FLASH Radiotherapy Using Single-Energy Proton PBS Transmission Beams for Hypofractionation Liver Cancer: Dose and Dose Rate Quantification

PurposeThis work aims to study the dose and ultra-high-dose rate characteristics of transmission proton pencil beam scanning (PBS) FLASH radiotherapy (RT) for hypofractionation liver cancer based on the parameters of a commercially available proton system operating under FLASH mode.Methods and MaterialsAn in-house treatment planning software (TPS) was developed to perform intensity-modulated proton therapy (IMPT) FLASH-RT planning. Single-energy transmission proton PBS plans of 4.5 Gy × 15 fractions were optimized for seven consecutive hepatocellular carcinoma patients, using 2 and 5 fields combined with 1) the minimum MU/spot chosen between 100 and 400, and minimum spot time (MST) of 2 ms, and 2) the minimum MU/spot of 100, and MST of 0.5 ms, based upon considerations in target uniformities, OAR dose constraints, and OAR FLASH dose rate coverage. Then, the 3D average dose rate distribution was calculated. The dose metrics for the mean dose of Liver-GTV and other major OARs were characterized to evaluate the dose quality for the different combinations of field numbers and minimum spot times compared to that of conventional IMPT plans. Dose rate quality was evaluated using 40 Gy/s volume coverage (V40Gy/s).ResultsAll plans achieved favorable and comparable target uniformities, and target uniformity improved as the number of fields increased. For OARs, no significant dose differences were observed between plans of different field numbers and the same MST. For plans using shorter MST and the same field numbers, better sparing was generally observed in most OARs and was statistically significant for the chest wall. However, the FLASH dose rate coverage V40Gy/s was increased by 20% for 2-field plans compared to 5-field plans in most OARs with 2-ms MST, which was less evident in the 0.5-ms cases. For 2-field plans, dose metrics and V40Gy/s of select OARs have large variations due to the beam angle selection and variable distances to the targets. The transmission plans generally yielded inferior dosimetric quality to the conventional IMPT plans.ConclusionThis is the first attempt to assess liver FLASH treatment planning and demonstrates that it is challenging for hypofractionation with smaller fractional doses (4.5 Gy/fraction). Using fewer fields can allow higher minimum MU/spot, resulting in higher OAR FLASH dose rate coverages while achieving similar plan quality compared to plans with more fields. Shorter MST can result in better plan quality and comparable or even better FLASH dose rate coverage.

Dynamics of fibrotic and vascular endothelial dysfunction markers in elderly hypertensive patients after ischemic stroke receiving beta-blockers

Aim. To compare the effect of beta-blocker therapy (bisoprolol and nebivolol) on the dynamics of fibrotic and vascular endothelial dysfunction markers in elderly hypertensive patients after ischemic stroke (IS).Material and methods. This prospective cohort study included 75 hypertensive patients who were admitted to the hospital due to IS. The mean age of patients was 67±6 years. The average National Institutes of Health Stroke Scale (NIHSS) score was 7±3. The followup period was 6 months. The control group consisted of 20 elderly people with hypertension without prior myocardial infarction. The patients were divided into groups based on received therapy: group 1 (n=38) — bisoprolol; group 2 (n=37) — nebivolol. The level of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) was determined by enzyme-linked immunosorbent assay (ELISAKit, USA). Vascular ultrasound was carried out using a LOGIQP9 (GE) system according to the Celermajer method.Results. After 6-month nebivolol, we revealed a decrease in the level of MMP-9 by 30,2% (p<0,01), TIMP-1 by 15,6% (p<0,05). After 6-month bisoprolol therapy, the level of MMP-9 decreased by 14,5% (p<0,05), while TIMP-1 did not change. Intergroup comparison found that when using nebivolol, there was a higher decrease in the level of MMP-9 by 15,7% (p<0,05), TIMP-1 by 9,7% (p<0,05), MMP-9/TIMP-1 by 7,8% (p<0,05) than with bisoprolol therapy. After 6-month bisoprolol therapy, there was a decrease in the proportion of patients with severe endothelial dysfunction (ED) by 7,9% (p<0,05). Two patients from the nebivolol group moved into mild ED category. The number of patients with moderate ED increased by 19% (p<0,01), while prevalence of severe ED decreased by 24,4% (p<0,01).Conclusion. The results obtained indicate that the beta-blocker nebivolol at an average dose of 8,55+1,75 mg/day significantly reduces the vascular fibrosis, normalizes the ratio of collagen synthesis and degradation markers, improves the vasodilation brachial artery properties in comparison with bisoprolol in elderly hypertensive patients after IS.

Ultrasound navigation during retrobulbar blockade in children with retinoblastoma and enucleation of the eyeball

BACKGROUND: The retrobulbar block in children is used to enucleate analgesia in the intra- and postoperative period and prevent oculocardiac reflex (OCD), postoperative nausea, and vomiting. However, when the block is performed blindly, it results in serious complications. AIM: This study aimed to evaluate the efficacy and safety of a retrobulbar block performed under ultrasound guidance compared with a retrobulbar block performed blindly during enucleation of the eyeball in children with retinoblastoma. MATERIALS AND METHODS: A prospective randomized controlled trial was performed. The study included 40 patients who met the inclusion criteria. The patients were divided into two groups: 20 patients who underwent ultrasound-guided retrobulbar blockade (RBВ + ultrasound) and 20 patients who underwent blindly retrobulbar blockade (RBВ). RESULTS: There was an insignificant decrease in intraoperative opioid requirements in the RBB + ultrasound group, where the average dose of fentanyl was 41.4 g/kg, and in the RBB group, 4.70.8 g/kg (p 0.05). The time before the administration of the first dose of analgesic in the postoperative period was 4.70.8 h in the RBB group and 11.73.3 h in the RBB + ultrasound group (p 0.05). VAS and CHIPPS scores obtained 6 h after the end of surgery in the RBB + ultrasound and RBB groups were 1.8 (1.2; 2) and 2.5 (3.8; 4.5) points (p 0.05), respectively. CONCLUSION: There was no statistically significant difference between the time of the retrobulbar blockade under ultrasound guidance and the retrobulbar regional block performed blindly. Retrobulbar blockade performed under ultrasound guidance provides a decrease in intraoperative opioid requirements, stable intraoperative hemodynamics, and longer postoperative analgesia.

Average corticosteroid dose and risk for HBV reactivation and hepatitis flare in patients with resolved hepatitis B infection

ObjectivesCorticosteroids remain the mainstay of treatment for rheumatic diseases but can cause hepatitis B virus (HBV) reactivation in patients with resolved HBV infection. Risk assessment and stratification are needed to guide the management of these patients before corticosteroid therapy.MethodsWe prospectively enrolled patients with negative hepatitis B surface antigen positive Anti-hepatitis B core status with or without corticosteroid use and determined corticosteroid exposure by calculating cumulative dose and time-weighted average daily dose of prednisone. The primary outcome was the time to a composite of HBV reactivation, hepatitis flare or severe hepatitis.ResultsAmong 1303 participants, the median of cumulative dose and time-weighted average dose of prednisone used in this cohort was 3000 mg (IQR: 300–6750 mg) and 15 mg/day (IQR: 10–20 mg/day), respectively. In multivariable analyses, cumulative dose showed inverted V-shaped relationship with primary events, which peaked at a cumulative dose of 1506 mg (HR: 3.72; 95% CI, 1.96 to 7.08). Quartiles of time-weighted average dose were independently associated with a monotonic increase in event risk (HR per quartile increase: 2.15; 95% CI, 1.56 to 2.98), reaching an HR of 49.48 (95% CI, 6.24 to 392.48) in the top quartile. The incidence of primary outcome was 16.67 per 100 person-years in the top quartile of time-weighted average dose (Q4>20 mg/day). Other quartiles all had an incidence of primary outcome less than 10 per 100 person-years.ConclusionPatients with time-weighted average prednisone dose greater than 20 mg/day would be classified as the high risk for HBV reactivation or hepatitis flare. Prophylactic Anti-HBV therapy may be needed for these high-risk patients.Trial registration numberChiCTR1900023955.

Structural Lesion Progression of the Sacroiliac Joint and Clinical Features in axSpA During TNFi Reduction: A Retrospective Cohort Study

Objective: In the clinic, some patients with axial spondyloarthritis (axSpA) have to reduce tumor necrosis factor inhibitor (TNFi) for various reasons. However, there are few studies about how to balance the relapse and TNFi reduction. Here we retrospectively analyzed the structural progression of the sacroiliac joint (SIJ) and clinical features in axSpA during TNFi reduction.Methods: A total of 108 patients with axSpA who followed up for 2 years and completed at least baseline, 12-month, and 24-month MRI scans of SIJ were divided into the tapering group (n = 63) and withdrawal group (n = 45) according to whether TNFi was stopped. We divided 2 years into five intervals, calculating the average dose quotient (DQ) for each of 540 intervals from 108 patients. By using generalized estimation equations with inverse probability of treatment weighting, we investigated the unbiased effects of average DQ on structural progression and treatment response.Results: The disease activity (such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, and ASDAS-ESR) and relapse rate were lower in the tapering group at 12 and 24 months (p &lt; 0.05). Δerosion (β = −0.0100, p = 0.00026) and Δthe Spondyloarthritis Research Consortium of Canada (SPARCC; β = −0.0959, p &lt; 0.0001) were negatively correlated with average DQ. The average DQ 30 (74.8%, 80.0%) or 41.6 (76.5%, 83%) was best to discriminate the status of treatment response or the status of bone marrow edema, but considering operability, the average DQ 25 (78.0%, 63.3%) was also acceptable especially for patients with HLA-B27 negative and non-severe fat metaplasia.Conclusion: Complete TNFi withdrawal was not recommended. Our study provided a referable strategy (tapering then maintained the average DQ over 30 or even 25) for patients who need TNFi reduction. Higher dose usage of TNFi was associated with a slower erosion progression of SIJ.

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

Quantification of Tc-99m macroaggregated albumin liver perfusion as a predictor of tumor response to intra-arterial therapy with yttrium 90 spheres

Objectives: It remains unclear whether quantifying the pre-therapy tumor Technetium 99m macro aggregated albumin (Tc 99m MAA) localization can accurately predict the response to Yttrium 90 (Y-90) spheres therapy. Present studies are limited and with contradictory results. The aim of this study is to determine if quantification of Tc-99m MAA in hepatic tumor lesion(s) on pretherapy planning nuclear scan can predict the degree of tumor response after radioembolization using Y-90 Spheres. Material and Methods: We retrospectively included patients with primary liver cancers or metastases who were treated with SirSpheres or TheraSpheres. All patients had a Tc-99m MAA scan with an average dose of 5.0mCi injected aseptically in either the right, left, or common hepatic artery. The patients were subsequently transferred for imaging using planar and single-photon emission computed tomography (SPECT) of the abdomen and planar images of the chest. We calculated geometric mean of radiotracer counts in the largest lesion in the lobe to be treated by placing same size region of interest (ROI) around the largest lesion on the anterior and posterior planar images. Subsequently, an irregular ROI around the liver or lobe to be treated were drawn to calculate the geometric mean of counts in the liver. The percent tracer accumulation in the largest lesion was calculated by dividing the geometric mean of counts in the largest lesion by the geometric mean of counts in the liver or lobe and multiplying by 100%. The size of this largest lesion was obtained on the most recent CT or magnetic resonance imaging (MRI) in cm in 2 directions prior to treatment with Y-90 Spheres. The extent of the response to Y-90 Spheres therapy was re-evaluated with 3 months follow-up MRI or CT by measuring the decrease in the largest lesion size. Comparison of the percent Tc-99 MAA count accumulation in the largest lesion on the pre-therapy scan with the reduction in size using anatomic imaging was performed. Results: A total of 30 patients were included (16 hepatocellular carcinoma, eight colorectal, three breast, one neuroendocrine, one cholangiocarcinoma, and one cervical metastases). There were 14 patients in stable disease or progressive disease group (SD/PD gp) and 16 patients in partial response or complete response group (PR/CR gp). The median lesion size was 3.5 cm in the PD/SD gp versus 2.8 cm in the PR/CR gp (P = 0.31). Additionally, the median delivered Y90 Spheres treatment dose was 51.3 mCi in the PD/SD versus 43.2 mCi in the PR/CR gp (P = 0.22). The percent median largest lesion to liver concentration was 21.9% in the PR/CR gp versus 23.3% in the PR/CR gp (P = 0.74). There was no significant difference in percent Tc-99m MAA distribution in the largest liver lesion between the SD/PD gp and the PR/CR gp. Conclusion: The degree of Tc-99m MAA localization in the largest tumor lesion in the liver compared to the remainder of the liver as quantified from planar images does not predict the response to Y-90 spheres therapy.

Deep learning-based 3D in vivo dose reconstruction with EPID for MR-LINACs: A proof of concept study

Objective: To develop a novel deep learning-based 3D in vivo dose reconstruction framework with electronic portal imaging device (EPID) for magnetic resonance-linear accelerators (MR-LINACs). Approach: The proposed method directly back-projected 2D portal dose into 3D patient coarse dose, which bypassed the complicated patient-to-EPID scatter estimation step used in conventional methods. A pre-trained convolutional neural network (CNN) was then employed to map the coarse dose to the final accurate dose. The electron return effect caused by the magnetic field was captured with the CNN model. Patient dose and portal dose datasets were synchronously generated with Monte Carlo simulation for 96 patients (78 cases for training and validation and 18 cases for testing) treated with fixed-beam intensity-modulated radiotherapy in four different tumor sites, including the brain, nasopharynx, lung, and rectum. Beam angles from the training dataset were further rotated 2–3 times, and doses were recalculated to augment the datasets. Results: The comparison between reconstructed doses and MC ground truth doses showed mean absolute errors < 0.88% for all tumor sites. The averaged 3D γ-passing rates (3%, 2 mm) were 97.42%±2.66% (brain), 98.53%±0.95% (nasopharynx), 99.41%±0.46% (lung), and 98.63%±1.01% (rectum). The dose volume histograms and indices also showed good consistency. The average dose reconstruction time, including back projection and CNN dose mapping, was less than 3 s for each individual beam. Significance: The proposed method can be potentially used for accurate and fast 3D dosimetric verification for online adaptive radiotherapy using MR-LINACs.

A Novel Proton Pencil Beam Scanning FLASH RT Delivery Method Enables Optimal OAR Sparing and Ultra-High Dose Rate Delivery: A Comprehensive Dosimetry Study for Lung Tumors

Purpose: While transmission proton beams have been demonstrated to achieve ultra-high dose rate FLASH therapy delivery, they are unable to spare normal tissues distal to the target. This study aims to compare FLASH treatment planning using single energy Bragg peak proton beams versus transmission proton beams in lung tumors and to evaluate Bragg peak plan optimization, characterize plan quality, and quantify organ-at-risk (OAR) sparing. Materials and Methods: Both Bragg peak and transmission plans were optimized using an in-house platform for 10 consecutive lung patients previously treated with proton stereotactic body radiation therapy (SBRT). To bring the dose rate up to the FLASH-RT threshold, Bragg peak plans with a minimum MU/spot of 1200 and transmission plans with a minimum MU/spot of 400 were developed. Two common prescriptions, 34 Gy in 1 fraction and 54 Gy in 3 fractions, were studied with the same beam arrangement for both Bragg peak and transmission plans (n = 40 plans). RTOG 0915 dosimetry metrics and dose rate metrics based on different dose rate calculations, including average dose rate (ADR), dose-averaged dose rate (DADR), and dose threshold dose rate (DTDR), were investigated. We then evaluated the effect of beam angular optimization on the Bragg peak plans to explore the potential for superior OAR sparing. Results: Bragg peak plans significantly reduced doses to several OAR dose parameters, including lung V7.4Gy and V7Gy by 32.0% (p < 0.01) and 30.4% (p < 0.01) for 34Gy/fx plans, respectively; and by 40.8% (p < 0.01) and 41.2% (p < 0.01) for 18Gy/fx plans, respectively, compared with transmission plans. Bragg peak plans have ~3% less in DADR and ~10% differences in mean OARs in DTDR and DADR relative to transmission plans due to the larger portion of lower dose regions of Bragg peak plans. With angular optimization, optimized Bragg peak plans can further reduce the lung V7Gy by 20.7% (p < 0.01) and V7.4Gy by 19.7% (p < 0.01) compared with Bragg peak plans without angular optimization while achieving a similar 3D dose rate distribution. Conclusion: The single-energy Bragg peak plans achieve superior dosimetry performances in OARs to transmission plans with comparable dose rate performances for lung cancer FLASH therapy. Beam angle optimization can further improve the OAR dosimetry parameters with similar 3D FLASH dose rate coverage.

Radiation Dose Assessment of the Fog Lead Acrylic Shields during Coronary Angiography: A Phantom Study

This study aimed to evaluate the effects of fogging on the effectiveness of a lead glass shield in protecting an operator from radiation exposure during conventional coronary angiography (CAG). Optically stimulated luminescence dosimeters (OSLDs) were used to measure the effects of fogged lead glass shields (FLSs) and clear lead glass shields (CLSs) on the radiation doses of a cardiac catheterization surgeon. We simulated the scatter radiation incident on the operator with five angiographic projections with 10-s exposures. Experiments were conducted with a field of view of 25 cm, maximum of 100 cm between the X-ray tube and image intensifier, and 80 cm between the image intensifier and operator. Lead glass fogging had no significant effect at any angiographic projection. The average dose at the lens of the eye, thyroid glands, and gonads did not differ significantly between FLS and CLS. Although most surgeons view ceiling-suspended shields as hindrances during surgical procedures, the radiation dose at the operator’s eyes and thyroid glands increased by 13 and 10 times without the shield. The fogging of the shield is probably caused by post-surgery UV decontamination or detergents. An operator has no cause for concern regarding the radiation protection afforded by an FLS during CAG procedures.