Target Conformity Research Articles

Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site.

DNA gyrases are enzymes that control the topology of DNA in bacteria cells. This is a vital function for bacteria. For this reason, DNA gyrases are targeted by widely used antibiotics such as quinolones. Recently, structural and biochemical investigations identified a new class of DNA gyrase inhibitors called NBTIs (i.e., novel bacterial topoisomerase inhibitors). NBTIs are particularly promising because they are active against multi-drug resistant bacteria, an alarming clinical issue. Structural data recently demonstrated that these NBTIs bind tightly to a newly identified pocket at the dimer interface of the DNA–protein complex. In the present study, we used molecular dynamics (MD) simulations and docking calculations to shed new light on the binding of NBTIs to this site. Interestingly, our MD simulations demonstrate the intrinsic flexibility of this binding site, which allows the pocket to adapt its conformation and form optimal interactions with the ligand. In particular, we examined two ligands, AM8085 and AM8191, which induced a repositioning of a key aspartate (Asp83B), whose side chain can rotate within the binding site. The conformational rearrangement of Asp83B allows the formation of a newly identified H-bond interaction with an NH on the bound NBTI, which seems important for the binding of NBTIs having such functionality. We validated these findings through docking calculations using an extended set of cognate oxabicyclooctane-linked NBTIs derivatives (~150, in total), screened against multiple target conformations. The newly identified H-bond interaction significantly improves the docking enrichment. These insights could be helpful for future virtual screening campaigns against DNA gyrase.

Improving Quality and Consistency in NRG Oncology Radiation Therapy Oncology Group 0631 for Spine Radiosurgery via Knowledge-Based Planning

Touse knowledge-based planning (KBP) as a method of producing high-quality, consistent, protocol-compliant treatment plans in a complex setting of spine stereotactic body radiation therapy on NRG Oncology Radiation Therapy Oncology Group (RTOG)0631. An internally developed KBP model was applied to an external validation cohort of 22 anonymized cases submitted under NRG Oncology RTOG 0631. The original and KBP plans were compared via their protocol compliance, target conformity and gradient index, dose to critical structures, and dose to surrounding normal tissues. The KBP model generated plans meeting all protocol objectives in a single optimization when tested on both internal and protocol-submitted NRG Oncology RTOG 0631 cases. Two submitted plans that were considered to have a protocol-unacceptable deviation were made protocol compliant through the use of the model. There were no statistically significant differences in protocol spinal cord metrics (D10% and D0.03cc) between the manually optimized plans and the KBP plans. The volume of planning target volume receiving prescription dose increased from 93.3%±3.2% to 98.3%±1.4% (P=.01) when using KBP. High-dose spillage to surrounding normal tissues (V105%) showed no significant differences (2.1±7.3cm3 for manual plans to 1.8±0.6cm3 with KBP), and dosimetric outliers with large amounts of spillage were eliminated through the use of KBP. Knowledge-based planning plans were also found to be significantly more consistent in several metrics, including target coverage and high dose outside of the target. Incorporation of KBP models into the clinical trial setting may have a profound impact on the quality of trial results, owing to the increase in consistency and standardization of planning, especially for treatment sites or techniques that are nonstandard.

Comparison of calculated dose distributions reported as dose-to-water and dose-to-medium for intensity-modulated radiotherapy of nasopharyngeal cancer patients

Advanced dose calculation algorithms for radiation therapy treatment planning can report external beam photon dose 2-sided, in terms of dose-to-medium (Dm) and dose-to-water (Dw). The purpose of our study was to determinate the effect of Dw and Dm reporting modes built in Elekta Monaco treatment planning system on intensity-modulated radiotherapy dose distributions for patients with nasopharyngeal cancer. For 13 patients involved in this retrospective study, 2 plans were created: 1 using Dw and another according to Dm reporting mode. Treatment plans were normalized such that 100% planning target volume should be covered by 95% of prescribed dose. Dose-volume constraints were assigned according to international standards. The comparison between dose distributions was performed evaluating quantities important for respective volumes of interest. For target volumes, heterogeneity index and conformity index methodology were used along with the maximum dose concept. Also, for the comparisons over particular organ at risk, maximum dose or mean dose as well as dose-volume concepts were used. For all target volumes and majority of organs at risk, the differences between 2 reporting modes are statistically insignificant, but this is not the case for bony structured organs at risks: mandible and cochlea. It was observed that Dw is higher than Dm with mean difference of 9.91% (p = 0.000009) of the mandible volume covered with 70 Gy. The same trend was observed for left and right cochlea with difference in mean dose of 8.74% (p = 0.037) and 6.87% (p = 0.029), respectively. The comparative analysis of dosimetric parameters in this study shows that the selection of reporting modes in Monaco treatment planning system can produce dose differences up to 15% in high-density volumes such as mandible and cochlea, which might have clinical consequences.

Prospective matched study on comparison of volumetric-modulated arc therapy and intensity-modulated radiotherapy for nasopharyngeal carcinoma: dosimetry, delivery efficiency and outcomes.

Background: The purpose of this study is to assess the feasibility of volumetric-modulated arc therapy (VMAT) for nasopharyngeal carcinoma (NPC) patients by comparing the physical dosimetry, delivery efficiency and clinical outcomes with intensity-modulated radiotherapy (IMRT).Methods: A prospective matched study was performed for patients with newly diagnosed NPC who underwent VMAT or IMRT. The patients in two groups were equally matched in terms of gender, age, tumor stage and chemotherapy. The target coverage, homogeneity index (HI) and conformity index (CI) of the planning target volume (PTV), organs at risk (OARs) sparing, average treatment time and clinical outcomes were analyzed.Results: From June 2013 to August 2015, a total of 80 patients were enrolled in this study, with 40 patients in each group. The coverage of PTV was similar for both groups. D2 was observed slight difference only in early stage disease (T1-2) (VMAT vs. IMRT, 7494±109 cGy vs. 7564±92 cGy; p=0.06). The HI of VMAT group was better than that of IMRT group (p=0.001), whereas CI was slightly worse (p=0.061). The maximum doses received by the brain stem, spinal cord, and optic nerve of VMAT were higher than those of IMRT (p<0.05). But the irradiation volumes in healthy tissue were generally lower for VMAT group, with significant differences in V20, V25 and V45 (p<0.05). With regard to the delivery efficiency compared with IMRT (1160 ± 204s), a 69% reduction in treatment time was achieved by VMAT (363 ± 162s). Both groups had 5 cases of nasopharyngeal residual lesions after radiotherapy. The 2-year estimated local relapse-free survival, regional relapse-free survival and locoregional relapse-free survival, distant metastasis-free survival, disease-free survival and overall survival were similar between two groups, with the corresponding rates of 100%, 97.4%, 97.4%, 90.0%, 90.0% and 92.4% in VMAT group, and 100%, 100%, 100%, 95.0%, 95.0% and 97.5% in IMRT group, respectively.Conclusions: Both VMAT and IMRT can meet the clinical requirements for the treatment of NPC. The short-term tumor regression rates and 2-year survival rates with the two techniques are comparable. The faster treatment time benefits of VMAT will enable more patients to receive precision radiotherapy.

A planning study for evaluation of feasibility and benefit of generalized equivalent uniform dose-assisted optimization in volumetric-modulated arc therapy for recurrent head and neck cancer

Background: Re-irradiation is effective but challenging on balancing the tumor control and late complications for recurrent head and neck cancer (HNC). The aim of this study was to investigate the feasibility of incorporating the biologically based generalized equivalent uniform dose (gEUD) objective function in the volumetric-modulated arc therapy (VMAT) treatment planning optimization process and to evaluate its benefit in such a clinical dilemma. Methods: Five recurrent HNC cases were selected. Respective original VMAT plan which fulfilled acceptable constraints was created using dose-volume (DV) optimization for each case in the first phase. Based on the DV plan, multiple corresponding plans incorporating the added single Max EUD objective for the spinal cord (SC) with stepwise stricter constraint for further biological optimization were generated for dosimetric comparison. Evaluated parameters compared between DV and DV-gEUD plans included target coverage, conformity index, homogeneity index, and sparing of organs at risk (OARs). Results: When adopting SC_gEUD90% and SC_gEUD80% as Max EUD constraint of SC, DV-gEUD optimization compared to DV optimization yielded 17.1% and 20.3%, reduction of the average D max of SC, respectively (both P value <0.05), with a non-inferior target coverage, similar conformity and slightly poorer homogeneity. The planning target volume/OAR geometry might be a factor impacting the extent of benefit provided by this gEUD-assisted optimization process. Conclusions: The method we recommended as gEUD-assisted optimization is feasible and efficient to produce better plan quality in the re-irradiation setting using VMAT for HNC to diminish the risk of myelopathy. More investigations are awaited for a better understanding of the correlation between the ɑ parameter and the OAR radiobiology.

Efficacy of a rectal spacer with prostate SABR-first UK experience.

This study assessed the use of implanted hydrogel rectal spacers for stereotactic ablative radiotherapy-volumetricmodulated arc therapy(SABR-VMAT) patients, investigating practicality, dosimetric impact, normal tissue complication probability (NTCP) and early toxicity. Data from the first 6 patients treated within a prostate SABR and rectal spacer trial were examined to determine spacer insertion tolerability, resultant changes in treatment planning and dosimetry and early toxicity effects. CT scans acquired prior to spacer insertion were used to generate SABR plans which were compared to post-insertion plans. Plans were evaluated for target coverage, conformity, and organs at risk doses with NTCPs also determined from resultant dose fluences. Early toxicity data were also collected. All patients had successful spacer insertion under local anaesthetic with maximal Grade1 toxicity. All plans were highly conformal, with no significant differences in clinical target volume dose coverage between pre- and post-spacer plans. Substantial improvements in rectal dose metrics were observed in post-spacer plans, e.g. rectal volume receiving 36Gy reduced by ≥42% for all patients. Median NTCP for Grade 2+ rectal bleeding significantly decreased from4.9to0.8%with the use of a rectal spacer (p = 0.031). To date, two episodes of acute Grade1 proctitis have been reported following treatment. The spacer resulted in clinically and statistically significant reduction in rectal doses for all patients. Advances in knowledge: This is one of the first studies to investigate the efficacy of a hydrogel spacer in prostate SABR treatments. Observed dose sparing of the rectum is predicted to result in meaningful clinical benefit.

Investigation the impact of maximum control point on dose calculation in Eclipse treatment planning system for lung SBRT

Purpose: Choosing an appropriate parameter on the computerized treatment planning systems (TPSs) influences on the accuracy of dose calculation. Several dosimetric parameters have been studied to achieve a more accurate dose and qualitative plan. The purpose of this study was to determine the impact of maximum control point on the dose calculation on Eclipse TPSs for lung Stereotactic Body Radiation Therapy (SBRT) considering the plan quality, the computation time and the treatment file size. Methods: Dose distributions for the 8 lung SBRT plans with varying maximum control point of 64, 166, and 320 were calculated by Eclipse TPSs with flattening filter free (FFF) beam. The treatment dose was prescribed at 85% isodose level of 54 Gy to the planning target volume (PTV). The dosimetric impact can be evaluated from target coverage, conformity index (CI), homogeneity index (HI), and organ at risk (OAR) doses, while the computation time and the file storage space were compared with the recommended number of control point. Results: The use of 64 control points per subfields tended to increase the dose at PTV and OARs comparing with the 166 and 320 control point plans, while the HI and CI values were similar. The average increases of OARs doses including the spinal cord, heart, esophagus and total lung depended on the photon beam energy. The higher average control point (AVG) number leaded to increase the computation time and the file size for both 6X-FFF and 10X-FFF photon beams. The correlations between AVG and plan storaage space were observed in the same ratio as the computation time. Conclusion: Using the minimal number of control point, the quantitative analysis in the PTV and OARs showed no clinically significant variation in dose, therefore choosing an optimal number of fixed control points leaded to balance the plan quality, the computation time and the file size.

Evaluation of MLC leaf transmission on IMRT treatment plan quality of patients with advanced lung cancer

The purpose of this paper was to evaluate the impact of leaf treatment of multileaf collimator (MLC) in plan quality of intensity-modulated radiotherapy (IMRT) of patients with advanced lung cancer. Five MLCs with different leaf transmissions (0.01%, 0.5%, 1.2%, 1.8%, and 3%) were configured for an accelerator in a treatment planning system. Correspondingly, 5 treatment plans with the same optimization setting were created and evaluated quantitatively for each patient (11 patients total) who was diagnosed with advanced lung cancer. All of the 5 plans for each patient met the dose requirement for the planning treatment volumes (PTVs) and had similar target dose homogeneity and conformity. On average, the doses to selected organs were as follows: (1) V5, V20, and the mean dose of total lung; (2) the maximum and mean dose to spinal cord planning organ-at-risk volume (PRV); and (3) V30 and V40 of heart, decreased slightly when MLC transmission was decreased, but with no statistical differences. There is a clear grouping of plans having total quality score (SD) value, which is used to evaluate plan quality: (1) more than 1 (patient nos. 1 to 3, 5, and 8), and more than 2.5 (patient no. 6); (2) less than 1 (patient nos. 7 and 10); (3) around 1 (patient nos. 4, 9, and 11). As MLC transmission increased, overall SD values increased as well and plan dose requirement was harder to meet. The clinical requirements were violated increasingly as MLC transmission became large. Total SD with and without normal tissue (NT) showed similar results, with no statistically significant differences. Therefore, decrease of MLC transmission did have minimum impact on plan, and it improved target coverage and reduced normal tissue radiation slightly, with no statistical significance. Plan quality could not be significantly improved by MLC transmission reduction. However, lower MLC transmission may have advantages on lung sparing to low- and intermediate-dose exposure. Besides conventional fraction, hyperfraction, or stereotactic body radiotherapy (SBRT), the reduction on lung sparing is still essential because it is highly relevant to radiation pneumonitis (RP). It has potential to diminish incidence of RP and improve patient's quality of life after irradiation with lowered MLC transmission.

23. Development of a software based on an anthropomorphic image atlas for image quality optimization in 3D angiography mode dynamic collimation system improving target conformity of spot scanning proton therapy: Comparison of dose calculations for two nozzles

Introduction In order to improve patient dose management [1] , a software was developed to enable the visualization of the effect of 3D angiography (3DA) protocol optimization on Image Quality (IQ) and radiation dose in interventional radiology. Methods For the four most representative anatomic areas of our clinical practice (liver, pelvis, lung, spleen), five reference protocols were set-up in our interventional radiology system (Innova IGS 540, GE Healthcare, Buc, France) with different IQ/dose preferences from low dose to high Image Quality (IQ). These preferences were defined by adjusting the Automatic Dose Rate and Image Quality (ADRIQ) strategy, the detail level and the rotation speed for 3DA sequences. For these 20 protocols, 3D angiography images were acquired on an anthropomorphic phantom (PBU-60, Kyoto Kagaku). All acquired images were qualitatively validated by a senior radiologist. These images were implemented in a home-made software (ProtoEnhanceIR) in order to optimize protocols by displaying the anthropomorphic images and associated Peak Skin Dose (PSD). The radiologist has the ability to select the most suitable protocols in regard with his own clinical practice. Then, the operator has the possibility to import selected protocols in the system. The PSD delivered to the anthropomorphic phantom by our 3DA clinical routine protocol (PSDRoutine) was compared to the PSD for the 3DA optimized protocol chosen by the senior radiologist in ProtoEnhanceIR (PSDProtoEnhanceIR). Results Compared to our 3DA clinical routine protocol, the chosen 3DA optimized protocol proposed by ProtoEnhanceIR allowed an average dose reduction of 69% while keeping clinical IQ (for lung, liver, pelvis and spleen PSDProtoEnhanceIR was 0.98 ± 0.09; 2.95 ± 0.43; 3.07 ± 0.27; 3.11 ± 0.34 mGy while PSDRoutine was 2.79 ± 0.12; 10.02 ± 0.89; 10.94 ± 1.31; 11.20 ± 0.58 mGy respectively). Conclusions The proposed software allows improvement of the IQ/dose balance of IR protocols according to radiologists’ preferences. From our clinical experience, ProtoEnhanceIR offers significant dose reduction opportunities while maintaining validated clinical IQ.

A knowledge-based approach to automated planning for hepatocellular carcinoma.

PurposeTo build a knowledge‐based model of liver cancer for Auto‐Planning, a function in Pinnacle, which is used as an automated inverse intensity modulated radiation therapy (IMRT) planning system.Methods and MaterialsFifty Tomotherapy patients were enrolled to extract the dose–volume histograms (DVHs) information and construct the protocol for Auto‐Planning model. Twenty more patients were chosen additionally to test the model. Manual planning and automatic planning were performed blindly for all twenty test patients with the same machine and treatment planning system. The dose distributions of target and organs at risks (OARs), along with the working time for planning, were evaluated.ResultsStatistically significant results showed that automated plans performed better in target conformity index (CI) while mean target dose was 0.5 Gy higher than manual plans. The differences between target homogeneity indexes (HI) of the two methods were not statistically significant. Additionally, the doses of normal liver, left kidney, and small bowel were significantly reduced with automated plan. Particularly, mean dose and V15 of normal liver were 1.4 Gy and 40.5 cc lower with automated plans respectively. Mean doses of left kidney and small bowel were reduced with automated plans by 1.2 Gy and 2.1 Gy respectively. In contrast, working time was also significantly reduced with automated planning.ConclusionsAuto‐Planning shows availability and effectiveness in our knowledge‐based model for liver cancer.

Photon optimizer (PO) vs progressive resolution optimizer (PRO): a conformality- and complexity-based comparison for intensity-modulated arc therapy plans

This study aimed to provide guidance on the advantages and limitations of a new optimizer, “photon optimizer” (PO), when compared with its predecessor, “progressive resolution optimizer” (PRO), for intensity-modulated arc therapy (IMAT) plans.Eleven study plans that included a cohort of prostate, head and neck, and brain treatment sites were optimized using both PRO and PO algorithms. A plan template using the same objectives for the same number of iterations was used for each optimized plan to obtain hypothetical treatment plans that would be comparable with a clinical plan. Analysis was performed using plan conformity-based parameters such as target volume coverage factor, conformation number and homogeneity indices, and plan complexity assessment parameters such as small aperture score, modulation indices, and monitor unit variation with arc angle for prostate, brain and head, and neck IMAT treatment plans.Plan conformality analysis demonstrated that conformation numbers, target volume coverage factors, and homogeneity indices produced by the 2 optimizers were comparable for most anatomic sites. IMAT treatment plans produced using the PRO optimizer were found to be less complex than plans produced using the PO optimizer, in terms of multileaf collimator (MLC) leaf position variability and modulation complexity scores. Similarly, the PRO optimizer was shown to produce treatment plans that used fewer monitor units (and generally fewer monitor unit per degree of arc rotation) than PO optimizer.This study demonstrated that the PO optimizer can produce IMAT treatment plans with a similar degree of dose conformity to the target volume and generally improved organ at risk sparing, compared with the PRO optimizer. Better coverage to organs at risk produced by plans optimized using PO was observed to have higher MLC variability and monitor units. Therefore, careful evaluation of treatment plan conformity and complexity before assessing its deliverability is recommended when implementing the routine use of PO optimizer.

Dosimetric feasibility of the hybrid Magnetic Resonance Imaging (MRI)-linac System (MRL) for brain metastases: The impact of the magnetic field

Background and purposeWe aimed to investigate the suitability of treating patients with single brain metastases using stereotactic radiosurgery (SRS) with the MRL and to characterize the dosimetric impact at tissue-air interfaces resulting primarily from the electron return effect (ERE). Material and methods24 patients treated for intact single brain metastases were analyzed. Three radiotherapy plans with the same prescribed dose were generated for each case: (1) noncoplanar volumetric modulated arc therapy (VMAT), (2) coplanar step-and-shoot intensity modulated radiotherapy (IMRT) on the MRL in the absence (MRLB=0), and (3) in the presence of the transverse magnetic field (MRLB=1.5). The plans were evaluated using cumulative dose–volume histograms and by calculation of Paddick conformity index (CI), V100%, V12Gy minus gross tumor volume (V12Gy – GTV), and V2Gy. At tissue-air boundaries, the dosimetric impact of the magnetic field was quantified using a 5 mm rim of tissue. ResultsAll plans met the target coverage and organs-at-risk planning objectives. Differences between all investigated dosimetric parameters significantly favored the VMAT plans as compared to the MRLB=0 and MRLB=1.5 plans, except for V2Gy. The mean V12Gy – GTV and V2Gy marginally favored the MRLB=0 plans compared to the MRLB=1.5 plans (mean difference: 0.45 cm3, p = 0.0019 and 16.46 cm3, p < 0.0001, respectively). The presence of the magnetic field resulted in a statistically significant but small increase in mean dose and D2cc in the skin (0.08 Gy, p < 0.0001 and 0.6 Gy, p < 0.0001, respectively) and around air cavities (0.07 Gy, p = 0.0092 and 0.3 Gy, p = 0.0004, respectively). ConclusionsIt is feasible to generate stereotactic radiation plans that satisfy clinical requirements using the MRL in the setting of single brain metastases. The dosimetric impact of the magnetic field including the ERE at tissue-air boundaries is minor and does not negatively impact target conformity or dose gradient.

Five-field IMRT class solutions and dosimetric planning guidelines for implementing accelerated partial breast irradiation

PurposeA comprehensive set of planning guidelines was developed to aid in achieving reproducible dosimetric results for external beam accelerated partial breast irradiation (APBI). The methodology for the development of class solutions for dosimetric planning of the APBI technique, including dose constraint recommendations, is presented for target coverage and conformity as well as normal tissues. Methods and materialsA conservative patient setup was simulated on a linear accelerator, and a comprehensive arrangement of gantry and couch angles was measured for clearance. This provided the foundation for available beam arrangements to develop reproducible and conformal 5-field intensity modulated radiation therapy partial breast plans. Forty patients were planned. Patient plans were assessed according to anatomy specific features, such as laterality and seroma location within the breast. ResultsClearance tables are presented to give permissible gantry and couch orientations according to measurements facilitated by patient simulation. Beam arrangement class solutions are presented for left- and right-sided APBI patients. Dosimetric recommendations are made based on the results of 40 patient plans. The median and range, describing target coverage and target conformity, are reported, as are normal tissue constraints for ipsilateral lung, ipsilateral breast, heart, liver, and contralateral breast. In all cases, the dose recommendations were at least as strict as multi-institutional APBI trials. In the case of ipsilateral lung and ipsilateral breast, the planning recommendations are more stringent. ConclusionsAPBI using a 5-field intensity modulated radiation therapy technique was comprehensively developed and evaluated to provide recommendations yielding highly conformal and reproducible treatment plans. This provides a clear method to implement external beam APBI planning and delivery.

Improving Quality and Consistency in Clinical Trials via Knowledge-Based Planning, NRG Oncology RTOG 0631

Consistency and standardization of radiotherapy planning quality for conducting a multi-institutional clinical trial are always challenging, and non-protocol compliant radiotherapy plans have been shown to impact patient outcomes. This study was aimed to utilize knowledge-based planning (KBP) as a method of producing high quality, consistent, protocol compliant treatment plans, in a complex setting of spine SBRT on RTOG 0631. An internally developed KBP model was applied to an external validation cohort of 22 anonymized cases submitted to NRG for RTOG 0631. The original and KBP plans were compared via their protocol scores, target conformity and gradient index, dose to critical structures, and dose to surrounding normal tissues. The KBP model generated plans meeting all protocol objectives in a single optimization when tested on both internal and external RTOG 0631 cases. Two external plans that were considered to have a protocol-unacceptable deviation were made protocol compliant through the use of the model. There were no statistically significant differences in conformity or gradient indices between the manually optimized plans and the KBP plans. The volume of PTV receiving prescription dose increased from 93.3 ± 3.2% to 99.5 ± 0.7% (P<0.001) when using KBP. High-dose spillage to surrounding normal tissues (V105%) showed no significant differences (2.1 ± 7.3 cc for manual plans to 1.2 ± 0.4 cc with KBP), and dosimetric outliers with large amounts of spillage were eliminated through the use of KBP. Incorporation of KBP models into the clinical trial setting may have a profound impact on the quality of trial results due to the increase in consistency and standardization of planning, especially for treatment sites or techniques that are non-standard. The KBP model will be made available on the Center for Innovation in Radiation Oncology website.

Coarse-Grained Directed Simulation.

Many free-energy sampling and quantum mechanics/molecular mechanics (QM/MM) computations on protein complexes have been performed where, by necessity, a single component is studied isolated in solution while its overall configuration is kept in the complex-like state by either rigid restraints or harmonic constraints. A drawback in these studies is that the system's native fluctuations are lost, both due to the change of environment and the imposition of the extra potential. Yet, we know that having both accurate structure and fluctuations is likely crucial to achieving correct simulation estimates for the subsystem within its native larger protein complex context. In this work, we provide a new approach to this problem by drawing on ideas developed to incorporate experimental information into a molecular simulation by relative entropy minimization to a target system. We show that by using linear biases on coarse-grained (CG) observables (such as distances or angles between large subdomains within a protein), we can maintain the protein in a particular target conformation while also preserving the correct equilibrium fluctuations of the subsystem within its larger biomolecular complex. As an application, we demonstrate this algorithm by training a bias that causes an actin monomer (and trimer) in solution to sample the same average structure and fluctuations as if it were embedded within a much larger actin filament. Additionally, we have developed a number of algorithmic improvements that accelerate convergence of the on-the-fly relative entropy minimization algorithms for this type of application. Finally, we have contributed these methods to the PLUMED open source free energy sampling software library.

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

Comparison of photon volumetric modulated arc therapy, intensity-modulated proton therapy, and intensity-modulated carbon ion therapy for delivery of hypo-fractionated thoracic radiotherapy

PurposeThe aim of the present study was to compare the dose distribution generated from photon volumetric modulated arc therapy (VMAT), intensity modulated proton therapy (IMPT), and intensity modulated carbon ion therapy (IMCIT) in the delivery of hypo-fractionated thoracic radiotherapy.Methods and materialsTen selected patients who underwent thoracic particle therapy between 2015 and 2016 were re-planned to receive a relative biological effectiveness (RBE) weighted dose of 60 Gy (i.e., GyE) in 15 fractions delivered with VMAT, IMPT, or IMCIT with the same optimization criteria. Treatment plans were then compared.ResultsThere were no significant differences in target volume dose coverage or dose conformity, except improved D95 was found with IMCIT compared with VMAT (p = 0.01), and IMCIT was significantly better than IMPT in all target volume dose parameters. Particle therapy led to more prominent lung sparing at low doses, and this result was most prominent with IMCIT (p < 0.05). Improved sparing of other thoracic organs at risk (OARs) was observed with particle therapy, and IMCIT further lowered the D1cc and D5cc for major blood vessels, as compared with IMPT (p = 0.01).ConclusionAlthough it was comparable to VMAT, IMCIT led to significantly better tumor target dose coverage and conformity than did IMPT. Particle therapy, compared with VMAT, improved thoracic OAR sparing. IMCIT, compared with IMPT, may further improve normal lung and major blood vessel sparing under limited respiratory motion.

Clinical implementation of IMRT step and shoot with simultaneous integrated boost for breast cancer: A dosimetric comparison of planning techniques

Purpose: Radiotherapy post-lumpectomy with two coplanar tangent beams is the standard treatment for women with early stage breast cancer. Despite the use of wedges as tissue compensators, the resultant plans often contains a significant dose gradient and 'hot spots' in excess of 15% or more of prescribed dose. In recent years a field-in-field (FIF) dose-compensation technique, which use two standard tangent fields and one or two (rarely three) small beams within these, was developed. It allows to obtain a more uniform dose throughout the target volume in the majority of cases but not in all. This study presents our experience to develop optimal intensity modulated radiation therapy (IMRT) techniques to be applied clinically in those cases where the traditional technique with two tangent fields or its variant field in field (FIF) are unable to achieve a satisfactory planning target volumes (PTVs) coverage and dose objectives to the organs at risk (OARs). Methods: We investigated two pure IMRT plans (named 3F-IMRT and 4F-IMRT) and a hybrid one (H-IMRT). Treatment plans were performed for 7 left-sided and 4 right-sided breasts using simultaneously integrated boost (SIB) planned technique with inverse optimization. Results were compared with those obtained with FIF technique. Dose prescribed was 45 Gy/20 fractions to the breast and 50 Gy /20 fractions to the lumpectomy cavity delivered in 5 fr/week. Dose–volume histograms were generated and parameters as target dose coverage, conformity and homogeneity as well as OARs dose distribution were analyzed. Finally the secondary cancer risk to contralateral breast due to radiation was evaluated as a further parameter for the choice of the optimal plan. Results: Compared to the FIF, the three IMRT plans provided the same target coverage and a better dose conformation, but a worst dose homogeneity of the boost target. The volume of the OARs, receiving higher doses than 15 Gy was reduced but was increased the volume receiving low doses. This causes the increase of the risk of radiation induced cancer, especially for the contralateral breast. For this organ, the highest value of the excess absolute risk (EAR) was associated to the 4F-IMRT, while the lower, to the FIF. Conclusion: The intensity-modulated radiation therapy techniques 5F-IMRT and 4F-IMRT were the best to be applied clinically in those cases, where the traditional technique of irradiation of the breast is unable to achieve the PTVs coverage and dose objectives to the OARs. However, all the IMRT techniques showed an increased volume of healthy tissues receiving low doses, so they should not be used in extensive manner and in particular should be avoided in the cases of young women due to the excess of risk to develop a secondary cancer.

Hypofractionation in postmastectomy breast irradiation. How safe are we in using standard tangentials?

Abstract Aim: Hypofractionation in breast radiotherapy is gaining increasing relevance in routine clinical practice; however, gray areas remain on its safety. Majority of data regarding the same pertains to the treatment of the conserved breast. This study aimed to compare the use of standard wedge-based tangentials (two-dimensional [2D] TW) versus 3D conformal radiotherapy field in the field (3DCRT FIF) with the intent of evaluating if the latter would provide a dosimetric advantage. Materials and Methods: Twenty-six postmastectomy patients were enrolled in this study. Comparative plans using 2D TW and 3DCRT FIF were generated to deliver 50 Gy in 25 fractions. Dosimetric parameters pertaining target dose, Homogeneity Index (HI), Conformity Index, and dose to normal structures were compared and analyzed. The parameters that achieved significance were evaluated using the hypofractionated plan. Results: The 3DCRT FIF plan showed better planning target volume coverage, V95% (P &lt; 0.001) and less cardiac dose (V30 and MD) as well as lung V20, V30, MD, and V5 for both lungs (P &lt; 0.001). The dose to the left descending coronary artery (LAD) was also less with a trend toward significance (P = 0.07). The 3DCRT FIF plan also improved HI (P = 0.02). However, the high-dose volume V107% and radiation exposure were not higher. The significant parameters were evaluated in the hypofractionated schedule of 40 Gy/15 Fr. The MD to the heart was 8.96 Gy in FIF plan versus 20.16 Gy in TW plan. The average V20 to the ipsilateral lung was 37.8% versus 65.2%. The average dose to the contralateral breast was 50% less, i.e., 3.92 Gy versus 8.96 Gy. Conclusion: The results of this study suggest that there would be a significant benefit of using 3DCRT FIF plans for patients being considered for hypofractionated radiotherapy in the postmastectomy setup.

Revision of orthovoltage chest wall treatment using Monte Carlo simulations.

Given the high local control rates observed in breast cancer patients undergoing chest wall irradiation by kilovoltage x-rays, we aimed to revisit this treatment modality by accurate calculation of dose distributions using Monte Carlo simulation. The machine components were simulated using the MCNPX code. This model was used to assess the dose distribution of chest wall kilovoltage treatment in different chest wall thicknesses and larger contour or fat patients in standard and mid sternum treatment plans. Assessments were performed at 50 and 100 cm focus surface distance (FSD) and different irradiation angles. In order to evaluate different plans, indices like homogeneity index, conformity index, the average dose of heart, lung, left anterior descending artery (LAD) and percentage target coverage (PTC) were used. Finally, the results were compared with the indices provided by electron therapy which is a more routine treatment of chest wall. These indices in a medium chest wall thickness in standard treatment plan at 50 cm FSD and 15 degrees tube angle was as follows: homogeneity index 2.57, conformity index 7.31, average target dose 27.43 Gy, average dose of heart, lung and LAD, 1.03, 2.08 and 1.60 Gy respectively and PTC 11.19%. Assessments revealed that dose homogeneity in planning target volume (PTV) and conformity between the high dose region and PTV was poor. To improve the treatment indices, the reference point was transferred from the chest wall skin surface to the center of PTV. The indices changed as follows: conformity index 7.31, average target dose 60.19 Gy, the average dose of heart, lung and LAD, 3.57, 6.38 and 5.05 Gy respectively and PTC 55.24%. Coverage index of electron therapy was 89% while it was 22.74% in the old orthovoltage method and also the average dose of the target was about 50 Gy but in the given method it was almost 30 Gy. The results of the treatment study show that the optimized standard and mid sternum treatment for different chest wall thicknesses is with 50 cm FSD and zero (vertical) tube angle, while in large contour patients, it is with 100 cm FSD and zero tube angle. Finally, chest wall kilovoltage and electron therapies were compared, which revealed that electron therapy produces a better dose distribution than kilovoltage therapy.