Dosimetric Analysis of Intra-Fraction Motion Detected by Surface-Guided Radiation Therapy During Linac Stereotactic Radiosurgery.

Purpose: Stereotactic radiosurgery (SRS) immobilization with an open face mask is more comfortable and less invasive than frame based, but concerns about intrafraction motion must be addressed. Surface-guided radiation therapy (SGRT) is an attractive option for intrafraction patient monitoring because it is continuous, has submillimeter accuracy, and uses no ionizing radiation. The purpose of this study was to investigate the dosimetric consequences of uncorrected intrafraction patient motion detected during frameless linac-based SRS. Methods and Materials: Fifty-five SRS patients were monitored during treatment using SGRT between January 1, 2017, and September 30, 2020. If SGRT detected motion >1 mm, imaging was repeated and the necessary shifts were made before continuing treatment. For the 25 patients with intrafraction 3-dimensional vector shifts of ≥1 mm, we moved the isocenter in the planning system using the translational shifts from the repeat imaging and recalculated the plans to determine the dosimetric effect of the shifts. Planning target volume (PTV) coverage, minimum gross tumor volume (GTV) dose (relative and absolute), and normal brain V12 were evaluated. Wilcoxon signed rank tests were used to compare planned and simulated dosimetric parameters and median 2 sample tests were used to investigate these differences between cone and multileaf collimator (MLC) plans. Results: For simulated plans, V12 increased by a median of 0.01 cc (P = .006) and relative GTV minimum dose and PTV coverage decreased by a median of 15.8% (P < .001) and 10.2 % (P < .001), respectively. Absolute minimum GTV dose was found to be significantly lower in the simulated plans (P < .001). PTV coverage decreased more for simulated cone plans than for simulated MLC plans (11.6% vs 4.7%, P = .011) but median V12 differences were found to be significantly larger for MLC plans (-0.34 cc vs -0.01 cc, P = .011). Differences in GTV minimum dose between cone and MLC plans were not statistically significant. Conclusions: SGRT detected clinically meaningful intrafraction motion during frameless SRS, which could lead to large underdoses and increased normal brain dose if uncorrected.

Failure modes and effects analysis for surface-guided DIBH breast radiotherapy.

Despite breast cancer prevalence and widespread adoption of deep inspiration breath-hold (DIBH) radiation techniques, few data exist on the error risks related to using surface-guided (SG) DIBH during breast radiation therapy (RT). Due to the increasingly technical nature of these methods and being a paradigm shift from traditional breast setups/treatments, the associated risk for error is high. Failure modes and effects analysis (FMEA) has been used in identifying risky RT processes yet is time-consuming to perform. A subset of RT staff and a hospital patient-safety representative performed FMEA to study SG-DIBH RT processes. After this group (cohort 1) analyzed these processes, additional scoring data were acquired from RT staff uninvolved in the original FMEA (cohort 2). Cohort 2 received abbreviated FMEA training while using the same process maps that cohort 1 had created, which was done with the goal of validating our results and exploring the feasibility of expedited FMEA training and efficient implementation elsewhere. An extensive review of the SG-DIBH RT process revealed 57 failure modes in 16 distinct steps. Risks deemed to have the highest priority, large risk priority number (RPN), and severity were addressed with policy changes, checklists, and standardization; of these, most were linked with operator error via manual inputs and verification. Reproducibility results showed that 5% of the average RPN between cohorts 1 and 2 was statistically different. Unexpected associations were noted between RPN and RT staff role; 12% of the physicist and therapist average scores were statistically different. Different levels of FMEA training yielded similar scoring within one RT department, suggesting a time-savings can be achieved with abbreviated training. Scores between professions, however, yielded significant differences suggesting the importance of involving staff across disciplines.

Contributing to Understand the Crosstalk between Brain and Periphery in Methylmercury Intoxication: Neurotoxicity and Extracellular Vesicles.

Human exposure to methylmercury (MeHg) is currently high in regions such as the Amazon. Understanding the molecular changes associated with MeHg-induced neurotoxicity and the crosstalk with the periphery is essential to support early diagnoses. This work aimed to evaluate cellular and molecular changes associated with behavioral alterations in MeHg acute exposure and the possible changes in extracellular vesicles (EVs) number and S100ß content. Adults male Wistar rats were orally treated with 5 mg/kg for four days. Behavioral performance, molecular and histological changes in the cerebellum, and plasma EVs were assessed. MeHg-intoxicated animals performed significantly worse in behavioral tests. MeHg increased the number of GFAP+ cells and GFAP and S100ß mRNA expression in the cerebellum but no change in NeuN+ or IBA-1+ cells number was detected. The number of exosomes isolated from plasma were decreased by the metal. S100B mRNA was detected in circulating plasma EVs cargo in MeHg exposure. Though preliminary, our results suggest astrocytic reactivity is displaying a protective role once there was no neuronal death. Interestingly, the reduction in exosomes number could be a new mechanism associated with MeHg-induced neurotoxicity and plasma EVs could represent a source of future biomarkers in MeHg intoxication.

Use of surface-guided radiation therapy in combination with IGRT for setup and intrafraction motion monitoring during stereotactic body radiation therapy treatments of the lung and abdomen.

BACKGROUND AND PURPOSE: Multiple techniques can be used to assist with more accurate patient setup and monitoring during Stereotactic body radiation therapy (SBRT) treatment. This study analyzes the accuracy of 3D surface mapping with Surface-guided radiation therapy (SGRT) in detecting interfraction setup error and intrafraction motion during SBRT treatments of the lung and abdomen. MATERIALS AND METHODS: Seventy-one patients with 85 malignant thoracic or abdominal tumors treated with SBRT were analyzed. For initial patient setup, an alternating scheme of kV/kV imaging or SGRT was followed by cone beam computed tomography (CBCT) for more accurate tumor volumetric localization. The CBCT six degree shifts after initial setup with each method were recorded to assess interfraction setup error. Patients were then monitored continuously with SGRT during treatment. If an intrafractional shift in any direction >2 mm for longer than 2 sec was detected by SGRT, then CBCT was repeated and the recorded deltas were compared to those detected by SGRT. RESULTS: Interfractional shifts after SGRT setup and CBCT were small in all directions with mean values of <5 mm and < 0.5 degrees in all directions. Additionally, 25 patients had detected intrafraction motion by SGRT during a total of 34 fractions. This resulted in 25 (73.5%) additional shifts of at least 2 mm on subsequent CBCT. When comparing the average vector detected shift by SGRT to the resulting vector shift on subsequent CBCT, no significant difference was found between the two. CONCLUSIONS: Surface-guided radiation therapy provides initial setup within 5 mm for patients treated with SBRT and can be used in place of skin marks or planar kV imaging prior to CBCT. In addition, continuous monitoring with SGRT during treatment was valuable in detecting potentially clinically meaningful intrafraction motion and was comparable in magnitude to shifts from additional CBCT scans. PTV margin reduction may be feasible for SBRT in the lung and abdomen when using SGRT for continuous patient monitoring during treatment.

Quality control of high-dose-rate brachytherapy: treatment delivery analysis using statistical process control.

PURPOSE: Statistical process control (SPC) is a quality control method used to ensure that a process is well controlled and operates with little variation. This study determined whether SPC was a viable technique for evaluating the proper operation of a high-dose-rate (HDR) brachytherapy treatment delivery system. METHODS AND MATERIALS: A surrogate prostate patient was developed using Vyse ordnance gelatin. A total of 10 metal oxide semiconductor field-effect transistors (MOSFETs) were placed from prostate base to apex. Computed tomography guidance was used to accurately position the first detector in each train at the base. The plan consisted of 12 needles with 129 dwell positions delivering a prescribed peripheral dose of 200 cGy. Sixteen accurate treatment trials were delivered as planned. Subsequently, a number of treatments were delivered with errors introduced, including wrong patient, wrong source calibration, wrong connection sequence, single needle displaced inferiorly 5 mm, and entire implant displaced 2 mm and 4 mm inferiorly. Two process behavior charts (PBC), an individual and a moving range chart, were developed for each dosimeter location. RESULTS: There were 4 false positives resulting from 160 measurements from 16 accurately delivered treatments. For the inaccurately delivered treatments, the PBC indicated that measurements made at the periphery and apex (regions of high-dose gradient) were much more sensitive to treatment delivery errors. All errors introduced were correctly identified by either the individual or the moving range PBC in the apex region. Measurements at the urethra and base were less sensitive to errors. CONCLUSIONS: SPC is a viable method for assessing the quality of HDR treatment delivery. Further development is necessary to determine the most effective dose sampling, to ensure reproducible evaluation of treatment delivery accuracy.

Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins.

Light chain amyloidosis (AL) involves overproduction of amyloidogenic light chain proteins (LC) leading to heart failure, yet the mechanisms underlying tissue toxicity remain unknown. We hypothesized that LC induces endothelial dysfunction in non-AL human microvasculature and apoptotic injury in human coronary artery endothelial cells (HCAECs). Adipose arterioles (n = 34, 50 ± 3 yr) and atrial coronary arterioles (n = 19, 68 ± 2 yr) from non-AL subjects were cannulated. Adipose arteriole dilator responses to acetylcholine/papaverine were measured at baseline and 1 h exposure to LC (20 µg/ml) from biopsy-proven AL subjects (57 ± 11 yr) without and with antioxidant cotreatment. Coronary arteriole dilation to bradykinin/papaverine was measured post-LC exposure. HCAECs were exposed to 1 or 24 h of LC. LC reduced dilation to acetylcholine (10(-4) M: 41.6 ± 7 vs. 85.8 ± 2.2% control, P < 0.001) and papaverine (81.4 ± 4.6 vs. 94.8 ± 1.3% control, P < 0.01) in adipose arterioles and to bradykinin (10(-6) M: 68.6 ± 6.2 vs. 90.9 ± 1.6% control, P < 0.001) but not papaverine in coronary arterioles. There was an increase in superoxide and peroxynitrite in arterioles treated with LC. Adipose arteriole dilation was restored by cotreatment with polyethylene glycol-superoxide dismutase and tetrahydrobiopterin but only partially restored by mitoquinone (mitochondria-targeted antioxidant) and gp91ds-tat (NADPH oxidase inhibitor). HCAECs exposed to LC showed reduced NO and increased superoxide, peroxynitrite, annexin-V, and propidium iodide compared with control. Brief exposure to physiological amounts of LC induced endothelial dysfunction in human adipose and coronary arterioles and increased apoptotic injury in coronary artery endothelial cells likely as a result of oxidative stress, reduced NO bioavailability, and peroxynitrite production. Microvascular dysfunction and injury is a novel mechanism underlying AL pathobiology and is a potential target for therapy.

Systemic and microvascular oxidative stress induced by light chain amyloidosis.

Light chain amyloidosis (AL) is a plasma cell dyscrasia associated with production of amyloidogenic immunoglobulin light chains (LC). Despite its often fatal course, the mechanism of injury remains unknown. We tested the hypothesis that AL is associated with oxidative stress by comparing serum protein carbonyl (a marker of protein oxidation and oxidative stress) in AL subjects (n=23, 60 ± 11 years) vs. controls (n=9, 54 ± 2 years); we also measured superoxide production (n=11) and dilator response to sodium nitroprusside (SNP, n=6) in isolated non-AL human adipose arterioles exposed to LC (20 µg/mL) purified from AL subjects for 1 h vs. control. Protein carbonyl was higher in AL patients (0.19 ± 0.04 vs. 0.003 ± 0.003 nmol/mg control, p=0.002). Post-exposure to LC proteins, arteriole superoxide was higher (1.89 ± 0.36 times control, p=0.03) with impaired dilation to SNP (10(-4) M, 54 ± 6 vs. 86 ± 4%, p=0.01, logEC50 -3.7 ± 0.2 vs. -6.7 ± 0.6, p=0.002). AL is associated with systemic oxidative stress and brief acute exposure to AL light chain proteins induces oxidative stress and microvascular dysfunction in human adipose arterioles. This novel mechanism of injury may be important in AL pathophysiology.

Prognostic implication of late gadolinium enhancement on cardiac MRI in light chain (AL) amyloidosis on long term follow up.

BACKGROUND: Light chain amyloidosis (AL) is a rare plasma cell dyscrasia associated with poor survival especially in the setting of heart failure. Late gadolinium enhancement (LGE) on cardiac MRI was recently found to correlate with myocardial amyloid deposition but the prognostic role is not established. The aim is to determine the prognostic significance of LGE in AL by comparing long term survival of AL patients with and without LGE. METHODS: Twenty nine consecutive patients (14 females; 62 +/- 11 years) with biopsy-proven AL undergoing cardiac MRI with gadolinium as part of AL workup were included. Survival was prospectively followed 29 months (median) following MRI and compared between those with and without LGE by Kaplan-Meier and log-rank analyses. RESULTS: LGE was positive in 23 subjects (79%) and negative in 6 (21%). Left ventricular ejection fraction was 66 +/- 17% in LGE-positive and 69 +/- 12% in LGE-negative patients (p = 0.8). Overall 1-year mortality was 36%. On follow-up, 14/23 LGE-positive and none of LGE-negative patients died (log rank p = 0.0061). Presenting New York Heart Association heart failure class was also associated with poor survival (p = 0.0059). Survival between two LGE groups stratified by heart failure class still showed a significant difference by a stratified log-rank test (p = 0.04). CONCLUSION: Late gadolinium enhancement is common and is associated with poor long-term survival in light chain amyloidosis, even after adjustment for heart failure class presentation. The prognostic significance of late gadolinium enhancement in this disease may be useful in patient risk-stratification.

Intraventricular dyssynchrony in light chain amyloidosis: a new mechanism of systolic dysfunction assessed by 3-dimensional echocardiography.

BACKGROUND: Light chain amyloidosis (AL) is a rare but often fatal disease due to intractable heart failure. Amyloid deposition leads to diastolic dysfunction and often preserved ejection fraction. We hypothesize that AL is associated with regional systolic dyssynchrony. The aim is to compare left ventricular (LV) regional synchrony in AL subjects versus healthy controls using 16-segment dyssynchrony index measured from 3-dimension-al (3D) echocardiography. METHODS: Cardiac 3D echocardiography full volumes were acquired in 10 biopsy-proven AL subjects (60 +/- 3 years, 5 females) and 10 healthy controls (52 +/- 1 years, 5 females). The LV was subdivided into 16 segments and the time from end-diastole to the minimal systolic volume for each of the 16 segments was expressed as a percent of the cycle length. The standard deviations of these times provided a 16-segment dyssynchrony index (16-SD%). 16-SD% was compared between healthy and AL subjects. RESULTS: Left ventricular ejection fraction was comparable (control vs. AL: 62.4 +/- 0.6 vs. 58.6 +/- 2.8%, p = NS). 16-SD% was significantly higher in AL versus healthy subjects (5.93 +/- 4.4 vs. 1.67 +/- 0.87%, p = 0.003). 16-SD% correlated with left ventricular mass index (R 0.45, p = 0.04) but not to left ventricular ejection fraction. CONCLUSION: Light chain amyloidosis is associated with left ventricular regional systolic dyssynchrony. Regional dyssynchrony may be an unrecognized mechanism of heart failure in AL subjects.

Myocardial dysfunction in the periinfarct and remote regions following anterior infarction in rats quantified by 2D radial strain echocardiography: an observational cohort study.

BACKGROUND: Heart failure from adverse ventricular remodeling follows myocardial infarction, but the contribution of periinfarct and remote myocardium to the development of cardiomyopathy remains poorly defined. 2D strain echocardiography (2DSE) is a novel and sensitive tool to measure regional myocardial mechanics. The aim is to quantify radial strain in infarcted (I), periinfarct (PI) and remote (R) myocardial regions acutely and chronically following anterior infarction in rats. METHODS: The left anterior coronary artery of male Sprague-Dawley rats (270-370 g) were occluded for 20-30 minutes and 2DSE was performed in the acute setting (n = 10; baseline and 60 minutes post-reperfusion) and in the chronic setting (n = 14; baseline, 1, 3 and 6 weeks). Using software, radial strain was measured in the mid-ventricle in short axis view. The ventricle was divided into 3 regions: I (anteroseptum, anterior and anterolateral), PI - (inferoseptum and inferolateral) and R - (inferior). Infarct size was measured using triphenyl tetrazolium chloride in the acute group. RESULTS: Following infarct, adverse remodeling occurred with progressive increase in left ventricular size, mass and reduced fractional shortening within 6 weeks. Radial strain decreased not only in the infarct but also in the periinfarct and remote regions acutely and chronically (I, PI, R, change vs. baseline, 60 minutes -32.7 +/- 8.7, -17.4 +/- 9.4, -13.5 +/- 11.6%; 6 weeks -24.4 +/- 8.2, -17.7 +/- 8.3, -15.2 +/- 8.4% respectively, all p < 0.05). Reduced radial strain in periinfarct and remote regions occurred despite minimal or absent necrosis (area of necrosis I, PI, R: 48.8 +/- 23, 5.1 +/- 6.6, 0 +/- 0%, p < 0.001 vs. I). CONCLUSION: Following left anterior coronary occlusion, radial strain decreased at 60 minutes and up to 6 weeks in the periinfarct and remote regions, similar to the reduction in the infarct region. This demonstrates early and chronic myopathic process in periinfarct and remote regions following myocardial infarction that may be an under recognized but important contributor to adverse left ventricular remodeling and progression to ischemic cardiomyopathy.

Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography.

Doxorubicin is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiomyopathy that may lead to heart failure. Conventional measures of ventricular function, such as fractional shortening, are insensitive in detecting early doxorubicin cardiomyopathy. We tested whether novel two-dimensional radial strain echocardiography (2DSE) can detect early doxorubicin injury following chronic administration in a rat model. 14 male Sprague Dawley rats (240 to 260 g) received doxorubicin 2.5 mg/k i.v. per wk for 10 (n=4) or 12 wk (n=10); 17 controls received saline (10 wk, n=7 and 12 wk, n=10). Serial 2DSE from 0 to 12 wk was done at the mid left ventricle using Vivid 7 echo (General Electric, Waukesha, WI, USA). With Q analysis software, radial strain was obtained. From the two-dimensional (2D) image, anatomical M-mode through the anterior/inferior walls was used to measure fractional shortening. Fibrosis (Masson's trichrome) and caspase-3 activity were measured from excised hearts. Radial strain was lower in the doxorubicin group (12 wk: 26.7+/-3 versus 38.3+/-2.6%, p=0.006), with significant difference by 8 wk whereas fractional shortening was lower with doxorubicin only after 12 wk (30.2+/-1.7 versus 37.6+/-1.4%, p=0.02). Doxorubicin group had lower cardiac mass (0.85+/-0.09 versus 1.14+/-0.04 g, p=0.001), higher caspase-3 activity (1.95+/-0.2 fold increase over control, p<0.0001) and fibrosis (3.9 +/- 0.7 versus 0.7+/-0.1%, p=0.005). Radial strain was related directly to cardiac mass (r=0.61, p=0.0007) and inversely to caspase-3 activity (r= -0.5, p=0.005). 2-dimensional radial strain echocardiography is useful in the early detection of doxorubicin cardiac injury and the reduction in radial strain is associated with histologic markers of doxorubicin cardiomyopathy.