The Efficacy of Metformin as a Therapeutic Agent in the Treatment of Acne Vulgaris: A Systematic Review.

A large portion of the world's population is affected by acne vulgaris (AV), with many of these individuals being adolescents. The underlying mechanism of AV is hyperkeratinization and Cutibacterium acnes infection of the pilosebaceous follicle secondary to excessive stimulation of sebaceous glands by androgens. Metformin is a biguanide medication primarily used in efforts to lower patients' sugar levels in the management of type 2 diabetes. It has been proven to reduce levels of circulating androgens in patients with insulin resistance, indicating its potential for treating AV. A search strategy was developed and performed using the databases Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Controlled Register of Trials (CENTRAL), and Web of Science. The keywords "metformin" and "acne" were searched, along with related Medical Subject Headings (MeSH) and other subject headings. Studies that met the inclusion criteria were controlled trials, published after 2010, and in the English language. Participants with and without comorbidities such as polycystic ovary syndrome (PCOS) were considered. Two independent reviewers screened studies based on predefined criteria and extracted data from each study, which were quantitatively combined. A total of 15 studies were included in this systematic review. Across the 15 studies, there were 1,046 participants, with 13 studies looking exclusively at women with PCOS. Of the remaining two studies, one examined males with altered metabolic profiles, while the other included men and women with moderate AV. Notable risks of bias included studies that did not exclusively state the blindness of the study. Of the studies that were examined, 13 showed that metformin reduces AV, with seven studies showing statistical significance. Acne vulgaris is an inflammatory condition that has plagued patients for years due to the limited treatment options available. The hyperglycemic medication metformin, used in the management of type 2 diabetes, is being explored as a novel therapeutic that can possibly be repurposed for the treatment of AV. The use of metformin in AV is hypothesized to disrupt the proposed linkage between insulin resistance and AV proliferation. This proposed research could offer physicians a new option for the treatment of AV as well as render an alternative AV treatment for patients.

A re-activation model for 169Yb intensity modulated brachytherapy sources accounting for spatiotemporal isotopic composition.

BACKGROUND: Intensity modulated brachytherapy based on partially shielded intracavitary and interstitial applicators is possible with a cost-effective 169Yb production method. 169Yb is a traditionally expensive isotope suitable for this purpose, with an average γ-ray energy of 93 keV. Re-activating a single 169Yb source multiple times in a nuclear reactor between clinical uses was shown to theoretically reduce cost by approximately 75% relative to conventional single-activation sources. With re-activation, substantial spatiotemporal variation in isotopic source composition is expected between activations via 168Yb burnup and 169Yb decay, resulting in time dependent neutron transmission, precursor usage, and reactor time needed per re-activation. PURPOSE: To introduce a generalized model of radioactive source production that accounts for spatiotemporal variation in isotopic source composition to improve the efficiency estimate of the 169Yb production process, with and without re-activation. METHODS AND MATERIALS: A time-dependent thermal neutron transport, isotope transmutation, and decay model was developed. Thermal neutron flux within partitioned sub-volumes of a cylindrical active source was calculated by raytracing through the spatiotemporal dependent isotopic composition throughout the source, accounting for thermal neutron attenuation along each ray. The model was benchmarked, generalized, and applied to a variety of active source dimensions with radii ranging from 0.4 to 1.0 mm, lengths from 2.5 to 10.5 mm, and volumes from 0.31 to 7.85 mm3, at thermal neutron fluxes from 1 × 1014 to 1 × 1015 n cm-2 s-1. The 168Yb-Yb2O3 density was 8.5 g cm-3 with 82% 168Yb-enrichment. As an example, a reference re-activatable 169Yb active source (RRS) constructed of 82%-enriched 168Yb-Yb2O3 precursor was modeled, with 0.6 mm diameter, 10.5 mm length, 3 mm3 volume, 8.5 g cm-3 density, and a thermal neutron activation flux of 4 × 1014 neutrons cm-2 s-1. RESULTS: The average clinical 169Yb activity for a 0.99 versus 0.31 mm3 source dropped from 20.1 to 7.5 Ci for a 4 × 1014 n cm-2 s-1 activation flux and from 20.9 to 8.7 Ci for a 1 × 1015 n cm-2 s-1 activation flux. For thermal neutron fluxes ≥2 × 1014 n cm-2 s-1, total precursor and reactor time per clinic-year were maximized at a source volume of 0.99 mm3 and reached a near minimum at 3 mm3. When the spatiotemporal isotopic composition effect was accounted for, average thermal neutron transmission increased over RRS lifetime from 23.6% to 55.9%. A 28% reduction (42.5 days to 30.6 days) in the reactor time needed per clinic-year for the RRS is predicted relative to a model that does not account for spatiotemporal isotopic composition effects. CONCLUSIONS: Accounting for spatiotemporal isotopic composition effects within the RRS results in a 28% reduction in the reactor time per clinic-year relative to the case in which such changes are not accounted for. Smaller volume sources had a disadvantage in that average clinical 169Yb activity decreased substantially below 20 Ci for source volumes under 1 mm3. Increasing source volume above 3 mm3 adds little value in precursor and reactor time savings and has a geometric disadvantage.

Disease-Modifying Treatments and Their Future in Alzheimer's Disease Management.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment, a loss of cholinergic neurons, and cognitive decline that insidiously progresses to dementia. The pathoetiology of AD is complex, as genetic predisposition, age, inflammation, oxidative stress, and dysregulated proteostasis all contribute to its development and progression. The histological hallmarks of AD are the formation and accumulation of amyloid-ß plaques and interfibrillar tau tangles within the central nervous system. These histological hallmarks trigger neuroinflammation and disrupt the physiological structure and functioning of neurons, leading to cognitive dysfunction. Most treatments currently available for AD focus only on symptomatic relief. Disease-modifying treatments (DMTs) that target the biology of the disease in hopes of slowing or reversing disease progression are desperately needed. This narrative review investigates novel DMTs and their therapeutic targets that are either in phase three of development or have been recently approved by the U.S. Food and Drug Administration (FDA). The target areas of some of these novel DMTs consist of combatting amyloid or tau accumulation, oxidative stress, neuroinflammation, and dysregulated proteostasis, metabolism, or circadian rhythm. Neuroprotection and neuroplasticity promotion were also key target areas. DMT therapeutic target diversity may permit improved therapeutic responses in certain subpopulations of AD, particularly if the therapeutic target of the DMT being administered aligns with the subpopulation's most prominent pathological findings. Clinicians should be cognizant of how these novel drugs differ in therapeutic targets, as this knowledge may potentially enhance the level of care they can provide to AD patients in the future.

Technical note: A simple method for patient-specific quality assurance for lateral targets on a 1.5 T MR-Linac.

The Elekta Unity magnetic resonance (MR) linac is limited to longitudinal couch motion and a sagittal-only laser, which restricts the ability to perform patient-specific quality assurance (PSQA) intensity-modulated radiotherapy (IMRT) measurements for very lateral targets. This work introduces a simple method to perform PSQA using the Sun Nuclear ArcCheck-MR phantom at left and right lateral positions without additional equipment or in-house construction. The proposed setup places the center of the phantom 1.3 cm vertical and 12.9 cm lateral to isocenter in either the left or right direction. Computed tomography (CT) scans are used to simulate the setup and create a QA plan template in the Monaco treatment planning system (TPS). The workflow is demonstrated for four patients, with an average axial distance from the center of the bore to the planning target volume (PTV) of 12.4 cm. Gamma pass rates were above 94% for all plans using global 3%/2 mm gamma criterion with a 10% threshold. Setup uncertainties are slightly larger for the proposed lateral setup compared to the centered setup on the Elekta platform (∼1 mm compared to ∼0.5 mm), but acceptable pass rates are achievable without optimizing shifts in the gamma analysis software. In general, adding the left and right lateral positions increases the axial area in the bore encompassed by the cylindrical measurement array by 147%, substantially increasing the flexibility of measurements for offset targets. Based on this work, we propose using the lateral QA setup if the closest distance to the PTV edge from isocenter is larger than the array radius (10.5 cm) or the percent of the PTV encompassed by the diode array would be increased with the lateral setup compared to the centered setup.

A biomaterial platform for T cell-specific gene delivery.

Efficient T cell engineering is central to the success of CAR T cell therapy but involves multiple time-consuming manipulations, including T cell isolation, activation, and transduction. These steps add complexity and delay CAR T cell manufacturing, which takes a mean time of 4 weeks. To streamline T cell engineering, we strategically combine two critical engineering solutions - T cell-specific lentiviral vectors and macroporous scaffolds - that enable T cell activation and transduction in a simple, single step. The T cell-specific lentiviral vectors (referred to as STAT virus) target T cells through the display of an anti-CD3 antibody and the CD80 extracellular domain on their surface and provide robust T cell activation. Biocompatible macroporous scaffolds (referred to as Drydux) mediate robust transduction by providing effective interaction between naïve T cells and viral vectors. We show that when unstimulated peripheral blood mononuclear cells (PBMCs) are seeded together with STAT lentivirus on Drydux scaffolds, T cells are activated, selectively transduced, and reprogrammed in a single step. Further, we show that the Drydux platform seeded with PBMCs and STAT lentivirus generates tumor-specific functional CAR T cells. This potent combination of engineered lentivirus and biomaterial scaffold holds promise for an effective, simple, and safe avenue for in vitro and in vivo T cell engineering. STATEMENT OF SIGNIFICANCE: Manufacturing T cell therapies involves lengthy and labor-intensive steps, including T cell selection, activation, and transduction. These steps add complexity to current CAR T cell manufacturing protocols and limit widespread patient access to this revolutionary therapy. In this work, we demonstrate the combination of engineered virus and biomaterial platform that, together, enables selective T cell activation and transduction in a single step, eliminating multistep T cell engineering protocols and significantly simplifying the manufacturing process.

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.

Re-centauring T cell antigen discovery around CD4+ T cells.

In a recent issue of Cell, Dezfulian et al. develop a genome-scale platform to enable high-throughput identification of CD4+ T cell epitopes. This platform enables unbiased screens to discover antigens recognized by CD4+ T cells in cancer, infectious diseases, and autoimmunity.

Integration and dosimetric validation of a dynamic collimation system for pencil beam scanning proton therapy.

Objective.To integrate a Dynamic Collimation System (DCS) into a pencil beam scanning (PBS) proton therapy system and validate its dosimetric impact.Approach.Uncollimated and collimated treatment fields were developed for clinically relevant targets using an in-house treatment plan optimizer and an experimentally validated Monte Carlo model of the DCS and IBA dedicated nozzle (DN) system. The dose reduction induced by the DCS was quantified by calculating the mean dose in 10- and 30-mm two-dimensional rinds surrounding the target. A select number of plans were then used to experimentally validate the mechanical integration of the DCS and beam scanning controller system through measurements with the MatriXX-PT ionization chamber array and EBT3 film. Absolute doses were verified at the central axis at various depths using the IBA MatriXX-PT and PPC05 ionization chamber.Main results.Simulations demonstrated a maximum mean dose reduction of 12% for the 10 mm rind region and 45% for the 30 mm rind region when utilizing the DCS. Excellent agreement was observed between Monte Carlo simulations, EBT3 film, and MatriXX-PT measurements, with gamma pass rates exceeding 94.9% for all tested plans at the 3%/2 mm criterion. Absolute central axis doses showed an average verification difference of 1.4% between Monte Carlo and MatriXX-PT/PPC05 measurements.Significance.We have successfully dosimetrically validated the delivery of dynamically collimated proton therapy for clinically relevant delivery patterns and dose distributions with the DCS. Monte Carlo simulations were employed to assess dose reductions and treatment planning considerations associated with the DCS.

The Role of Testosterone Therapy in Men's Health.

Over the last 3 decades, there has been an increased interest in testosterone replacement therapy. This trend is a result of an aging population, endocrine disruptors in our foods and environment and rising obesity rates. In addition, there has been a surge in Men's Health clinics and online direct-to-consumer Web sites, making testosterone replacement therapy much more readily accessible. As more men seek to increase their testosterone levels, more long-term random control studies are needed to gain better insight into testosterone optimization to support the anecdotal observation commonly experienced in the practice setting.

Testicular Cancer: The Unmet Needs of a Younger Generation of Cancer Survivors.

Unmet holistic needs of various cancer populations, with examples including prostate, bladder, gynecologic, kidney, penile, breast, and colorectal, along with holistic impacts of cancer on older adults, have been defined by a growing number of systematic reviews. Unfortunately, there continues to be a lack of clinical insight into the unique needs of younger men with testicular cancer. Survival rate based on low mortality rates and good prognosis if early detection and treatment implementation grows the number of men who need support as long-term survivors with an average life expectancy of approximately 30 to 50 years after treatment. Providers and clinicians need to approach testicular cancer survivors with the tools and strategies that meet these unmet needs for navigation from diagnosis through survivorship. When strategies of specific resources and education are implemented based on the unique needs of these individuals, positive outcomes and increased health care-related quality of life will be prevalent.

PETRA: A pencil beam trimming algorithm for analytical proton therapy dose calculations with the dynamic collimation system.

BACKGROUND: The Dynamic Collimation System (DCS) has been shown to produce superior treatment plans to uncollimated pencil beam scanning (PBS) proton therapy using an in-house treatment planning system (TPS) designed for research. Clinical implementation of the DCS requires the development and benchmarking of a rigorous dose calculation algorithm that accounts for pencil beam trimming, performs monitor unit calculations to produce deliverable plans at all beam energies, and is ideally implemented with a commercially available TPS. PURPOSE: To present an analytical Pencil bEam TRimming Algorithm (PETRA) for the DCS, with and without its range shifter, implemented in the Astroid TPS (.decimal, Sanford, Florida, USA). MATERIALS: PETRA was derived by generalizing an existing pencil beam dose calculation model to account for the DCS-specific effects of lateral penumbra blurring due to the nickel trimmers in two different planes, integral depth dose variation due to the trimming process, and the presence and absence of the range shifter. Tuning parameters were introduced to enable agreement between PETRA and a measurement-validated Dynamic Collimation Monte Carlo (DCMC) model of the Miami Cancer Institute's IBA Proteus Plus system equipped with the DCS. Trimmer position, spot position, beam energy, and the presence or absence of a range shifter were all used as variables for the characterization of the model. The model was calibrated for pencil beam monitor unit calculations using procedures specified by International Atomic Energy Agency Technical Report Series 398 (IAEA TRS-398). RESULTS: The integral depth dose curves (IDDs) for energies between 70 MeV and 160 MeV among all simulated trimmer combinations, with and without the ranger shifter, agreed between PETRA and DCMC at the 1%/1 mm 1-D gamma criteria for 99.99% of points. For lateral dose profiles, the median 2-D gamma pass rate for all profiles at 1.5%/1.5 mm was 99.99% at the water phantom surface, plateau, and Bragg peak depths without the range shifter and at the surface and Bragg peak depths with the range shifter. The minimum 1.5%/1.5 mm gamma pass rates for the 2-D profiles at the water phantom surface without and with the range shifter were 98.02% and 97.91%, respectively, and, at the Bragg peak, the minimum pass rates were 97.80% and 97.5%, respectively. CONCLUSION: The PETRA model for DCS dose calculations was successfully defined and benchmarked for use in a commercially available TPS.

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.

Dosimetric delivery validation of dynamically collimated pencil beam scanning proton therapy.

Objective. Pencil beam scanning (PBS) proton therapy target dose conformity can be improved with energy layer-specific collimation. One such collimator is the dynamic collimation system (DCS), which consists of four nickel trimmer blades that intercept the scanning beam as it approaches the lateral extent of the target. While the dosimetric benefits of the DCS have been demonstrated through computational treatment planning studies, there has yet to be experimental verification of these benefits for composite multi-energy layer fields. The objective of this work is to dosimetrically characterize and experimentally validate the delivery of dynamically collimated proton therapy with the DCS equipped to a clinical PBS system.Approach. Optimized single field, uniform dose treatment plans for 3 × 3 × 3 cm3target volumes were generated using Monte Carlo dose calculations with depths ranging from 5 to 15 cm, trimmer-to-surface distances ranging from 5 to 18.15 cm, with and without a 4 cm thick polyethylene range shifter. Treatment plans were then delivered to a water phantom using a prototype DCS and an IBA dedicated nozzle system and measured with a Zebra multilayer ionization chamber, a MatriXX PT ionization chamber array, and Gafchromic™ EBT3 film.Main results. For measurements made within the SOBPs, average 2D gamma pass rates exceeded 98.5% for the MatriXX PT and 96.5% for film at the 2%/2 mm criterion across all measured uncollimated and collimated plans, respectively. For verification of the penumbra width reduction with collimation, film agreed with Monte Carlo with differences within 0.3 mm on average compared to 0.9 mm for the MatriXX PT.Significance. We have experimentally verified the delivery of DCS-collimated fields using a clinical PBS system and commonly available dosimeters and have also identified potential weaknesses for dosimeters subject to steep dose gradients.

An exploration of financial toxicity among low-income patients with cancer in Central Texas: A mixed methods analysis.

OBJECTIVE: Financial toxicity is of increasing concern in the United States. The Comprehensive Score for Financial Toxicity (COST) is a validated measure; however, it has not been widely utilized among low-income patients and may not fully capture financial toxicity in this population. Furthermore, the relationships between financial toxicity, quality of life (QOL), and patient well-being are poorly understood. We describe the experience of financial toxicity among low-income adults receiving cancer care. We hypothesized that higher financial toxicity would be associated with less income and lower quality of life. Qualitative interviews focused on the financial impact of cancer treatment. METHOD: This study was conducted at a cancer clinic in Central Texas. Quantitative and qualitative data were collected in Fall and Spring 2018, respectively. The quantitative sample (N = 115) was dichotomized by annual income (<$15,000 vs. >$15,000). Outcomes included financial toxicity (COST), quality of life (FACT-G), and patient well-being (PROMIS measures: Anxiety, Depression, Fatigue, Pain Interference, and Physical Function). Associations between quality of life, patient well-being, and financial toxicity were evaluated using linear regression. Sequential qualitative interviews were conducted with a subsample of 12 participants. RESULTS: Patients with <$15k had significantly lower levels of QOL and patient well-being such as depression and anxiety compared to patients with >$15k across multiple measures. A multivariate linear regression found QOL (Β = 0.17, 95% CI = 0.05, 0.29, p = 0.008) and insurance status (Β = -3.79, 95% CI = -7.42, -0.16, p = 0.04), but not income, were significantly associated with financial toxicity. Three qualitative themes regarding patient's access to cancer care were identified: obtaining healthcare coverage, maintaining financial stability, and receiving social support. SIGNIFICANCE OF RESULTS: Low-income patients with cancer face unique access barriers and are at risk for forgoing treatment or increased symptom burdens. Comprehensive assessment and financial navigation may improve access to care, symptom management, and reduce strain on social support systems.

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.

A novel optimization algorithm for enabling dynamically collimated proton arc therapy.

The advent of energy-specific collimation in pencil beam scanning (PBS) proton therapy has led to an improved lateral dose conformity for a variety of treatment sites, resulting in better healthy tissue sparing. Arc PBS delivery has also been proposed to enhance high-dose conformity about the intended target, reduce skin toxicity, and improve plan robustness. The goal of this work was to determine if the combination of proton arc and energy-specific collimation can generate better dose distributions as a logical next step to maximize the dosimetric advantages of proton therapy. Plans were optimized using a novel DyNamically collimated proton Arc (DNA) genetic optimization algorithm that was designed specifically for the application of proton arc therapy. A treatment planning comparison study was performed by generating an uncollimated two-field intensity modulated proton therapy and partial arc treatments and then replanning these treatments using energy-specific collimation as delivered by a dynamic collimation system, which is a novel collimation technology for PBS. As such, we refer to this novel treatment paradigm as Dynamically Collimated Proton Arc Therapy (DC-PAT). Arc deliveries achieved a superior target conformity and improved organ at risk (OAR) sparing relative to their two-field counterparts at the cost of an increase to the low-dose, high-volume region of the healthy brain. The incorporation of DC-PAT using the DNA optimizer was shown to further improve the tumor dose conformity. When compared to the uncollimated proton arc treatments, the mean dose to the 10mm of surrounding healthy tissue was reduced by 11.4% with the addition of collimation without meaningfully affecting the maximum skin dose (less than 1% change) relative to a multi-field treatment. In this case study, DC-PAT could better spare specific OARs while maintaining better target coverage compared to uncollimated proton arc treatments. While this work presents a proof-of-concept integration of two emerging technologies, the results are promising and suggest that the addition of these two techniques can lead to superior treatment plans warranting further development.

Antigen identification and high-throughput interaction mapping by reprogramming viral entry.

Deciphering immune recognition is critical for understanding a broad range of diseases and for the development of effective vaccines and immunotherapies. Efforts to do so are limited by a lack of technologies capable of simultaneously capturing the complexity of adaptive immunoreceptor repertoires and the landscape of potential antigens. To address this, we present receptor-antigen pairing by targeted retroviruses, which combines viral pseudotyping and molecular engineering approaches to enable one-pot library-on-library interaction screens by displaying antigens on the surface of lentiviruses and encoding their identity in the viral genome. Antigen-specific viral infection of cell lines expressing human T or B cell receptors allows readout of both antigen and receptor identities via single-cell sequencing. The resulting system is modular, scalable and compatible with any cell type. These techniques provide a suite of tools for targeted viral entry, molecular engineering and interaction screens with broad potential applications.

Mechanical Characterization and Validation of the Dynamic Collimation System Prototype for Proton Radiotherapy.

Radiation therapy is integral to cancer treatments for more than half of patients. Pencil beam scanning (PBS) proton therapy is the latest radiation therapy technology that uses a beam of protons that are magnetically steered and delivered to the tumor. One of the limiting factors of PBS accuracy is the beam cross-sectional size, similar to how a painter is only as accurate as the size of their brush allows. To address this, collimators can be used to shape the beam along the tumor edge to minimize the dose spread outside of the tumor. Under development is a dynamic collimation system (DCS) that uses two pairs of nickel trimmers that collimate the beam at the tumor periphery, limiting dose from spilling into healthy tissue. Herein, we establish the dosimetric and mechanical acceptance criteria for the DCS based on a functioning prototype and Monte Carlo methods, characterize the mechanical accuracy of the prototype, and validate that the acceptance criteria are met. From Monte Carlo simulations, we found that the trimmers must be positioned within ±0.5 mm and ±1.0 deg for the dose distributions to pass our gamma analysis. We characterized the trimmer positioners at jerk values up to 400 m/s3 and validated their accuracy to 50 µm. We measured and validated the rotational trimmer accuracy to ±0.5 deg with a FARO® ScanArm. Lastly, we calculated time penalties associated with the DCS and found that the additional time required to treat one field using the DCS varied from 25-52 s.

The dosimetric enhancement of GRID profiles using an external collimator in pencil beam scanning proton therapy.

PURPOSE: The radiobiological benefits afforded by spatially fractionated (GRID) radiation therapy pairs well with the dosimetric advantages of proton therapy. Inspired by the emergence of energy-layer specific collimators in pencil beam scanning (PBS), this work investigates how the spot spacing and collimation can be optimized to maximize the therapeutic gains of a GRID treatment while demonstrating the integration of a dynamic collimation system (DCS) within a commercial beamline to deliver GRID treatments and experimentally benchmark Monte Carlo calculation methods. METHODS: GRID profiles were experimentally benchmarked using a clinical DCS prototype that was mounted to the nozzle of the IBA-dedicated nozzle system. Integral depth dose (IDD) curves and lateral profiles were measured for uncollimated and GRID-collimated beamlets. A library of collimated GRID dose distributions were simulated by placing beamlets within a specified uniform grid and weighting the beamlets to achieve a volume-averaged tumor cell survival equivalent to an open field delivery. The healthy tissue sparing afforded by the GRID distribution was then estimated across a range of spot spacings and collimation widths, which were later optimized based on the radiosensitivity of the tumor cell line and the nominal spot size of the PBS system. This was accomplished by using validated models of the IBA universal and dedicated nozzles. RESULTS: Excellent agreement was observed between the measured and simulated profiles. The IDDs matched above 98.7% when analyzed using a 1%/1-mm gamma criterion with some minor deviation observed near the Bragg peak for higher beamlet energies. Lateral profile distributions predicted using Monte Carlo methods agreed well with the measured profiles; a gamma passing rate of 95% or higher was observed for all in-depth profiles examined using a 3%/2-mm criteria. Additional collimation was shown to improve PBS GRID treatments by sharpening the lateral penumbra of the beamlets but creates a trade-off between enhancing the valley-to-peak ratio of the GRID delivery and the dose-volume effect. The optimal collimation width and spot spacing changed as a function of the tumor cell radiosensitivity, dose, and spot size. In general, a spot spacing below 2.0 cm with a collimation less than 1.0 cm provided a superior dose distribution among the specific cases studied. CONCLUSIONS: The ability to customize a GRID dose distribution using different collimation sizes and spot spacings is a useful advantage, especially to maximize the overall therapeutic benefit. In this regard, the capabilities of the DCS, and perhaps alternative dynamic collimators, can be used to enhance GRID treatments. Physical dose models calculated using Monte Carlo methods were experimentally benchmarked in water and were found to accurately predict the respective dose distributions of uncollimated and DCS-collimated GRID profiles.

Investigating aperture-based approximations to model a focused dynamic collimation system for pencil beam scanning proton therapy.

Purpose. The Dynamic Collimation System (DCS) is an energy layer-specific collimation device designed to reduce the lateral penumbra in pencil beam scanning proton therapy. The DCS consists of two pairs of nickel trimmers that rapidly and independently move and rotate to intercept the scanning proton beam and an integrated range shifter to treat targets less than 4 cm deep. This work examines the validity of a single aperture approximation to model the DCS, a commonly used approximation in commercial treatment planning systems, as well as higher-order aperture-based approximations for modeling DCS-collimated dose distributions.Methods. An experimentally validated TOPAS/Geant4-based Monte Carlo model of the DCS integrated with a beam model of the IBA pencil beam scanning dedicated nozzle was used to simulate DCS- and aperture-collimated 100 MeV beamlets and composite treatment plans. The DCS was represented by three different aperture approximations: a single aperture placed halfway between the upper and lower trimmer planes, two apertures located at the upper and lower trimmer planes, and four apertures, located at both the upstream and downstream faces of each pair of trimmers. Line profiles and three-dimensional regions of interest were used to evaluate the validity and limitations of the aperture approximations investigated.Results. For pencil beams without a range shifter, minimal differences were observed between the DCS and single aperture approximation. For range shifted beamlets, the single aperture approximation yielded wider penumbra widths (up to 18%) in the X-direction and sharper widths (up to 9.4%) in the Y-direction. For the example treatment plan, the root-mean-square errors (RMSEs) in an overall three-dimensional region of interest were 1.7%, 1.3%, and 1.7% for the single aperture, two aperture, and four aperture models, respectively. If the region of interest only encompasses the lateral edges outside of the target, the resulting RMSEs were 1.7%, 1.1%, and 0.5% single aperture, two aperture, and four aperture models, respectively.Conclusions. Monte Carlo simulations of the DCS demonstrated that a single aperture approximation is sufficient for modeling pristine fields at the Bragg depth while range shifted fields require a higher-order aperture approximation. For the treatment plan considered, the double aperture model performed the best overall, however, the four-aperture model most accurately modeled the lateral field edges at the expense of increased dose differences proximal to and within the target.