Maximum Dose Research Articles

Identification of predictive factors for better outcomes in LINAC-based radiation treatment for cerebral cavernous malformation

The effectiveness of radiation therapy in the treatment of cerebral cavernous malformations (CCM) remains debatable. However, numerous studies have shown a reduction in hemorrhage risk following radiotherapy for CCM. Therefore, herein, we share our experiences utilizing linear accelerator (LINAC)-based radiation for treating CCMs, with the aim of identifying the key factors influencing the therapeutic outcomes. We conducted a retrospective review of all patients with non-brainstem CCMs who underwent radiation treatment, as recorded in the NOVALIS registry at our institution. T2-weighted MR images were used for volumetric assessments using the iPlan radiotherapy planning software. To determine the independent predictors of nidus volume reduction and perilesional brain edema (PBE), we performed multivariate Cox regression analysis to calculate hazard ratios. Twenty patients with 31 non-brainstem CCMs were enrolled in this study. Analysis revealed age as an independent predictive factor for both nidus volume reduction and PBE after radiation treatment for CCM. Furthermore, a single fraction dose of 17 Gy or more was identified as an independent predictor of nidus volume decrease, while a single fraction dose of 18 Gy or more was found to be an independent risk factor for PBE in patients with CCM following LINAC-based radiation therapy. LINAC-based radiation therapy for non-brainstem CCMs with a single fraction radiation dose between 16.5 and 17.5 Gy, or a biologically equivalent dose of approximately 120 Gy, may be the most effective at reducing nidus volume and limiting side effects, particularly in patients under the age of 55 years. We further observed that the risk of PBE increased as the maximum radiation dose delivered to a 1 cc volume of the surrounding normal brain exceeded approximately 17.3 Gy. Therefore, we believe that calculating the D1cc of the normal brain may help to predict the occurrence of PBE when radiotherapy is administered to non-brainstem CCMs.

The Right Gastroepiploic Artery as a Potential Organ at Risk in Neoadjuvant Chemoradiation for Esophageal and Gastroesophageal Cancers.

Preoperative chemoradiation is a standard of care for esophageal and gastroesophageal cancer. A gastric conduit is usually used for anastomosis with the right gastroepiploic artery (RGEA) being the sole arterial supply to the gastric remnant after such surgeries. Hence, lowering the radiation dose to this vessel may lower the risks of postoperative complications related to poor vasculature. Herein, we report our experience in contouring and replanning cases of distal esophageal/gastroesophageal carcinomas so that the radiation doses to the RGEA could be minimized. Radiation plans of patientswith lower esophageal/gastroesophageal carcinomas were retrieved from our database. Identification and delineation of the RGEA was done and replanning was performed with the aim to keep the maximal and mean doses as well as the V10Gy and V20Gy of the RGEA as low as possible without compromising target volume coverage. Results: We achieved significant dose reductions in most of the dosimteric parameters in our selected cases without compromising target coverage. Lowering the dose to the RGEA, a potential organ-at-risk that may impact the postoperative course after neoadjuvant chemoradiation, is feasible.

Multidisciplinary proactive e-consults to improve guideline-directed medical therapies for patients with diabetes and chronic kidney disease: an implementation study

IntroductionWe hypothesized that multidisciplinary, proactive electronic consultation (MPE) could overcome barriers to prescribing guideline-directed medical therapies (GDMTs) for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).Research design...

Maximum dose of AbobotulinumtoxinA: Is there room for more?

Maximum dose of AbobotulinumtoxinA: Is there room for more?

TREAT TRIAL: MULTI-CENTER CROSS-SECTIONAL TREATMENT EVALUATION OF APPARENT RESISTANT HYPERTENSION IN BELGIUM

Objective: The goal of the TREAT study is to evaluate the prevalence of apparent treatment-resistant hypertension (aRHT) in a Belgian setting and to evaluate which determining factor of pseudo-resistant hypertension contributes the most to this prevalence: white coat hypertension (WCH), underdosing of adequate drugs or poor adherence to prescribed medicines. Design and method: TREAT is a single-visit, multicentric, non-interventional, cross-sectional survey. Inclusion criteria were the following: patients over 18 years old receiving 3 or more antihypertensive molecules and referred to specialized hospital centres for aRHT. The data were collected according to the patient’s medical records. Self-reported adherence to antihypertensive treatment was collected and a Hill-bone medication adherence scale was also proposed. Results: A total of 232 patients were included. Mean anti-hypertensive treatment duration was 10.6(±9.1) years. Patients were treated with a mean of 3.8(±1.1) antihypertensive molecules and 2.8(±1.1) antihypertensive pills. Only 48.5% of the aRHT patients were treated with the triple therapy recommended by the 2023 ESH hypertension guidelines (i.e. renin-angiotensin-aldosterone system inhibitor (RAASi), calcium channel blocker (CCB) and diuretic), and only 29.1% of patients were treated with the maximal recommended dose. Inadequate dosing was mostly present with diuretics, only 60% of patients was treated with at least half the maximum dose of a diuretic. WCH was present in 11% of patients in whose ambulatory BP measurements were available in records (n=136). Therapeutic adherence was self-reported as poor or moderate in 17.6% of patients (n=41). The Hill-bone medication adherence scale (n=140, 60.4%) showed a mean score of 12(±4.2) (good adherence). In this cohort, 31.8% of patients seemed to have true resistant hypertension. Conclusions: Among patients referred to specialized centres for aRHT, about 2/3 of patients have in reality pseudo-resistant hypertension. Whereas WCH and poor adherence seems to be limited in our dataset, many patients were polymedicated with non-recommended combinations of antihypertensive molecules in 1 out of 2 patients, with inadequate dosing in 2 out of 3 patients. Pseudo-resistant hypertension seems in our cohort to be mainly related to under-use of triple combination therapy and most likely also due to underdosing.

Assessment of the Dosimetric Index from IMRT and Rapid arc Plan for Oropharyngeal Cancer with Simultaneous Integrated Boost (SIB) Technique in Combination with EUD-based NTCP and TCP Radiobiological Models.

The current research compared radiobiological and dosimetric results for simultaneous integrated boost (SIB) plans employing RapidArc and IMRT planning procedures in oropharyngeal cancer from head-and-neck cancer (HNC) patients. The indigenously developed Python-based software was used in this study for generation and analysis. Twelve patients with forty-eight total plans with SIB were planned using Rapid arc (2 and 3 arcs) and IMRT (7 and 9 fields) and compared with radiobiological models Lyman, Kutcher, Burman (LKB) and EUD (Equivalent Uniform Dose) along with physical index such as homogeneity index(HI), conformity index(CI) of target volumes. These models' inputs are the dose-volume histograms (DVHs) calculated by the treatment planning system (TPS). The values obtained vary from one model to the other for the same technique and patient. The maximum dose to the brainstem and spinal cord and the mean dose to the parotids were analysed both dosimetrically and radiobiologically, such as the LKB model effective volume, equivalent uniform dose, EUD-based normal tissue complication probability, and normal tissue integral dose. The mean and max dose to target volume with conformity, homogeneity index, tumor control probability compared with treatment times, and monitor units. Rapid arc (3 arcs) resulted in significantly better OAR sparing, dose homogeneity, and conformity. The findings indicate that the rapid arc plan has improved dose distribution in the target volume compared with IMRT, but the tumor control probability obtained for the two planning methods, Rapid arc (3 arcs) and IMRT (7 fields), are similar. The treatment time and monitor units for the Rapid arc (3 arcs) were superior to other planning methods and considered to be standard in head & neck radiotherapy.

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia

A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. ClinicalTrials.gov Identifier: NCT04738123.

Effect of Implantable Cardioverter-defibrillators in Nonischemic Heart Failure According to Background Medical Therapy: Extended Follow-up of the DANISH Trial

The Heart Failure Collaboratory (HFC) score integrates types and dosages of guideline-directed pharmacotherapies for heart failure (HF) with reduced ejection fraction (HFrEF). We examined the effects of cardioverter-defibrillator (ICD) implantation according to the modified HFC (mHFC) score in 1116 patients with nonischemic HFrEF from the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic HF on Mortality (DANISH). Patients were assigned scores for renin-angiotensin-system inhibitors, beta-blockers and mineralocorticoid receptor antagonists (0, no use; 1, < 50% of maximum dosage; 2, ≥ 50% of maximum dosage). The maximum score was 6, corresponding to ≥ 50% of maximum dosage for all therapies. The median baseline mHFC score was 4, and the median follow-up was 9.5 years. Compared with an mHFC score of 3-4, an mHFC score of 1-2 was associated with a higher rate of all-cause death (mHFC = 1-2: adjusted HR 1.67 [95% CI, 1.23-2.28]; mHFC = 3-4, reference; mHFC = 5-6: adjusted HR 1.07 [95% CI, 0.87-1.31]). ICD implantation did not reduce all-cause death compared with control (reference) (HR 0.89 [95% CI, 0.74-1.08]), regardless of mHFC score (mHFC = 1-2: HR 0.98 [95% CI, 0.56-1.71]; mHFC = 3-4: HR 0.89 [95% CI,0.66-1.20]; mHFC = 5-6: HR 0.85 [95% CI, 0.64-1.12]; Pinteraction, 0.65). Similarly, ICD implantation did not reduce cardiovascular death (HR 0.87 [95% CI, 0.70-1.09]), regardless of mHFC score (Pinteraction, 0.59). The ICD group had a lower rate of sudden cardiovascular death (HR, 0.60 [95% CI,0.40-0.92]); this association was not modified by mHFC score (Pinteraction, 0.35). Lower mHFC scores were associated with higher rates of all-cause death. ICD implantation did not result in an overall survival benefit in patients with nonischemic HFrEF, regardless of mHFC score.

Association between pre-treatment with statin and its inhibitory effect on the onset of coronary artery disease at the time of coronary computed tomography angiography: a new look at an old medication.

Coronary artery stenosis is often advanced by the time coronary computed tomography angiography (CCTA). Statins are the most important anti-lipidemic medication for improving the prognosis of coronary artery disease (CAD) patients. Although lipid-lowering therapy using statins appears to have been established as a method for preventing CAD, there remains the problem that CAD cannot be completely suppressed. In this study, we investigated whether pre-treatment with statin could significantly inhibit the onset of CAD when patients received CCTA for screening of CAD. The subjects were 1164 patients who underwent CCTA as screening for CAD. CAD was diagnosed when 50% or more coronary stenosis was present in the coronary arteries. Patient backgrounds were investigated by age, gender, body mass index, coronary risk factors [family history of cardiovascular diseases, smoking history, hypertension (HTN), diabetes mellitus (DM), dyslipidemia, chronic kidney disease (CKD) or metabolic sydrome] and medications. Patients were classified into two groups according to the presence or absence of statin pre-administration during CCTA [statin (-) group (n = 804) and (+) group (n = 360)]. Compared with the statin (-) group, the statin (+) group was significantly older and had higher rates of family history, HTN, and DM. The statin (+) group had a significantly higher % CAD than the statin (-) group. Serum levels of low-density lipoprotein cholesterol (LDL-C) were significantly lower in the statin (+) group than in the statin (-) group. There was no significant difference in either high-density lipoprotein cholesterol levels or triglyceride levels between the two groups. Age, male gender, HTN, DM and pre-treatment with statin were all associated with CAD (+) in all patients. In addition, factors that contributed to CAD (+) in the statin (-) group were age, male gender, and DM, and factors that contributed to CAD (+) in the statin (+) group were age, smoking, HTN and % maximum dose of statin. At the time of CCTA, the statin (+) group had a high rate of CAD and coronary artery stenosis progressed despite a reduction of LDL-C levels. To prevent the onset of CAD, in addition to strict control of other coronary risk factors (HTN etc.), further LDL cholesterol-lowering therapy may be necessary.

Is there any radiation-induced brachial plexopathy after hypofractionated postmastectomy radiotherapy with helical tomotherapy?

Radiation-induced brachial plexopathy (RIBP) is one of the most concerning late radiation effects after hypofractionated postmastectomy radiotherapy (HF-PMRT) to the chest wall and regional lymph nodes. The purpose of this study was to investigate the RIBP events occurring in breast cancer patients after HF-PMRT using intensity-modulated radiation therapy (IMRT) by helical tomotherapy. Furthermore, the dosimetric parameters of the ipsilateral brachial plexus were reported. Breast cancer patients who underwent HF-PMRT using the IMRT via HT at our institute were included. In the first cohort, subjective RIBP symptoms were measured using a QuickDASH questionnaire, whereas objective RIBP events were assessed using a comprehensive physical evaluation in the second cohort. The ipsilateral brachial plexus from all eligible patients' treatment plans was contoured, and the dosimetric parameters were explored. From March 2014 to December 2022, 229 patients were enrolled; 107 and 72 individuals were in the first and second cohorts, respectively. The first cohort's median follow-up period was 27 months, and the second cohort was 31 months. In the first cohort, 80 patients (74.77%) had a normal function, 21 (19.63%) had a mild grade, and 6 (5.61%) had a moderate grade; no severe or very severe RIBP was observed. However, the comprehensive physical evaluation of the second cohort indicated no RIBP events. Dosimetric analysis revealed that the median maximum dose was 44.52, 44.52, and 44.60 Gy; the median mean dose was 33.00, 32.23, and 32.33 Gy; and the median dose at 0.03 cc was 44.33, 44.36, and 44.39 Gy for all patients, patients in the first and second cohort, respectively. Each dosimetric parameter was evaluated, and no statistically significant differences were detected. The absence of RIBP events supports the safety of employing HF-PMRT by HT for the chest wall and all regional lymph nodes. We propose that applying the ICRU Report 83 criteria for IMRT planning, which limit the maximum dose (107% of the prescribed dose) to less than 2% of the planning target volume and exclude the brachial plexus region from the maximal dose area, is a practical way to minimize the risk of RIBP from HF-PMRT.

Doses to the right coronary artery and the left anterior descending coronary artery and death from ischemic heart disease after breast cancer radiotherapy: a case-control study in a population-based cohort.

Doses to the coronary arteries in breast cancer (BC) radiotherapy (RT) have been suggested to be a risk predictor of long-term cardiac toxicity after BC treatment. We investigated the dose-risk relationships between near maximum doses (Dmax) to the right coronary artery (RCA) and left anterior descending coronary artery (LAD) and ischemic heart disease (IHD) mortality after BC RT. In a cohort of 2,813 women diagnosed with BC between 1958 and 1992 with a follow-up of at least 10 years, we identified 134 cases of death due to IHD 10-19 years after BC diagnosis. For each case, one control was selected within the cohort matched for age at diagnosis. 3D-volume and 3D-dose reconstructions were obtained from individual RT charts. We estimated the Dmax to the RCA and the LAD and the mean heart dose (MHD). We performed conditional logistic regression analysis comparing piecewise spline transformation and simple linear modeling for best fit. There was a linear dose-risk relationship for both the Dmax to the RCA (odds ratio [OR]/Gray [Gy] 1.03 [1.01-1.05]) and the LAD (OR/Gy 1.04 [1.02-1.06]) in a multivariable model. For MHD there was a linear dose-risk relationship (1,14 OR/Gy [1.08-1.19]. For all relationships, simple linear modelling was superior to spline transformations. Doses to both the RCA and LAD are independent risk predictors of long-term cardiotoxicity after RT for BC In addition to the LAD, the RCA should be regarded as an organ at risk in RT planning.

Gamma Ray Induced Changes in Polycarbonate/Poly(Methyl Methacrylate)/Polystyrene Blend Films: Linear and Nonlinear Optical Properties

In our research described in this article, we used a solution casting technique to prepare a blend film containing polycarbonate (PC), poly (methyl methacrylate) (PMMA), and polystyrene (PS) polymers. Samples from the prepared PC/PMMA/PS films were irradiated with γ ray doses ranging from 20 to 160 kGy. We used UV-vis spectroscopy to investigate the resulting effects of the γ ray irradiation on the optical properties of the prepared films. When the γ ray dose was increased up to 160 kGy, the maximum dose used, the direct bandgap was decreased from 3.68 to 2.90 eV, associated with an increase of Urbach energy from 0.82 to 1.03 eV. Also, we used the optical dielectric loss (ε″) to detect the type of microelectronic transition for the PC/PMMA/PS blend films, which was found to be a direct allowed transition. The γ ray effects on the absorbance, extinction coefficient, refractive index, dielectric parameters, optical conductivity and the nonlinear parameters of the blend films were studied. The enhancement in the optical properties indicated that the γ radiation is a useful tool that allows the application of the resulting PC/PMMA/PS blend films in optoelectronic devices.

Assessing Impact of Manual Topping and Suckericide Application at Different Stages on FCV Tobacco Quality and Yield

Tobacco (Nicotiana tabacum L.) topping is one of the essential practice to obtain good quality and adequate yield. The suckericide (Flumetralin as a best herbicide and plant growth regulator). For the purpose to compare topping as manual and herbicide application the experiment was conducted on flue cured Virginia (FCV) tobacco at Tobacco Research Station, Khan Ghari, Mardan during 2021-2022. The experiment was conducted in RCB design with three replications and five treatments (Control, Manual de-suckering, 1000, 1200, 1500 ml of Flumetralin ha-1). Treatments were applied at three stages (button stage, early flowering stage and late flowering stage). The data revealed that topping timing and maximum dose (1500 ml ha-1) of (Flumetralin) resulted maximum (896 cm-2) leaf area, less number (14) of sucker plant-1, lower (132 g) green weight and dry weight (20.30 g) of sucker plot-1, more cured weight (5.08 kg) of leaves plot-1 and maximum yield (3038) kg ha-1, lower nicotine contents (2.26) and less sugar contents (16.24) at button stage. Moreover, Flumetralin application on at button stage resulted less sucker growth and enhanced leaf yield. I suggest that the tobacco K399 with the application of suckericide and growth regulator (Flumetralin) have the potential to incorporate in further breeding program for low content of nicotine, reduced sugar content and high yield.

Analysis of polydisperse polymer adsorption on porous cellulose fibers.

The adsorption of cationic water-soluble polymers onto negatively charged porous wood pulp fibers is an essential aspect of papermaking. Adsorption data can be displayed as a direct plot of the amount adsorbed, Γ, versus the amount of polymer added or as an isotherm plot showing the amount adsorbed versus the residual unadsorbed polymer. In either data presentation, the analysis is more transparent if the units of each axis are the same (e.g., mg/g or meq/g), giving dimensionless slopes. Values for Γmax, ΓI, f I , and Γme can be extracted from many isotherms where: Γmax is the maximum capacity of the fibers to adsorb polymer; ΓI is the y-axis isotherm intercept and gives the maximum dose that can be fully adsorbed; f I is the slope of the direct plot at ΓI, and f I is the mass fraction of the added polymer that can access interior (pore) surfaces; and, Γme is the saturated amount of polymer adsorbed on exterior surfaces. Additionally, the molecular weight distribution of theadsorbing polymer in conjunction with the adsorption isotherm can be used to estimate the molecular weight distributions of adsorbed polymer on interior and exterior fiber surfaces as functions of the polymer dose.

Application of stoichiometric CT number calibration method for dose calculation of tissue heterogeneous volumes in boron neutron capture therapy.

Monte Carlo simulation code is commonly used for the dose calculation of boron neutron capture therapy. In the past, dose calculation was performed assuming a homogeneous mass density and elemental composition inside the tissue, regardless of the patient's age or sex. Studies have shown that the mass density varies with patient to patient, particularly for those that have undergone surgery or radiotherapy. A method to convert computed tomography numbers into mass density and elemental weights of tissues has been developed and applied in the dose calculation process using Monte Carlo codes. A recent study has shown the variation in the computed tomography number between different scanners for low- and high-density materials. The aim of this study is to investigate the effect of the elemental composition inside each calculation voxel on the dose calculation and the application of the stoichiometric CT number calibration method for boron neutron capture therapy planning. Monte Carlo simulation package Particle and Heavy Ion Transport code System was used for the dose calculation. Firstly, a homogeneous cubic phantom with the material set to ICRU soft tissue (four component), muscle, fat, and brain was modelled and the NeuCure BNCT system accelerator-based neutron source was used. The central axis depth dose distribution was simulated and compared between the four materials. Secondly, a treatment plan of the brain and the head and neck region was simulated using a dummy patient dataset. Three models were generated; (1) a model where only the fundamental materials were considered (simple model), a model where each voxel was assigned a mass density and elemental weight using (2) the Nakao20 model, and (3) the Schneider00 model. The irradiation conditions were kept the same between the different models (irradiation time and irradiation field size) and the near maximum (D1%) and mean dose to the organs at risk were calculated and compared. A maximum percentage difference of approximately 5% was observed between the different materials for the homogeneous phantom. With the dummy patient plan, a large dose difference in the bone (greater than 12%) and region near the low-density material (mucosal membrane, 7%-11%) was found between the different models. A stoichiometric CT number calibration method using the newly developed Nakao20 model was applied to BNCT dose calculation. The results indicate the importance of calibrating the CT number to elemental composition for each individual CT scanner for the purpose of BNCT dose calculation along with the consideration of heterogeneity of the material composition inside the defined region of interest.

Clinical VMAT machine parameter optimization for localized prostate cancer using deep reinforcement learning.

Volumetric modulated arc therapy (VMAT) machine parameter optimization (MPO) remains computationally expensive and sensitive to input dose objectives creating challenges for manual and automatic planning. Reinforcement learning (RL) involves machine learning through extensive trial-and-error, demonstrating performance exceeding humans, and existing algorithms in several domains. To develop and evaluate an RL approach for VMAT MPO for localized prostate cancer to rapidly and automatically generate deliverable VMAT plans for a clinical linear accelerator (linac) and compare resultant dosimetry to clinical plans. We extended our previous RL approach to enable VMAT MPO of a 3D beam model for a clinical linac through a policy network. It accepts an input state describing the current control point and predicts continuous machine parameters for the next control point, which are used to update the input state, repeating until plan termination. RL training was conducted to minimize a dose-based cost function for prescription of 60Gy in 20 fractions using CT scans and contours from 136 retrospective localized prostate cancer patients, 20 of which had existing plans used to initialize training. Data augmentation was employed to mitigate over-fitting, and parameter exploration was achieved using Gaussian perturbations. Following training, RL VMAT was applied to an independent cohort of 15 patients, and the resultant dosimetry was compared to clinical plans. We also combined the RL approach with our clinical treatment planning system (TPS) to automate final plan refinement, and creating the potential for manual review and edits as required for clinical use. RL training was conducted for 5000 iterations, producing 40 000 plans during exploration. Mean±SD execution time to produce deliverable VMAT plans in the test cohort was 3.3±0.5 s which were automatically refined in the TPS taking an additional 77.4±5.8 s. When normalized to provide equivalent target coverage, the RL+TPS plans provided a similar mean±SD overall maximum dose of 63.2±0.6Gy and a lower mean rectum dose of 17.4±7.4 compared to 63.9±1.5Gy (p=0.061) and 21.0±6.0 (p=0.024) for the clinical plans. An approach for VMAT MPO using RL for a clinical linac model was developed and applied to automatically generate deliverable plans for localized prostate cancer patients, and when combined with the clinical TPS shows potential to rapidly generate high-quality plans. The RL VMAT approach shows promise to discover advanced linac control policies through trial-and-error, and algorithm limitations and future directions are identified and discussed.

Dosimetric impact of contour editing on CT and MRI deep-learning autosegmentation for brain OARs.

To establish the clinical applicability of deep-learning organ-at-risk autocontouring models (DL-AC) for brain radiotherapy. The dosimetric impact of contour editing, prior to model training, on performance was evaluated for both CT and MRI-based models. The correlation between geometric and dosimetric measures was also investigated to establish whether dosimetric assessment is required for clinical validation. CT and MRI-based deep learning autosegmentation models were trained using edited and unedited clinical contours. Autosegmentations were dosimetrically compared to gold standard contours for a test cohort. D1%, D5%, D50%, and maximum dose were used as clinically relevant dosimetric measures. The statistical significance of dosimetric differences between the gold standard and autocontours was established using paired Student's t-tests. Clinically significant cases were identified via dosimetric headroom to the OAR tolerance. Pearson's Correlations were used to investigate the relationship between geometric measures and absolute percentage dose changes for each autosegmentation model. Except for the right orbit, when delineated using MRI models, the dosimetric statistical analysis revealed no superior model in terms of the dosimetric accuracy between the CT DL-AC models or between the MRI DL-AC for any investigated brain OARs. The number of patients where the clinical significance threshold was exceeded was higher for the optic chiasm D1% than other OARs, for all autosegmentation models. A weak correlation was consistently observed between the outcomes of dosimetric and geometric evaluations. Editing contours before training the DL-AC model had no significant impact on dosimetry. The geometric test metrics were inadequate to estimate the impact of contour inaccuracies on dose. Accordingly, dosimetric analysis is needed to evaluate the clinical applicability of DL-AC models in the brain.

Timing of Worsening Renal Function in Patients Hospitalized for Heart Failure Exacerbation Who Were Being Treated With Intravenous Diuretic Therapy.

This retrospective observational study investigated the incidence of worsening renal function (WRF) in patients hospitalized for heart failure (HF) and treated with intravenous diuretics in Japan.Methods and Results: Associations between WRF at any point and HF treatments, and the effects of WRF on outcomes were evaluated (Diagnosis Procedure Combination database). Of 1,788 patients analyzed (mean [±SD] age 80.5±10.2 years; 54.4% male), 641 (35.9%) had WRF during a course of hospitalization for worsening HF: 208 (32.4%) presented with WRF before admission (BA-WRF; estimated glomerular filtration rate decreased by ≥25% from baseline at least once between 30 days prior to admission and admission); 44 (6.9%) had WRF that persisted before and after admission (P-WRF); and 389 (60.7%) had WRF develop after admission (AA-WRF). Delayed initial diuretic administration, higher maximum doses of intravenous diuretics during hospitalization, and diuretic readministration during hospitalization were associated with a significantly higher incidence of AA-WRF. Patients with WRF at any time point were at higher risk of death during hospitalization compared with patients without WRF, with adjusted hazard ratios of 3.56 (95% confidence interval [CI] 2.23-5.69) for BA-WRF, 3.23 (95% CI 2.21-4.71) for AA-WRF, and 13.16 (95% CI 8.19-21.15) for P-WRF (all P<0.0001). Forty percent of WRF occurred before admission for acute HF; there was no difference in mortality between patients with BA-WRF and AA-WRF.

Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19

The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments. This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024. Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg). Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity. Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure. In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients. ClinicalTrials.gov Identifier: NCT04593940.

E075 Sacroiliitis potentially induced by isotretinoin: two case reports

Abstract Background/Aims Isotretinoin is a potent retinoid medication widely used to treat severe acne. Isotretinoin’s adverse effects range from well-documented dermatological side effects like dry skin to less common systemic manifestations. Sacroiliitis can arise from rheumatic and nonrheumatic causes. There has been limited attention in the literature to the rare occurrence of sacroiliitis as an adverse effect of isotretinoin. The precise mechanisms remain poorly understood, but the emergence of case reports suggests a potential link in immunomodulation through the alteration of cytokine balance and degradation of synovial membranes in joints. We present two patients with severe acne history who developed bilateral sacroiliitis within several weeks after starting isotretinoin Methods Case 1: A 19 year old male, started on 20 mg daily isotretinoin for acne vulgaris, experienced severe hip and lower back pain after one month, impacting his mobility. On examination, he displayed painful hip movements. Lumbar flexion was restricted and painful, with a 2 cm measurement on the Schober’s test. Medical investigation showed an elevation of erythrocyte sedimentation rate (ESR): 66mm/h, and C-reactive protein (CRP): 81 mg/l. HLA B27 was negative. X-ray radiography of the sacroiliac joint was normal, but the MRI examination showed the presence of bilateral sacroiliitis. Case 2: A 34 year old female received a six-months isotretinoin treatment for severe acne, with doses ranging from 20-40 mg daily. Then, in 2018, after a six-year gap, she received another isotretinoin course at 30 mg daily. Four months later, she began to experience gradual, intermittent lower back pain associated with 30 minutes of early morning stiffness. Her vital signs were stable, but she exhibited restricted and painful lumbar flexion. Her investigations revealed normal ESR and CRP. HLA B27 was negative. Her sacroiliac joint X-ray showed normal results, but her MRI indicated bilateral active sacroiliitis. Results Following the discontinuation of isotretinoin in both cases, NSAIDs were administered, which effectively relieved the pain. Our management of isotretinoin-induced sacroiliitis follows guidelines adapted from the ASAS-EULAR algorithm for axial spondyloarthritis. The algorithm entails an initial treatment with NSAIDs if no contraindications and to be titrated up to the maximum effective dose before considering biological/ targeted synthetic disease-modifying antirheumatic drugs. Conclusion The two cases highlight the rare but noteworthy association between isotretinoin therapy and sacroiliitis. In patients presenting with unexplained musculoskeletal symptoms during isotretinoin treatment at any point, clinicians should raise suspicions on the adverse effects of medication. Further research is needed to elucidate the immunomodulatory pathways involved in this association. Disclosure H. Almansoori: None. N. Alnuaimi: None. S. Alhosani: None. M. Alshehhi: None. S.A. Al Nokhatha: None.