Biological Planning of Radiation Dose Based on In Vivo Dosimetry for Postoperative Vaginal-Cuff HDR Interventional Radiotherapy (Brachytherapy)

(1) Background: Postoperative vaginal-cuff HDR interventional radiotherapy (brachytherapy) is a standard treatment in early-stage endometrial cancer. This study reports the effect of in vivo dosimetry-based biological planning for two different fractionation schedules on the treatment-related toxicities. (2) Methods: 121 patients were treated. Group A (82) received 21 Gy in three fractions. Group B (39) received 20 Gy in four fractions. The dose was prescribed at a 5 mm depth or to the applicator surface according to the distance between the applicator and the rectum. In vivo dosimetry measured the dose of the rectum and/or urinary bladder. With a high measured dose, the dose prescription was changed from a 5 mm depth to the applicator surface. (3) Results: The median age was 66 years with 58.8 months mean follow-up. The dose prescription was changed in 20.7% of group A and in 41% of group B. Most toxicities were grade 1–2. Acute urinary toxicities were significantly higher in group A. The rates of acute and late urinary toxicities were significantly higher with a mean bladder dose/fraction of >2.5 Gy and a total bladder dose of >7.5 Gy. One patient had a vaginal recurrence. (4) Conclusions: Both schedules have excellent local control and acceptable rates of toxicities. Using in vivo dosimetry-based biological planning yielded an acceptable dose to the bladder and rectum.

A Dry Powder Platform for Nose-to-Brain Delivery of Dexamethasone: Formulation Development and Nasal Deposition Studies

Nasal route of administration offers a unique opportunity of brain targeted drug delivery via olfactory and trigeminal pathway, providing effective CNS concentrations at lower doses and lower risk for adverse reactions compared to systemic drug administration. Therefore, it has been recently proposed as a route of choice for glucocorticoids to control neuroinflammation processes in patients with severe Covid-19. However, appropriate delivery systems tailored to enhance their efficacy yet need to emerge. In this work we present the development of sprayable brain targeting powder delivery platform of dexamethasone sodium phosphate (DSP). DSP-loaded microspheres, optimised employing Quality-by-Design approach, were blended with soluble inert carriers (mannitol or lactose monohydrate). Powder blends were characterized in terms of homogeneity, flow properties, sprayability, in vitro biocompatibility, permeability and mucoadhesion. Nasal deposition studies were performed using 3D printed nasal cavity model. Mannitol provided better powder blend flow properties compared to lactose. Microspheres blended with mannitol retained or enlarged their mucoadhesive properties and enhanced DSP permeability across epithelial model barrier. DSP dose fraction deposited in the olfactory region reached 17.0% revealing the potential of developed powder platform for targeted olfactory delivery. The observed impact of nasal cavity asymmetry highlighted the importance of individual approach when aiming olfactory region.

Impact of radiotherapy in head and neck regions on periodontal and oral hygiene conditions

Objective: Evaluate the influence of head and neck radiotherapy dose on periodontal tissue for to understanding of its adverse effects, and consequently to propose strategies to reduce its severity. Methodology: An observational, longitudinal and prospective study with intraoral clinical examinations performed before radiotherapy (T0) and immediately after the end of radiation therapy. The clinical data collected regarding oral and periodontal hygiene conditions were visible plaque index (VPI), gingival bleeding index (GBI), probing depth (PD), gingival recession area, clinical attachment level (CAL), degree of mobility and presence or absence of suppuration. In addition, data such as radiation dose, fractionation and duration of radiotherapy were reported. Results: Fourteen patients were evaluated, of which 11 had periodontitis after the radiotherapy, and 9 had poor oral hygiene conditions after the radiotherapy. Seven of the 11 subjects with periodontitis presented tumors in the oral cavity. There was a decrease in visible plaque index (VPI) and gingival bleeding index (GBI). The research was unable to establish a significant association between radiation therapy and oral hygiene condition and periodontitis. Conclusion: Poor oral hygiene conditions predominated in the sample, which can be associated with the presence of debilitating conditions. Direct radiation on the oral cavity may have an influence on the development of periodontitis. The development of gingivitis only and periodontitis was not influenced by dose, fraction or duration of radiotherapy in the study period.

Reinforcement Learning for Radiotherapy Dose Fractioning Automation

External beam radiotherapy cancer treatment aims to deliver dose fractions to slowly destroy a tumor while avoiding severe side effects in surrounding healthy tissues. To automate the dose fraction schedules, this paper investigates how deep reinforcement learning approaches (based on deep Q network and deep deterministic policy gradient) can learn from a model of a mixture of tumor and healthy cells. A 2D tumor growth simulation is used to simulate radiation effects on tissues and thus training an agent to automatically optimize dose fractionation. Results show that initiating treatment with large dose per fraction, and then gradually reducing it, is preferred to the standard approach of using a constant dose per fraction.

EFEK HEPATOPROTEKTOR FRAKSI TIDAK TERSABUNKAN DARI DALMS TERHADAP KONDISI STRES OKSIDATIF PADA TIKUS WISTAR

Palm oil fatty acid distillate (POFAD) is a byproduct of the process of refining palm oil, which still contains compounds. As a result of the increasing production of palm oil in Indonesia and POFAD, making POFAD has the potential as a source of tocotrienols, which can act as natural antioxidants and protect the liver against oxidative stress. The purpose of this study was to study the effects of hepatoprotection of the non-atomized fraction of POFAD in vivo and to find out the best dose of non-soapy fraction of POFAD on MDA levels, SOD of rat liver, and histopathological features in oxidative stress conditions due to waste cooking oil intake. The study design used was a Completely Randomized Design (CRD) which was composed of 6 treatment groups consisting of negative (normal), positive (indiscriminate) control groups, non-dose fraction I (100 mg/kg BW) fractions, non-soapy fractions dose II (200 mg/kg body weight), non-atomic dose III (500 mg/kg body weight), the non-dose fraction (1000 mg/kg body weight) and each treatment were repeated four times. Observational data obtained were processed statistically with the ANOVA test and continued with the Smallest Significant Difference Test (BNT) processed with SPSS for Windows 16 series. The results of this study indicate that the non-soapy fraction of palm oil fatty acid distillates has the ability to protect the liver from organ damage to dose III, namely the administration of non-soapy fractions at a dose of 500 mg/kg body weight.

Vitamin A Absorption Determined in Rats Using a Plasma Isotope Ratio Method

ABSTRACT Background Better methods are needed for determining vitamin A absorption efficiency. Objective Our objective was to measure vitamin A absorption in rats by adapting a plasma isotope ratio method previously used to determine cholesterol absorption. Methods Male Sprague-Dawley rats [n = 14; 340 ± 16 g (mean ± SD)] received an oral tracer dose of [3H]retinyl acetate in oil plus an intravenous dose of [14C]vitamin A–labeled lymph prepared in a donor rat that had received [14C]retinyl acetate intraduodenally. Blood samples were collected on days 1, 2, 3, 6, 9, and 12, and plasma was analyzed for 3H and 14C; vitamin A absorption was calculated for each sample as (fraction of oral dose/fraction of intravenous dose) × 100. Radioactivity was also measured in feces and urine collected as pools on days 3, 6, 9, and 12 and in liver and remaining carcass on day 12. Results Vitamin A absorption calculated as the plasma isotope ratio was >100% on day 1, 78% ± 5% on day 6, 76% ± 5% on day 9, and 74% ± 5% on day 12; fitting the data to an exponential function plus a constant predicted an absorption of 75% by day 14. Recovery of the oral dose in feces (day 0 to day 6) was low (6.2% ± 0.84%, n = 10) and the mean isotope ratio in day 9–12 urine pool was lower than that in plasma. Conclusions The plasma isotope ratio holds promise for estimating vitamin A absorption, but additional work is needed to determine how long studies need to be and if the doses should be administered simultaneously. For application of this method in humans, artificial chylomicrons labeled with a stable isotope of retinyl acetate could be used for the intravenous dose, with a different isotope required for the oral dose.

O05 Physiologically based pharmacokinetic modelling to characterize acetaminophen pharmacokinetics and NAPQI formation in non-pregnant and pregnant women

BackgroundLittle is known about the pharmacokinetics (PK) of acetaminophen during different stages of pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen PK throughout pregnancy.MethodsPBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen PK were considered. The models were evaluated using goodness-of-fit-plots and through comparison of predicted PK profiles with in-vivo PK data. Predictions were performed to illustrate the concentrations at steady state (Css-mean), used as indicator for efficacy of acetaminophen achieved following 1000 mg q6h. Furthermore, as measurement for potential hepatotoxicity, the molar dose fraction of acetaminophen converted to NAPQI was estimated.ResultsPBPK models successfully predicted the PK of acetaminophen and its metabolites in populations of non-pregnant and pregnant women. Predictions resulted in lowest Css-mean in the third trimester (4.5 mg/L), while Css-mean was 6.7, 5.6 and 4.9 mg/L in non-pregnant, first and second trimester populations, respectively. Assuming a constant increased activity of CYP2E1 throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first (11.0%), followed by second (9.0%) and third trimester (8.2%), compared to non-pregnant women (7.1%).ConclusionRisk for drug related hepatotoxicity in pregnant women might be increased as more NAPQI is produced during pregnancy compared to non-pregnant women, especially during the first trimester. However, lack of information on the detoxifying capacity precludes any strong conclusions.Disclosure(s)Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.

Experimental hypofractionated IMRT breast dosimetry in a thorax phantom

The present research proposal aimed to measure absorbed dose in a thorax phantom with synthetic breasts provided by an Intensity-Modulate Radiation Therapy (IMRT) protocol in an arbitrary RT center. As methods, a thorax simulator was prepared by the Ionizing Radiation Research Group (NRI) and radiochromic films were used for dose measurements. Tomographic images were taken at NRI phantom. Expositions were procedure in the Elektra 6MV LINAC. Hypofractionated regime was considered with a dose fraction of 2,7Gy in 16 fractions at the prescribed dose of 43.2 Gy at 95% of PTV. The dose comparison from the treatment planning system (TPS), Xio (Elekta) and from the experimental data was performed. The internal two-dimensional dose maps in the breast, at the skin on the left and contra-lateral breasts, heart and lungs. The measurements showed that the internal mean doses taken at the synthetic breast presented mean dose above the prescribed dose. Moreover, in general, doses to organs at risk (OARs) were within the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. The non-full reproduction of the build-up region in the films had occurred due to the assymetrical positioning of the films in the inner breast, in the addition to their non-constant distance from the skin. Hot regions were present, may be due to the beam angulation chosen and the increase of MUs in the IMRT plane. As conclusions, the films can supply details and information that TPS does not provide. Assertiveness in clinical IMRT protocols can improve the prognosis and effectiveness of breast cancer treatment bring-ing possible clinical benefits.