Radiographic Alignment in Deformity Patients Treated With Personalized Interbody Devices: Early Experience From the COMPASS Registry.

BACKGROUND: Literature supports the need for improved techniques to achieve spinopelvic alignment and reduce complication rates in patients with adult spinal deformity (ASD). Personalized interbody devices were developed to address this need and are under evaluation in the multicenter Clinical Outcome Measures in Personalized aprevo (circle R superscript) Spine Surgery (COMPASS (TM suprascript) registry. This report presents interim COMPASS pre- and postoperative sagittal alignment results and complication rates for a subcohort of COMPASS patients diagnosed and surgically treated for spinal deformity. METHODS: COMPASS is a postmarket observational registry of patients enrolled either before or after index surgery and then followed prospectively for 24 months. Sagittal alignment was assessed with SRS-Schwab modifiers for pelvic incidence minus lumbar lordosis, pelvic tilt, and T1 pelvic angle. Summed SRS-Schwab modifiers were utilized to assign overall deformity status as mild, moderate, or severe. Complications were extracted from patient medical records. RESULTS: The study included 67 patients from 9 centers. Preoperative severe deformity was observed in 66% of patients. Index surgeries included implantation of a median of 2 personalized interbody devices by anterior, lateral, or transforaminal approaches and with a median of 8 posteriorly instrumented levels. Overall postoperative sagittal alignment improved with a significant decrease in the mean sum of SRS-Schwab modifiers that correlated strongly to improvements in pelvic incidence minus lumbar lordosis. Among 44 patients with preoperative severe overall deformity, 16 improved to moderate and 9 to mild deformity. Complications occurred for 13 patients (19.4%), including 1 mechanical complication requiring revision 9 months after surgery and none related to personalized interbody devices. CONCLUSIONS: This study demonstrates that ASD patients whose treatment included personalized interbody devices can obtain favorable postoperative alignment status comparable to published results and with no complications related to the personalized interbody devices. CLINICAL RELEVANCE: This study contributes to growing evidence that personalized interbody devices contribute to improved sagittal alignment in ASD patients by directly adjusting the orientation of adjacent vertebra.

A Projection Integration Method for X-ray Collimator Design.

One of the recent trends in radiation therapy is to increase conformal and accurate dose delivery such as in stereotactic radiosurgery (SRS). Treating small lesions and brain disorders requires the accurate placement of small radiation fields deep inside the human cranium. To design a collimator meeting these requirements, a new numerical concept was developed, which is presented here. The algorithm proposed here can generate beam profiles of plural collimation apertures and arbitrary initial beam spot distributions in a time-efficient method. It is an ideal tool to optimize collimator design for penumbra, dose rate, and field size. The intensity of the source beam spot is divided into slices, and each slice is projected onto the treatment plane at the isocenter through the collimator apertures. The illuminated field range and intensity are determined by geometry and the intensity of that slice of beam source, respectively. By integrating the projected intensity across all the slices of the source profile, the profile on the treatment plane is obtained. The algorithm is used to generate beam profiles of a conical pencil beam collimator system and compare them to the Monte Carlo simulation as well as measurements. It can also be used to demonstrate the impact of collimator shape on the beam penumbra, dose rate, and field size. The projection integration method provides a quick and informative tool for collimator design. The results were validated with the Monte Carlo simulation and measurements. This method was demonstrated to be effective for optimizing beam characteristics.

Investigation of a novel 2.5 MV sintered diamond target beam for intracranial linac-based stereotactic treatments.

PURPOSE: This work investigates the small-field dosimetric characteristics of a 2.5 MV sintered diamond target beam and its feasibility for use in linac-based intracranial stereotactic treatments. Due to the increased proportion of low energy photons in the low-Z beam, it was hypothesized that this novel beam would provide sharper dose fall-off compared to the 6 MV beam owing to the reduced energy, and therefore range, of secondary electrons. MATERIAL AND METHODS: Stereotactic treatments of ocular melanoma and trigeminal neuralgia were simulated for 2.5 MV low-Z and 6 MV beams using Monte Carlo to calculate dose in a voxelized anatomical phantom. Two collimation methods were investigated, including a 5x3 mm2 HDMLC field and a 4 mm cone to demonstrate isolated and combined effects of geometric and radiological contributions to the penumbral width. RESULTS: The measured 2.5 MV low-Z dosimetric profiles demonstrated reduced penumbra by 0.5 mm in both the inline and crossline directions across all depths for both collimation methods, compared to 6 MV. In both treatment cases, the 2.5 MV low-Z beam collimated with the 4 mm cone produced the sharpest dose fall off in profiles captured through isocenter. This improved fall-off resulted in a 59% decrease to the maximum brainstem dose in the trigeminal neuralgia case for the 2.5 MV low-Z MLC collimated beam compared to 6 MV. Reductions to the maximum and mean doses to ipsilateral and contralateral OARs in the ocular melanoma case were observed for the 2.5 MV low-Z beam compared to 6 MV with both collimation methods. CONCLUSIONS: While the low dose rate of this novel beam prohibits immediate clinical translation, the results of this study support the further development of this prototype beam to decrease toxicity in intracranial SRS treatments. .

A single center, inter-observer evaluation of vestibular schwannoma stereotactic radiosurgery and its dosimetric impact.

The aim of this work was to evaluate the inter- and intra-observer variation in contouring vestibular schwannoma (VS) and the organs-at-risk (OAR), and its dosimetric impact in Volumetric Modulated Arc Therapy (VMAT). Three VS typical cases were contoured by four clinicians. The Agreement Volume Index (AVI) appeared to be notably higher in VS than in OARs, such that the dose coverage of VS is fairly robust. In OARs, the largest variation was +1.02Gy in dmax for the brainstem, +0.78Gy in dmean for the cochlea and +1.05Gy in dmax of the trigeminal nerve. Accordingly, it was decided that all VS delineations for stereotactic radiosurgery (SRS), and all frame-based SRS contouring in general, should always be reviewed by a second physician. In addition, the retrospective presentation of VS cases at daily peer review meetings has also been adopted to ensure that the consensus is constantly updated, as well as for training purposes.

Impact of TP53 mutations on brain metastasis control in non-small cell lung cancer patients undergoing stereotactic radiosurgery.

Purpose: To investigate whether TP53 variants may be correlated with overall survival and local control following stereotactic radiosurgery (SRS) for brain metastases (BMs) from non-small cell lung cancer (NSCLC). Methods: Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified. Overall survival and freedom from local intracranial progression (FFLIP) were estimated via Kaplan-Meier method. Cox models assessed TP53 variant status (pathogenic variant, PV; variant not detected, ND). Results: 255 patients underwent molecular profiling for TP53, among whom 144 (56%) had a TP53 PV. Median follow-up was 11.6 months. OS was not significantly different across TP53 status. A trend toward superior FFLIP was observed for PV (95% CI 62.9 months-NR) versus ND patients (95% CI 29.4 months-NR; p=0.06). Superior FFLIP was observed for patients with one TP53 variant versus those with TP53 ND. Conclusion: Among NSCLC patients with BMs, the potential association between TP53 status and post-SRS FFLIP warrants further investigation in a larger prospective cohort.

The Effect of Global Spinal Alignment on the Cervical Degeneration in Patients with Degenerative Lumbar Scoliosis.

PURPOSE: To elucidate the effect of global spinal alignment on the cervical degeneration in Patients with Degenerative Lumbar Scoliosis (DLS). METHODS: A total of 117 patients with DLS and 42 controls were analysed. DLS patients (study group) were categorized according to the SRS-Schwab classification. Patients with lumbar spinal stenosis were reviewed as a control group. Spinopelvic parameters were measured in cervical and full-length spine radiographs. Cervical degeneration was assessed using the Cervical Degeneration Index (CDI) scoring system. RESULTS: There were significant differences in C2-7 sagittal vertical axis, T1 Slope, thoracic kyphosis, Lumbar Lordosis (LL), and pelvic tilt between DLS and control groups. Although the DLS and control groups did not differ significantly with regard to CDI scores, a striking difference was noted when sagittal spinopelvic modifiers were considered individually. Patients with a Pelvic Incidence minus Lumbar Lordosis (PI-LL) modifier grade of ++ had significantly higher CDI scores than those with 0, and patients with a PI-LL or Sagittal Vertical Axis (SVA) modifier grade of ++ had significantly higher CDI scores than control group. Disk narrowing scores were highest in patients with a PI-LL modifier grades of ++ followed by those with +. Additionally, CDI scores were more associated with LL rather than cervical lordosis. CONCLUSIONS: Patients with DLS may be at greater risk of cervical spine degeneration, especially those with a PI-LL or SVA modifier grade of ++. Surgical strategy for DLS patients should be more carefully selected considering the restoration of LL.

Localization of EFA6A, an exchange factor for Arf6, in Z-lines and sarcoplasmic reticulum membranes in addition to myofilaments in I-domains of skeletal myofibers of peri-natal mice.

Membrane trafficking and actin-remodeling are critical for well-maintained integrity of the cell organization and activity, and they require Arf6 (ADP ribosylation factor 6) activated by GEF (guanine nucleotide exchange factor) including EFA6 (exchange factor for Arf6). In the present immuno-electron microscopic study following previous immunohistochemical study by these authors (Chomphoo et al., 2020) of in situ skeletal myoblasts and myotubes of pre-and perinatal mice, the immunoreactivity for EFA6A was found to be localized at Z-bands and sarcoplasmic reticulum (SR) membranes in I-domains as well as I-domain myofilaments of skeletal myofibers of perinatal mice. Based on the previous finding that EFA6 anchored on the neuronal postsynaptic density via α-actinin which is known to be shared by muscular Z-bands, the present finding suggests that EFA6A is also anchored on Z-bands via α-actinin and involved in the membrane trafficking and actin-remodeling in skeletal myofibers. The localization of EFA6A-immunoreactivity in I-domain SR suggests a differential function in the membrane traffic between the I- and A-domain intracellular membranes in perinatal skeletal myofibers.

A mini review of plan quality and secondary cancer risk in CyberKnife M6 radiosurgery for benign intracranial tumors.

With advancements in medical technology, stereotactic radiosurgery (SRS) has become an essential option for treating benign intracranial tumors. Due to its minimal side effects and high local control rate, SRS is widely applied. This paper evaluates the plan quality and secondary cancer risk (SCR) in patients with benign intracranial tumors treated with the CyberKnife M6 system. The CyberKnife M6 robotic radiosurgery system features both multileaf collimator (MLC) and IRIS variable aperture collimator systems, providing different treatment options. The study included 15 patients treated with the CyberKnife M6 system, examining the differences in plan quality and SCR between MLC and IRIS systems. Results showed that MLC and IRIS plans had equal PTV (planning target volume) coverage (98.57% vs. 98.75%). However, MLC plans demonstrated better dose falloff and conformity index (CI: 1.81 ± 0.26 vs. 1.92 ± 0.27, P = 0.025). SCR assessment indicated that MLC plans had lower cancer risk estimates, with IRIS plans having average LAR (lifetime attributable risk) and EAR (excess absolute risk) values approximately 25% higher for cancer induction and 15% higher for sarcoma induction compared to MLC plans. The study showed that increasing tumor volume increases SCR probability, but there was no significant difference between different plans in PTV and brainstem analyses.

Timing of stereotactic radiosurgery within the first-line systemic treatment in non-small cell lung cancer brain metastases: a retrospective single-center cohort study.

Background: Stereotactic radiosurgery/radiotherapy (SRS/SRT) and novel systemic treatments, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), have demonstrated to be effective in managing brain metastases in non-small cell lung cancer (NSCLC). However, the optimal treatment sequence of SRS/SRT and TKI/ICI remains uncertain. This retrospective monocentric analysis addresses this question by comparing the outcomes of patients with NSCLC brain metastases who received upfront SRS/SRT versus those who were initially treated with TKI/ICI. Methods: All patients treated with SRS/SRT and TKI/ICI for NSCLC brain metastases were collected from a clinical database. The patients who received first-line TKI or ICI for the treatment of brain metastases were then selected for further analysis. Within this cohort, a comparative analysis between upfront SRS/SRT and patients initially treated with TKI/ICI was conducted, assessing key parameters such as overall survival (OS), intracranial progression-free survival (iPFS) and treatment-related toxicity. Both OS and iPFS were defined as the time from SRS/SRT to either death or disease progression, respectively. Results: The analysis encompassed 54 patients, of which 34 (63.0%) patients received SRS/SRT and TKI/ICI as their first-line therapy. Of the latter, 17 (50.0%) patients received upfront SRS/SRT and 17 (50.0%) were initially treated with TKI/ICI; 24 (70.6%) received SRS/SRT and ICI, and 10 (29.4%) received SRS/SRT and TKI. The cohorts did not significantly differ in the univariable analyses for the following parameters: sex, age, histology, molecular genetics, disease stage at study treatment, performance status, number of brain metastases, treatment technique, tumor volume, target volume, disease progression, radiation necrosis, dosimetry. While no significant differences were found in terms of iPFS and OS between patients treated with upfront SRS/SRT and patients initially treated with TKI, upfront SRS/SRT demonstrated significantly superior OS when compared to patients initially treated with ICI (median OS not reached vs. 17.5 months; mean 37.8 vs. 23.6 months; P=0.03) with no difference in iPFS. No significant differences in treatment-related toxicity were observed among the cohorts. Conclusions: In this retrospective, single-center cohort study, patients treated with upfront SRS/SRT demonstrated significantly longer OS compared to patients initially treated with ICI in the cohort receiving first-line therapy for brain metastases. However, given the retrospective design and the limited cohort size, definitive conclusions cannot be drawn from these findings. Nevertheless, the results suggest that the timing of SRS/SRT may play an important role in treatment outcomes. Further investigation, preferably through prospective randomized trials, is warranted to provide more conclusive answers to this important question.

Single versus multiple fraction stereotactic radiosurgery for medium-sized brain metastases (4-14 cc in volume): reducing or fractionating the radiosurgery dose?

Background and purpose: Stereotactic radiosurgery (SRS) of brain metastases (BM) and resection cavities is a widely used and effective treatment modality. Based on target lesion size and anatomical location, single fraction SRS (SF-SRS) or multiple fraction SRS (MF-SRS) are applied. Current clinical recommendations conditionally recommend either reduced dose SF-SRS or MF-SRS for medium-sized BM (2-2.9 cm in diameter). Despite excellent local control rates, SRS carries the risk of radionecrosis (RN). The purpose of this study was to assess the 12-months local control (LC) rate and 12-months RN rate of this specific patient population. Materials and methods: This single-center retrospective study included 54 patients with medium-sized intact BM (n=28) or resection cavities (n=30) treated with either SF-SRS or MF-SRS. Follow-up MRI was used to determine LC and RN using a modification of the "Brain Tumor Reporting and Data System" (BT-RADS) scoring system. Results: The 12-month LC rate following treatment of intact BM was 66.7% for SF-SRS and 60.0% for MF-SRS (p=1.000). For resection cavities, the 12-month LC rate was 92.9%% after SF-SRS and 46.2% after MF-SRS (p=0.013). For intact BM, RN rate was 17.6% for SF-SRS and 20.0% for MF-SRS (p=1.000). For resection cavities, RN rate was 28.6% for SF-SRS and 20.0% for MF-SRS (p=1.000). Conclusion: Patients with intact BM showed no statistically significant differences in 12-months LC and RN rate following SF-SRS or MF-SRS. In patients with resection cavities the 12-months LC rate was significantly better following SF-SRS, with no increase in the RNFS.

Effect of modulation factor and low dose threshold level on gamma pass rates of single isocenter multi-target SRT treatment plans.

PURPOSE: SRS MapCHECK (SMC) is a commercially available patient-specific quality assurance (PSQA) tool for stereotactic radiosurgery (SRS) applications. This study investigates the effects of degree of modulation, location off-axis, and low dose threshold (LDT) selection on gamma pass rates (GPRs) between SMC and treatment planning system, Analytical Anisotropic Algorithm (AAA), or Vancouver Island Monte Carlo (VMC++ algorithm) system calculated dose distributions. METHODS: Volumetric-modulated arc therapy (VMAT) plans with modulation factors (MFs) ranging from 2.7 to 10.2 MU/cGy were delivered to SMC at isocenter and 6 cm off-axis. SMC measured dose distributions were compared against AAA and VMC++ via gamma analysis (3%/1 mm) with LDT of 10% to 80% using SNC Patient software. RESULTS: Comparing on-axis SMC dose against AAA and VMC++ with LDT of 10%, all AAA-calculated plans met the acceptance criteria of GPR ≥ 90%, and only one VMC++ calculated plan was marginally outside the acceptance criteria with pass rate of 89.1%. Using LDT of 80% revealed decreasing GPR with increasing MF. For AAA, GPRs reduced from 100% at MF of 2.7 MU/cGy to 57% at MF of 10.2 MU/cGy, and for VMC++ calculated plans, the GPRs reduced from 89% to 60% in the same MF range. Comparison of SMC dose off-axis against AAA and VMC++ showed more pronounced reduction of GPR with increasing MF. For LDT of 10%, AAA GPRs reduced from 100% to 83% in the MF range of 2.7 to 9.8 MU/cGy, and VMC++ GPR reduced from 100% to 91% in the same range. With 80% LDT, GPRs dropped from 100% to 42% for both algorithms. CONCLUSIONS: MF, dose calculation algorithm, and LDT selections are vital in VMAT-based SRT PSQA. LDT of 80% enhances sensitivity of gamma analysis for detecting dose differences compared to 10% LDT. To achieve better agreement between calculated and SMC dose, it is recommended to limit the MF to 4.6 MU/cGy on-axis and 3.6 MU/cGy off-axis.

Evaluating effectiveness of clustering algorithms in multiple target stereotactic radiosurgery.

Objective. Single-isocenter-multiple-target technique for stereotactic radiosurgery (SRS) can reduce treatment duration but risks compromised dose coverage due to potential rotational errors. Clustering targets into two groups can reduce isocenter-target distances, mitigating the impact of rotational uncertainty. However, a comprehensive evaluation of clustering algorithms for SRS is absent. This study addresses this gap by introducing the SRS Target Clustering Framework (Framework), a comprehensive tool that utilizes commonly used clustering algorithms to generate efficient cluster configurations.Approach. The Framework incorporates four distinct optimization objectives based on two key metrics: the isocenter-target distance and the ratio of this distance to the target radius. Agglomerative and weighted agglomerative clustering are employed for minimax and weighted minimax objectives, respectively. K-means and weighted k-means are utilized for sum-of-squares and weighted sum-of-squares objectives. We applied the Framework to 126 SRS plans, comparing results to ground truth solutions obtained through a brute force algorithm.Main results. For the minimax objective, the average maximum isocenter-target distance from agglomerative clustering (4.8 cm) was slightly higher than the ground truth (4.6 cm). Similarly, the weighted agglomerative clustering achieved an average maximum ratio of 15.1 compared to the ground truth of 14.6. Notably, both k-means and weighted k-means clustering showed close agreement (within a precision of 0.1) with the ground truth for average root-mean-square target-isocenter distance and ratio (3.6 cm and 11.1, respectively).Significance. These results demonstrate the Framework's effectiveness in generating clusters for SRS targets. The proposed approach has the potential to become a valuable tool in SRS treatment planning. Furthermore, this study is the first to investigate clustering algorithms for both minimizing maximum and sum-of-squares uncertainty in SRS.

Determinants of cerebral radionecrosis in animal models: A systematic review.

BACKGROUND: Radionecrosis is a common complication in radiation oncology, while mechanisms and risk factors have yet to be fully explored. We therefore conducted a systematic review to understand the pathogenesis and identify factors that significantly affect the development. METHODS: We performed a systematic literature search based on the PRISMA guidelines using PubMed, Ovid, and Web of Science databases. The complete search strategy can be found as a preregistered protocol on PROSPERO (CRD42023361662). RESULTS: We included 83 studies, most involving healthy animals (n = 72, 86.75 %). High doses of hemispherical irradiation of 30 Gy in rats and 50 Gy in mice led repeatedly to radionecrosis among different studies and set-ups. Higher dose and larger irradiated volume were associated with earlier onset. Fractionated schedules showed limited effectiveness in the prevention of radionecrosis. Distinct anatomical brain structures respond to irradiation in various ways. White matter appears to be more vulnerable than gray matter. Younger age, more evolved animal species, and genetic background were also significant factors, whereas sex was irrelevant. Only 13.25 % of the studies were performed on primary brain tumor bearing animals, no studies on brain metastases are currently available. CONCLUSION: This systematic review identified various factors that significantly affect the induction of radionecrosis. The current state of research neglects the utilization of animal models of brain tumors, even though patients with brain malignancies constitute the largest group receiving brain irradiation. This latter aspect should be primarily addressed when developing an experimental radionecrosis model for translational implementation.

Multi-institutional investigation into the robustness of intra-cranial multi-target stereotactic radiosurgery plans to patient setup errors.

PURPOSE: This study aimed to analyse correlations between planning factors including plan geometry and plan complexity with robustness to patient setup errors. METHODS: Multiple-target brain stereotactic radiosurgery (SRS) plans were obtained through the Trans-Tasman Radiation Oncology Group (TROG) international treatment planning challenge (2018). The challenge dataset consisted of five intra-cranial targets with a 20 Gy prescription. Setup error was simulated using an in-house tool. Dose to targets was assessed via dose covering 99 % (D99 %) of gross tumour volume (GTV) and 98 % of planning target volume (PTV). Dose to organs at risk was assessed using volume of normal brain receiving 12 Gy and maximum dose covering 0.03 cc of brainstem. Plan complexity was assessed via edge metric, modulation complexity score, mean multi-leaf collimator (MLC) gap, mean MLC speed and plan modulation. RESULTS: Even for small (0.5 mm/°) errors, GTV D99 % was reduced by up to 20 %. The strongest correlation was found between lower complexity plans (larger mean MLC gap and lower edge metric) and higher robustness to setup error. Lower complexity plans had 1 %-20 % fewer targets/scenarios with GTV D99 % falling below the specified tolerance threshold. These complexity metrics correlated with 100 % isodose volume sphericity and dose conformity, though similar conformity was achievable with a range of complexities. CONCLUSIONS: A higher level of importance should be directed towards plan complexity when considering plan robustness. It is recommended when planning multi-target SRS, larger MLC gaps and lower MLC aperture irregularity be considered during plan optimisation due to higher robustness should patient positioning errors occur.

Repeated HyperArc radiosurgery for recurrent intracranial metastases and dosimetric analysis of recurrence pattern to account for diffuse dose effect on microscopical disease.

Aims: Evaluate effectiveness and safety of multiple HyperArc courses and patterns of progression in patients affected by BMs with intracranial progression. Methods: 56 patients were treated for 702 BMs with 197 (range 2-8) HyperArc courses in case of exclusive intracranial progression. Primary end-point was the overall survival (OS), secondary end-points were intracranial progression-free survival (iPFS), toxicity, local control (LC), neurological death (ND), and whole-brain RT (WBRT)-free survival. Site of progression was evaluated against isodoses levels (0, 1, 2, 3, 5, 7, 8, 10, 13, 15, 20, and 24 Gy.). Results: The 1-year OS was 70 %, and the median was 20.8 months (17-36). At the univariate analysis (UVA) biological equivalent dose (BED) > 51.3 Gy and non-melanoma histology significantly correlated with OS. The median time to iPFS was 4.9 months, and the 1-year iPFS was 15 %. Globally, 538 new BMs occurred after the first HA cycle in patients with extracranial disease controlled. 96.4 % of them occurred within the isodoses range 0-7 Gy as follows: 26.6 % (0 Gy), 16.5 % (1 Gy), 16.5 % (2 Gy), 20.1 % (3 Gy), 13.1 % (5 Gy), 3.4 % (7 Gy) (p = 0.00). Radionecrosis occurred in 2 metastases (0.28 %). No clinical toxicity of grade 3 or higher occurred during follow-up. One- and 2-year LC was 90 % and 79 %, respectively. At the UVA BED > 70 Gy and non-melanoma histology were significant predictors of higher LC. The 2-year WBRT-free survival was 70 %. After a median follow-up of 17.4 months, 12 patients deceased by ND. Conclusion: Intracranical relapses can be safely and effectively treated with repeated HyperArc, with the aim to postpone or avoid WBRT. Diffuse dose by volumetric RT might reduce microscopic disease also at relatively low levels, potentially acting as a virtual CTV. Neurological death is not the most common cause of death in this population, which highlights the impact of extracranial disease on overall survival.

Safety, Tolerability, and EEG-Based Target Engagement of STP1 (PDE3,4 Inhibitor and NKCC1 Antagonist) in a Randomized Clinical Trial in a Subgroup of Patients with ASD.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1's mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

Stereotactic Radiosurgery with Volumetric Modulated Arc Radiotherapy: Final Results of a Multi-arm Phase I Trial (DESTROY-2).

AIMS: To present the final results of a phase I trial on stereotactic radiosurgery (SRS) delivered using volumetric modulated arc therapy (VMAT) in patients with primary or metastatic tumors in different extracranial sites. MATERIALS AND METHODS: The DESTROY-2 trial, planned as a prospective dose escalation study in oligometastatic (one to five lesions) cancer patients relied on the delivery of a single high dose of radiation utilizing high-precision technology. The primary study endpoint was the definition of the maximum tolerated dose (MTD) of SRS-VMAT. The secondary objectives of the study were the evaluation of safety, efficacy, and long-term outcomes. All patients consecutively observed at our radiotherapy unit matching the inclusion criteria were enrolled. Each enrolled subject was included in a different phase I study arm, depending on the tumor site and the disease stage (lung, liver, bone, other), and sequentially assigned to a particular dose level. RESULTS: Two hundred twenty seven lesions in 164 consecutive patients (male/female: 97/67, median age: 68 years; range: 29-92) were treated. The main primary tumors were: prostate cancer (60 patients), colorectal cancer (47 patients), and breast cancer (39 patients). The maximum planned dose level was achieved in all study arms, and the MTD was not exceeded. 34 Gy, 32 Gy, 24 Gy, and 24 Gy were established as the single-fraction doses for treating lung, liver, bone, and other extracranial lesions, respectively. The prescribed BED 2Gyα/ß:10 to the planning target volume ranged from 26.4 Gy to 149.6 Gy. Twenty-seven patients (16.5%) experienced grade 1-2 and only one grade 3 acute toxicity, which was a pulmonary one. In terms of late toxicity, we registered only 5 toxicity>G2: a G3 gastro-intestinal one, three G3 bone toxicity, and a G3 laryngeal toxicity. The overall response was available for 199 lesions: 107 complete response (53.8%), 50 partial response (25.1%), and 31 stable disease (15.6%), leading to an overall response rate of 94.5%. Progression was registered only in 11 cases (5.5%). The overall response rate in each arm ranged from 88.6% to 96.4%. The overall two-year local control, distant metastasis free survival, disease free survival, and overall survival were 81.7%, 33.0%, 25.4%, and 78.7% respectively. CONCLUSION: In conclusion, the planned doses of 34 Gy, 32 Gy, 24 Gy, and 24 Gy were successfully administered as single-fractions for the treatment of lung, liver, bone, and other extracranial lesions, respectively, in a prospective SRS dose-escalation trial. No dose-limiting toxicities were registered, and minimal acute and late toxicity were reported. New indications for SRS are currently being studied in oligoprogressive patients receiving targeted drugs or in combination with immunotherapy. The DESTROY-2 trial represents, in our opinion, a credible starting point for future modern radiosurgery trials.

Clinical impact of DVH uncertainties.

Dose-volume histograms (DVH), along with dose and volume metrics, are central to radiotherapy planning. As such, errors have the potential to significantly impact the selection of appropriate treatment plans. Dose distributions that pass tests in one TPS may fail the same tests when transferred to another, even if using identical structures and dose grid information. This work shows the design and implementation of methods for assessing the accuracy of dose and volume computations performed by treatment planning systems (TPS), and other analytical tools. We demonstrate examples where differences in calculations between systems can change the assessment of a plan's clinical acceptability. Our work also provides a more detailed DVH analysis of single targets than earlier published studies. This is relevant for SRS plans and small structure dose assessments. Very small structures are a particular problem because of their coarse digital representation, and the impact of this is thoroughly examined. Reference DVH curves were derived mathematically, based on Gaussian dose distributions centered on spherical structures. The structures and dose distributions were generated synthetically, and imported into RayStation, MasterPlan, and ProKnow. Corresponding DVHs were analytically derived and taken as ground truth references, for comparison with the commercial DVH calculations. Two commonly used dose metrics PCI and MGI were used to determine the limit of calculation accuracy for small structures. In addition, to measure the DVH differences between a larger range of commercial DVH calculators, the D95 metric from a set of real clinical plans was compared across both the 3 DVH calculators under test, and across a further six TPSs from other hospitals. We show that even slight deviations between the results of DVH calculators can lead to plan check failures, and we illustrate this with the commonly used D95 planning metric. We present clinical data across eight planning systems that highlight instances where plan checks would pass in one software and fail in another due to DVH calculation differences. For the smallest volumes tested, errors of up to 20% were observed in the DVHs. RayStation was tested down to a 3 mm radius sphere (≈0.1 cc) and this showed close to 10% error, reducing to 1% for 10 mm radius (≈4.0 cc) and 0.1% for 20 mm radius (≈33 cc). In clinical plans, the variation in D95 was up to 9% for the smallest volumes, and typically around 2% in the range 0.5 cc-20 cc, and 1% in 20 cc-70 cc, falling to <0.1% for large volumes. Paddick Conformity Index (PCI) and Modified Gradient Index (MGI) are commonly used plan quality indicators for very small volumes. For volumes ≈0.1 cc we observed errors of up to 40% in PCI, and up to 75% in MGI. Our study extends the range of tested DVH calculators in published work, and shows their performance over a wider range of volume sizes. We provide quantitative evidence of the critical need to test the accuracy of DVH calculators in the TPS before clinical use. This work is particularly relevant for both stereotactic plan evaluation and for assessment of small volume doses in published dose constraint recommendations. We demonstrate that significant errors can occur in DVHs for volumes less than 1 cc, even if the volumes themselves are calculated accurately. Even for large structures, deviations between the outputs of DVH calculators can lead to indicated or reported plan check failures if they do not include appropriate tolerances. We urge caution in the use of DVH metrics for these very small volumes and recommend that appropriate DVH uncertainty tolerances are set in organ dose constraints when using them to evaluate clinical plans.

Off-iso Winston-Lutz test on seven linear accelerators.

PURPOSE: The aim of this study is to find optimal gantry, collimator, and couch angles for performing single isocenter, multiple target stereotactic radiosurgery (SIMT-SRS). Nineteen angle sets were tested across seven linear accelerators for radiation-isocenter coincidence and off-isocenter coincidence. The off-isocenter Winston-Lutz test was performed to evaluate the accuracy of isocenter alignment for each angle set, and optimal angle sets as well as maximum off-isocenter distance to target for each angle set was determined. The influence of simulated patient weight on off-iso Winston-Lutz test accuracy was also inspected. METHOD: The SNC MultiMet-WL phantom and MultiMet-WL QA Software v2.1 were used for the direct measurement and analysis of the off-iso Winston-Lutz test (also referred to as Winston-Lutz-Gao test). A two-step method was developed to ensure precise initial placement of the target. Nineteen beams were delivered at 6X energy and 2 × 2 cm field size to each of six targets on the MultiMet Cube with couch kicks at five cardinal angles (90°, 45°, 0°, 315°, and 270°). To reduce imaging uncertainty, only EPID was used in target alignment and test image acquisition. A total of 200 Ibs (90.7 kg) of weight was also used to mimic patient weight. All tests were performed on both the free table and the weighted table. RESULTS: For two new TrueBeam machines, the maximum offset was within the 1 mm tolerance when the off-iso distance is less than 7 cm. Two older VitalBeam machines exhibited unfavorable gantry, couch, and collimator (GCC) angle sets: Linac No. 3 at (0,90,0), (0,270,0) and Linac No. 4 at (0,45,45) and (0,90,0). The C-Series Linacs failed in the majority of GCC angle sets, with Linac No. 5 exhibiting a maximum offset of 1.53 mm. Four of seven machines show a clear trend that offset increases with off-isocenter distance. Additionally, the IGRT table was less susceptible to the addition of simulated patient weight than the ExactCouch. CONCLUSION: Among the seven linear accelerators addressed, newer model machines such as the Varian TrueBeam were more precise than older models, especially in comparison to the C-Series Linacs. The newer machines are more suitable for delivering SIMT-SRS procedures in all GCC angle sets, and the results indicate that newer TrueBeams are capable of performing SIMT-SRS procedures at all angle sets for targets of off-iso distances up to 7 cm. The trend that offset between the target center and radiation field center increases with off-iso distance, however, does not always hold true across machines. This may be comprised by the EPID's severe off-axis horn effect. Lastly, the IGRT couch was less susceptible to patient weight compared to ExactCouch in the off-isocenter Winston-Lutz test.

Evaluating stereotactic accuracy with patient-specific MRI distortion corrections for frame-based radiosurgery.

PURPOSE: This study examines how MRI distortions affect frame-based SRS treatments and assesses the need for clinical distortion corrections. METHODS: The study included 18 patients with 80 total brain targets treated using frame-based radiosurgery. Distortion within patients' MRIs were corrected using Cranial Distortion Correction (CDC) software, which utilizes the patient's CT to alter planning MRIs to reduce inherent intra-cranial distortion. Distortion was evaluated by comparing the original planning target volumes (PTVORIG) to targets contoured on corrected MRIs (PTVCORR). To provide an internal control, targets were also re-contoured on uncorrected (PTVRECON) MRIs. Additional analysis was done to assess if 1 mm expansions to PTVORIG targets would compensate for patient-specific distortions. Changes in target volumes, DICE and JACCARD similarity coefficients, minimum PTV dose (Dmin), dose to 95% of the PTV (D95%), and normal tissue receiving 12 Gy (V12Gy), 10 Gy (V10Gy), and 5 Gy (V5Gy) were calculated and evaluated. Student's t-tests were used to determine if changes in PTVCORR were significantly different than intra-contouring variability quantified by PTVRECON. RESULTS: PTVRECON and PTVCORR relative changes in volume were 6.19% ± 10.95% and 1.48% ± 32.92%. PTVRECON and PTVCORR similarity coefficients were 0.90 ± 0.08 and 0.73 ± 0.16 for DICE and 0.82 ± 0.12 and 0.60 ± 0.18 for JACCARD. PTVRECON and PTVCORR changes in Dmin were -0.88% ± 8.77% and -12.9 ± 17.3%. PTVRECON and PTVCORR changes in D95% were -0.34% ± 5.89 and -8.68% ± 13.21%. The 1 mm expanded PTVORIG targets did not entirely cover 14 of the 80 PTVCORR targets. Normal tissue changes (V12Gy, V10Gy, V5Gy) calculated with PTVRECON were (-0.09% ± 7.39%, -0.38% ± 5.67%, -0.08% ± 2.04%) and PTVCORR were (-2.14% ± 7.34%, -1.42% ± 5.45%, -0.61% ± 1.93%). Except for V10Gy, all PTVCORR changes were significantly different (p < 0.05) than PTVRECON. CONCLUSION: MRIs used for SRS target delineation exhibit notable geometric distortions that may compromise optimal dosimetric accuracy. A uniform 1 mm expansion may result in geometric misses; however, the CDC algorithm provides a feasible solution for rectifying distortions, thereby enhancing treatment precision.