Effect of erenumab on the reversion from chronic migraine to episodic migraine in an Asian population: A post hoc analysis of the DRAGON study.

BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene-related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date. OBJECTIVE: Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration). METHODS: Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double-blind treatment period. In addition, migraine-related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non-reverters using the Headache Impact Test-6 (HIT-6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS). RESULTS: Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1-2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT-6 total score for reverters versus non-reverters compared to placebo (erenumab: -9.5 [0.6] vs. -5.1 [0.5]; placebo: -8.9 [0.7] vs. -4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: -22.1 [1.2] vs. -6.3 [1.8]; placebo: -19.9 [1.3] vs. -7.9 [1.6]). Substantial improvements were reported in MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non-reverters in erenumab treatment groups (MPFID-PI: -5.9 [0.3] vs. -1.9 [0.6]; MPFID-EA: -7.9 [0.4] vs. -3.4 [0.6]) and in placebo (MPFID-PI: -5.4 [0.4] vs. -1.0 [0.5]; MPFID-EA: -7.1 [0.5] vs. -3.2 [0.5]). CONCLUSIONS: This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient-reported outcomes in the erenumab group.

Performance evaluation of rural water environment governance based on AHP: a case study of the Beitang River Basin.

Rural water environment governance in China still lacks a systematic and comprehensive assessment protocol to help analyze and improve such governance performance. The Analytic Hierarchy Process (AHP) method was employed in this study to build a governance assessment system that integrates ecological conditions, water pollution control, and public satisfaction. To cover these topics, the assessment system is composed of an indicator layer that is customized to rural water environment governance in China. The Beitang River, located in the rural region of Hangzhou, Zhejiang, China, was presented as a case study. Field investigation provided raw data for this assessment. A questionnaire survey was conducted to interview local residents on the governance performance. An additional survey with executives who played major roles in the governance was performed to reconstruct a water environment assessment on the Beitang River prior to the governance, in order to highlight the effects of the governance through contrast. The results showed consistency in the questionnaire survey and the assessment system. The AHP assessment system was able to reflect the improvement in the water quality, river ecology, and residential welfare after the governance, and suggested limits and future directions in the following upgrade programs for the river basin.

Influence of additional methanol on both pre- and post-denitrification processes in treating municipal wastewater.

Changes in functional properties of biological denitrification in the long-term use of methanol were explored in both pre- and post-denitrification processes. The two systems employed were sequencing batch reactor (SBR) using post-denitrification in temporal sequence, and Carrousel oxidation ditch, which was equipped with a separate pre-denitrification zone. In the SBR, stable nitrate reduction rates reached after 37 days elapsed with addition of methanol (TOC/N = 1.4-1.8) at the start of anoxic phase, and specific denitrification rate increased from 0.378 mgNOx-N·(gVSS·h)-1 to 2.406 mgNOx-N·(gVSS·h)-1. Besides, by means of nitrogen uptake rate (NUR) batch tests based on methanol-adapted sludge, the appropriate range of TOC/N ratios for complete denitrification was estimated to be 1.10-2.68. By comparison, the Carrousel oxidation ditch that was fed with methanol in the anaerobic zone took fewer days (29 days) to obtain a constant effluent nitrate. Moreover, the denitrification yield in ditch was elevated from an initial value of 0.082 mgTN/mgCOD to 0.123 mgTN/mgCOD, and the nitrogen removal efficiency reached up to a level of 68%. The focus on denitrification potential with external methanol is valuable to provide information for developing carbon dosage control, as well as predict the nitrate effluent quality of the plant.

A phase 3, randomised, placebo-controlled study of erenumab for the prevention of chronic migraine in patients from Asia: the DRAGON study.

ABSTACT: BACKGROUND: DRAGON was a phase 3, randomised, double-blind, placebo-controlled study which evaluated the efficacy and safety of erenumab in patients with chronic migraine (CM) from Asia not adequately represented in the global pivotal CM study. METHODS: DRAGON study was conducted across 9 Asian countries or regions including mainland China, India, the Republic of Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. Patients (N = 557) with CM (aged 18-65 years) were randomised (1:1) to receive once-monthly subcutaneous erenumab 70 mg or matching placebo for 12 weeks. The primary endpoint was the change in monthly migraine days (MMD) from baseline to the last 4 weeks of the 12-week double-blind treatment phase (DBTP). Secondary endpoints included achievement of ≥ 50% reduction in MMD, change in monthly acute headache medication days, modified migraine disability assessment (mMIDAS), and safety. Study was powered for the primary endpoint of change from baseline in MMD. RESULTS: At baseline, the mean (SD) age was 41.7 (± 10.9) years, and 81.5% (n = 454) patients were women. The mean migraine duration was 18.0 (± 11.6) years, and the mean MMD was 19.2 (± 5.4). 97.8% (n = 545) randomised patients completed the DBTP. Overall, demographics and baseline characteristics were balanced between the erenumab and placebo groups except for a slightly higher proportion of women in the placebo group. At Week 12, the adjusted mean change from baseline in MMD was - 8.2 days for erenumab and - 6.6 days for placebo, with a statistically significant difference for erenumab versus placebo (adjusted mean difference vs placebo: - 1.57 [95%CI: - 2.83, - 0.30]; P = 0.015). A greater proportion of patients treated with erenumab achieved ≥ 50% reduction in MMD versus placebo (47.0% vs 36.7%, P = 0.014). At Week 12, greater reductions in monthly acute headache medication days (- 5.34 vs - 4.66) and mMIDAS scores (- 14.67 vs - 12.93) were observed in patients treated with erenumab versus placebo. Safety and tolerability profile of erenumab was comparable to placebo, except the incidence of constipation (8.6% for erenumab vs 3.2% for placebo). CONCLUSION: DRAGON study demonstrated the efficacy and safety of erenumab 70 mg in patients with CM from Asia. No new safety signals were observed during the DBTP compared with the previous trials. TRIAL REGISTRATION: NCT03867201.

A comparison of two methodologies for radiotherapy treatment plan optimization and QA for clinical trials.

BACKGROUND AND PURPOSE: The efficacy of clinical trials and the outcome of patient treatment are dependent on the quality assurance (QA) of radiation therapy (RT) plans. There are two widely utilized approaches that include plan optimization guidance created based on patient-specific anatomy. This study examined these two techniques for dose-volume histogram predictions, RT plan optimizations, and prospective QA processes, namely the knowledge-based planning (KBP) technique and another first principle (FP) technique. METHODS: This analysis included 60, 44, and 10 RT plans from three Radiation Therapy Oncology Group (RTOG) multi-institutional trials: RTOG 0631 (Spine SRS), RTOG 1308 (NSCLC), and RTOG 0522 (H&N), respectively. Both approaches were compared in terms of dose prediction and plan optimization. The dose predictions were also compared to the original plan submitted to the trials for the QA procedure. RESULTS: For the RTOG 0631 (Spine SRS) and RTOG 0522 (H&N) plans, the dose predictions from both techniques have correlation coefficients of >0.9. The RT plans that were re-optimized based on the predictions from both techniques showed similar quality, with no statistically significant differences in target coverage or organ-at-risk sparing. The predictions of mean lung and heart doses from both methods for RTOG1308 patients, on the other hand, have a discrepancy of up to 14 Gy. CONCLUSIONS: Both methods are valuable tools for optimization guidance of RT plans for Spine SRS and Head and Neck cases, as well as for QA purposes. On the other hand, the findings suggest that KBP may be more feasible in the case of inoperable lung cancer patients who are treated with IMRT plans that have spatially unevenly distributed beam angles.

Intelligent Nanocomposites with Intrinsic Blood-Brain-Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma.

The blood-brain barrier (BBB) is the most important obstacle to improving the clinical outcomes of diagnosis and therapy of glioblastoma. Thus, the development of a novel nanoplatform that can efficiently traverse the BBB and achieve both precise diagnosis and therapy is of great importance. Herein, an intelligent nanoplatform based on holo-transferrin (holo-Tf) with in situ growth of MnO2 nanocrystals is constructed via a reformative mild biomineralization process. Furthermore, protoporphyrin (ppIX), acting as a sonosensitizer, is then conjugated into holo-Tf to obtain MnO2 @Tf-ppIX nanoparticles (TMP). Because of the functional inheritance of holo-Tf during fabrication, TMP can effectively traverse the BBB for highly specific magnetic resonance (MR) imaging of orthotopic glioblastoma. Clear suppression of tumor growth in a C6 tumor xenograft model is achieved via sonodynamic therapy. Importantly, the experiments also indicate that the TMP nanoplatform has satisfactory biocompatibility and biosafety, which favors potential clinical translation.

Retrospective quality metrics review of stereotactic radiosurgery plans treating multiple targets using single-isocenter volumetric modulated arc therapy.

PURPOSE: To characterize key plan quality metrics in multi-target stereotactic radiosurgery (SRS) plans treated using single-isocenter volumetric modulated arc therapy (VMAT) in comparison to dynamic conformal arc (DCA) plans treating single target. To investigate the feasibility of quality improvement in VMAT planning based on previous planning knowledge. MATERIALS AND METHODS: 97 VMAT plans of multi-target and 156 DCA plans of single-target treated in 2017 at a single institution were reviewed. A total of 605 targets were treated with these SRS plans. The prescription dose was normalized to 20 Gy in all plans for this analysis. Two plan quality metrics, target conformity index (CI) and normal tissue volume receiving more than 12 Gy (V12Gy), were calculated for each target. The distribution of V12Gy per target was plotted as a function of the target volume. For multi-target VMAT plans, the number of targets being treated in the same plan and the distance between targets were calculated to evaluate their impact on V12Gy. VMAT plans that had a large deviation of V12Gy from the average level were re-optimized to determine the possibility of reducing the variation of V12Gy in VMAT planning. RESULTS: Conformity index of multi-target VMAT plans were lower than that of DCA plans while the mean values of 12 Gy were comparable. The V12Gy for a target in VMAT plan did not show apparent dependence on the total number of targets or the distance between targets. The distribution of V12Gy exhibited a larger variation in VMAT plans compared to DCA plans. Re-optimization of outlier plans reduced V12 Gy by 33.9% and resulted in the V12Gy distribution in VMAT plans more closely resembling that of DCA plans. CONCLUSION: The benchmark data on key plan quality metrics were established for single-isocenter multi-target SRS planning. It is feasible to use this knowledge to guide VMAT planning and reduce high V12Gy outliers.

Technical Note: Investigation of the dosimetric impact of stray radiation on the Common Control Unit of the IBA Blue Phantom2.

PURPOSE: This technical note aims to investigate the dosimetric impact of stray radiation on the Common Control Unit (CCU) of the IBA Blue Phantom2 and the measured beam data. METHODS: Three CCUs of the same model were used for the study. The primary test CCU was placed at five distances from the radiation beam central axis. At each distance, a set of depth dose and beam profiles for two open and two wedge fields were measured. The field sizes were 10 × 10 cm2 and 30 × 30 cm2 for the open fields, and 30 × 30 cm2 and 15 × 15 cm2 for the 30° and 60° wedges, respectively. The other two CCUs were used to cross check the data of the primary CCU. Assuming the effect of stray radiation on the data measured at the farthest reachable distance 4.5 m is negligible, the dosimetric impact of stray radiation on the CCU and consequently on the measured data can be extracted for analysis by comparing it with those measured at shorter distances. RESULTS: The results of three CCUs were consistent. The dosimetric impact of stray radiation was greater for lower energies at larger field sizes. For open fields, the data variation was up to 4.5% for depth dose curves and 7.1% for beam profiles. For wedge fields, the data variation was up to 9.3% for depth dose curves and 10.6% for beam profiles. Moreover, for wedge field profiles in the wedge direction, they became flatter as the CCU was placed closer to the primary radiation beam, manifesting smaller wedge angles. CONCLUSION: The stray radiation added a uniform background noise on all measured data. The magnitude of the noise is inversely proportional to the square of the distance of the CCU to the primary radiation beam, approximately following the inverse square law.

MR-Based Radiomics Nomogram of Cervical Cancer in Prediction of the Lymph-Vascular Space Invasion preoperatively.

BACKGROUND: Lymph-vascular space invasion (LVSI) is an unfavorable prognostic factor in cervical cancer. Unfortunately, there are no current clinical tools for the preoperative prediction of LVSI. PURPOSE: To develop and validate an axial T1 contrast-enhanced (CE) MR-based radiomics nomogram that incorporated a radiomics signature and some clinical parameters for predicting LVSI of cervical cancer preoperatively. STUDY TYPE: Retrospective. POPULATION: In all, 105 patients were randomly divided into two cohorts at a 2:1 ratio. FIELD STRENGTH/SEQUENCE: T1 CE MRI sequences at 1.5T. ASSESSMENT: Univariate analysis was performed on the radiomics features and clinical parameters. Multivariate analysis was performed to determine the optimal feature subset. The receiver operating characteristic (ROC) analysis was performed to evaluate the performance of prediction model and radiomics nomogram. STATISTICAL TESTS: The Mann-Whitney U-test and the chi-square test were used to evaluate the performance of clinical characteristics and LVSI status by pathology. The minimum-redundancy/maximum-relevance and recursive feature elimination methods were applied to select the features. The radiomics model was constructed using logistic regression. RESULTS: Three radiomics features and one clinical characteristic were selected. The radiomics nomogram showed favorable discrimination between LVSI and non-LVSI groups. The AUC was 0.754 (95% confidence interval [CI], 0.6326-0.8745) in the training cohort and 0.727 (95% CI, 0.5449-0.9097) in the validation cohort. The specificity and sensitivity were 0.756 and 0.828 in the training cohort and 0.773 and 0.692 in the validation cohort. DATA CONCLUSION: T1 CE MR-based radiomics nomogram serves as a noninvasive biomarker in the prediction of LVSI in patients with cervical cancer preoperatively. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1420-1426.

LINAC based stereotactic radiosurgery for multiple brain metastases: guidance for clinical implementation.

Introduction: Stereotactic radiosurgery (SRS) is a promising treatment option for patients with multiple brain metastases (BM). Recent technical advances have made LINAC based SRS a patient friendly technique, allowing for accurate patient positioning and a short treatment time. Since SRS is increasingly being used for patients with multiple BM, it remains essential that SRS be performed with the highest achievable quality in order to prevent unnecessary complications such as radionecrosis. The purpose of this article is to provide guidance for high-quality LINAC based SRS for patients with BM, with a focus on single isocenter non-coplanar volumetric modulated arc therapy (VMAT). Methods: The article is based on a consensus statement by the study coordinators and medical physicists of four trials which investigated whether patients with multiple BM are better palliated with SRS instead of whole brain radiotherapy (WBRT): A European trial (NCT02353000), two American trials and a Canadian CCTG lead intergroup trial (CE.7). This manuscript summarizes the quality assurance measures concerning imaging, planning and delivery. Results: To optimize the treatment, the interval between the planning-MRI (gadolinium contrast-enhanced, maximum slice thickness of 1.5 mm) and treatment should be kept as short as possible (< two weeks). The BM are contoured based on the planning-MRI, fused with the planning-CT. GTV-PTV margins are minimized or even avoided when possible. To maximize efficiency, the preferable technique is single isocenter (non-)coplanar VMAT, which delivers high doses to the target with maximal sparing of the organs at risk. The use of flattening filter free photon beams ensures a lower peripheral dose and shortens the treatment time. To bench mark SRS treatment plan quality, it is advisable to compare treatment plans between hospitals. Conclusion: This paper provides guidance for quality assurance and optimization of treatment delivery for LINAC-based radiosurgery for patients with multiple BM.

Evaluation of dosimetric uncertainty caused by MR geometric distortion in MRI-based liver SBRT treatment planning.

PURPOSE: MRI-based treatment planning is a promising technique for liver stereotactic-body radiation therapy (SBRT) treatment planning to improve target volume delineation and reduce radiation dose to normal tissues. MR geometric distortion, however, is a source of potential error in MRI-based treatment planning. The aim of this study is to investigate dosimetric uncertainties caused by MRI geometric distortion in MRI-based treatment planning for liver SBRT. MATERIALS AND METHODS: The study was conducted using computer simulations. 3D MR geometric distortion was simulated using measured data in the literature. Planning MR images with distortions were generated by integrating the simulated 3D MR geometric distortion onto planning CT images. MRI-based treatment plans were then generated on the planning MR images with two dose calculation methods: (1) using original CT numbers; and (2) using organ-specific assigned CT numbers. Dosimetric uncertainties of various dose-volume-histogram parameters were determined as their differences between the simulated MRI-based plans and the original clinical CT-based plans for five liver SBRT cases. RESULTS: The average simulated distortion for the five liver SBRT cases was 2.77 mm. In the case of using original CT numbers for dose calculation, the average dose uncertainties for target volumes and critical structures were <0.5 Gy, and the average target volume percentage at prescription dose uncertainties was 0.97%. In the case of using assigned CT numbers, the average dose uncertainties for target volumes and critical structures were <1.0 Gy, and the average target volume percentage at prescription dose uncertainties was 2.02%. CONCLUSIONS: Dosimetric uncertainties caused by MR geometric distortion in MRI-based liver SBRT treatment planning was generally small (<1 Gy) when the distortion is 3 mm.

An in-house protocol for improved flood field calibration of TrueBeam FFF cine imaging.

PURPOSE: TrueBeams equipped with the 40 × 30 cm2 Electronic Portal Imaging Devices (EPIDs) are prone to image saturation at the image center when used with flattening filter free (FFF) photon energies. While cine imaging during treatment may not saturate because the beam is attenuated by the patient, the flood field calibration is affected when the standard calibration procedure is followed. Here, we describe the hardware and protocol to achieve improved image quality for this model of TrueBeam EPID. MATERIALS & METHODS: A stainless steel filter of uniform thickness was designed to have sufficient attenuation to avoid panel saturation. The cine imaging flood field calibration was acquired with the filter in place for the FFF energies under the standard calibration geometry (SID = 150 cm). Image quality during MV cine was assessed with & without the modified flood field calibration using a low contrast resolution phantom and an anthropomorphic phantom. RESULTS: When the flood field is acquired without the filter in place, a pixel gain artifact is clearly present in the image center which may be mis-attributed to panel saturation in the subject image. At the image center, the artifact obscured all low contrast inserts and was also visible on the anthropomorphic phantom. Using the filter for flood field calibration eliminates the artifact. CONCLUSION: TrueBeams equipped with the 40 × 30 cm2 IDU can utilize a modified flood field calibration procedure for FFF photon energies that improves image quality for cine MV imaging.

AAPM-RSS Medical Physics Practice Guideline 9.a. for SRS-SBRT.

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8,000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: Must and Must Not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. Should and Should Not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances. Approved by AAPM Professional Council 3-31-2017 and Executive Committee 4-4-2017.

An efficient calculation method for pharmacokinetic parameters in brain permeability study using dynamic contrast-enhanced MRI.

PURPOSE: To develop an efficient method for calculating pharmacokinetic (PK) parameters in brain DCE-MRI permeability studies. METHODS: A linear least-squares fitting algorithm based on a derivative expression of the two-compartment PK model was proposed to analytically solve for the PK parameters. Noise in the expression was minimized through low-pass filtering. Simulation studies were conducted in which the proposed method was compared with two existing methods in terms of accuracy and efficiency. Five in vivo brain studies were demonstrated for potential clinical application. RESULTS: In the simulation studies using chosen parameter values, the calculated percent difference of K(trans) by the proposed method was <5.0% with a temporal resolution (Δt) < 5 s, and the accuracies of all parameter results were better or comparable to existing methods. When analyzed within certain parameter intensity ranges, the proposed method was more accurate than the existing methods and improved the efficiency by a factor of up to 458 for a Δt = 1 s and up to 38 for a Δt = 5 s. In the in vivo study, the calculated parameters using the proposed method were comparable to those using the existing methods with improved efficiencies. CONCLUSIONS: An efficient method was developed for the accurate and efficient calculation of parameters in brain DCE-MRI permeability studies.

Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis.

Psoriasis is a chronic autoimmune disease affecting the skin and characterized by aberrant keratinocyte proliferation and function. Immune cells infiltrate the skin and release proinflammatory cytokines that play important roles in psoriasis. The Th17 network, including IL-23 and IL-22, has recently emerged as a critical component in the pathogenesis of psoriasis. IL-22 and IL-23 signaling is dependent on the JAK family of protein tyrosine kinases, making JAK inhibition an appealing strategy for the treatment of psoriasis. In this study, we report the activity of SAR-20347, a small molecule inhibitor with specificity for JAK1 and tyrosine kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose dependently (1 nM-10 µM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild-type mice with SAR-20347 significantly reduced IL-12-induced IFN-γ production and IL-22-dependent serum amyloid A to similar extents, indicating that, in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes and proinflammatory cytokine levels compared with both TYK2 mutant mice and wild-type controls. Taken together, these data indicate that targeting both JAK1- and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis.

On the sensitivity of TG-119 and IROC credentialing to TPS commissioning errors.

We investigate the sensitivity of IMRT commissioning using the TG-119 C-shape phantom and credentialing with the IROC head and neck phantom to treatment planning system commissioning errors. We introduced errors into the various aspects of the commissioning process for a 6X photon energy modeled using the analytical anisotropic algorithm within a commercial treatment planning system. Errors were implemented into the various components of the dose calculation algorithm including primary photons, secondary photons, electron contamination, and MLC parameters. For each error we evaluated the probability that it could be committed unknowingly during the dose algorithm commissioning stage, and the probability of it being identified during the verification stage. The clinical impact of each commissioning error was evaluated using representative IMRT plans including low and intermediate risk prostate, head and neck, mesothelioma, and scalp; the sensitivity of the TG-119 and IROC phantoms was evaluated by comparing dosimetric changes to the dose planes where film measurements occur and change in point doses where dosimeter measurements occur. No commissioning errors were found to have both a low probability of detection and high clinical severity. When errors do occur, the IROC credentialing and TG 119 commissioning criteria are generally effective at detecting them; however, for the IROC phantom, OAR point-dose measurements are the most sensitive despite being currently excluded from IROC analysis. Point-dose measurements with an absolute dose constraint were the most effective at detecting errors, while film analysis using a gamma comparison and the IROC film distance to agreement criteria were less effective at detecting the specific commissioning errors implemented here.

Diode-based transmission detector for IMRT delivery monitoring: a validation study.

The purpose of this work was to evaluate the potential of a new transmission detector for real-time quality assurance of dynamic-MLC-based radiotherapy. The accuracy of detecting dose variation and static/dynamic MLC position deviations was measured, as well as the impact of the device on the radiation field (surface dose, transmission). Measured dose variations agreed with the known variations within 0.3%. The measurement of static and dynamic MLC position deviations matched the known deviations with high accuracy (0.7-1.2 mm). The absorption of the device was minimal (~ 1%). The increased surface dose was small (1%-9%) but, when added to existing collimator scatter effects could become significant at large field sizes (≥ 30 × 30 cm2). Overall the accuracy and speed of the device show good potential for real-time quality assurance.

Identification and characterization of HIV-1 latent viral reservoirs in peripheral blood.

Plasma viral load and CD4 counts are effective for clinical monitoring, but they do not give a full representation of HIV-1 quasispecies in cellular reservoirs, the major repository of replication-competent HIV-1 in infected individuals. We sought to develop a diagnostic system that might stimulate the replication-competent HIV-1 reservoirs for enhanced clinical monitoring, including selection of antiretroviral regimens. Whole-blood samples from 45 HIV-infected individuals were collected into 1 ViraStim HIV-1 activation tube and 1 EDTA tube. Samples were tested for viral load and cell type-specific HIV-1 replication. Further, 7 matched activated/nonactivated samples were sequenced using the Trugene HIV-1 genotyping kit. The percentage of patients with replication-competent virus in peripheral blood mononuclear cells (PBMCs) varied, depending on the baseline plasma viral load in the EDTA tubes. Six out of 24 patients with a starting plasma viral load of <20 copies/ml (cp/ml), 6 out of 8 patients with starting viral loads of >20 and <1,000 cp/ml, and 8 out of 13 patients with starting viral loads of >1,000 all showed increases in viral replication of >5-fold. These increases came from cellular reservoirs in blood as determined by simultaneous ultrasensitive subpopulation staining/hybridization in situ (SUSHI). When resistance genotypes in plasma from activation tubes were compared to those from EDTA tubes for 7 patients, all patients showed additional mutations in the activation tube, while 3 patients demonstrated additional genotypic resistance determinants. We show that HIV-1 viral replication can be stimulated directly from infected whole blood. The sequencing results showed that 3 of 7 cases demonstrated additional drug resistance following stimulation.

Dosimetric comparison of preoperative single-fraction partial breast radiotherapy techniques: 3D CRT, noncoplanar IMRT, coplanar IMRT, and VMAT.

The purpose of this study was to compare dosimetric parameters of treatment plans among four techniques for preoperative single-fraction partial breast radiotherapy in order to select an optimal treatment technique. The techniques evaluated were noncoplanar 3D conformal radiation therapy (3D CRT), noncoplanar intensity-modulated radiation therapy (IMRTNC), coplanar IMRT (IMRTCO), and volumetric-modulated arc therapy (VMAT). The planning CT scans of 16 patients in the prone position were used in this study, with the single-fraction prescription doses of 15 Gy for the first eight patients and 18 Gy for the remaining eight patients. Six (6) MV photon beams were designed to avoid the heart and contralateral breast. Optimization for IMRT and VMAT was performed to reduce the dose to the skin and normal breast. All plans were normalized such that 100% of the prescribed dose covered greater than 95% of the clinical target volume (CTV) consisting of gross tumor volume (GTV) plus 1.5 cm margin. Mean homogeneity index (HI) was the lowest (1.05 ± 0.02) for 3D CRT and the highest (1.11 ± 0.04) for VMAT. Mean conformity index (CI) was the lowest (1.42 ± 0.32) for IMRTNC and the highest (1.60 ± 0.32) for VMAT. Mean of the maximum point dose to skin was the lowest (73.7 ± 11.5%) for IMRTNC and the highest (86.5 ± 6.68%) for 3D CRT. IMRTCO showed very similar HI, CI, and maximum skin dose to IMRTNC (differences <1%). The estimated mean treatment delivery time, excluding the time spent for patient positioning and imaging, was 7.0 ± 1.0, 8.3 ± 1.1, 9.7 ± 1.0, and 11.0 ± 1.5min for VMAT, IMRTCO, IMRTNC and 3D CRT, respectively. In comparison of all four techniques for preoperative single-fraction partial breast radiotherapy, we can conclude that noncoplanar or coplanar IMRT were optimal in this study as IMRT plans provided homogeneous and conformal target coverage, skin sparing, and relatively short treatment delivery time.

Quantitative comparison of automatic and manual IMRT optimization for prostate cancer: the benefits of DVH prediction.

A recent publication indicated that the patient anatomical feature (PAF) model was capable of predicting optimal objectives based on past experience. In this study, the benefits of IMRT optimization using PAF-predicted objectives as guidance for prostate were evaluated. Three different optimization methods were compared.1) Expert Plan: Ten prostate cases (16 plans) were planned by an expert planner using conventional trial-and-error approach started with institutional modified OAR and PTV constraints. Optimization was stopped at 150 iterations and that plan was saved as Expert Plan. 2) Clinical Plan: The planner would keep working on the Expert Plan till he was satisfied with the dosimetric quality and the final plan was referred to as Clinical Plan. 3) PAF Plan: A third sets of plans for the same ten patients were generated fully automatically using predicted DVHs as guidance. The optimization was based on PAF-based predicted objectives, and was continued to 150 iterations without human interaction. DMAX and D98% for PTV, DMAX for femoral heads, DMAX, D10cc, D25%/D17%, and D40% for bladder/rectum were compared. Clinical Plans are further optimized with more iterations and adjustments, but in general provided limited dosimetric benefits over Expert Plans. PTV D98% agreed within 2.31% among Expert, Clinical, and PAF plans. Between Clinical and PAF Plans, differences for DMAX of PTV, bladder, and rectum were within 2.65%, 2.46%, and 2.20%, respectively. Bladder D10cc was higher for PAF but < 1.54% in general. Bladder D25% and D40% were lower for PAF, by up to 7.71% and 6.81%, respectively. Rectum D10cc, D17%, and D40% were 2.11%, 2.72%, and 0.27% lower for PAF, respectively. DMAX for femoral heads were comparable (< 35 Gy on average). Compared to Clinical Plan (Primary + Boost), the average optimization time for PAF plan was reduced by 5.2 min on average, with a maximum reduction of 7.1min. Total numbers of MUs per plan for PAF Plans were lower than Clinical Plans, indicating better delivery efficiency. The PAF-guided planning process is capable of generating clinical-quality prostate IMRT plans with no human intervention. Compared to manual optimization, this automatic optimization increases planning and delivery efficiency, while maintainingplan quality.