Volume Parameters Research Articles

Population Pharmacokinetic Modeling of Different Formulations of Inclacumab Using Phase 1 Data in Healthy Participants

Introduction: P-selectin is a cell adhesion molecule that contributes to vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Inclacumab is a recombinant, fully human, immunoglobulin G4 monoclonal antibody that selectively binds to P-selectin to prevent binding with P-selectin glycoprotein ligand-1. Inclacumab was previously evaluated by Roche in clinical trials with healthy participants and patients with cardiovascular disease and is now being developed as a potential treatment to reduce the frequency of VOCs in individuals with SCD. Changes in the manufacturing of inclacumab have resulted in 3 formulations/drug materials: Roche v0.1, Roche v0.2, and Global Blood Therapeutics (GBT). GBT-manufactured inclacumab utilizes a similar formulation and the same cell line as Roche v0.2 (Roche v0.1 utilizes a different cell line), and analytical and nonclinical comparability between Roche v0.2 and GBT inclacumab have been demonstrated (Mihaila et al. Expert Opin Biol Ther 2022). Here we report results from a population pharmacokinetic (PopPK) model developed to compare the pharmacokinetics (PK) of different formulations using data from 4 phase 1 clinical studies in healthy participants administered Roche v0.1, Roche v0.2, or GBT inclacumab. The objectives were to develop a PopPK model to describe inclacumab PK in healthy adult participants and to quantify potential differences in inclacumab PK associated with different formulations/drug materials. Methods: A PopPK model was developed using single- and multiple-dose PK data from healthy participants who received intravenous (IV) inclacumab across 4 studies (BP21112 [Roche v0.1, single ascending dose (SAD)], BP21617 [Roche v0.1, multiple ascending dose], BP28134 [Roche v0.2, SAD], and GBT2104-111 [GBT, SAD]). Evaluable participants had ≥1 measurable postdose concentration with an associated sample time, relevant dosing information prior to each measurable concentration, and no protocol violation that could confound PK analyses. A nonlinear mixed effects model was fit to the inclacumab plasma concentration-time data using first-order conditional estimation with eta-epsilon interaction in NONMEM ® (v7.3). Model selection was based on the plausibility of parameter estimates, goodness-of-fit plots, and the objective function value. The final model was evaluated using a prediction-corrected visual predictive check (pcVPC). Results: The PopPK dataset comprised 145 healthy participants, of which 2622 inclacumab plasma concentrations (84.9%) from 143 participants were evaluable (Roche v0.1: n=68 [47.6%]; Roche v0.2: n=60 [42.0%]; GBT: n=15 [10.5%]). Median (range) age and body weight were 42 (21-63) years and 73.2 (45.8-109) kg, respectively. Nominal doses ranged from 0.03 to 40 mg/kg IV; 23.8% of participants received 3 mg/kg and 29.4% received 20 mg/kg. A 3-compartment disposition model with parallel linear clearance (CL=0.125 L/d) and nonlinear (concentration-dependent; V max=1.19 mg/d; K m=0.784 μg/mL) clearance from the central compartment described the plasma concentration-time data. The effect of drug material was incorporated a priori as relative bioavailability term F in the base model using exploratory analyses of observed exposures. Dosing of Roche v0.1 and Roche v0.2 inclacumab resulted in 23% and 2% higher exposure than GBT inclacumab, respectively. Between-subject variability was estimated for linear clearance, nonlinear clearance, and all volume parameters, and residual error was described using a proportional model (Table). Of the tested covariates, baseline body weight was a statistically significant covariate effect and was included on all linear clearance and volume terms. Model qualification by pcVPC showed good predictive performance of the final model. Conclusions: The PopPK of IV inclacumab in healthy participants was described by a 3-compartment disposition model with parallel linear and nonlinear clearances. Estimated relative exposure of Roche v0.2 and GBT-manufactured inclacumab was similar, indicating comparability in drug exposure. Understanding the relationship between exposure and dose for different formulations facilitates more accurate assessment of safety data across multiple clinical studies. These data provide support for the ongoing phase 3 clinical development in SCD using GBT-manufactured inclacumab without further clinical comparability testing.

Influence analysis of complex crack geometric parameters on mechanical properties of soft rock

Soft rocks, such as coal, are affected by sedimentary effects, and the surrounding rock mass of underground coal mines is generally soft and rich in joints and cracks. A clear and deep understanding of the relationship between crack geometric parameters and rock mechanics properties in cracked rock is greatly important to the design of engineering rock mass structures. In this study, computed tomography (CT) scanning was used to extract the internal crack network of coal specimens. Based on the crack size and dominant crack number, the parameters of crack area, volume, length, width, and angle were statistically analyzed by different sampling thresholds. In addition, the Pearson correlation coefficients between the crack parameters and uniaxial compression rock mechanics properties (uniaxial compressive strength UCS, elasticity modulus E) were calculated to quantitatively analyze the impact of each parameter. Furthermore, a method based on Pearson coefficients was used to grade the correlation between crack geometric parameters and rock mechanical properties to determine threshold values. The results indicated that the UCS and E of the specimens changed with the varied internal crack structures of the specimens, the crack parameters of area, volume, length and width all showed negative correlations with UCS and E, and the dominant crack played an important role both in weakening strength and stiffness. The crack parameters of the angle are all positively correlated with the UCS and E. More crack statistics can significantly improve the correlation between the parameters of the crack angle and the rock mechanics properties, and the statistics of the geometric parameters of at least 16 cracks or the area larger than 5 mm2 are suggested for the analysis of complex cracked rock masses or physical reproduction using 3D printing. The results are validated and further analyzed with triaxial tests. The findings of this study have important reference value for future research regarding the accurate and efficient selection of a few cracks with a significant influence on the rock mechanical properties of surrounding rock mass structures in coal engineering.

Dose to Organ at Risk and its Characteristic Variation with the Clinically Used Different Prescription Levels for Early-stage Left-sided Breast Cancer

AimsTo evaluate the organ at risk (OAR) dose and its characteristic variation with different clinically usable prescription doses (RxD) for breast and chest wall radiotherapy in patients with early-stage left-sided breast cancer. Materials and methodsIn total, 145 patients with early-stage breast cancers (T1N0M0-T2N0M0) on the left side were treated with radiotherapy after a modified radical mastectomy or breast conservation surgery, with a mean age of 45.1 ± 21.6 years. The patient received 4050 cGy of field-in-field (three-dimensional conformal radiotherapy) treatment limited to the breast or chest wall, excluding the supraclavicular node, axillary node and internal mammary chain, over 15 fractions. Additional plans of 5000 cGy/25 fractions, 4500 cGy/20 fractions and 2600 cGy/5 fractions were created with no or minor changes to the original plan. Mathematical modelling was used to study the distinctive change in the dose–volume characteristics for various OARs as a function of the RxD. OAR dosages, both absolute and normalised, were expressed in terms of the RxD. The mathematical (functional) relationship between OAR doses and different prescription levels was deduced by the least squares fit method. ResultThe left lung mean dose, V5Gy (%), V10Gy (%) and V20Gy (%) and the heart mean dose, V10Gy (%) and V20Gy (%) were evaluated. The dose–volume parameters showed a parabolic variation (x2) with the RxD. Prescription normalised OAR doses showed a linear relationship with the RxD; relative dose increased with diminishing RxD. Normalised lung and heart mean doses exhibited saturation (linear relationship) with RxD variation. Paired sample t-test results between RxD versus all evaluated parameters were found to be statistically significant (P = 0.004). The Pearson correlation coefficient between different prescription levels for left lung mean dose (range 0.942–1.0), heart mean dose (range 1.0–1.0), left lung V5Gy (%) (range 0.987–1.0), left lung V10Gy (%) (range 0.991–0.999), heart V10Gy (%) (range 0.998–1.0). ConclusionThe functional form of absolute OAR dose–volume parameters versus RxD is parabolic and the RxD normalised OAR dose–volume parameter versus RxD is a straight line with a negative slope as RxD increases. This indicates an increase in the relative OAR dose–volume parameters if the RxD is reduced. This study is the first of its kind to compare the OAR doses as a function of clinically used degenerate prescription levels. These data will help to comprehend the OAR doses while adopting a new dose fractionation regimen and reviewing the radiotherapy treatment plans.

Multiscale topology optimization of gradient lattice structure based on volume parametric modeling

In this study, a volume parametric modeling method of lattice structure is proposed, and an efficient multiscale topology optimization framework is realized based on isogeometric analysis (IGA) to construct the gradient lattice structure. The skeleton model is constructed, which can accurately describe the topology structure and improve data utilization and computational efficiency. Based on the skeleton model, a uniform volume parameter lattice structure with an arbitrary topology of multiple types of unit cells is constructed, which is suitable for IGA. Moreover, multiscale topology optimization based on IGA is realized to construct the gradient lattice structure. The same data model is used in modeling, analysis, and optimization, which can accurately represent the geometric shape without discretization errors. At the same time, the multiscale topology optimization iteration is realized by adjusting the density of control points. The optimized model can be directly analyzed and re-optimized, thus realizing the integrated design of lattice structure modeling, simulation, and optimization. The effectiveness and robustness of the algorithm are verified by several mechanical parts and freeform models. These examples show that the gradient lattice structure has higher strength and better stress distribution than the uniform lattice structure under the same boundary conditions.

Vaginal Dose Reduction by Changing the Ovoid Loading Pattern in Image Guided Intracavitary Brachytherapy of Cervix.

Locally advanced cervical cancer is frequently treated using a combination of external beam radiotherapy and brachytherapy. Radiotherapy often leads to vaginal morbidity, which poses a significant problem. This study aims to analyze the impact of reducing ovoid loading on dosimetry. We analyzed forty-five CT-based intracavitary brachytherapy plans from fifteen patients. Three plan sets were created for the 45 applications: a standard loading plan (A), a plan with reduced ovoid loading (B), and a tandem-only loading plan (C). We generated Dose-Volume Histograms and recorded dose volume parameters for the three plan sets. The D90 for the Clinical Target Volume (CTV) did not show significant differences among the three plan sets (p = 0.20). The average D90 values for plans A, B, and C were 8.15Gy, 8.16Gy, and 7.4Gy, respectively. No statistically significant differences were observed in D2cc bladder (p = 0.09) (average values: 6.8Gy, 6.5Gy, and 5.9Gy for plans A, B, and C, respectively) and D2cc sigmoid (p = 0.43) (average values: 2.8Gy, 2.6Gy, and 2.4Gy, respectively) among the three plan sets. However, there was a statistically significant difference in D2cc rectum (p < 0.001) (average values: 4Gy, 3.3Gy, and 1.8Gy, respectively), as well as in vaginal dose points (p < 0.001). Reducing ovoid loading significantly decreased the doses to vaginal dose points and the rectum without compromising the dose to the Clinical Target Volume (CTV). Therefore, in carefully selected cases, the adoption of tandem-only loading or reduced ovoid loading could be considered to minimize vaginal morbidity following high dose rate intracavitary brachytherapy.

Evaluation of Left Atrial Function in Patients with Paroxysmal Atrial Fibrillation Using Left Atrial Automatic Myocardial Functional Imaging Ultrasonography.

To evaluate volume and strain of the left atrium (LA) in people suffering from paroxysmal atrial fibrillation which is not valvular (NVPAF) using the new technology of left atrial automatic myocardial function imaging (AFILA) and to analyze prognostic factors in patients with NVPAF by follow-up. Between August 2019 and August 2022, a total of 80 NVPAF patients and 60 normal control patients who were hospitalized in the Department of Cardiology were included in the study. The LA volume and strain parameters of the two groups were analyzed. The differences in LA function (LAF) parameters were compared between the two groups to generate the receiver operating characteristic curve (ROC) and calculate the area under the curve (AUC), sensitivity, and specificity of each parameter. Follow-up was conducted on the 80 NVPAF patients included, their treatment methods after admission and their rehospitalization due to heart events were recorded, and independent risk factors influencing the prognosis of NVPAF were obtained. A total of 140 patients participated in the study, including 80 in the NVPAF group and 60 in the normal control group. There was no statistically significant difference in age and sex between the two groups. Compared to the normal group, the LA minimum volume (LAVmin), LA maximum volume (LAVmax), and volume at onset of LA contraction (LAVpreA) in the NVPAF group were significantly increased. The LA emptying fraction (LAEF) was significantly decreased, and LA reservoir strain (S_R), LA conduit strain (S_CD), and LA contractile strain (S_CT) were significantly compromised (P < 0.05). There was no significant difference in LA evacuation volume (LAEV) reduction (P > 0.05). Logistic regression analysis of LAF parameters in NVPAF patients showed that LAEF and S_R were independently correlated with NVPAF (odds ratio values: 0.883 (0.827-0.943), P < 0.001; 0.916 (0.569-1.474), P = 0.047). The ROC curve results showed that LAEF had a high efficiency in the diagnosis of NVPAF, with P < 0.001, AUC of 0.843, sensitivity of 0.788, and specificity of 0.867. For the LA strain parameters, the S_R test efficiency was higher, with P < 0.001, AUC of 0.762, sensitivity of 0.713, and specificity of 0.783. There was a strong correlation between S_R and LAEF in patients with no end event and those with end event. The ROC curve revealed that the S_R was better than LAEF in predicting prognosis of patients with AF (AUC = 0.914, P < 0.0001 vs. AUC = 0.876, P < 0.0001). S_R of 10.5 and LAEF of 21 were the cut-off values for endpoint events in NVPAF patients, with sensitivity of 0.909 and 0.727 and specificity of 0.904 and 0.901, respectively. AFILA ultrasound technology comprehensively evaluated the LA size and function in patients with NVPAF. The LAEF and S_R were independently correlated with NVPAF and can determine the prognosis of patients with NVPAF.

Effect of anesthesia induction with butorphanol on postoperative nausea and vomiting: A randomized controlled trial

BACKGROUND Postoperative nausea and vomiting (PONV) are common complications that affect the recovery and well-being of elderly patients undergoing gastrointestinal laparoscopic surgery. AIM To investigate the effect of butorphanol on PONV in this patient population. METHODS A total of 110 elderly patients (≥ 65 years old) who underwent gastrointestinal laparoscopic surgery were randomly assigned to receive butorphanol (40 μg/kg) or sufentanil (0.3 μg/kg) during anesthesia induction in a 1:1 ratio. The measured outcomes included the incidence of PONV at 48 h after surgery, intraoperative dose of propofol and remifentanil, Bruggrmann Comfort Scale score in the postanesthesia care unit (PACU), number of compressions for postoperative patient-controlled intravenous analgesia (PCIA), and time to first flatulence after surgery. RESULTS The results revealed a noteworthy reduction in the occurrence of PONV at 24 h after surgery in the butorphanol group, when compared to the sufentanil group (T1: 23.64% vs 5.45%, T2: 43.64% vs 20.00%, P &lt; 0.05). However, no significant variations were observed between the two groups, in terms of the clinical characteristics, such as the PONV or motion sickness history, intraoperative and postoperative 48-h total infusion volume and hemodynamic parameters, intraoperative dose of propofol and remifentanil, number of postoperative PCIA compressions, time until the first occurrence of postoperative flatulence, and incidence of PONV at 48 h post-surgery (all, P &gt; 0.05). Furthermore, patients in the butorphanol group were more comfortable, when compared to patients in the sufentanil group in the PACU. CONCLUSION The present study revealed that butorphanol can be an efficacious substitute for sufentanil during anesthesia induction to diminish PONV within 24 h following gastrointestinal laparoscopic surgery in the elderly, simultaneously improving patient comfort in the PACU.

Association of MRI Volume Parameters in Predicting Patient Outcome at Time of Initial Diagnosis of Glioblastoma.

Patients with glioblastoma (GBM) may demonstrate varying patterns of infiltration and relapse. Improving the ability to predict these patterns may influence the management strategies at the time of initial diagnosis. This study aims to examine the impact of the ratio (T2/T1) of the non-enhancing volume in T2-weighted images (T2) to the enhancing volume in MRI T1-weighted gadolinium-enhanced images (T1gad) on patient outcome. A retrospective audit was performed from established prospective databases in patients managed consecutively with radiation therapy (RT) for GBM between 2016 and 2019. Patient, tumour and treatment-related factors were assessed in relation to outcome. Volumetric data from the initial diagnostic MRI were obtained via the manual segmentation of the T1gd and T2 abnormalities. A T2/T1 ratio was calculated from these volumes. The initial relapse site was assessed on MRI in relation to the site of the original T1gad volume and surgical cavity. The major endpoints were median relapse-free survival (RFS) from the date of diagnosis and site of initial relapse (defined as either local at the initial surgical site or any distance more than 20 mm from initial T1gad abnormality). The analysis was performed for association between known prognostic factors as well as the radiological factors using log-rank tests for subgroup comparisons, with correction for multiple comparisons. One hundred and seventy-seven patients with GBM were managed consecutively with RT between 2016 and 2019 and were eligible for the analysis. The median age was 62 years. Seventy-four percent were managed under a 60Gy (Stupp) protocol, whilst 26% were on a 40Gy (Elderly) protocol. Major neuroanatomical subsites were Lateral Temporal (18%), Anterior Temporal (13%) and Medial Frontal (10%). Median volumes on T1gd and T2 were 20 cm3 (q1-3:8-43) and 37 cm3 (q1-3: 17-70), respectively. The median T2/T1 ratio was 2.1. For the whole cohort, the median OS was 16.0 months (95%CI:14.1-18.0). One hundred and forty-eight patients have relapsed with a median RFS of 11.4 months (95%CI:10.4-12.5). A component of distant relapse was evident in 43.9% of relapses, with 23.6% isolated relapse. Better ECOG performance Status (p = 0.007), greater extent of resection (p = 0.020), MGMT methylation (p < 0.001) and RT60Gy Dose (p = 0.050) were associated with improved RFS. Although the continuous variable of initial T1gd volume (p = 0.39) and T2 volume (p = 0.23) were not associated with RFS, the lowest T2/T1 quartile (reflecting a relatively lower T2 volume compared to T1gd volume) was significantly associated with improved RFS (p = 0.016) compared with the highest quartile. The lowest T2/T1 ratio quartile was also associated with a lower risk of distant relapse (p = 0.031). In patients diagnosed with GBM, the volumetric parameters of the diagnostic MRI with a ratio of T2 and T1gad abnormality may assist in the prediction of relapse-free survival and patterns of relapse. A further understanding of these relationships has the potential to impact the design of future radiation therapy target volume delineation protocols.

Determinants of NT-proBNP Levels in patients with a systemic right ventricle: a new cut-off level for risk stratification?

Abstract Introduction The role of N-terminal natriuretic peptide (NT-proBNP) in the risk prediction of patients with a systemic left ventricle is indisputable. However, its value in patients with a systemic right ventricle (sRV) is not well defined. Method Ninety-eight patients with NT-proBNP values at baseline from the randomized clinical trial SERVE were included. The correlation between baseline NT-proBNP values and parameters of bi-ventricular volumes and function quantified by cardiac magnetic resonance was assessed by means of adjusted linear regression models. The prognostic value of NT-proBNP and other established prognostic markers were assessed by means of adjusted cox proportional hazards model, survival analysis and c-statistic. The primary outcome was defined as the occurrence of either clinically relevant arrhythmia, heart failure or death. Results Median age [interquartile range, IQR] at baseline was 39 years [32,48] and 32% were female. Median NT-proBNP was 238 [137,429] ng/L. Coefficients of determination for the relationship between NT-proBNP levels and right ventricular end-systolic and end-diastolic volume index, and ejection fraction (RVEF) were +0.481, p&amp;lt;0.001; +0.427, p&amp;lt;0.001; and -0.561, p&amp;lt;0.001, respectively. The sex and age adjusted hazard ratio [95% confidence interval, CI] for NT-proBNP values above the 75th percentile (429ng/L) showed an exponential increase (Figure) and there was a significant difference in survival comparing the group above our cut-off value and the group below it (Table). After adjusting for age and sex, the prognostic value of NT-proBNP was comparable to the prognostic value of RVEF and predicted VO2 max (C-statistic: 0.71, 0.72 and 0.71, respectively). Conclusion NT-proBNP levels correlated significantly with right ventricular parameters assessed by means of CMR. Measurement of NT-proBNP is a reliable and convenient tool for the prediction of adverse outcomes in patients with a sRV and using the cut-off value of 429ng/L could assist in the risk stratification for this population.

A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50mL had a significantly shorter median duration of observation (2.6 vs. 8.8years; p=0.001). At 5years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio=2.09; p=0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

Sex-specific differences in bi-atrial strain in elite athletes: results from the ELITE cohort

Abstract Background Athletes frequently demonstrate increased atrial volumes as a result of physiological adaptation to sports. In the general population, atrial dilatation is associated with decreased atrial function, measured as atrial ejection fraction and strain. However, studies on bi-atrial function in athletes have been limited and have primarily focused on male endurance athletes. Purpose To determine sex-specific differences in left- and right atrial strain in elite athletes. Methods The study population consisted of elite athletes included in the ELITE-cohort older than 16 years of age and exercising ≥10 hours per week and competing at the highest national, international or Olympic level in the Netherlands. All included athletes underwent a standardised resting transthoracic echocardiogram. Left- and right atrial (LA/RA) reservoir-, conduit- and cntractile- strain were measured with grey-scale-based 2D Speckle tracking software in the four- and two-chamber views and bi-atrial volume and function parameters were collected. Results A total of 166 elite athletes were included (48.2% female, media age 25 years [22, 28]), with athletic disciplines road cycling 25.3%, hockey 16.9%, rowing 14.5%, soccer 12.7%, water polo 9.6%, sailing 6.0%, track cycling 3.6%, and other 11.6%. There were no sex differences in age and training hours (18 hours per week). Athletic disciplines were evenly distributed among female- and male athletes. Female athletes had a lower BSA than male athletes (1.8 cm2 [1.7, 1.9] vs 2.1 cm2 [1.9, 2.2], p &amp;lt;0.001). Female athletes had similar LAESVi (36.5 ml/cm2 [32.0, 42.0] vs 36.5 ml/cm2 [31.0, 47.8]) and LAESAi (11.2 cm2/m2 [9.5, 12.2] vs 10.6 cm2/m2 [9.0, 11.9]) compared with male athletes. Female athletes had a higher LAEF (63.2 ±6.2% vs 60.7 ±5.8%, p =0.007) and greater LA deformation than male elite athletes during the reservoir- (34.7 ±6.2% vs 31.4 ±4.9%, p &amp;lt;0.001) and conduit phase (-25.2 ±5.2% vs -22.6 ±3.7% p &amp;lt;0.001). LA deformation during the contractile phase (-9.0% [-12.0, -7.0] vs – 9.0% [-11,-7]) was similar (figure 1). Female athletes had a lower RAESVi (29.5 ml/m2 [25.2, 36.4] vs 35.3 ml/m2 [28.5, 41.9], p &amp;lt;0.01) but there were no differences in RAEF (42.6 ±10.3% vs 45.2 ±11.1%) and RAESAi (9.8cm2/m2 [8.8, 11.3] vs 10.1 cm2/m2 [8.8-11.3]). There were no differences in RA reservoir- (30.7 ±7.6% vs 29.4 ±8.0%), conduit (-21.4 ±6.6% vs -20 ±6.6%) and contractile strain (-9.0% [-11.0, -6.8] vs -9.0% [-11.8, -7.0]) (figure 2). Conclusion In both male and female elite athletes, the LA is of comparable area and volume. However, in female athletes LA deformation is greater during the reservoir and conduit phases, resulting in a greater LA ejection fraction in the presence of similar LA contractile deformation. Conversely, RA volumes were smaller in female athletes, but deformation was similar compared with male athletes. Our findings suggest the presence of sex-specific atrial exercised-induced adaptation.Figure 1.Figure 2.

Rectum and Bladder Toxicity in Postoperative Prostate Bed Irradiation: Dose-Volume Parameters Analysis.

Although prostate cancer treatment is increasingly effective, its toxicities pose a major concern. The aim of our study was to assess the rate of adverse events (AEs) and the prognostic value of dose-volume histogram (DVH) parameters for the occurrence of treatment toxicity in patients treated with post-prostatectomy prostate bed radiotherapy (RT). The AEs were scored according to the CTCAE v.5.0. The rectum and bladder were contoured according to the RTOG Guidelines. The DVH parameters were assessed using data exported from the ECLIPSE treatment-planning system. Genitourinary (GU) and gastrointestinal (GI) toxicity were analysed using consecutive dose thresholds for the percentage of an organ at risk (OAR) receiving a given dose and the QUANTEC dose constraints. A total of 213 patients were included in the final analysis. Acute grade 2 or higher (≥G2) GU AEs occurred in 18.7% and late in 21.3% of patients. Acute ≥G2 GI toxicity occurred in 11.7% and late ≥G2 in 11.2% of the patients. Five patients experienced grade 4 AEs. The most common adverse effects were diarrhoea, proctitis, cystitis, and dysuria. The most significant predictors of acute ≥G2 GI toxicity were rectum V47 and V46 (p < 0.001 and p < 0.001) and rectum wall V46 (p = 0.001), whereas the most significant predictors of late ≥G2 GI AEs were rectum wall V47 and V48 (p = 0.019 and p = 0.021). None of the bladder or bladder wall parameters was significantly associated with the risk of acute toxicity. The minimum doses to bladder wall (p = 0.004) and bladder (p = 0.005) were the most significant predictors of late ≥G2 GU toxicity. Postoperative radiotherapy is associated with a clinically relevant risk of AEs, which is associated with DVH parameters, and remains even in patients who fulfil commonly accepted dose constraints. Considering the lack of survival benefit of postoperative adjuvant RT, our results support delaying treatment through an early salvage approach to avoid or defer toxicity.

Ebsteins anomaly management in Central and South Eastern European (CESEE) countries: current status and improvement needed

Abstract Background Ebstein anomaly (EA) of the tricuspid valve (TV) as a rare congenital heart disease (CHD) is characterized by variable morphology, hemodynamics and clinical course, associated heart defects as well. Moreover, whether and when to intervene on TV remains a big challenge. Patients with EA should therefore be managed in expert centres equipped with all diagnostic and treatment tools according to ESC guidelines (ESC-GL), including cardiac magnetic resonance (CMR) as the gold standard. Aim of the study The aim of the study was to characterize EA patient population from selected countries within Central-Southern-Eastern Europe (CESEE), evaluate the management in relation to ESC-GL and determine optimal parameters for long-term follow-up (FU) feasible in CESEE. Material and methods In retrospective cross-sectional study from 9 CESEE countries, 203 adult patients with EA were included: median age 39y, 58% women. Determined were age at diagnosis, EA complications (associated CHD, arrythmias), cardiosurgery. ECHO and CMR right ventricular (RV) characteristics, NTproBNP, 6-minute walking distance (6MWD) were analysed as follows: ECHO parameters: long-axis RV end-diastolic dimension (RVEDD,mm), long-axis end-diastolic right to left ventricle diameter ratio (RV/LV), tricuspid annular plane systolic excursion (TAPSE,mm), RV fractional area change (FAC,%), RV tissue Doppler myocardial velocity (m/s). CMR-derived analysed parameters were: ejection fraction (EF,%), indexed end-diastolic volume (EDVi,ml/m²). Results Patients were diagnosed at age &amp;lt;1y/1-18y/&amp;gt;18y in: 29,6%/31.1%/39.3%. NYHA I/II/III/IV was as follows: 41.6%/37%/22.5%/0%, median NTproBNP: 160ng/l, 6MWD: 473m. CMR-characteristics were: median RVEF: 43.2%, EDVi: 118ml/m². CMR was absent in 60% cases. Associated CHD/arrhythmias were present at 46,7%/64,4. TV surgery were indicated / underwent 30,7% patients at mean age 32y. Performed was daSilva cone-repair/other valvuloplasty/valve replacement in 36,4%/25,5%/38,2%. CMR-derived EDV correlates significantly (P&amp;lt;0.001) with ECHO-based RVEDD and RV/LV ratio. No correlations between CMR-derived EF and ECHO functional parameters were found. Conclusion Although patients with EA in CESSE region are diagnosed late, the characteristics correspond to data published so far. Despite large heterogeneity including various associated complications, patient´s care in the CESEE region does not fully meet the requirements of ESC-GL. Mainly, CMR as a golden standard for EA evaluation is not widely accessible and so not performed. Therefore, an inconsistency in management and differences in therapeutic approach is a consequence. In these conditions in view of our previously proven experience, that the RV/LV ratio correlates significantly with CMR volume parameters, ECHO could serve as a reliable and decisive imaging method in FU, however insufficient in relation to ESC-GL.

Adaptation of application of drop area method to characterize hydrophobicity of materials

The drop area can characterize hydrophobicity of materials. To improve accuracy of the drop area method, a large number of drop profiles with different contact angles, drop volumes and liquid parameters (Δρ/γ) are numerically generated. Based on the generated profiles, the influences of contact angle, drop volume and liquid parameter on the drop area and its sensitivity dS/dθ are systematically investigated. The results reveal that the sensitivity of the drop area method reduces with increasing contact angle, and increases with increasing drop volume and liquid parameter. The drop area method is particularly suitable for application in the case with small contact angle and at the same time, the drop volume and liquid parameter should be not so low. The relationship between water drop area and contact angle at some common drop volumes is obtained by numerical calculation. The concept of critical contact angle for the drop area method is proposed and the values of critical contact angle corresponding to different water drop volumes are presented. And it can be used to determine whether the drop area method or the static contact angle method should be selected. Finally, the contact angle method and the drop area method are used to measure hydrophobicity of glass and silicone rubber with different water drop volumes. The results validate the above analysis and at the same time it is consistent with the corresponding numerical calculation. This work is helpful to improve the accuracy in the drop area method and to generalize the use of it.

Abstract 11590: Body Mass-Corrected Estimated Plasma Volume at Discharge Predicts Mortality of Heart Failure Patients With Non-Normal and Normal Left Ventricular Ejection Fraction

Introduction: Estimated plasma volume(ePV) is a parameter of body fluid volume and an indicator for residual congestion. Even in the era of novel cardioprotective drugs, achieving adequate body fluid volume with heart failure is sometimes challenging. We investigated the prognosis of heart failure patients with a one-time evaluation of ePV at discharge corrected by body mass index (BMI). Since current heart failure treatment algorithms follow different paths with left ventricular ejection fraction (LVEF), we also examined whether these groups have a difference in prognosis prediction. Methods: This is a single-center, prospective observational study. A total of 1427 consecutive heart failure hospitalizations, excluding acute coronary syndromes, were included from January 2018 to June 2022. We evaluated 858 patients, excluding repeat hospitalizations of the same patient, in-hospital deaths, transfers for cardiac surgery and forced discharges, and missing data. A prognosis investigation was conducted for all patients. BMI and ePV (ml, Hakim's formula) was calculated from height, weight, and hematocrit at discharge. Survival analysis was performed with ePV divided by BMI (ePV/BMI). The primary endpoint was all-cause death. Results: Median of 527 days of post-discharge observation, 286 deaths occurred. BMI and ePV at discharge show a positive significant correlation in both normal (≧50%) and non-normal LVEF (&lt;50%) groups. Among the mortality group during follow-up, ePV/BMI at discharge was significantly higher than the non-mortality group. Survival analysis with Kaplan-Meier curve by ePV/BMI three tertiles (Low, Medium, High) in normal (66.8% vs 50.1% vs 44.0%, Logrank P&lt;0.001), non-normal LVEF (72.2% vs 69.3% vs 49.6%, Logrank P&lt;0.001) and overall (70.6% vs 55.5% vs 47.4%, Logrank P&lt;0.001) population had a significantly worse three-year prognosis in the high ePV/BMI group. Multivariable Cox proportional hazard model with covariant univariable predictive factors shows higher ePV/BMI tertile, as well as a continuous variable of ePV/BMI, was predictive factor of death in normal, non-normal LVEF and overall population. Conclusions: Even after therapeutic intervention, ePV/BMI at discharge is a useful predictor of heart failure prognosis.

Abstract 15044: The Relationship of Pericardial Fat With Metabolic Change and Myocardial Remodelling Following Bariatric Surgery

Introduction: Pericardial fat is a cardiometabolic risk factor that can be quantified from routine cardiovascular magnetic resonance (CMR) studies. However the extent to which this is modifiable, and its relationship with cardiometabolic markers remains unclear. Aims: Determine the effect of bariatric surgery on pericardial fat and associate with cardiometabolic improvements post-surgery. Methods: Thirty-eight people referred for bariatric surgery were assessed pre-operatively using CMR, blood biomarkers and anthropometry. Six months post-operatively, twenty-seven participants underwent paired follow-up assessments. Pericardial fat was quantified manually from routine short axis cine stacks by a single blinded clinical observer. Linear regression was used to assess the association of pericardial fat volume and cardiometabolic parameters, at baseline and changes pre- vs post-surgery. Results: At baseline, pericardial fat volume was associated with multiple cardiometabolic parameters including weight (r=0.46 p=0.004), fasting insulin (r=-0.46, p=0.007) hepatic fat concentration (Hepafat) (r=0.37 p=0.029) and LV mass (r=0.38, p=0.019). Pericardial fat remained independently associated with waist circumference after adjusting for the above (β=0.68, 95% CI: 1.24,9.23, p=0.012). At 6 months post-bariatric surgery pericardial adipose tissue reduced by an average of 29% (95% CI: -21-36%, p&lt;0.001). This change was associated with improvements in fasting insulin levels even after adjusting for changes in weight, Hepafat and LV mass (β=0.72, 95% CI: 0.15, 0.70, p=0.005). Conclusion: Pericardial fat in obesity associates with multiple adverse cardiometabolic parameters, including waist circumference. Bariatric surgery causes a significant reduction in pericardial fat which associates with reduced insulin resistance, providing a potential modifiable mechanism to reduce cardiovascular risk in patients living with obesity.

Abstract 13469: A Comprehensive Echocardiographic Assessment of Patients With Chronic Myeloid Leukemia on Dasatinib

Background: Dasatinib, a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML), is known to cause cardiotoxicities; however, little is known about the echocardiographic changes associated with this drug. Here we present a comprehensive echocardiographic assessment of patients with CML on dasatinib receiving care at a quaternary facility. Methods: We performed a retrospective cohort analysis on consecutive adult patients with CML receiving dasatinib between 2017-2022 who had a baseline and follow-up echocardiogram. Comprehensive clinical, laboratory and advanced echocardiographic data with speckle-tracking analyses (Tomtec Arena, Germany) were included. Results: Among 41 adult patients with CML (average age 64±16 years old, 39% female) who were prescribed with dasatinib (initial dose 100mg once daily), at baseline, 7 (17%) patients had heart failure with preserved ejection fraction (HFpEF), 11 (27%) coronary artery disease, and 3 (7%) pulmonary hypertension. There was a statistically significant increase in the indexed LV end-diastolic diameter and LV mass in pre- vs post-dasatinib echocardiograms; however, there was no significant change in ejection fraction or global longitudinal strain. There was no significant change in RV structure or function measures. There was a significant increase in LA volume index and decrease in lateral e’ velocity in pre- vs post-dasatinib echocardiograms. A trend towards declining LA reservoir strain post-dasatinib was noted. Ten (24%) patients had a progression in diastology grading after the initiation of dasatinib. Five out of 7 patients with HFpEF at baseline had progression in diastolic function post-dasatinib. Conclusions: Dasatinib was associated with significant changes in LV end-diastolic diameter, LV mass, LA volume, and diastolic parameters in patients with CML. These findings require further corroboration with a larger patient cohort and correlation with clinical outcomes.

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems, Part II: Long-Term Stability and Clinical Ocular Biopermanence.

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in several tissues and organs causing, among others, severe eye symptoms. The high instability of cysteamine eye drops makes it difficult to develop formulations with an acceptable shelf life to be prepared in hospital pharmacy departments. Previously, a new compounded formulation of cysteamine eye drops in hyaluronic acid (HA) packaged in innovative single-dose systems was developed. Long-term stability at -20 °C of this formulation was studied considering the content of cysteamine, pH, osmolality, viscosity, and microbiological analysis. The oxygen permeability of single-dose containers was also studied and an ocular biopermanence study was conducted in healthy volunteers measuring lacrimal stability and volume parameters. Data confirm that cysteamine concentration remained above 90% for 120 days, all parameters remaining within the accepted range for ophthalmic formulations. The permeability of the containers was reduced over time, while ocular biopermanence was maintained despite the freezing process and storage time. 0.55% cysteamine hydrochloride formulation in HA and packaged in single-dose containers preserved at -20 °C is stable for 120 days protected from light, presenting high potential for its translation into clinical practice when commercial presentations are not available.

Left ventricular remodeling in perimenopausal women

Aim to reveal specific features of the left ventricle (LV) structural and functional state and the pro-inflammatory status indicators in women of perimenopausal age.&#x0D; Material and methods. The cross-sectional study included 80 women (age 45 to 55 years) who were divided into 2 groups: a menopausal transition group and an early postmenopausal group according to the STRAW + 10 classification. Anthropometric measurements were taken; blood tests for homocysteine C, interleukin-6 (IL6), C-reactive protein (CRP), and echocardiography were performed according to the standard technique.&#x0D; Results. The study findings were as follows: 1. women in early postmenopause had higher levels of CRP when compared with women in the menopausal transition (4.5 (1.5; 8.0) mg/l versus 2.5 (0.6; 7.4) mg/l), in obese women, the level of IL6 was higher than in normal-weight women regardless of menopausal status (1.8 (0.6; 2.8) pg/ml versus 0.6 (0.2; 1.3) pg/ml); 2. the distribution of participants according to the type of myocardial remodeling did not differ in the comparison groups; 3. the presence of arterial hypertension and menopause was associated with myocardial hypertrophy; 4. significant differences were found in the distribution of myocardial geometry in women with obesity and overweight when compared to women with a normal body mass index (BMI) regardless of menopausal status; 5. significant direct correlation was registered between the structural and volume parameters of the LV and age, blood pressure, BMI, waist to hips circumference ratio. A positive correlation was found between the level of pro-inflammatory biomarkers and structural parameters of LV.&#x0D; Conclusion. In women of perimenopausal age, a myocardial remodeling was revealed that could not be explained by traditional risk factors. The activation of the systemic inflammatory response in menopause and obesity was accompanied by the pathological LV remodeling and myocardial hypertrophy.

Assessment of longitudinal brain development using super-resolution magnetic resonance imaging following fetal surgery for open spina bifida.

Prenatal surgery is offered for selected fetuses with open spina bifida (OSB) to improve long-term outcome. We studied the effect of fetal OSB surgery on brain development using advanced magnetic resonance imaging (MRI) techniques to quantify the volume, surface area and shape of cerebral structures and to analyze surface curvature by means of parameters that correspond to gyrification. We compared MRI data from 29 fetuses with OSB before fetal surgery (mean gestational age (GA), 23 + 3 weeks) and at 1 and 6 weeks after surgery, with that of 36 GA-matched control fetuses (GA range, 21 + 2 to 36 + 2 weeks). Automated super-resolution reconstruction provided three-dimensional isotropic volumetric brain images. Unmyelinated white matter, cerebellum and ventricles were segmented automatically and refined manually, after which volume, surface area and shape parameter (volume/surface area) were quantified. Mathematical markers (shape index (SI) and curvedness) were used to measure gyrification. Parameters were assessed according to lesion type (myelomeningocele vs myeloschisis (MS)), postoperative persistence of hindbrain herniation (HH) and the presence of supratentorial anomalies, namely partial agenesis of the corpus callosum (pACC) and heterotopia (HT). Growth in ventricular volume per week and change in shape parameter per week were higher at 6 weeks after surgery in fetuses with OSB compared with controls (median, 2500.94 (interquartile range (IQR), 1689.70-3580.80) mm3 /week vs 708.21 (IQR, 474.50-925.00) mm3 /week; P < 0.001 and 0.075 (IQR, 0.047-0.112) mm/week vs 0.022 (IQR, 0.009-0.042) mm/week; P = 0.046, respectively). Ventricular volume growth increased 6 weeks after surgery in cases with pACC (P < 0.001) and those with persistent HH (P = 0.002). During that time period, the change in unmyelinated white-matter shape parameter per week was decreased in OSB fetuses compared with controls (0.056 (IQR, 0.044-0.092) mm/week vs 0.159 (IQR, 0.100-0.247) mm/week; P = 0.002), particularly in cases with persistent HH (P = 0.011), MS (P = 0.015), HT (P = 0.022), HT with corpus callosum anomaly (P = 0.017) and persistent HH with corpus callosum anomaly (P = 0.007). At 6 weeks postoperatively, despite OSB fetuses having a lower rate of change in curvedness compared with controls (0.061 (IQR, 0.040-0.093) mm-1 /week vs 0.094 (IQR, 0.070-0.146) mm-1 /week; P < 0.001), reversing the trend seen at 1 week after surgery (0.144 (IQR, 0.099-0.236) mm-1 /week vs 0.072 (IQR, 0.059-0.081) mm-1 /week; P < 0.001), gyrification, as determined using SI, appeared to be increased in OSB fetuses overall compared with controls. This observation was more prominent in fetuses with pACC and those with severe ventriculomegaly (P-value range, < 0.001 to 0.006). Following fetal OSB repair, volume, shape and curvedness of ventricles and unmyelinated white matter differed significantly compared with those of normal fetuses. Morphological brain changes after fetal surgery were not limited to effects on the circulation of cerebrospinal fluid. These observations may have implications for postnatal neurocognitive outcome. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.