascin following ICH have not been elucidated.Methods:ICH in rats was induced by stereotactic, intrastriatal injection of type IV collagenase. Monascin was administered twice daily by gastric perfusion for 14 days after ICH induction. Long-term neurological scores (T maze, Garcia scales, rotor rod test, and Morris water maze), hematoma volume, as well as iron overload around hematoma and brain atrophy were evaluated at 7, 14, and 28 days after ICH.Results:The results showed that monascin improved long-term neurological deficits, spatial memory performance, learning ability, and brain shrinkage after ICH. Monascin also reduced hematoma volume at 7 days and iron content at 7 and 14 days after ICH.Conclusion:PPAR γ and Nrf2 play a crucial role in hematoma clearance after ICH in rat. As a dual agonist of PPAR γ and Nrf2, monascin improved long-term outcomes by facilitating hematoma clearance, and by attenuating iron overload and brain atrophy after experimental ICH. ]]> <![CDATA[Dosimetric accuracy of delivering SBRT using dynamic arcs on Cyberknife]]> https://www.researchpad.co/article/elastic_article_6902 Several studies have demonstrated potential improvements in treatment time through the use of dynamic arcs for delivery of stereotactic body radiation therapy (SBRT) on Cyberknife. However, the delivery system has a finite accuracy, so that potential exists for dosimetric uncertainties. This study estimates the expected dosimetric accuracy of dynamic delivery of SBRT, based on realistic estimates of the uncertainties in delivery parameters.MethodsFive SBRT patient cases (prostate A — conventional, prostate B — brachytherapy‐type, lung, liver, partial left breast) were retrospectively studied. Treatment plans were produced for a fixed arc trajectory using fluence optimization, segmentation, and direct aperture optimization. Dose rate uncertainty was modeled as a smoothly varying random fluctuation of ± 1.0%, ±2.0% or ± 5.0% over a time period of 10, 30 or 60 s. Multileaf collimator uncertainty was modeled as a lag in position of each leaf up to 0.25 or 0.5 mm. Robot pointing error was modeled as a shift of the target location, with the direction of the shift chosen as a random angle with respect to the multileaf collimator and with a random magnitude in the range 0.0–1.0 mm at the delivery nodes and with an additional random magnitude of 0.5–1.0 mm in between the delivery nodes. The impact of the errors was investigated using dose‐volume histograms.ResultsUncertainty in dose rate has the effect of varying the total monitor units delivered, which in turn produces a variation in mean dose to the planning target volume. The random sampling of dose rate error produces a distribution of mean doses with a standard deviation proportional to the magnitude of the dose rate uncertainty. A lag in multileaf collimator position of 0.25 or 0.5 mm produces a small impact on the delivered dose. In general, an increase in the PTV mean dose of around 1% is observed. An error in robot pointing of the order of 1 mm produces a small increase in dose inhomogeneity to the planning target volume, sometimes accompanied by an increase in mean dose by around 1%.ConclusionsBased upon the limited data available on the dose rate stability and geometric accuracy of the Cyberknife system, this study estimates that dynamic arc delivery can be accomplished with sufficient accuracy for clinical application. Dose rate variation produces a change in dose to the planning target volume according to the perturbation of total monitor units delivered, while multileaf collimator lag and robot pointing error typically increase the mean dose to the planning target volume by up to 1%. ]]> <![CDATA[Development of a CT number calibration audit phantom in photon radiation therapy: A pilot study]]> https://www.researchpad.co/article/elastic_article_6761 In photon radiation therapy, computed tomography (CT) numbers are converted into values for mass density (MD) or relative electron density to water (RED). CT‐MD or CT‐RED calibration tables are relevant for human body dose calculation in an inhomogeneous medium. CT‐MD or CT‐RED calibration tables are influenced by patient imaging (CT scanner manufacturer, scanning parameters, and patient size), the calibration process (tissue‐equivalent phantom manufacturer, and selection of tissue‐equivalent material), differences between tissue‐equivalent materials and standard tissues, and the dose calculation algorithm applied; however, a CT number calibration audit has not been established. The purposes of this study were to develop a postal audit phantom, and to establish a CT number calibration audit process.MethodsA conventional stoichiometric calibration conducts a least square fit of the relationships between the MD, material weight, and measured CT number, using two parameters. In this study, a new stoichiometric CT number calibration scheme has been empirically established, using three parameters to harmonize the calculated CT number with the measured CT number for air and lung tissue. In addition, the suitable material set and the minimal number of materials required for stoichiometric CT number calibration were determined. The MDs and elemental weights from the International Commission on Radiological Protection Publication 110 were used as standard tissue data, to generate the CT‐MD and CT‐RED calibration tables. A small‐sized, CT number calibration phantom was developed for a postal audit, and stoichiometric CT number calibration with the phantom was compared to the CT number calibration tables registered in the radiotherapy treatment planning systems (RTPSs) associated with five radiotherapy institutions.ResultsWhen a least square fit was performed for the stoichiometric CT number calibration with the three parameters, the calculated CT number showed better agreement with the measured CT number. We established stoichiometric CT number calibration using only two materials because the accuracy of the process was determined not by the number of used materials but by the number of elements contained. The stoichiometric CT number calibration was comparable to the tissue‐substitute calibration, with a dose difference less than 1%. An outline of the CT number calibration audit was demonstrated through a multi‐institutional study.ConclusionsWe established a new stoichiometric CT number calibration method for validating the CT number calibration tables registered in RTPSs. We also developed a CT number calibration phantom for a postal audit, which was verified by the performances of multiple CT scanners located at several institutions. The new stoichiometric CT number calibration has the advantages of being performed using only two materials, and decreasing the difference between the calculated and measured CT numbers for air and lung tissue. In the future, a postal CT number calibration audit might be achievable using a smaller phantom. ]]> <![CDATA[Automatic configuration of the reference point method for fully automated multi‐objective treatment planning applied to oropharyngeal cancer]]> https://www.researchpad.co/article/elastic_article_6758 In automated treatment planning, configuration of the underlying algorithm to generate high‐quality plans for all patients of a particular tumor type can be a major challenge. Often, a time‐consuming trial‐and‐error tuning procedure is required. The purpose of this paper is to automatically configure an automated treatment planning algorithm for oropharyngeal cancer patients.MethodsRecently, we proposed a new procedure to automatically configure the reference point method (RPM), a fast automatic multi‐objective treatment planning algorithm. With a well‐tuned configuration, the RPM generates a single Pareto optimal treatment plan with clinically favorable trade‐offs for each patient. The automatic configuration of the RPM requires a set of computed tomography (CT) scans with corresponding dose distributions for training. Previously, we demonstrated for prostate cancer planning with 12 objectives that training with only 9 patients resulted in high‐quality configurations. This paper further develops and explores the new automatic RPM configuration procedure for head and neck cancer planning with 22 objectives. Investigations were performed with planning CT scans of 105 previously treated unilateral or bilateral oropharyngeal cancer patients together with corresponding Pareto optimal treatment plans. These plans were generated with our clinically applied two‐phase ε‐constraint method (Erasmus‐iCycle) for automated multi‐objective treatment planning, ensuring consistent high quality and Pareto optimality of all plans. Clinically relevant, nonconvex criteria, such as dose‐volume parameters and NTCPs, were included to steer the RPM configuration.ResultsTraining sets with 20–50 patients were investigated. Even with 20 training plans, high‐quality configurations of the RPM were feasible. Automated plan generation with the automatically configured RPM resulted in Pareto optimal plans with overall similar or better quality than that of the Pareto optimal database plans.ConclusionsAutomatic configuration of the RPM for automated treatment planning is feasible and drastically reduces the time and workload required when compared to manual tuning of an automated treatment planning algorithm. ]]> <![CDATA[What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?]]> https://www.researchpad.co/article/N2ae8ca0d-0984-42d5-93a4-fb99576bd49e Sudden death characterizes the mode of demise in 30–50% of patients with chronic heart failure and a reduced ejection fraction. Occasionally, these events have an identifiable pathophysiological trigger, e.g. myocardial infarction, catecholamine surges, or electrolyte imbalances, but in most circumstances, there is no acute precipitating mechanism. Instead, adverse left ventricular remodelling and fibrosis creates an exceptionally fragile and highly vulnerable substrate, which can be characterized using the model developed in theoretical physics of ‘self-organizing criticality’. This framework has been applied to describe the genesis of avalanches, nodes of traffic congestion unrelated to an accident, the abrupt system-wide failure of electrical grids, and the initiation of cancer and neurodegenerative diseases. Self-organizing criticality within the ventricular myocardium relies on complex adaptations to progressive stress and stretch, which evolve inevitably to an abrupt end (termed ‘cascading failure’), even though the rate of deterioration of the underlying disease process has not changed. The result is acute circulatory collapse (i.e. sudden death) in the absence of an identifiable triggering event. Cascading failure in a severely remodelled or fibrotic heart can become manifest electrically as a first-time ventricular tachyarrhythmia that is responsive to the shock delivered by an implantable cardioverter-defibrillator (ICD). Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. This conceptual framework explains why anti-remodelling and antifibrotic interventions (i.e. neurohormonal antagonists and cardiac resynchronization) reduce the risk of sudden death in patients with heart failure in the absence of an ICD and provide incremental benefits in those with an ICD. The adoption of anti-remodelling and antifibrotic treatments may explain why the incidence of sudden death in clinical trials of heart failure has declined dramatically over the past 10–15 years, independent of the use of ICDs.

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<![CDATA[Beyond 2D: effects of photobiomodulation in 3D tissue-like systems]]> https://www.researchpad.co/article/Nf85eca20-9f22-4e1d-8569-dca99edf5d7d Significance: Currently, various scaffolds with immobilized cells are widely used in tissue engineering and regenerative medicine. However, the physiological activity and cell viability in such constructs might be impaired due to a lack of oxygen and nutrients. Photobiomodulation (PBM) is a promising method of preconditioning cells to increase their metabolic activity and to activate proliferation or differentiation.

Aim: Investigation of the potential of PBM for stimulation of cell activities in hydrogels.

Approach: Mesenchymal stromal cells (MSCs) isolated from human gingival mucosa were encapsulated in modified fibrin hydrogels with different thicknesses and concentrations. Constructs with cells were subjected to a single-time exposure to red (630 nm) and near-infrared (IR) (840 nm) low-intensity irradiation. After 3 days of cultivation, the viability and physiological activity of the cells were analyzed using confocal microscopy and a set of classical tests for cytotoxicity.

Results: The cell viability in fibrin hydrogels depended both on the thickness of the hydrogels and the concentration of gel-forming proteins. The PBM was able to improve cell viability in hydrogels. The most pronounced effect was achieved with near-IR irradiation at the 840-nm wavelength.

Conclusions: PBM using near-IR light can be applied for stimulation of MSCs metabolism and proliferation in hydrogel-based constructs with thicknesses up to 3 mm.

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<![CDATA[15-Keto prostaglandin E2 suppresses STAT3 signaling and inhibits breast cancer cell growth and progression]]> https://www.researchpad.co/article/N44129cc9-e36f-437c-ab21-83fac94c401b

Overproduction of prostaglandin E2 (PGE2) has been linked to enhanced tumor cell proliferation, invasiveness and metastasis as well as resistance to apoptosis. 15-Keto prostaglandin E2 (15-keto PGE2), a product formed from 15-hydroxyprostaglandin dehydrogenase-catalyzed oxidation of PGE2, has recently been shown to have anti-inflammatory and anticarcinogenic activities. In this study, we observed that 15-keto PGE2 suppressed the phosphorylation, dimerization and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) in human mammary epithelial cells transfected with H-ras (MCF10A-ras). 15-Keto PGE2 inhibited the migration and clonogenicity of MCF10A-ras cells. In addition, subcutaneous injection of 15-keto PGE2 attenuated xenograft tumor growth and phosphorylation of STAT3 induced by breast cancer MDA-MB-231 cells. However, a non-electrophilic analogue, 13,14-dihydro-15-keto PGE2 failed to inhibit STAT3 signaling and was unable to suppress the growth and transformation of MCF10A-ras cells. These findings suggest that the α,β-unsaturated carbonyl moiety of 15-keto PGE2 is essential for its suppression of STAT3 signaling. We observed that the thiol reducing agent, dithiothreitol abrogated 15-keto PGE2-induced STAT3 inactivation and disrupted the direct interaction between 15-keto PGE2 and STAT3. Furthermore, a molecular docking analysis suggested that Cys251 and Cys259 residues of STAT3 could be preferential binding sites for this lipid mediator. Mass spectral analysis revealed the covalent modification of recombinant STAT3 by 15-keto PGE2 at Cys259. Taken together, thiol modification of STAT3 by 15-keto PGE2 inactivates STAT3 which may account for its suppression of breast cancer cell proliferation and progression.

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<![CDATA[Acute exacerbations of chronic respiratory disease: Progress and opportunities]]> https://www.researchpad.co/article/N77f1ab19-bd13-4a84-8f3f-5c7351e5ab24 ]]> <![CDATA[Split chimeric antigen receptor-modified T cells targeting glypican-3 suppress hepatocellular carcinoma growth with reduced cytokine release]]> https://www.researchpad.co/article/N50bfc0b6-929a-44e1-b893-d1beb5be9a7a

Background:

Human glypican-3 (hGPC3) is a protein highly expressed in hepatocellular carcinoma (HCC) but limited in normal tissues, making it an ideal target for immunotherapy. The adoptive transfer of hGPC3-specific chimeric antigen receptor T (CAR-T) cells for HCC treatment has been conducted in clinical trials. Due to the rigid construction, conventional CAR-T cells have some intrinsic limitations, like uncontrollable overactivation and inducing severe cytokine release syndrome.

Methods:

We redesigned the hGPC3-specific CAR by splitting the traditional CAR into two parts. By using coculturing assays and a xenograft mouse model, the in vitro and in vivo cytotoxicity and cytokine release of the split anti-hGPC3 CAR-T cells were evaluated against various HCC cell lines and compared with conventional CAR-T cells.

Results:

In vitro data demonstrated that split anti-hGPC3 CAR-T cells could recognize and lyse hGPC3+ HepG2 and Huh7 cells in a dose-dependent manner. Impressively, split anti-hGPC3 CAR-T cells produced and released a significantly lower amount of proinflammatory cytokines, including IFN-γ, TNF-α, IL-6, and GM-CSF, than conventional CAR-T cells. When injected into immunodeficient mice inoculated subcutaneously with HepG2 cells, our split anti-hGPC3 CAR-T cells could suppress HCC tumor growth, but released significantly lower levels of cytokines than conventional CAR-T cells.

Conclusions:

We describe here for the first time the use of split anti-hGPC3 CAR-T cells to treat HCC; split anti-hGPC3 CAR-T cells could suppress tumor growth and reduce cytokine release, and represent a more versatile and safer alternative to conventional CAR-T cells treatment.

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<![CDATA[Secukinumab for psoriasis in a patient with familial Mediterranean fever]]> https://www.researchpad.co/article/Nd5b255b7-780f-43e1-80cf-8739a0f792b6 ]]> <![CDATA[Correction of hyperopia by intrastromal cutting and liquid filler injection]]> https://www.researchpad.co/article/N4abc16ca-8a0a-44de-8115-52ddb630c59d

Abstract.

Correction of hyperopia requires an increase of the refractive power by steepening of the corneal surface. Present refractive surgical techniques based on corneal ablation (LASIK) or intrastromal lenticule extraction (SMILE) are problematic due to epithelial regrowth. Recently, it was shown that correction of low hyperopia can be achieved by implanting intracorneal inlays or allogeneic lenticules. We demonstrate a steepening of the anterior corneal surface after injection of a transparent, liquid filler material into a laser-dissected intrastromal pocket. We performed the study on ex-vivo porcine eyes. The increase of the refractive power was evaluated by optical coherence tomography (OCT). For a circular pocket, injection of 1μl filler material increased the refractive power by +4.5 diopters. An astigmatism correction is possible when ellipsoidal intrastromal pockets are created. Injection of 2μl filler material into an ellipsoidal pocket increased the refractive power by +10.9  dpt on the short and +5.1  dpt on the long axis. OCT will enable to monitor the refractive change during filler injection and is thus a promising technique for real-time dosimetry.

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<![CDATA[Models of care across the continuum of exacerbations for patients with chronic obstructive pulmonary disease]]> https://www.researchpad.co/article/N7802aa09-7837-4533-ba8d-1b0ca879ee88

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with significant morbidity and mortality, and treatments require a multidisciplinary approach to address patient needs. This review considers different models of care across the continuum of exacerbations (1) chronic care and self-management interventions with the action plan, (2) domiciliary care for severe exacerbation and the impact on readmission prevention and (3) the discharge care bundle for management beyond the acute exacerbation episode. Self-management strategies include written action plans and coaching with patient and family support. Self-management interventions facilitate the delivery of good care, can reduce exacerbations associated with admission, be cost-effective and improve quality of life. Hospitalization as a complication of exacerbation is not always unavoidable. Domiciliary care has been proposed as a solution to replace part, and perhaps even all, of the patient’s in-hospital stay, and to reduce hospital bed days, readmission rates and costs; low-risk patients can be identified using risk stratification tools. A COPD discharge bundle is another potentially important approach that can be considered to improve the management of COPD exacerbations complicated by hospital admission; it comprised treatments that have demonstrated efficacy, such as smoking cessation, personalized pharmacotherapy and non-pharmacotherapy such as pulmonary rehabilitation. COPD bundles may also improve the transition of care from the hospital to the community following exacerbation and may reduce readmission rates. Future models of care should be personalized – providing patient education aiming at behaviour changes, identifying and treating co-morbidities, and including outcomes that measure quality of care rather than focusing only on readmission quantity within 30 days.

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<![CDATA[Thulium fiber laser ablation of kidney stones using an automated, vibrating fiber]]> https://www.researchpad.co/article/N5ef08dd5-d82a-412a-804f-55139a6f1538

Abstract.

Our preliminary study investigates an automated, vibrating fiber optic tip for dusting of kidney stones during thulium fiber laser (TFL) lithotripsy. A (0.75-mm diameter and 5-mm length) magnetic bead was attached to the fiber jacket, centered 2 cm from distal fiber tip. A solenoid was placed parallel to the fiber with a 0.5-mm gap between solenoid and magnetic bead on fiber. The solenoid was used to create a magnetic force on the bead, inducing fiber vibration. Calibration tests for fiber motion in both air and water were performed. The ablation crater characteristics (surface area, volume, depth, and major/minor axis) of uric acid stones were measured using optical coherence tomography, after delivery of 1500 TFL pulses at 1908 nm, 33 mJ, 500  μs, and up to 300 Hz, through 50-, 100-, and 150-μm-core fibers. The resonant frequency was dependent on fiber diameter and rigidity, with a cutoff pivot point for optimum vibration amplitude at 4 cm. Maximum fiber displacement is about 1 mm in water and 4 mm in air. For 50-, 100-, and 150-μm-core fibers, ablated surface area averaged 1.7, 1.7, and 2.8 times greater with vibrating fiber than fixed fiber, respectively. For these fibers, ablation volume averaged 1.1, 1.5, and 1.1 times greater with vibrating fiber than fixed fiber, given a fixed energy per pulse, respectively. Our preliminary study demonstrates the functionality of an automated, vibrating fiber system for stone “dusting,” with significantly larger surface area but similar ablation volumes as a fixed fiber. Future studies will focus on optimization of fiber parameters (especially displacement) and miniaturization of system components to facilitate integration into ureteroscopes.

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<![CDATA[Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy]]> https://www.researchpad.co/article/Nb631b24c-08a3-4b86-8898-4b34130cb168

Background:

Intrathecal administration of nusinersen in adult spinal muscular atrophy (SMA) patients presents challenges owing to severe scoliosis and previous spinal surgery with metal implantation. In patients with a complex spinal situation, the potential risks of the intrathecal administration may lead to delayed treatment initiation.

Methods:

In this study, we analyzed 53 CT-guided lumbar punctures of 11 adult nonambulatory SMA type 2 and 3 patients. All patients had scoliosis and six patients had previously undergone metal implantation.

Results:

Drug administration was successful in 100% of the patients and none of the patients opted for treatment discontinuation. Complete osseous fusion precluded conventional posterior interlaminar access in eight lumbar punctures in four patients, which required alternative routes including transforaminal punctures and translaminar drilling. Median duration of all lumbar punctures was 9 min and median radiation exposure was 100 mGy* cm. The most common adverse event was post-lumbar puncture syndrome that occurred in five lumbar punctures (9.4%).

Conclusions:

Our data demonstrate that nusinersen can be successfully, safely, and rapidly administered in adult SMA patients with complex spinal conditions and suggest the translaminar drilling technique as an alternative delivery route. Therefore, intrathecal nusinersen treatment should not be withheld from patients because of severe spine deformities, however, drug efficacy in adult SMA patients needs to be investigated in further studies.

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<![CDATA[Treatment planning optimization with beam motion modeling for dynamic arc delivery of SBRT using Cyberknife with multileaf collimation]]> https://www.researchpad.co/article/Nd330b7d3-9516-4025-a5b7-f20cf3172056

Purpose

The use of dynamic arcs for delivery of stereotactic body radiation therapy (SBRT) on Cyberknife is investigated, with a view to improving treatment times. This study investigates the required modeling of robot and multileaf collimator (MLC) motion between control points in the trajectory and then uses this to develop an optimization method for treatment planning of a dynamic arc with Cyberknife. The resulting plans are compared in terms of dose‐volume histograms and estimated treatment times with those produced by a conventional beam arrangement.

Methods

Five SBRT patient cases (prostate A — conventional, prostate B — brachytherapy‐type, lung, liver, and partial left breast) were retrospectively studied. A suitable arc trajectory with control points spaced at 5° was proposed and treatment plans were produced for typical clinical protocols. The optimization consisted of a fluence optimization, segmentation, and direct aperture optimization using a gradient descent method. Dose delivered by the moving MLC was either taken to be the dose delivered discretely at the control points or modeled using effective fluence delivered between control points. The accuracy of calculated dose was assessed by recalculating after optimization using five interpolated beams and 100 interpolated apertures between each optimization control point. The resulting plans were compared using dose‐volume histograms and estimated treatment times with those for a conventional Cyberknife beam arrangement.

Results

If optimization is performed based on discrete doses delivered at the arc control points, large differences of up to 40% of the prescribed dose are seen when recalculating with interpolation. When the effective fluence between control points is taken into account during optimization, dosimetric differences are <2% for most structures when the plans are recalculated using intermediate nodes, but there are differences of up to 15% peripherally. Treatment plan quality is comparable between the arc trajectory and conventional body path. All plans meet the relevant clinical goals, with the exception of specific structures which overlap with the planning target volume. Median estimated treatment time is 355 s (range 235–672 s) for arc delivery and 675 s (range 554–1025 s) for conventional delivery.

Conclusions

The method of using effective fluence to model MLC motion between control points is sufficiently accurate to provide for accurate inverse planning of dynamic arcs with Cyberknife. The proposed arcing method produces treatment plans with comparable quality to the body path, with reduced estimated treatment delivery time.

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<![CDATA[Hybrid modeling frameworks of tumor development and treatment]]> https://www.researchpad.co/article/Nb950e9d4-7208-4273-bb0e-aa4804489757

Abstract

Tumors are complex multicellular heterogeneous systems comprised of components that interact with and modify one another. Tumor development depends on multiple factors: intrinsic, such as genetic mutations, altered signaling pathways, or variable receptor expression; and extrinsic, such as differences in nutrient supply, crosstalk with stromal or immune cells, or variable composition of the surrounding extracellular matrix. Tumors are also characterized by high cellular heterogeneity and dynamically changing tumor microenvironments. The complexity increases when this multiscale, multicomponent system is perturbed by anticancer treatments. Modeling such complex systems and predicting how tumors will respond to therapies require mathematical models that can handle various types of information and combine diverse theoretical methods on multiple temporal and spatial scales, that is, hybrid models. In this update, we discuss the progress that has been achieved during the last 10 years in the area of the hybrid modeling of tumors. The classical definition of hybrid models refers to the coupling of discrete descriptions of cells with continuous descriptions of microenvironmental factors. To reflect on the direction that the modeling field has taken, we propose extending the definition of hybrid models to include of coupling two or more different mathematical frameworks. Thus, in addition to discussing recent advances in discrete/continuous modeling, we also discuss how these two mathematical descriptions can be coupled with theoretical frameworks of optimal control, optimization, fluid dynamics, game theory, and machine learning. All these methods will be illustrated with applications to tumor development and various anticancer treatments.

This article is characterized under:

  • Analytical and Computational Methods > Computational Methods

  • Translational, Genomic, and Systems Medicine > Therapeutic Methods

  • Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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<![CDATA[Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization]]> https://www.researchpad.co/article/N1c9e569f-0d83-4103-8190-d1533ca4dc6e

Background:

Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE).

Methods:

In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan–Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR.

Results:

This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30–60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0–65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child–Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively.

Conclusions:

SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.

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<![CDATA[Treatment of bilateral popliteal artery aneurysms]]> https://www.researchpad.co/article/N643d14d7-2700-45a8-a411-2a754e468157

Abstract

Popliteal artery aneurysms are the most frequent type of peripheral aneurysm, accounting for 85% of the all of these aneurysms. Usually asymptomatic, they are generally diagnosed during clinical examination. Incidence is higher among males and seniors. They are bilateral in 50% of the cases and 60% are associated with abdominal aortic aneurysms. This paper describes a 72-year-old male patient who presented with two bilateral pulsatile masses, one in each popliteal region, was otherwise asymptomatic, and had a history of hypertension and dyslipidemia. Clinical examination and ultrasound imaging confirmed a diagnosis of bilateral aneurysms of the popliteal arteries. Popliteal artery aneurysms can be treated with open bypass surgery, with or without aneurysm resection, or with endovascular surgery. This Therapeutic Challenge discusses these possibilities.

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<![CDATA[An extended dose–volume model in high dose‐rate brachytherapy – Using mean‐tail‐dose to reduce tumor underdosage]]> https://www.researchpad.co/article/N28ce0472-4234-4538-857c-2bd084ad1253

Purpose

High dose–rate brachytherapy is a method of radiotherapy for cancer treatment in which the radiation source is placed within the body. In addition to give a high enough dose to a tumor, it is also important to spare nearby healthy organs [organs at risk (OAR)]. Dose plans are commonly evaluated using the so‐called dosimetric indices; for the tumor, the portion of the structure that receives a sufficiently high dose is calculated, while for OAR it is instead the portion of the structure that receives a sufficiently low dose that is of interest. Models that include dosimetric indices are referred to as dose–volume models (DVMs) and have received much interest recently. Such models do not take the dose to the coldest (least irradiated) volume of the tumor into account, which is a distinct weakness since research indicates that the treatment effect can be largely impaired by tumor underdosage even to small volumes. Therefore, our aim is to extend a DVM to also consider the dose to the coldest volume.

Methods

An improved DVM for dose planning is proposed. In addition to optimizing with respect to dosimetric indices, this model also takes mean dose to the coldest volume of the tumor into account.

Results

Our extended model has been evaluated against a standard DVM in ten prostate geometries. Our results show that the dose to the coldest volume could be increased, while also computing times for the dose planning were improved.

Conclusion

While the proposed model yields dose plans similar to other models in most aspects, it fulfils its purpose of increasing the dose to cold tumor volumes. An additional benefit is shorter solution times, and especially for clinically relevant times (of minutes) we show major improvements in tumour dosimetric indices.

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<![CDATA[Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome]]> https://www.researchpad.co/article/Nbf4747df-a1c8-4ae2-bb07-73e781a9ac44

Increasing evidences support the notion that the impairment of intracellular degradative machinery is responsible for the accumulation of oxidized/misfolded proteins that ultimately results in the deposition of protein aggregates. These events are key pathological aspects of “protein misfolding diseases”, including Alzheimer disease (AD). Interestingly, Down syndrome (DS) neuropathology shares many features with AD, such as the deposition of both amyloid plaques and neurofibrillary tangles. Studies from our group and others demonstrated, in DS brain, the dysfunction of both proteasome and autophagy degradative systems, coupled with increased oxidative damage. Further, we observed the aberrant increase of mTOR signaling and of its down-stream pathways in both DS brain and in Ts65Dn mice.

Based on these findings, we support the ability of intranasal rapamycin treatment (InRapa) to restore mTOR pathway but also to restrain oxidative stress resulting in the decreased accumulation of lipoxidized proteins. By proteomics approach, we were able to identify specific proteins that showed decreased levels of HNE-modification after InRapa treatment compared with vehicle group. Among MS-identified proteins, we found that reduced oxidation of arginase-1 (ARG-1) and protein phosphatase 2A (PP2A) might play a key role in reducing brain damage associated with synaptic transmission failure and tau hyperphosphorylation. InRapa treatment, by reducing ARG-1 protein-bound HNE levels, rescues its enzyme activity and conceivably contribute to the recovery of arginase-regulated functions. Further, it was shown that PP2A inhibition induces tau hyperphosphorylation and spatial memory deficits. Our data suggest that InRapa was able to rescue PP2A activity as suggested by reduced p-tau levels.

In summary, considering that mTOR pathway is a central hub of multiple intracellular signaling, we propose that InRapa treatment is able to lower the lipoxidation-mediated damage to proteins, thus representing a valuable therapeutic strategy to reduce the early development of AD pathology in DS population.

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