Generation of Blastocyst-like Structures from Mouse Embryonic and Adult Cell Cultures.

A single mouse blastomere from an embryo until the 8-cell stage can generate an entire blastocyst. Whether laboratory-cultured cells retain a similar generative capacity remains unknown. Starting from a single stem cell type, extended pluripotent stem (EPS) cells, we established a 3D differentiation system that enabled the generation of blastocyst-like structures (EPS-blastoids) through lineage segregation and self-organization. EPS-blastoids resembled blastocysts in morphology and cell-lineage allocation and recapitulated key morphogenetic events during preimplantation and early postimplantation development in vitro. Upon transfer, some EPS-blastoids underwent implantation, induced decidualization, and generated live, albeit disorganized, tissues in utero. Single-cell and bulk RNA-sequencing analysis revealed that EPS-blastoids contained all three blastocyst cell lineages and shared transcriptional similarity with natural blastocysts. We also provide proof of concept that EPS-blastoids can be generated from adult cells via cellular reprogramming. EPS-blastoids provide a unique platform for studying early embryogenesis and pave the way to creating viable synthetic embryos by using cultured cells.

Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (SPARE) for patients with newly diagnosed glioblastoma.

INTRODUCTION: Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We report our initial experience evaluating toxicity and tolerability of scalp-sparing radiation with concurrent TTFields. METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed glioblastoma were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent temozolomide (75 mg/m2 daily), and TTFields. Maintenance therapy included standard temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity for concurrent TTFields with chemoradiation in newly diagnosed glioblastoma. RESULTS: We report the first ten patients on the trial. Eight were male, and two were female, with median age 61 years (range 49 to 73 years). Median KPS was 90 (range 70-90). Median follow-up was 7.9 months (2.8 to 17.9 months). Nine (90%) patients with unmethylated MGMT promotor, and one with methylated. Median time from surgery to radiation was 33 days (28 to 49 days). All patients completed concurrent chemoradiation plus TTFields without radiation or TTFields treatment interruption or discontinuation. Scalp dose constraints were achieved for all patients, with mean dose having a median value of 7.7 Gy (range 4.9 to 13.2 Gy), D20cc median 22.6 Gy (17.7 to 36.8 Gy), and D30cc median 19.8 Gy (14.8 to 33.4 Gy). Average daily use during concurrent phase had median value of 83.5% and 77% for maintenance. There was no related ≥ Grade 3 toxicity. Skin toxicity (erythema, dermatitis, pruritus) was noted in 80% of patients, however, these were limited to Grade 1 or 2 events which resolved spontaneously or responded to topical medications. Eight patients (80%) had progression, with median PFS of 6.9 months (range 2.8 to 9.6 months). CONCLUSIONS: Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trial is warranted to define therapeutic advantages of concurrent TTFields with chemoradiation. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03477110.

Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas.

Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30-35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma.

Dosimetric validation for an automatic brain metastases planning software using single-isocenter dynamic conformal arcsDosimetric validation for an automatic brain metastases planning software using single-isocenter dynamic conformal arcs.

An automatic brain-metastases planning (ABMP) software has been installed in our institution. It is dedicated for treating multiple brain metastases with radiosurgery on linear accelerators (linacs) using a single-setup isocenter with noncoplanar dynamic conformal arcs. This study is to validate the calculated absolute dose and dose distribution of ABMP. Three types of measurements were performed to validate the planning software: 1, dual micro ion chambers were used with an acrylic phantom to measure the absolute dose; 2, a 3D cylindrical phantom with dual diode array was used to evaluate 2D dose distribution and point dose for smaller targets; and 3, a 3D pseudo-in vivo patient-specific phantom filled with polymer gels was used to evaluate the accuracy of 3D dose distribution and radia-tion delivery. Micro chamber measurement of two targets (volumes of 1.2 cc and 0.9 cc, respectively) showed that the percentage differences of the absolute dose at both targets were less than 1%. Averaged GI passing rate of five different plans measured with the diode array phantom was above 98%, using criteria of 3% dose difference, 1 mm distance to agreement (DTA), and 10% low-dose threshold. 3D gel phantom measurement results demonstrated a 3D displacement of nine targets of 0.7 ± 0.4 mm (range 0.2 ~ 1.1 mm). The averaged two-dimensional (2D) GI passing rate for several region of interests (ROI) on axial slices that encompass each one of the nine targets was above 98% (5% dose difference, 2 mm DTA, and 10% low-dose threshold). Measured D95, the minimum dose that covers 95% of the target volume, of the nine targets was 0.7% less than the calculated D95. Three different types of dosimetric verification methods were used and proved the dose calculation of the new automatic brain metastases planning (ABMP) software was clinical acceptable. The 3D pseudo-in vivo patient-specific gel phantom test also served as an end-to-end test for validating not only the dose calculation, but the treatment delivery accuracy as well.

Learning Optical Flow and Scene Flow With Bidirectional Camera-LiDAR Fusion.

In this paper, we study the problem of jointly estimating the optical flow and scene flow from synchronized 2D and 3D data. Previous methods either employ a complex pipeline that splits the joint task into independent stages, or fuse 2D and 3D information in an "early-fusion" or "late-fusion" manner. Such one-size-fits-all approaches suffer from a dilemma of failing to fully utilize the characteristic of each modality or to maximize the inter-modality complementarity. To address the problem, we propose a novel end-to-end framework, which consists of 2D and 3D branches with multiple bidirectional fusion connections between them in specific layers. Different from previous work, we apply a point-based 3D branch to extract the LiDAR features, as it preserves the geometric structure of point clouds. To fuse dense image features and sparse point features, we propose a learnable operator named bidirectional camera-LiDAR fusion module (Bi-CLFM). We instantiate two types of the bidirectional fusion pipeline, one based on the pyramidal coarse-to-fine architecture (dubbed CamLiPWC), and the other one based on the recurrent all-pairs field transforms (dubbed CamLiRAFT). On FlyingThings3D, both CamLiPWC and CamLiRAFT surpass all existing methods and achieve up to a 47.9% reduction in 3D end-point-error from the best published result. Our best-performing model, CamLiRAFT, achieves an error of 4.26% on the KITTI Scene Flow benchmark, ranking 1st among all submissions with much fewer parameters. Besides, our methods have strong generalization performance and the ability to handle non-rigid motion.

Novel frameless LINAC radiosurgery solution for uveal melanoma.

Introduction: Radiation treatment has replaced enucleation as an organ-preservation treatment for patients with uveal melanoma (UM). We developed a novel non-invasive, frameless LINAC based solution for fractionated stereotactic radiosurgery (fSRS) treatment. Methods: We designed and constructed the a stereotactic ocular localization box that can be attached and indexed to a stereotactic LINAC tabletop. It contains adjustable LED lights as a gaze focus point and CCD camera for monitoring of the patient's eye position. The device also has 6 infrared spheres compatible with the ExacTRAC IGRT system. Treatment plans were developed using iPLAN Dose version 4.5, with conformal dynamic arcs and 6MV photon beam in flattening filter free mode, dosed to 50Gy in 5 fractions. During treatment, patients were instructed to stare at the light when a radiation beam is prepared and ready for delivery. Eye movement was tracked throughout treatment. Residual setup errors were recorded for evaluation. Results: The stereotactic ocular localization box was 3D-printed with polylactic acid material and attached to the stereotactic LINAC tabletop. 10 patients were treated to evaluate the feasibility, tolerability and setup accuracy. Median treatment time for each arc is 17.3 ± 2.4 seconds (range: 13.8-23.4). After ExacTRAC setup, the residual setup errors are -0.1 ± 0.3 mm laterally, -0.1 ± 0.3 mm longitudinally, and 0 ± 0.2 mm vertically. The residue rotational errors are -0.1 ± 0.3 degree pitch, 0.1 ± 0.2 degree roll, and 0 ± 0.2 degree couch rotation. All patients received treatment successfully. Conclusion: We successfully developed a novel non-invasive frameless mask-based LINAC solution for SRS for uveal melanoma, or other ocular tumors. It is well tolerated with high set up accuracy. Future directions for this localization box would include a multi-center trial to assess the efficacy and reproducibility in the fabrication and execution of such a solution for UM therapy.

Efficacy of scalp-sparing volumetric-modulated arc therapy approach in reducing scalp radiation dose for patients with glioblastoma: a cross-sectional study.

BACKGROUND: Radiation is integral to the treatment of glioblastoma (GBM). However, radiation-induced scalp toxicity can negatively impact patients' quality of life. Volumetric modulated arc therapy (VMAT) optimizes the dose to organs at risk (OARs). We hypothesize that a scalp-sparing VMAT (SSV) approach can significantly reduce undesirable doses to the scalp without compromising the target dose. METHODS: This is a retrospective cross-sectional study of GBM patients who originally received radiation with non-SSV. We contoured the scalp as a 5 mm rind-like structure beneath the skin above the level of the foramen magnum. We replanned our patients using SSV techniques. We compared dosimetric data for the scalp, planning target volume (PTV), and select critical normal structures between non-SSV and SSV plans. RESULTS: Nineteen patients with newly diagnosed GBMs were included in our study. All patients received 60 Gy in 30 fractions. 9 patients received it in a single course. The rest received 46 Gy in 23 fractions to an initial volume followed by 14 Gy in 7 fractions to a cone-down volume (split course). New VMAT plans were generated after adding the scalp as an OAR. The median scalp volume was 416 cm3 (363-468 cm3). The median reductions in scalp Dmin, Dmax, and Dmean were 43.5% (-100% to 0%), 2.8% (+13.4% to -24.9%), and 15.7% (+2.1% to -39.9%) respectively. Median reductions in scalp D20cc and D30 cc were 19.5% (-2.7% to -54.5%), and 19.0% (-5.3% to -39.5%) respectively. The median volumes of the scalp receiving 30 Gy, 40 Gy, and 50 Gy were reduced by 42.3% (-70.6% to -12.5%), 72% (-100% to -2.3%), and 92.4% (-100% to +5.4%) respectively. There were no significant differences in the doses delivered to the PTV, brainstem, optic nerves, and optic chiasm between SSV and non-SSV plans. CONCLUSIONS: SSV can significantly reduce scalp radiation dose without compromising target coverage or critical normal structure doses. This may translate into reduced acute and late radiation toxicity to the scalp. A prospective trial evaluating the clinical benefits of SSV is ongoing (NCT03251027).

SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B.

Aging is a major risk factor contributing to pathophysiological changes in the heart, yet its intrinsic mechanisms have been largely unexplored in primates. In this study, we investigated the hypertrophic and senescence phenotypes in the hearts of aged cynomolgus monkeys as well as the transcriptomic and proteomic landscapes of young and aged primate hearts. SIRT2 was identified as a key protein decreased in aged monkey hearts, and engineered SIRT2 deficiency in human pluripotent stem cell-derived cardiomyocytes recapitulated key senescence features of primate heart aging. Further investigations revealed that loss of SIRT2 in human cardiomyocytes led to the hyperacetylation of STAT3, which transcriptionally activated CDKN2B and, in turn, triggered cardiomyocyte degeneration. Intra-myocardial injection of lentiviruses expressing SIRT2 ameliorated age-related cardiac dysfunction in mice. Taken together, our study provides valuable resources for decoding primate cardiac aging and identifies the SIRT2-STAT3-CDKN2B regulatory axis as a potential therapeutic target against human cardiac aging and aging-related cardiovascular diseases.

Clinical Evaluation of an Auto-Segmentation Tool for Spine SBRT Treatment.

Purpose: Spine SBRT target delineation is time-consuming due to the complex bone structure. Recently, Elements SmartBrush Spine (ESS) was developed by Brainlab to automatically generate a clinical target volume (CTV) based on gross tumor volume (GTV). The aim of this project is to evaluate the accuracy and efficiency of ESS auto-segmentation. Methods: Twenty spine SBRT patients with 21 target sites treated at our institution were used for this retrospective comparison study. Planning CT/MRI images and physician-drawn GTVs were inputs for ESS. ESS can automatically segment the vertebra, split the vertebra into 6 sectors, and generate a CTV based on the GTV location, according to the International Spine Radiosurgery Consortium (ISRC) Consensus guidelines. The auto-segmented CTV can be edited by including/excluding sectors of the vertebra, if necessary. The ESS-generated CTV contour was then compared to the clinically used CTV using qualitative and quantitative methods. The CTV contours were compared using visual assessment by the clinicians, relative volume differences (RVD), distance of center of mass (DCM), and three other common contour similarity measurements such as dice similarity coefficient (DICE), Hausdorff distance (HD), and 95% Hausdorff distance (HD95). Results: Qualitatively, the study showed that ESS can segment vertebra more accurately and consistently than humans at normal curvature conditions. The accuracy of CTV delineation can be improved significantly if the auto-segmentation is used as the first step. Conversely, ESS may mistakenly split or join different vertebrae when large curvatures in anatomy exist. In this study, human interactions were needed in 7 of 21 cases to generate the final CTVs by including/excluding sectors of the vertebra. In 90% of cases, the RVD were within ±15%. The RVD, DCM, DICE, HD, and HD95 for the 21 cases were 3% ± 12%, 1.9 ± 1.5 mm, 0.86 ± 0.06, 13.34 ± 7.47 mm, and 4.67 ± 2.21 mm, respectively. Conclusion: ESS can auto-segment a CTV quickly and accurately and has a good agreement with clinically used CTV. Inter-person variation and contouring time can be reduced with ESS. Physician editing is needed for some occasions. Our study supports the idea of using ESS as the first step for spine SBRT target delineation to improve the contouring consistency as well as to reduce the contouring time.

Scalp-Sparing Radiation With Concurrent Temozolomide and Tumor Treating Fields (SPARE) for Patients With Newly Diagnosed Glioblastoma.

Introduction: Standard-of-care treatment for patients with newly diagnosed glioblastoma (GBM) after surgery or biopsy includes concurrent chemoradiation followed by maintenance temozolomide (TMZ) with tumor treating fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report the results of our trial evaluating the safety of TTFields used concurrently with chemoradiation. Methods: This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a Karnofsky performance score (KPS) of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with TMZ (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included TMZ and continuation of TTFields. Scalp-sparing radiation treatment was used to reduce radiation dermatitis. Radiation treatment was delivered through the TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment. Results: There were 30 patients enrolled, including 20 (66.7%) men and 10 (33.3%) women, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). A total of 12 (40%) patients received a gross total resection and 18 (60%) patients had a subtotal resection. A total of 12 (40%) patients had multifocal disease at presentation. There were 20 (66.7%) patients who had unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promotor status and 10 (33.3%) patients who had methylated MGMT promoter status. Median follow-up was 15.2 months (range 1.7 to 23.6 months). Skin adverse events were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. The primary end point was met; no TTFields discontinuation occurred during the evaluation period due to high grade scalp toxicity. A total of 27 (90%) patients had progression, with a median progression-free survival (PFS) of 9.3 months (95% confidence interval (CI): 8.5-11.6 months). The 1-year progression-free survival was 23% (95% CI: 12%-45%). The median overall survival (OS) was 15.8 months (95% CI: 12.5 months-infinity). The 1-year overall survival was 66% (95% CI: 51%-86%). Conclusions: Concurrent TTFields with scalp-sparing chemoradiation is a feasible and well-tolerated treatment option with limited toxicity. A phase 3, randomized clinical trial (EF-32, clinicaltrials.gov Identifier: NCT04471844) investigating the clinical benefit of concurrent TTFields with chemoradiation treatment is currently enrolling. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT03477110.

Frameless Angiography-Based Gamma Knife Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations: A Proof-of-Concept Study.

BACKGROUND: Traditional Gamma Knife radiosurgery (GKRS) of brain arteriovenous malformations (AVMs) using digital subtraction angiography (DSA) requires head immobilization using a stereotactic frame. OBJECTIVE: We describe our protocol of frameless GKRS using DSA while maintaining high spatial resolution for precision. METHODS: This study is a retrospective review of patients with unruptured AVMs who underwent frameless GKRS. Magnetic resonance imaging and 3-dimensional DSA were obtained without a stereotactic frame for all patients. The imaging studies were merged for contouring of the AVM nidus. During GKRS treatment, patients were immobilized using an individually molded thermoplastic mask. RESULTS: Thirty-one patients were included in the analysis. The median age is 45.0 years (interquartile range [IQR]: 28.0-55.0). The median nidus size is 3.0 cm (IQR: 2.0-3.4). One patient had a Spetzler-Martin grade I, 11 had a grade II, 11 had a grade III, 6 had a grade IV, and 2 had a grade V AVM. Eleven patients underwent preradiosurgical embolization, 3 patients had previous microsurgical resection and/or embolization, and 1 patient had prior radiosurgery. The median administered dose was 20 Gy (IQR: 18.0-21.0). All patients completed their treatment with the planned radiation dose without complications. CONCLUSION: This is the first study that integrates DSA in the treatment planning of brain AVMs using GKRS without utilizing a stereotactic head frame. Frameless GKRS provides numerous advantages over frame-based techniques including improved patient experience and the capability of fractionation and thus expanding the eligibility of more AVMs for radiosurgery, while maintaining high spatial resolution of the AVM using angiography data.

Dosimetric comparison of Gamma Knife® IconTM and linear accelerator-based fractionated stereotactic radiotherapy (FSRT) plans for the re-irradiation of large (>14 cm3) recurrent glioblastomas.

Our objective is to investigate dosimetric differences between clinically deliverable Gamma Knife® (GK) Icon™ and linac-based FSRT plans on the basis of normal brain dose sparing for large (>14 cm3) recurrent glioblastomas (GBM). Sixteen patients with large, recurrent GBM were treated using re-irradiation via linac-based FSRT, 35 Gy in 10 fractions. For each patient, a new GK FSRT plan was created in Leksell GammaPlan® V11 (LGP). To maintain clinical deliverability, the LGP optimization included a planning goal of treatment time <20 minutes per fraction. Dosimetric comparison of coverage and normal brain dose between the linac and GK treatment plans was performed in MIM. The GK FSRT plans had significantly (p < 0.05) lower mean normal brain dose values (-8.85%), mean values of normal brain V20 (-32.4%) and V12 (-25.9%), and a lower mean V4 (-10.0%). GK FSRT plans have the potential to reduce the risk of radiation-related toxicities.

Chemical combinations potentiate human pluripotent stem cell-derived 3D pancreatic progenitor clusters toward functional ß cells.

Human pluripotent stem cell (hPSC)-derived pancreatic ß cells are an attractive cell source for treating diabetes. However, current derivation methods remain inefficient, heterogeneous, and cell line dependent. To address these issues, we first devised a strategy to efficiently cluster hPSC-derived pancreatic progenitors into 3D structures. Through a systematic study, we discovered 10 chemicals that not only retain the pancreatic progenitors in 3D clusters but also enhance their potentiality towards NKX6.1+/INS+ ß cells. We further systematically screened signaling pathway modulators in the three steps from pancreatic progenitors toward ß cells. The implementation of all these strategies and chemical combinations resulted in generating ß cells from different sources of hPSCs with high efficiency. The derived ß cells are functional and can reverse hyperglycemia in mice within two weeks. Our protocol provides a robust platform for studying human ß cells and developing hPSC-derived ß cells for cell replacement therapy.

Accuracy of dose-volume metric calculation for small-volume radiosurgery targets.

PURPOSE: For stereotactic radiosurgery (SRS), accurate evaluation of dose-volume metrics for small structures is necessary. The purpose of this study was to compare the DVH metric capabilities of five commercially available SRS DVH analysis tools (Eclipse, Elements, Raystation, MIM, and Velocity). METHODS: DICOM RTdose and RTstructure set files created using MATLAB were imported and evaluated in each of the tools. Each structure set consisted of 50 randomly placed spherical targets. The dose distributions were created on a 1-mm grid using an analytic model such that the dose-volume metrics of the spheres were known. Structure sets were created for 3, 5, 7, 10, 15, and 20 mm diameter spheres. The reported structure volume, V100% [cc], and V50% [cc], and the RTOG conformity index and Paddick Gradient Index, were compared with the analytical values. RESULTS: The average difference and range across all evaluated target sizes for the reported structure volume was - 4.73%[-33.2,0.2], 0.11%[-10.9, 9.5], -0.39%[-12.1, 7.0], -2.24%[-21.0, 1.3], and 1.15%[-15.1,0.8], for TPS-A through TPS-E, respectively. The average difference and range for the V100%[cc] (V20Gy[cc]) was - 0.4[-24.5,9.8], -2.73[-23.6, 1.1], -3.01[-23.6, 0.6], -3.79[-27.3, 1.3], and 0.26[-6.1,2.6] for TPS-A through TPS-E, respectively. For V50%[cc](V10Gy[cc]) in TPS-A through TPS-E the average and ranger were - 0.05[-0.8,0.4], -0.18[-1.2, 0.5], -0.44[-1.4, 0.3], -0.26[-1.8, 2.6], and 0.09[-1.4,2.7]. CONCLUSION: This study expanded on the previously published literature to quantitatively compare the DVH analysis capabilities of software commonly used for SRS plan evaluation and provides freely available and downloadable analytically derived set of ground truth DICOM dose and structure files for the use of radiotherapy clinics. The differences between systems highlight the need for standardization and/or transparency between systems, especially when evaluating plan quality for multi-institutional clinical trials.

Phase Ib Clinical Trial of IGV-001 for Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. PATIENTS AND METHODS: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4-6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. RESULTS: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001-treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine-DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. CONCLUSIONS: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).

Evaluation of Elements Spine SRS Plan Quality for SRS and SBRT Treatment of Spine Metastases.

Purpose: The Elements Spine Stereotactic Radiosurgery treatment planning system uses automated volumetric modulated arc radiotherapy that can provide a highly conformal dose distribution to targets, which can provide superior sparing of the spinal cord. This study compares the dosimetric quality of Elements plans with the clinical plans of 20 spine stereotactic radiosurgery/stereotactic body radiation therapy (SRS/SBRT) patients treated at our institution. Methods: Twenty spine SRS/SBRT patients who were clinically treated at our institution were replanned using the automated Elements planning workflow with prespecified templates. Elements automatically evaluates the size and shape of the target to determine if splitting the PTV into simplistic subvolumes, each treated by their own arc(s), would increase conformity and spinal cord sparing. The conformity index, gradient index, PTV D 5%, and maximum and mean cord dose were evaluated for the Elements and clinical plans. Treatment delivery efficiency was also analyzed by comparing the total number of monitor units and the modulation factor. Wilcoxon rank-sum tests were performed on the statistics. Results: Elements split the PTV for 50% of cases, requiring four or six arcs. Overall, Elements plans were found to be superior to clinical plans in conformity index, gradient index, and maximum cord dose. The PTV D 5% and cord mean dose for the Elements plans trended higher and lower, respectively. The numbers of monitor units and modulation factor were also higher for Elements plans, although the differences were not significant. Conclusion: Automated Elements plans achieved superior conformity and cord dose sparing compared to clinical plans and PTV splitting successfully improved spinal cord sparing.

Localization and Completion for 3D Object Interactions.

Finding where and what objects to put into an existing scene is a common task for scene synthesis and robot/character motion planning. Existing frameworks require development of hand-crafted features suitable for the task, or full volumetric analysis that could be memory intensive and imprecise. In this paper, we propose a data-driven framework to discover a suitable location and then place the appropriate objects in a scene. Our approach is inspired by computer vision techniques for localizing objects in images: using an all directional depth image (ADD-image) that encodes the 360-degree field of view from samples in the scene, our system regresses the images to the positions where the new object can be located. Given several candidate areas around the host object in the scene, our system predicts the partner object whose geometry fits well to the host object. Our approach is highly parallel and memory efficient, and is especially suitable for handling interactions between large and small objects. We show examples where the system can hang bags on hooks, fit chairs in front of desks, put objects into shelves, insert flowers into vases, and put hangers onto laundry rack.

Geometric and dosimetric effects of image co-registration workflows for Gamma Knife frameless radiosurgery.

The Gamma Knife® Icon™ CBCT facilitates frameless radiosurgery. In the vendor-recommended workflow, MRI is co-registered directly to CBCT for planning. Alternatively, MRI is co-registered to a diagnostic CT, which is then co-registered to CBCT. Our objective is to evaluate if this additional CT is necessary for more accurate registrations. Nine small spherical targets were generated onto 14 patient data-sets. Single-shot treatment plans were created. Geometric and dosimetric differences between the two workflows were determined. Mean target displacement was 0.5±0.3mm; average PTV coverage loss was 4.3±5.0%. For 19 clinical targets in 14 patients, the mean displacement and coverage change was 0.6±0.4mm and 1.3±1.6%. Eleven surrogate landmarks were contoured on a phantom MRI and registered to the CBCT using both workflows. The registration uncertainty was 0.50±0.65mm and 0.32±0.47mm for the MRI-CT-CBCT and MRI-CBCT respectively. As neither workflow was significantly more accurate, the additional CT is unnecessary for most cases.

Interinstitutional Plan Quality Assessment of 2 Linac-Based, Single-Isocenter, Multiple Metastasis Radiosurgery Techniques.

PURPOSE: Interest and application of stereotactic radiosurgery for multiple brain metastases continue to increase. Various planning systems are available for linear accelerator (linac)-based single-isocenter multiple metastasis radiosurgery. Two of the most advanced systems are BrainLAB Multiple Metastases Elements (MME), a dynamic conformal arc (DCA) approach, and Varian RapidArc (RA), a volumetric modulated arc therapy (VMAT) approach. In this work, we systematically compared plan quality between the 2 techniques. METHODS AND MATERIALS: Thirty patients with 4 to 10 metastases (217 total; median 7.5; Vmin = 0.014 cm3; Vmax = 17.73 cm3) were planned with both Varian RA and MME at 2 different institutions with extensive experience in each respective technique. All plans had a single isocenter and used Varian linac equipped with high-definition multileaf collimator. RA plans used 2 to 4 noncoplanar VMAT arcs with 10 MV flattening filter-free beam. MME plans used 4 to 9 noncoplanar DCAs and 6 MV flattening filter-free beam, (minimum planning target volume [PTVmin] = 0.49 cm3; PTVmax = 27.32 cm3; PTVmedian = 7.05 cm3). Prescriptions were 14 to 24 Gy in a single fraction. Target coverage goal was 99% of volume receiving prescription dose (D99% ≥ 100%). Plans were evaluated by Radiation Therapy Oncology Group/Paddick conformity index (CI) score, 12 Gy volume (V12Gy), V8Gy, V5Gy, mean brain dose (Dmean), and beam-on time. RESULTS: Conformity was favorable among RA plans (median: MME CIRTOG = 1.38; RA CIRTOG = 1.21; P < .0001). V12Gy and V8Gy were lower for RA plans (median: MME V12 = 23.7 cm3; RA V12 = 19.2 cm3; P = .0001; median: MME V8Gy = 53.6 cm3; RA V8Gy = 44.1 cm3; P = .024). V5Gy was lower for MME plans (median: MME V5Gy = 141.4 cm3; RA V5Gy = 142.8 cm3; P = .009). Mean brain was lower for MME plans (median: MME Dmean = 2.57 Gy; RA Dmean = 2.76 Gy; P < .0001). CONCLUSIONS: For linac-based multiple metastasis stereotactic radiosurgery, RapidArc VMAT facilitates favorable conformity and V12Gy/V8Gy volume compared with the MME DCA plan. MME planning facilitates reduced dose spill at levels ≤V5Gy.

Dosimetric Performance and Planning/Delivery Efficiency of a Dual-Layer Stacked and Staggered MLC on Treating Multiple Small Targets: A Planning Study Based on Single-Isocenter Multi-Target Stereotactic Radiosurgery (SRS) to Brain Metastases.

Purpose: To evaluate the dosimetric performance and planning/delivery efficiency of a dual-layer MLC system for treating multiple brain metastases with a single isocenter. Materials and Methods: 10 patients each with 6-10 targets with volumes from 0.11 to 8.57 cc, and prescription doses from 15 to 24 Gy, were retrospectively studied. Halcyon has only coplanar delivery mode. Halcyon V1 MLC modulates only with the lower layer at 1 cm resolution, whereas V2 MLC modulates with both layers at an effective resolution of 0.5 cm. For each patient five plans were compared varying MLC and beam arrangements: the clinical plan using multi-aperture dynamic conformal arc (DCA) and non-coplanar arcs, Halcyon-V1 using coplanar-VMAT, Halcyon-V2 using coplanar-VMAT, HDMLC-0.25 cm using coplanar-VMAT, and HDMLC-0.25 cm using non-coplanar-VMAT. All same-case plans were generated following the same planning protocol and normalization. Conformity index (CI), gradient index (GI), V12Gy, V6Gy, V3Gy, and brain mean dose were compared. Results: All VMAT plans met clinical constraints for critical structures. For targets with diameter < 1 cm, Halcyon plans showed inferior CI among all techniques. For targets with diameter >1 cm, Halcyon VMAT plans had CI similar to non-coplanar VMAT plans, and better than non-coplanar clinical DCA plans. For GI, Halcyon MLC plans performed similarly to coplanar HDMLC plans and inferiorly compared to non-coplanar HDMLC plans. All coplanar VMAT plans (Halcyon MLC and HDMLC) and clinical DCA plans had similar V12Gy, but were inferior compared to non-coplanar VMAT plans. Halcyon plans had slightly reduced V3Gy and mean brain dose compared to HDMLC plans. The difference between Halcyon V1 and V2 is only significant in CI of tumors less than 1cm in diameter. Halcyon plans required longer optimization than Truebeam VMAT plans, but had similar delivery efficiency. Conclusion: For targets with diameter >1 cm, Halcyon's dual-layer stacked and staggered MLC is capable of producing similar dose conformity compared to HDMLC while reducing low dose spill to normal brain tissue. GI and V12Gy of Halcyon MLC plans were, in general, inferior to non-coplanar DCA or VMAT plans using HDMLC, likely due to coplanar geometry and wider MLC leaves. HDMLC maintained its advantage in CI for smaller targets with diameter <1 cm.