Accuracy of robotic radiosurgery in renal cell carcinoma.

PURPOSE: Although emerging clinical evidence supports robotic radiosurgery as a highly effective treatment option for renal cell carcinoma (RCC) less than 4 cm in diameter, delivery uncertainties and associated target volume margins have not been studied in detail. We assess intrafraction tumor motion patterns and accuracy of robotic radiosurgery in renal tumors with real-time respiratory tracking to optimize treatment margins. METHODS: Delivery log files from 165 consecutive treatments of RCC were retrospectively analyzed. Five components were considered for planning target volume (PTV) margin estimation: (a) The model error from the correlation model between patient breath and tumor motion, (b) the prediction error from an algorithm predicting the patient breathing pattern, (c) the targeting error from the treatment robot, (d) the inherent total accuracy of the system for respiratory motion tracking, and (e) the margin required to cover potential target rotation, simulated with PTV rotations up to 10°. RESULTS: The median tumor motion was 10.5 mm, 2.4 mm and 4.4 mm in the superior-inferior, left-right, and anterior-posterior directions, respectively. The root of the sum of squares of all contributions to the system's inaccuracy results in a minimum PTV margin of 4.3 mm, 2.6 mm and 3.0 mm in the superior-inferior, left-right and anterior-posterior directions, respectively, assuming optimal fiducial position and neglecting target deformation. CONCLUSIONS: We have assessed kidney motion and derived PTV margins for the treatment of RCC with robotic radiosurgery, which helps to deliver renal treatments in a more consistent manner and potentially further improve outcomes.

Mitolnc controls cardiac BCAA metabolism and heart hypertrophy by allosteric activation of BCKDH.

Enzyme activity is determined by various different mechanisms, including posttranslational modifications and allosteric regulation. Allosteric activators are often metabolites but other molecules serve similar functions. So far, examples of long non-coding RNAs (lncRNAs) acting as allosteric activators of enzyme activity are missing. Here, we describe the function of mitolnc in cardiomyocytes, a nuclear encoded long non-coding RNA, located in mitochondria and directly interacting with the branched-chain ketoacid dehydrogenase (BCKDH) complex to increase its activity. The BCKDH complex is critical for branched-chain amino acid catabolism (BCAAs). Inactivation of mitolnc in mice reduces BCKDH complex activity, resulting in accumulation of BCAAs in the heart and cardiac hypertrophy via enhanced mTOR signaling. We found that mitolnc allosterically activates the BCKDH complex, independent of phosphorylation. Mitolnc-mediated regulation of the BCKDH complex constitutes an important additional layer to regulate the BCKDH complex in a tissue-specific manner, evading direct coupling of BCAA metabolism to ACLY-dependent lipogenesis.

Self-Shielding Gyroscopic Radiosurgery: A Prospective Experience and Analysis of the First 100 Patients.

Background Stereotactic radiosurgery is a well-established treatment option for the management of various benign and malignant brain tumors. It can be delivered with several treatment platforms, usually requiring shielded radiation vaults to meet regulatory safety requirements. Recent technical advances have led to the first self-shielding platform enabling the delivery of gyroscopic radiosurgery (GRS). Given the limited number of GRS treatment platforms, the novelty of its characteristics, and the lack of available data, we report our prospective experience with the first 100 patients treated with GRS. Materials and methods Patients undergoing GRS for the treatment of intracranial tumors were enrolled in this prospective study. Patient and treatment characteristics, including patient satisfaction, were collected and analyzed. Results A total of 100 patients with 155 tumors were treated. The most commonly treated tumors comprised brain metastases (BM) (49%), vestibular schwannomas (31%), and meningiomas (14%). The median prescription dose for malignant and benign tumors was 20 and 13 Gy, respectively. The median prescription isodose line was 56%. Gross tumor volumes were small, with a median of 0.37 cc for BM and 0.92 cc for the other entities. The median total treatment time was 40 minutes. Dosimetric performance indices showed median values of 1.20 (conformity index), 1.24 (new conformity index), 1.74 (homogeneity index), and 3.13 (gradient index). Volumetric assessment of the treated tumors showed an overall decrease in size at the first available follow-up. Most patients were satisfied with the treatment experience. Conclusion Our first prospective experience of the use of GRS is favorable. Analyses of the dosimetric performance, treatment times, volumetric assessment, and patient satisfaction demonstrate its suitability for stereotactic treatments of intracranial tumors. Further prospective clinical and dosimetric analyses for GRS are pending.

Automated isocenter optimization approach for treatment planning for gyroscopic radiosurgery.

BACKGROUND: Radiosurgery is a well-established treatment for various intracranial tumors. In contrast to other established radiosurgery platforms, the new ZAP-X® allows for self-shielding gyroscopic radiosurgery. Here, treatment beams with variable beam-on times are targeted towards a small number of isocenters. The existing planning framework relies on a heuristic based on random selection or manual selection of isocenters, which often leads to a higher plan quality in clinical practice. PURPOSE: The purpose of this work is to study an improved approach for radiosurgery treatment planning, which automatically selects the isocenter locations for the treatment of brain tumors and diseases in the head and neck area using the new system ZAP-X® . METHODS: We propose a new method to automatically obtain the locations of the isocenters, which are essential in gyroscopic radiosurgery treatment planning. First, an optimal treatment plan is created based on a randomly selected nonisocentric candidate beam set. The intersections of the resulting subset of weighted beams are then clustered to find isocenters. This approach is compared to sphere-packing, random selection, and selection by an expert planner for generating isocenters. We retrospectively evaluate plan quality on 10 acoustic neuroma cases. RESULTS: Isocenters acquired by the method of clustering result in clinically viable plans for all 10 test cases. When using the same number of isocenters, the clustering approach improves coverage on average by 31 percentage points compared to random selection, 15 percentage points compared to sphere packing and 2 percentage points compared to the coverage achieved with the expert selected isocenters. The automatic determination of location and number of isocenters leads, on average, to a coverage of 97 ± 3% with a conformity index of 1.22 ± 0.22, while using 2.46 ± 3.60 fewer isocenters than manually selected. In terms of algorithm performance, all plans were calculated in less than 2 min with an average runtime of 75 ± 25 s. CONCLUSIONS: This study demonstrates the feasibility of an automatic isocenter selection by clustering in the treatment planning process with the ZAP-X® system. Even in complex cases where the existing approaches fail to produce feasible plans, the clustering method generates plans that are comparable to those produced by expert selected isocenters. Therefore, our approach can help reduce the effort and time required for treatment planning in gyroscopic radiosurgery.

Towards fast adaptive replanning by constrained reoptimization for intra-fractional non-periodic motion during robotic SBRT.

BACKGROUND: Periodic and slow target motion is tracked by synchronous motion of the treatment beams in robotic stereotactic body radiation therapy (SBRT). However, spontaneous, non-periodic displacement or drift of the target may completely change the treatment geometry. Simple motion compensation is not sufficient to guarantee the best possible treatment, since relative motion between the target and organs at risk (OARs) can cause substantial deviations of dose in the OARs. This is especially evident when considering the temporally heterogeneous dose delivery by many focused beams which is typical for robotic SBRT. Instead, a reoptimization of the remaining treatment plan after a large target motion during the treatment could potentially reduce the actually delivered dose to OARs and improve target coverage. This reoptimization task, however, is challenging due to time constraints and limited human supervision. PURPOSE: To study the detrimental effect of spontaneous target motion relative to surrounding OARs on the delivered dose distribution and to analyze how intra-fractional constrained replanning could improve motion compensated robotic SBRT of the prostate. METHODS: We solve the inverse planning problem by optimizing a linear program. When considering intra-fractional target motion resulting in a change of geometry, we adapt the linear program to account for the changed dose coefficients and delivered dose. We reduce the problem size by only reweighting beams from the reference treatment plan without motion. For evaluation we simulate target motion and compare our approach for intra-fractional replanning to the conventional compensation by synchronous beam motion. Results are generated retrospectively on data of 50 patients. RESULTS: Our results show that reoptimization can on average retain or improve coverage in case of target motion compared to the reference plan without motion. Compared to the conventional compensation, coverage is improved from 87.83 % to 94.81 % for large target motion. Our approach for reoptimization ensures fixed upper constraints on the dose even after motion, enabling safer intra-fraction adaption, compared to conventional motion compensation where overdosage in OARs can lead to 21.79 % higher maximum dose than planned. With an average reoptimization time of 6 s for 200 reoptimized beams our approach shows promising performance for intra-fractional application. CONCLUSIONS: We show that intra-fractional constrained reoptimization for adaption to target motion can improve coverage compared to the conventional approach of beam translation while ensuring that upper dose constraints on VOIs are not violated.

Single-fraction prostate-specific membrane antigen positron emission tomography- and multiparametric magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer local recurrences.

OBJECTIVE: To analyse the efficacy and safety of focal prostate-specific membrane antigen positron emission tomography (PSMA-PET)- and multiparametric magnetic resonance imaging (mpMRI)-guided single-fraction stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer (PCa) local recurrences. PATIENTS AND METHODS: Patients with PSMA-PET-positive PCa local recurrences treated with single-fraction SBRT between 2016 and 2020 were included. Identification for subsequent recurrences or metastatic spread based on increasing prostate-specific antigen (PSA) levels were evaluated using PSMA-PET imaging. RESULTS: A total of 64 patients were identified. Patients received various treatments before SBRT (31 patients with radical prostatectomy [RP], 18 external beam radiotherapy [EBRT] with RP, five EBRT, and the remaining 10 other combinations). The median follow-up was 21.6 months. The median PSA level before SBRT was 1.47 ng/mL. All patients received a single-fraction treatment with a median prescription dose and isodose line of 21 Gy and 65%, respectively. At the time of SBRT, six patients (9%) received an androgen deprivation therapy (ADT). PSA levels decreased after SBRT (P = 0.03) and three local recurrences were detected during the follow-up. The progression-free survival after 1-, 2-, and 3-years was 85.3%, 65.9%, and 51.2%, respectively. Six patients (9%) started ADT after SBRT due to disease progression. The rates of newly started ADT after 1-, 2-, and 3-years were 1.8%, 7.3%, and 22.7%, respectively. Grade 1 or 2 toxicities occurred in six patients (9%); no high-grade toxicity was observed. CONCLUSION: While the available data for SBRT in the PCa local recurrence setting describe outcomes for fractionated irradiations, the findings of this first analysis of single-fraction, PSMA-PET- and mpMRI-guided focal SBRT are encouraging. Such treatment appears to be a safe, efficient, and time-saving therapy even in intensively pretreated patients. Recurrence-directed treatments can delay the use of ADT and could avoid prostate bed irradiation in selected patients.

Self-Shielding Gyroscopic Radiosurgery-A First Clinical Experience, Case Series, and Dosimetric Comparison.

BACKGROUND: Self-shielding gyroscopic radiosurgery (GRS) represents a technical innovation in the field of stereotactic radiosurgery. GRS does not require a radiation vault and is optimized for radiosurgical treatments. Reports on its usage are limited. We describe the first clinical experience of GRS at our institution to assess the application of GRS in the treatment of cranial tumors. Moreover, we perform a dosimetric comparison to robotic radiosurgery (RRS) with vestibular schwannoma (VS) GRS patients. METHODS: Patients who were treated with GRS between July and November 2021 were included. Patient, tumor, and dosimetric characteristics were retrospectively summarized and analyzed. RESULTS: Forty-one patients with 48 intracranial tumors were included. Tumor entities mostly comprised VS, brain metastases, and meningiomas. The median prescription dose and isodose line were 13.5 Gy and 50.0% for benign neoplasia versus 20 Gy and 60.0% for malignant tumors, respectively. The mean planning target volume was 1.5 cubic centimeters. All patients received a single-fraction treatment without encountering any technical setup difficulties. Treatment plan comparisons with RRS revealed comparable plan characteristics, dose gradients, and organs at risk doses. Significant differences were detected concerning the new conformity index and number of monitor units per treatment (both P < 0.01). CONCLUSIONS: This case series provides more evidence on the usage of self-shielding GRS in the management of cranial tumors. Dosimetric comparisons for VS cases revealed mostly equivalent dosimetric characteristics to RRS. Further clinical and physical analyses for GRS are underway.

AI-based optimization for US-guided radiation therapy of the prostate.

OBJECTIVES: Fast volumetric ultrasound presents an interesting modality for continuous and real-time intra-fractional target tracking in radiation therapy of lesions in the abdomen. However, the placement of the ultrasound probe close to the target structures leads to blocking some beam directions. METHODS: To handle the combinatorial complexity of searching for the ultrasound-robot pose and the subset of optimal treatment beams, we combine CNN-based candidate beam selection with simulated annealing for setup optimization of the ultrasound robot, and linear optimization for treatment plan optimization into an AI-based approach. For 50 prostate cases previously treated with the CyberKnife, we study setup and treatment plan optimization when including robotic ultrasound guidance. RESULTS: The CNN-based search substantially outperforms previous randomized heuristics, increasing coverage from 93.66 to 97.20% on average. Moreover, in some cases the total MU was also reduced, particularly for smaller target volumes. Results after AI-based optimization are similar for treatment plans with and without beam blocking due to ultrasound guidance. CONCLUSIONS: AI-based optimization allows for fast and effective search for configurations for robotic ultrasound-guided radiation therapy. The negative impact of the ultrasound robot on the plan quality can successfully be mitigated resulting only in minor differences.

Robotic CyberKnife radiosurgery for small choroidal melanomas.

Plaque brachytherapy is the most common procedure for the treatment of small choroidal melanoma, especially in posteriorly located tumors. However, there is only little information on outcome after treatment with stereotactic radiosurgery, for example, CyberKnife radiosurgery. We reviewed patients with choroidal melanoma (maximum tumor height 4 mm) treated with CyberKnife radiosurgery. Demographic information, tumor dimension, complications, metastasis and overall survival during the whole follow-up were tracked and analyzed with a specific focus on local tumor control and potential risk factors. One hundred eighty-eight patients (102 female, 54.2%) with a median age of 63 years [interquartile range (IQR): 54-73 years] were analyzed over a median of 46 months (IQR: 24-62 months). Metastasis occurred in 14 patients (7.4%) in median of 18 months after treatment (IQR: 13-47 months) and survival was achieved in 178 patients (94.7%). Within the observation period, eye retention was observed in 166 patients (88.3%). Superior local control was achieved in patients who received a prescription dose of at least 21 Gy or more (91.6%; P = 0.04). Other potential risk factors incrementing local control were treatment planning with missing MRI in advance and too small target delineation during the planning process. Radiosurgery (CyberKnife) in a single, outpatient procedure is suitable for the treatment of small choroidal melanoma. We found local control rate after 3 years compared to the standard treatment with plaque brachytherapy. On the study side, 15 years of CyberKnife treatment allowed to identify risk factors that might increment local control and thus improve treatment regimens.

Dose quantification in carbon ion therapy using in-beam positron emission tomography.

This work presents an iterative method for the estimation of the absolute dose distribution in patients undergoing carbon ion therapy, via analysis of the distribution of positron annihilations resulting from the decay of positron-emitting fragments created in the target volume. The proposed method relies on the decomposition of the total positron-annihilation distributions into profiles of the three principal positron-emitting fragment species - 11C, 10C and 15O. A library of basis functions is constructed by simulating a range of monoenergetic 12C ion irradiations of a homogeneous polymethyl methacrylate phantom and measuring the resulting one-dimensional positron-emitting fragment profiles and dose distributions. To estimate the dose delivered during an arbitrary polyenergetic irradiation, a linear combination of factors from the fragment profile library is iteratively fitted to the decomposed positron annihilation profile acquired during the irradiation, and the resulting weights combined with the corresponding monoenergetic dose profiles to estimate the total dose distribution. A total variation regularisation term is incorporated into the fitting process to suppress high-frequency noise. The method was evaluated with 14 different polyenergetic 12C dose profiles in a polymethyl methacrylate target: one which produces a flat biological dose, 10 with randomised energy weighting factors, and three with distinct dose maxima or minima within the spread-out Bragg peak region. The proposed method is able to calculate the dose profile with mean relative errors of 0.8%, 1.0% and 1.6% from the 11C, 10C, 15O fragment profiles, respectively, and estimate the position of the distal edge of the SOBP to within an average of 0.7 mm, 1.9 mm and 1.2 mm of its true location.

Feasibility and analysis of CNN-based candidate beam generation for robotic radiosurgery.

PURPOSE: Robotic radiosurgery offers the flexibility of a robotic arm to enable high conformity to the target and a steep dose gradient. However, treatment planning becomes a computationally challenging task as the search space for potential beam directions for dose delivery is arbitrarily large. We propose an approach based on deep learning to improve the search for treatment beams. METHODS: In clinical practice, a set of candidate beams generated by a randomized heuristic forms the basis for treatment planning. We use a convolutional neural network to identify promising candidate beams. Using radiological features of the patient, we predict the influence of a candidate beam on the delivered dose individually and let this prediction guide the selection of candidate beams. Features are represented as projections of the organ structures which are relevant during planning. Solutions to the inverse planning problem are generated for random and CNN-predicted candidate beams. RESULTS: The coverage increases from 95.35% to 97.67% for 6000 heuristically and CNN-generated candidate beams, respectively. Conversely, a similar coverage can be achieved for treatment plans with half the number of candidate beams. This results in a patient-dependent reduced averaged computation time of 20.28%-45.69%. The number of active treatment beams can be reduced by 11.35% on average, which reduces treatment time. Constraining the maximum number of candidate beams per beam node can further improve the average coverage by 0.75 percentage points for 6000 candidate beams. CONCLUSIONS: We show that deep learning based on radiological features can substantially improve treatment plan quality, reduce computation runtime, and treatment time compared to the heuristic approach used in clinics.

Magnetic Resonance Imaging-Based Robotic Radiosurgery of Arteriovenous Malformations.

OBJECTIVE: CyberKnife offers CT- and MRI-based treatment planning without the need for stereotactically acquired DSA. The literature on CyberKnife treatment of cerebral AVMs is sparse. Here, a large series focusing on cerebral AVMs treated by the frameless CyberKnife stereotactic radiosurgery (SRS) system was analyzed. METHODS: In this retrospective study, patients with cerebral AVMs treated by CyberKnife SRS between 2005 and 2019 were included. Planning was MRI- and CT-based. Conventional DSA was not coregistered to the MRI and CT scans used for treatment planning and was only used as an adjunct. Obliteration dynamics and clinical outcome were analyzed. RESULTS: 215 patients were included. 53.0% received SRS as first treatment; the rest underwent previous surgery, embolization, SRS, or a combination. Most AVMs were classified as Spetzler-Martin grade I to III (54.9%). Hemorrhage before treatment occurred in 46.0%. Patients suffered from headache (28.8%), and seizures (14.0%) in the majority of cases. The median SRS dose was 18 Gy and the median target volume was 2.4 cm³. New neurological deficits occurred in 5.1% after SRS, with all but one patient recovering. The yearly post-SRS hemorrhage incidence was 1.3%. In 152 patients who were followed-up for at least three years, 47.4% showed complete AVM obliteration within this period. Cox regression analysis revealed Spetzler-Martin grade (P = 0.006) to be the only independent predictor of complete obliteration. CONCLUSIONS: Although data on radiotherapy of AVMs is available, this is one of the largest series, focusing exclusively on CyberKnife treatment. Safety and efficacy compared favorably to frame-based systems. Non-invasive treatment planning, with a frameless SRS robotic system might provide higher patient comfort, a less invasive treatment option, and lower radiation exposure.

Comparative study of alternative Geant4 hadronic ion inelastic physics models for prediction of positron-emitting radionuclide production in carbon and oxygen ion therapy.

The distribution of fragmentation products predicted by Monte Carlo simulations of heavy ion therapy depend on the hadronic physics model chosen in the simulation. This work aims to evaluate three alternative hadronic inelastic fragmentation physics options available in the Geant4 Monte Carlo radiation physics simulation framework to determine which model most accurately predicts the production of positron-emitting fragmentation products observable using in-beam PET imaging. Fragment distributions obtained with the BIC, QMD, and INCL + + physics models in Geant4 version 10.2.p03 are compared to experimental data obtained at the HIMAC heavy-ion treatment facility at NIRS in Chiba, Japan. For both simulations and experiments, monoenergetic beams are applied to three different block phantoms composed of gelatin, poly(methyl methacrylate) and polyethylene. The yields of the positron-emitting nuclei 11C, 10C and 15O obtained from simulations conducted with each model are compared to the experimental yields estimated by fitting a multi-exponential radioactive decay model to dynamic PET images using the normalised mean square error metric in the entrance, build up/Bragg peak and tail regions. Significant differences in positron-emitting fragment yield are observed among the three physics models with the best overall fit to experimental 12C and 16O beam measurements obtained with the BIC physics model.

Good fertilization results associated with high IL-1beta concentrations in follicular fluid of IVF patients.

OBJECTIVE: To determine the levels of interleukin-1 beta (IL-1beta) in follicular fluid and embryo culture fluid after controlled ovarian hyperstimulation and to assess the association of this cytokine with the outcome of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment and embryo transfer. STUDY DESIGN: A total of 256 couples undergoing the IVF/ICSI program were included in this prospective study. Zygote quality, embryo and blastocyst morphology were evaluated, and embryo transfer was performed 5 days after oocyte recovery. IL-1beta concentrations were measured in follicular fluid and embryo culture fluid of the third and fifth culture days. RESULTS: Embryo replacement was performed with a median of 2 embryos per cycle. In all, 44 clinical pregnancies were achieved in 256 assisted reproductive technology (ART) cycles (pregnancy rate: 19.8% per transfer). Follicular fluid concentrations of IL-1P were not significantly different in pregnant (2.1 pg/mL) and nonpregnant women (2.7 pg/mL). Follicular fluid of lVF, but not ICSI, patients with good fertilization rates (> 90%) contained significantly higher levels of IL-1beta (3.3 pg/ mL) than did follicular fluid of women with fertilization rates < or = 90% (2.0 pg/mL, p < 0.05). No correlation was found between intrafollicular IL-1beta and zygote morphology, day 3 and day 5 embryo morphology. There was no relationship between IL-1beta in culture fluid supernatants and embryonic development. CONCLUSION: In IVF patients high levels of intrafollicular IL-1beta were associated with good fertilization rates. There seems to be no correlation between IL-1beta concentrations in follicular fluid or embryo culture fluid and embryo morphology or pregnancy outcome of ART cycles.