A Technique to Enable Efficient Adaptive Radiation Therapy: Automated Contouring of Prostate and Adjacent Organs.

Purpose: The purpose of this work was to investigate the use of a segmentation approach that could potentially improve the speed and reproducibility of contouring during magnetic resonance-guided adaptive radiation therapy. Methods and Materials: The segmentation algorithm was based on a hybrid deep neural network and graph optimization approach that also allows rapid user intervention (Deep layered optimal graph image segmentation of multiple objects and surfaces [LOGISMOS] + just enough interaction [JEI]). A total of 115 magnetic resonance-data sets were used for training and quantitative assessment. Expert segmentations were used as the independent standard for the prostate, seminal vesicles, bladder, rectum, and femoral heads for all 115 data sets. In addition, 3 independent radiation oncologists contoured the prostate, seminal vesicles, and rectum for a subset of patients such that the interobserver variability could be quantified. Consensus contours were then generated from these independent contours using a simultaneous truth and performance level estimation approach, and the deviation of Deep LOGISMOS + JEI contours to the consensus contours was evaluated and compared with the interobserver variability. Results: The absolute accuracy of Deep LOGISMOS + JEI generated contours was evaluated using median absolute surface-to-surface distance which ranged from a minimum of 0.20 mm for the bladder to a maximum of 0.93 mm for the prostate compared with the independent standard across all data sets. The median relative surface-to-surface distance was less than 0.17 mm for all organs, indicating that the Deep LOGISMOS + JEI algorithm did not exhibit a systematic under- or oversegmentation. Interobserver variability testing yielded a mean absolute surface-to-surface distance of 0.93, 1.04, and 0.81 mm for the prostate, seminal vesicles, and rectum, respectively. In comparison, the deviation of Deep LOGISMOS + JEI from consensus simultaneous truth and performance level estimation contours was 0.57, 0.64, and 0.55 mm for the same organs. On average, the Deep LOGISMOS algorithm took less than 26 seconds for contour segmentation. Conclusions: Deep LOGISMOS + JEI segmentation efficiently generated clinically acceptable prostate and normal tissue contours, potentially limiting the need for time intensive manual contouring with each fraction.

Intra-fraction motion of pelvic oligometastases and feasibility of PTV margin reduction using MRI guided adaptive radiotherapy.

Purpose: This study assesses the impact of intra-fraction motion and PTV margin size on target coverage for patients undergoing radiation treatment of pelvic oligometastases. Dosimetric sparing of the bowel as a function of the PTV margin is also evaluated. Materials and methods: Seven patients with pelvic oligometastases previously treated on our MR-linac (35 Gy in 5 fractions) were included in this study. Retrospective adaptive plans were created for each fraction on the daily MRI datasets using PTV margins of 5 mm, 3 mm, and 2 mm. Dosimetric constraint violations and GTV coverage were measured as a function of PTV margin size. The impact of intra-fraction motion on GTV coverage was assessed by tracking the GTV position on the cine MR images acquired during treatment delivery and creating an intra-fraction dose distribution for each IMRT beam. The intra-fraction dose was accumulated for each fraction to determine the total dose delivered to the target for each PTV size. Results: All OAR constraints were achieved in 85.7%, 94.3%, and 100.0% of fractions when using 5 mm, 3 mm, and 2 mm PTV margins while scaling to 95% PTV coverage. Compared to plans with a 5 mm PTV margin, there was a 27.4 ± 12.3% (4.0 ± 2.2 Gy) and an 18.5 ± 7.3% (2.7 ± 1.4 Gy) reduction in the bowel D0.5cc dose for 2 mm and 3 mm PTV margins, respectively. The target dose (GTV V35 Gy) was on average 100.0 ± 0.1% (99.6 - 100%), 99.6 ± 1.0% (97.2 - 100%), and 99.0 ± 1.4% (95.0 - 100%), among all fractions for the 5 mm, 3 mm, and 2 mm PTV margins on the adaptive plans when accounting for intra-fraction motion, respectively. Conclusion: A 2 mm PTV margin achieved a minimum of 95% GTV coverage while reducing the dose to the bowel for all patients.

Simulating an intra-fraction adaptive workflow to enable PTV margin reduction in MRIgART volumetric modulated arc therapy for prostate SBRT.

Purpose: This study simulates a novel prostate SBRT intra-fraction re-optimization workflow in MRIgART to account for prostate intra-fraction motion and evaluates the dosimetric benefit of reducing PTV margins. Materials and methods: VMAT prostate SBRT treatment plans were created for 10 patients using two different PTV margins, one with a 5 mm margin except 3 mm posteriorly (standard) and another using uniform 2 mm margins (reduced). All plans were prescribed to 36.25 Gy in 5 fractions and adapted onto each daily MRI dataset. An intra-fraction adaptive workflow was simulated for the reduced margin group by synchronizing the radiation delivery with target position from cine MRI imaging. Intra-fraction delivered dose was reconstructed and prostate DVH metrics were evaluated under three conditions for the reduced margin plans: Without motion compensation (no-adapt), with a single adapt prior to treatment (ATP), and lastly for intra-fraction re-optimization during delivery (intra). Bladder and rectum DVH metrics were compared between the standard and reduced margin plans. Results: As expected, rectum V18 Gy was reduced by 4.4 ± 3.9%, D1cc was reduced by 12.2 ± 6.8% (3.4 ± 2.3 Gy), while bladder reductions were 7.8 ± 5.6% for V18 Gy, and 9.6 ± 7.3% (3.4 ± 2.5 Gy) for D1cc for the reduced margin reference plans compared to the standard PTV margin. For the intrafraction replanning approach, average intra-fraction optimization times were 40.0 ± 2.9 seconds, less than the time to deliver one of the four VMAT arcs (104.4 ± 9.3 seconds) used for treatment delivery. When accounting for intra-fraction motion, prostate V36.25 Gy was on average 96.5 ± 4.0%, 99.1 ± 1.3%, and 99.6 ± 0.4 for the non-adapt, ATP, and intra-adapt groups, respectively. The minimum dose received by the prostate was less than 95% of the prescription dose in 84%, 36%, and 10% of fractions, for the non-adapt, ATP, and intra-adapt groups, respectively. Conclusions: Intra-fraction re-optimization improves prostate coverage, specifically the minimum dose to the prostate, and enables PTV margin reduction and subsequent OAR sparing. Fast re-optimizations enable uninterrupted treatment delivery.

Initial clinical applications treating pediatric and adolescent patients using MR-guided radiotherapy.

Purpose: To demonstrate the clinical applications and feasibility of online adaptive magnetic resonance image guided radiotherapy (MRgRT) in the pediatric, adolescent and young adult (AYA) population. Methods: This is a retrospective case series of patients enrolled onto a prospective study. All pediatric (age < 18) and AYA patients (age< 30), treated on the Elekta Unity MR linear accelerator (MRL) from 2019 to 2021 were enrolled onto a prospective registry. Rationale for MRgRT included improved visualization of and alignment to the primary tumor, re-irradiation in a critical area, ability to use smaller margins, and need for daily adaptive replanning to minimize dose to adjacent critical structures. Step-and-shoot intensity-modulated radiation treatment (IMRT) plans were generated for all Unity patients with a dose grid of 3 mm and a statistical uncertainty of < 1% per plan. Results: A total of 15 pediatric and AYA patients have been treated with median age of 13 years (range: 6 mos - 27 yrs). Seven patients were <10 yo. The clinical applications of MRgRT included Wilms tumor with unresectable IVC thrombus (n=1), Ewing sarcoma (primary and metastatic, n=3), recurrent diffuse intrinsic pontine glioma (DIPG, n=2), nasopharyngeal carcinoma (n=1), clival chordoma (n=1), primitive neuroectodermal tumor of the pancreas (n=1), recurrent gluteo-sacral germ cell tumor (n=1), C-spine ependymoma (n=1), and posterior fossa ependymoma (n=1). Two children required general anesthesia. One AYA patient could not complete the MRgRT course due to tumor-related pain exacerbated by longer treatment times. Two AYA patients experienced anxiety related to treatment on the MRL, one of which required daily Ativan. No patient experienced treatment interruptions or unexpected toxicity. Conclusion: MRgRT was well-tolerated by pediatric and AYA patients. There was no increased use of anesthesia outside of our usual practice. Dosimetric advantages were seen for patients with tumors in critical locations such as adjacent to or involving optic structures, stomach, kidney, bowel, and heart.

Clinical Implementational and Site-Specific Workflows for a 1.5T MR-Linac.

MR-guided adaptive radiotherapy (MRgART) provides opportunities to benefit patients through enhanced use of advanced imaging during treatment for many patients with various cancer treatment sites. This novel technology presents many new challenges which vary based on anatomic treatment location, technique, and potential changes of both tumor and normal tissue during treatment. When introducing new treatment sites, considerations regarding appropriate patient selection, treatment planning, immobilization, and plan-adaption criteria must be thoroughly explored to ensure adequate treatments are performed. This paper presents an institution's experience in developing a MRgART program for a 1.5T MR-linac for the first 234 patients. The paper suggests practical treatment workflows and considerations for treating with MRgART at different anatomical sites, including imaging guidelines, patient immobilization, adaptive workflows, and utilization of bolus.

Reducing MRI-guided radiotherapy planning and delivery times via efficient leaf sequencing and segment shape optimization algorithms.

Objective.Extended treatment session times are an operational limitation in magnetic resonance imaging guided adaptive radiotherapy (MRIgRT). In this study a novel leaf sequencing algorithm called optimal fluence levels (OFL) and an optimization algorithm called pseudo gradient descent (PGD) are evaluated with respect to plan quality, beam complexity, and the ability to reduce treatment session times on the Elekta Unity MRIgRT system.Approach.Ten total patients were evaluated on this Institutional Review Board approved study: three with prostate cancer, three with oligometastases, two with pancreatic cancer, and two with liver cancer. Plans were generated using the clinical Monaco Hyperion optimizer and leaf sequencer and then re-optimized using OFL and PGD (OFL + PGD) while holding all IMRT constraints and planning parameters constant. All plans were normalized to ensure 95% of the PTV received the prescription dose. A paired t-test was used to evaluate statistical significance.Main Results.Plan quality in terms of dosimetric OAR sparing was found to be equivalent between the OFL + PGD and conventional Monaco Hyperion optimizer plans. The OFL + PGD plans had a reduction in optimization time of 51.4% ± 5.0% (p = 0.002) and reduction in treatment delivery time of 10.6% ± 7.5% (p = 0.005). OFL + PGD generated plans had on average 13.2% ± 12.6% fewer multi-leaf collimator (MLC) segments (p = 0.009) and 0.1 ± 0.1 lower plan averaged beam modulation (PM) (p = 0.004) relative to the Monaco Hyperion plans.Significance.The OFL + PGD algorithms more quickly generate Unity treatment plans that are faster to deliver than with the conventional approach and without compromising dosimetric plan quality. This is likely due to a delivery complexity reduction enabled by OFL + PGD relative to the Monaco Hyperion plans.

Dose accumulation for MR-guided adaptive radiotherapy: From practical considerations to state-of-the-art clinical implementation.

MRI-linear accelerator (MR-linac) devices have been introduced into clinical practice in recent years and have enabled MR-guided adaptive radiation therapy (MRgART). However, by accounting for anatomical changes throughout radiation therapy (RT) and delivering different treatment plans at each fraction, adaptive radiation therapy (ART) highlights several challenges in terms of calculating the total delivered dose. Dose accumulation strategies-which typically involve deformable image registration between planning images, deformable dose mapping, and voxel-wise dose summation-can be employed for ART to estimate the delivered dose. In MRgART, plan adaptation on MRI instead of CT necessitates additional considerations in the dose accumulation process because MRI pixel values do not contain the quantitative information used for dose calculation. In this review, we discuss considerations for dose accumulation specific to MRgART and in relation to current MR-linac clinical workflows. We present a general dose accumulation framework for MRgART and discuss relevant quality assurance criteria. Finally, we highlight the clinical importance of dose accumulation in the ART era as well as the possible ways in which dose accumulation can transform clinical practice and improve our ability to deliver personalized RT.

Analysis of patient-specific quality assurance for Elekta Unity adaptive plans using statistical process control methodology.

The Elekta Unity MR-linac utilizes daily magnetic resonance imaging (MRI) for online plan adaptation. In the Unity workflow, adapt to position (ATP) and adapt to shape (ATS) treatment planning options are available which represent a virtual shift or full re-plan with contour adjustments respectively. Both techniques generate a new intensity modulated radiation therapy (IMRT) treatment plan while the patient lies on the treatment table and thus adapted plans cannot be measured prior to treatment delivery. A statistical process control methodology was used to analyze 512 patient-specific IMRT QA measurements performed on the MR-compatible SunNuclear ArcCheck with a gamma criterion of 3%/2 mm using global normalization and a 10% low dose threshold. The lower control limit (LCL) was determined from 68 IMRT reference plan measurements, and a one-sided process capability ratio ( C p , l ) was used to assess the pass rates from 432 measured ATP and 80 measured ATS plans. Further analysis was performed to assess differences between SBRT or conventional fractionation pass rates and to determine whether there was any correlation between the pass rates and plan complexity. The LCL of the reference plans was determined to be a gamma pass rate of 0.958, and the C p , l of the measured ATP plans and measured ATS plans were determined to be 1.403 and 0.940 for ATP and ATS plans, respectively, while a C p , l of 0.902 and 1.383 was found for SBRT and conventional fractionations respectively. For plan complexity, no correlation was found between modulation degree and gamma pass rate, but a statistically significant correlation was observed between the beam-averaged aperture area and gamma pass rate. All adaptive plans passed the TG-218 guidelines, but the ATS and SBRT plans tended to have a smaller beam-averaged aperture area with slightly lower gamma pass rates.

Commissioning of a 1.5T Elekta Unity MR-linac: A single institution experience.

MR image-guided radiotherapy has the potential to improve patient care, but integration of an MRI scanner with a linear accelerator adds complexity to the commissioning process. This work describes a single institution experience of commissioning an Elekta Unity MR-linac, including mechanical testing, MRI scanner commissioning, and dosimetric validation. Mechanical testing included multileaf collimator (MLC) positional accuracy, measurement of radiation isocenter diameter, and MR-to-MV coincidence. Key MRI tests included magnetic field homogeneity, geometric accuracy, image quality, and the accuracy of navigator-triggered imaging for motion management. Dosimetric validation consisted of comparison between measured and calculated PDDs and profiles, IMRT measurements, and end-to-end testing. Multileaf collimator positional accuracy was within 1.0 mm, the measured radiation isocenter walkout was 0.20 mm, and the coincidence between MR and MV isocenter was 1.06 mm, which is accounted for in the treatment planning system (TPS). For a 350-mm-diameter spherical volume, the peak-to-peak deviation of the magnetic field homogeneity was 4.44 ppm and the geometric distortion was 0.8 mm. All image quality metrics were within ACR recommendations. Navigator-triggered images showed a maximum deviation of 0.42, 0.75, and 3.0 mm in the target centroid location compared to the stationary target for a 20 mm motion at 10, 15, and 20 breaths per minute, respectively. TPS-calculated PDDs and profiles showed excellent agreement with measurement. The gamma passing rate for IMRT plans was 98.4 ± 1.1% (3%/ 2 mm) and end-to-end testing of adapted plans showed agreement within 0.4% between ion-chamber measurement and TPS calculation. All credentialing criteria were satisfied in an independent end-to-end test using an IROC MRgRT phantom.

Commissioning and performance evaluation of RadCalc for the Elekta unity MRI-linac.

Recent availability of MRI-guided linear accelerators has introduced a number of clinical challenges, particularly in the context of online plan adaptation. Paramount among these is verification of plan quality prior to patient treatment. Currently, there are no commercial products available for monitor unit verification that fully support the newly FDA cleared Elekta Unity 1.5 T MRI-linac. In this work, we investigate the accuracy and precision of RadCalc for this purpose, which is a software package that uses a Clarkson integration algorithm for point dose calculation. To this end, 18 IMRT patient plans (186 individual beams) were created and used for RadCalc point dose calculations. In comparison with the primary treatment planning system (Monaco), mean point dose deviations of 0.0 ± 1.0% (n = 18) and 1.7 ± 12.4% (n = 186) were obtained on a per-plan and per-beam basis, respectively. The dose plane comparison functionality within RadCalc was found to be highly inaccurate, however, modest improvements could be made by artificially shifting jaws and multi leaf collimator positions to account for the dosimetric shift due to the magnetic field (67.3% vs 96.5% mean 5%/5 mm gamma pass rate).

The commissioning and validation of Monaco treatment planning system on an Elekta VersaHD linear accelerator.

Accurate beam modeling is essential to help ensure overall accuracy in the radiotherapy process. This study describes our experience with beam model validation of a Monaco treatment planning system on a Versa HD linear accelerator. Data were collected such that Monaco beam models could be generated using three algorithms: collapsed cone (CC) and photon Monte Carlo (MC) for photon beams, and electron Monte Carlo (eMC) for electron beams. Validations are performed on measured percent depth doses (PDDs) and profiles, for open-field point-doses in homogenous and heterogeneous media, and for obliquely incident electron beams. Gamma analysis is used to assess the agreement between calculation and measurement for intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans, including volumetric modulated arc therapy for stereotactic body radiation therapy (VMAT SBRT). For all relevant conditions, gamma index values below 1 are obtained when comparing Monaco calculated PDDs and profiles with measured data. Point-doses in a water medium are found to be within 2% agreement of commissioning data in 99.5% and 98.6% of the points computed by MC and CC, respectively. All point-dose calculations for the eMC algorithm in water are within 4% agreement of measurement, and 92% of measurements are within 3%. In heterogeneous media of air and cortical bone, both CC and MC yielded better than 3% agreement with ion chamber measurements. eMC yielded 3% agreement to measurement downstream of air with oblique beams of up to 27°, 5% agreement distal to bone, and within 4% agreement at extended source to surface distance (SSD) for all electron energies except 6 MeV. The 6-MeV point of measurement is on a steep dose gradient which may impact the magnitude of discrepancy measured. The average gamma passing rate for IMRT/VMAT plans is 96.9% (±2.1%) and 98.0% (±1.9%) for VMAT SBRT when evaluated using 3%/2 mm criteria. Monaco beam models for the Versa HD linac were successfully commissioned for clinical use.

Is SBRT Boost Feasible for PET Positive Lymph Nodes for Cervical Cancer? Evaluation using Tumor Control Probability and QUANTEC Criteria.

PURPOSE: This study aimed to examine the feasibility of stereotactic body radiation therapy (SBRT) as an external beam radiation therapy boost to positron emission tomography (PET) positive lymph nodes (LN) in patients with cervical cancer and to evaluate overall tumor control probability (TCP) increase. METHODS AND MATERIALS: Ten patients with cervical cancer and PET positive LN metastasis who received external beam radiation therapy (45 Gy), followed by a 3-dimensional conformal radiation therapy boost (5.4-9 Gy) and tandem-and-ovoid high-dose-rate brachytherapy (16-30 Gy) were retrospectively enrolled in this study. SBRT plans were generated using 21 Gy, 24 Gy, or 30 Gy as a replacement for 3-dimensional conformal radiation therapy boost. The 2 Gy-per-fraction equivalent dose maps were made using an α/ß value of 10 for PET positive LNs and 3 for organs at risk (OARs). TCP values were calculated using a logistic TCP model, where 2 input parameters (D50 and Gamma50 = 2) were modeled by 2 clinical outcomes: our institution and the literature. OAR sparing was evaluated using Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) dose limits. RESULTS: Thirty percent of 10 patients receiving conventional boost experienced recurrence. The TCP of the SBRT schemes was 88% ± 7% (97% ± 2%; 21 Gy), 96% ± 1% (99% ± 0%; 24 Gy), and 99% ± 1% (100% ± 0%; 30 Gy), and the conventional LN-boost TCP value was 25% ± 11% (58% ± 15%) when TCP input parameters were based on published clinical outcome data for LN SBRT treatments (institutional outcome data). The tumor coverage doses (D90) of the SBRT boost plans were on average 32.34 Gyαß=10 (21 Gy), 37.78 Gyαß=10 (24 Gy), and 55.54Gyαß=10 (30 Gy) higher than the conventional LN boost plan. The QUANTEC OAR dose constraints were met for the bladder, rectum, and bowel in all cases for the SBRT LN 21 Gy group, and in 90% and 70% of cases in the SBRT LN 24 Gy and SBRT LN 30 Gy groups, respectively. CONCLUSIONS: An SBRT boost dose of 30 Gy can be delivered without compromising QUANTEC OAR limits. The use of SBRT increases TCP values, regardless of the input parameters.

Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement.

PURPOSE: These studies were undertaken to determine if fexapotide triflutate 2.5 mg transrectal injectable (FT) has significant long-term (LT) safety and efficacy for the treatment of benign prostatic hyperplasia (BPH). METHODS: Two placebo controlled double-blind randomized parallel group trials with 995 BPH patients at 72 sites treated 3:2 FT:placebo, with open-label FT crossover (CO) re-injection in 2 trials n = 344 and long-term follow-up (LF) 2-6.75 years (mean 3.58 years, median 3.67 years; FT re-injection CO mean 4.27 years, median 4.42 years) were evaluated. 12 months post-treatment patients elected no further treatment, approved oral medications, FT, or interventional treatment. Primary endpoint variable was change in Symptom Score (IPSS) at 12 months and at LF. CO primary co-endpoints were 3-year incidence of (1) surgery for BPH in FT treated CO patients versus patients crossed over to oral BPH medications and (2) surgery or acute urinary retention in FT-treated CO placebo patients versus placebo patients crossed over to oral BPH medications. 28 CO secondary endpoints assessed surgical and symptomatic outcomes in FT reinjected patients versus conventional BPH medication CO and control subgroups at 2 and 3 years. RESULTS: FT injection had no significant safety differences from placebo. LF IPSS change from baseline was higher in FT treated patients compared to placebo (median FT group improvement - 5.2 versus placebo - 3.0, p < 0.0001). LF incidence of AUR (1.08% p = 0.0058) and prostate cancer (PCa) (1.1% p = 0.0116) were both reduced in FT treated patients. LF incidence of intervention for BPH was reduced in the FT group versus oral BPH medications (8.08% versus 27.85% at 3 years, p < 0.0001). LF incidence of intervention or AUR in placebo CO group with FT versus placebo CO group with oral medications was reduced (6.07% versus 33.3% at 3 years, p < 0.0001). 28/28 secondary efficacy endpoints were reached in LF CO re-injection studies. CONCLUSIONS: FT 2.5 mg is a safe and effective transrectal injectable for LT treatment of BPH. FT treated patients also had reduced need for BPH intervention, and reduced incidence of PCa and AUR.

Three-month primary efficacy data for the SUCCESS Trial; a phase III, multi-center, prospective, randomized, controlled study treating female stress urinary incontinence with the vesair intravesical balloon.

AIMS: The SUCCESS trial is a phase III study of the Vesair® balloon in the United States for female stress urinary incontinence (SUI). The purpose of this manuscript is to present the 3 month primary efficacy and tolerability outcome data. METHODS: The SUCCESS trial is a multi-center, prospective, single blind, randomized, sham-controlled study. Subjects were randomized on a 2.33:1 basis to either Vesair balloon placement or placebo. The primary efficacy endpoint was a composite of both a >50% reduction from baseline on 1 h provocative pad weight test and a ≥10-point improvement in symptoms on the Incontinence Quality of Life Survey (I-QOL) questionnaire assessed at the 3 month study visit. RESULTS: A total of 221 subjects were randomized, including 157 treatment arm subjects and 64 controls. The 3 month composite primary efficacy endpoint was achieved in 42.1% of treatment group subjects compared with 28.1% of controls on intention-to-treat analysis (p = 0.046). Treatment arm subjects were significantly more likely to report at least a 50% reduction in incontinence frequency on 7-day voiding diary (55.2% vs 32.3%, P = 0.002, ITT) and more commonly reported their incontinence was improved on Patient Global Impression of Improvement in Incontinence (PGI-I) at 3 months compared with controls (58.0% vs 37.7%, P = 0.007, ITT). No device- or procedure-related serious adverse events nor unanticipated adverse events were reported and no cases of urinary retention were observed. All adverse events fully resolved following balloon removal. CONCLUSIONS: In this phase three trial, the Vesair intravesical balloon achieved 3 month primary and secondary endpoints both objectively and subjectively.

Twelve-Month Efficacy and Safety Data for the "Stress Incontinence Control, Efficacy and Safety Study": A Phase III, Multicenter, Prospective, Randomized, Controlled Study Treating Female Stress Urinary Incontinence Using the Vesair Intravesical Balloon.

OBJECTIVES: The "Stress Incontinence Control, Efficacy and Safety Study" (SUCCESS) is a phase III study of the Vesair Balloon in women with stress urinary incontinence who had failed conservative therapy, and either failed surgery, were not candidates for surgery, or chose not to have surgery. The safety and efficacy of the balloon at 12 months is reported for those participants in the treatment arm who elected to continue with the SUCCESS trial beyond the primary end point at 3 months. METHODS: The SUCCESS trial is a multicenter, prospective, single-blinded, randomized, sham-controlled study. Participants were randomized on a 2.33:1 basis to either Vesair Balloon placement or placebo. The primary efficacy end point was a composite of both a greater than 50% reduction from baseline on 1-hour provocative pad weight test and an at least 10-point improvement in symptoms on the Incontinence Quality of Life questionnaire assessed at the 3-month study visit. Patients in the treatment arm who opted to continue in the trial were followed up prospectively up to 12 months. RESULTS: A total of 221 participants were randomized, including 157 in the treatment arm and 64 in the control arm. Sixty-seven participants in the treatment arm (42.7% of participants enrolled) were evaluated at 12 months, with 56.3% achieving the composite end point and 78.7% having greater than 50% reduction in pad weight from baseline in a per-protocol analysis. In an intent-to-treat analysis treating all participants who did not continue with the balloon as failures, 24% of the participants achieved the composite end point and 33.6% had a greater than 50% reduction in pad weight from baseline. Treatment-related adverse events in this group included dysuria (40.1%), gross hematuria (36.9%), and urinary tract infection (26.1%). CONCLUSIONS: In this phase III trial, symptom relief was maintained for those participants who continued therapy for 12 months. The balloon was found to be safe with no device- or procedure-related serious adverse events reported. Additional studies are warranted to determine which patient populations are more tolerant of the balloon and to assess the efficacy and safety of its longer-term use. Additional screening methods, including screening patients for balloon tolerability, are warranted to reduce participant withdrawals.

Implementation of respiratory-gated VMAT on a Versa HD linear accelerator.

The accurate delivery of respiratory-gated volumetric modulated arc therapy (VMAT) treatment plans presents a challenge since the gantry rotation and collimator leaves must be repeatedly stopped and set into motion during each breathing cycle. In this study, we present the commissioning process for an Anzai gating system (AZ-733VI) on an Elekta Versa HD linear accelerator and make recommendations for successful clinical implementation. The commissioning tests include central axis dose consistency, profile consistency, gating beam-on/off delay, and comparison of gated versus nongated gamma pass rates for patient-specific quality assurance using four clinically commissioned photon energies: 6 MV, 6 FFF, 10 MV, and 10 FFF. The central axis dose constancy between gated and nongated deliveries was within 0.6% for all energies and the analysis of open field profiles for gated and nongated deliveries showed an agreement of 97.8% or greater when evaluated with a percent difference criteria of 1%. The measurement of the beam-on/off delay was done by evaluating images of a moving ball-bearing phantom triggered by the gating system and average beam-on delays of 0.22-0.29 s were observed. No measurable beam-off delay was present. Measurements of gated VMAT dose distributions resulted in decrements as high as 9% in the gamma passing rate as compared to nongated deliveries when evaluated against the planned dose distribution at 3%/3 mm. By decreasing the dose rate, which decreases the gantry speed during gated delivery, the gamma passing rates of gated and nongated treatments can be made equivalent. We present an empirically derived formula to limit the maximum dose rate during VMAT deliveries and show that by implementing a reduced dose rate, a gamma passing rate of greater than 95% (3%/3 mm) was obtained for all plan measurements.

Compromise and Synergy in High-Efficiency Thermoelectric Materials.

The past two decades have witnessed the rapid growth of thermoelectric (TE) research. Novel concepts and paradigms are described here that have emerged, targeting superior TE materials and higher TE performance. These superior aspects include band convergence, "phonon-glass electron-crystal", multiscale phonon scattering, resonant states, anharmonicity, etc. Based on these concepts, some new TE materials with distinct features have been identified, including solids with high band degeneracy, with cages in which atoms rattle, with nanostructures at various length scales, etc. In addition, the performance of classical materials has been improved remarkably. However, the figure of merit zT of most TE materials is still lower than 2.0, generally around 1.0, due to interrelated TE properties. In order to realize an "overall zT > 2.0," it is imperative that the interrelated properties are decoupled more thoroughly, or new degrees of freedom are added to the overall optimization problem. The electrical and thermal transport must be synergistically optimized. Here, a detailed discussion about the commonly adopted strategies to optimize individual TE properties is presented. Then, four main compromises between the TE properties are elaborated from the point of view of the underlying mechanisms and decoupling strategies. Finally, some representative systems of synergistic optimization are also presented, which can serve as references for other TE materials. In conclusion, some of the newest ideas for the future are discussed.

Plasma Fibrinogen Qualification as a Drug Development Tool in Chronic Obstructive Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease Biomarker Qualification Consortium.

The COPD Foundation Biomarker Qualification Consortium (CBQC) is a unique public-private partnership established in 2010 between the COPD Foundation, the pharmaceutical industry, and academic chronic obstructive pulmonary disease (COPD) experts with advisors from the U.S. NHLBI and the Food and Drug Administration (FDA). This was a direct response to the 2009 publication of a guidance on qualification of drug development tools by the FDA. Although data were believed to be available from publicly funded and industry-funded studies that could support qualification of several tools, the necessary data resided in disparate databases. The initial intent of the CBQC was to integrate these data and submit a dossier for the qualification. This led to the FDA qualification of plasma fibrinogen as a prognostic or enrichment biomarker for all-cause mortality and COPD exacerbations in July 2015. It is the first biomarker drug development tool qualified for use in COPD under the FDA's drug development tool qualification program. This perspective summarizes the FDA's qualification process, the formation of the CBQC, and the effort that led to a successful outcome for plasma fibrinogen and discusses implications for future biomarker qualification efforts.

Plasma Fibrinogen as a Biomarker for Mortality and Hospitalized Exacerbations in People with COPD.

BACKGROUND: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly-funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials. METHODS: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine high vs. low fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models. RESULTS: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants. CONCLUSIONS: Fibrinogen levels ≥ 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population.