Effect of Paclitaxel Stereochemistry on X-ray-Triggered Release of Paclitaxel from CaWO4/Paclitaxel-Coloaded PEG-PLA Nanoparticles.

For many locally advanced tumors, the chemotherapy-radiotherapy (CT-RT) combination ("chemoradiation") is currently the standard of care. Intratumoral (IT) CT-based chemoradiation has the potential to overcome the limitations of conventional systemic CT-RT (side effects). For maximizing the benefits of IT CT-RT, our laboratory has previously developed a radiation-controlled drug release formulation, in which anticancer drug paclitaxel (PTX) and radioluminescent CaWO4 (CWO) nanoparticles (NPs) are co-encapsulated with poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) block copolymers ("PEG-PLA/CWO/PTX NPs"). These PEG-PLA/CWO/PTX NPs enable radiation-controlled release of PTX and are capable of producing sustained therapeutic effects lasting for at least one month following a single IT injection. The present article focuses on discussing our recent finding about the effect of the stereochemical structure of PTX on the efficacy of this PEG-PLA/CWO/PTX NP formulation. Stereochemical differences in two different PTX compounds ("PTX-S" from Samyang Biopharmaceuticals and "PTX-B" from Biotang) were characterized by 2D heteronuclear/homonuclear NMR, Raman spectroscopy, and circular dichroism measurements. The difference in PTX stereochemistry was found to significantly influence their water solubility (WS); PTX-S (WS ≈ 4.69 µg/mL) is about 19 times more water soluble than PTX-B (WS ≈ 0.25 µg/mL). The two PTX compounds showed similar cancer cell-killing performances in vitro when used as free drugs. However, the subtle stereochemical difference significantly influenced their X-ray-triggered release kinetics from the PEG-PLA/CWO/PTX NPs; the more water-soluble PTX-S was released faster than the less water-soluble PTX-B. This difference was manifested in the IT pharmacokinetics and eventually in the survival percentages of test animals (mice) treated with PEG-PLA/CWO/PTX NPs + X-rays in an in vivo human tumor xenograft study; at short times (<1 month), concurrent PEG-PLA/CWO/PTX-S NPs produced a greater tumor-suppression effect, whereas PEG-PLA/CWO/PTX-B NPs had a longer-lasting radio-sensitizing effect. This study demonstrates the importance of the stereochemistry of a drug in a therapy based on a controlled release formulation.

The Dosimetric Outcome of a Rotational Planning Target Volume in Patients With Oropharyngeal Cancers.

An isotropic expanded Planning Target Volume (PTV) neglects patient's off-axis rotation. This study designs a rotational PTV that is used instead of the standard 3-mm Clinical Target Volume (CTV) expanded PTV in oropharyngeal cancers with the goal to reduce pharyngeal constrictor muscle (PCM) mean dose. 10 patients were retrospectively evaluated. For off-axis rotation, the image was rotated around the longitudinal axis (cervical spinal canal) ± 5 degrees. These new CTVs were combined to form the rotational PTV. The standard and rotational treatment plans were designed with the goal to keep the superior and middle PCM-CTV70 mean dose to less than 50 Gy. There were a 355 cGy reduction in the superior PCM mean dose (form 5332 to 4977 cGy) and a 506 cGy reduction in middle PCM mean dose (from 4185 to 3679 cGy). 60% of patients may have at least a 20% reduction in dysphagia probability based on a Normal Tissue Complication Probability (NTCP) formula. The superior and middle PCM mean dose were reduced to less than 50 Gy in 40 and 20% of cases. There was an association between superior PCM mean dose and overlap volume of PTV70 and superior PCM in both standard (r = 0.92, p = 0.001) and rotational (r = 0.84, p = 0.002) plans. This association was present for middle PCM and PTV70 (r = 0.52, p = 0.02 and r = 0.62, p = 0.006). Rotational PTV can lower the mean dose to superior and middle PCMs, ultimately leading to lower dysphagia rates.

The effect of designing a rotational planning target volume on sparing pharyngeal constrictor muscles in patients with oropharyngeal cancer.

BACKGROUND: Planning target volume (PTV) has been used to account for variations in tissue, patient and beam position. In oropharyngeal cancers, an isotropic expanded PTV has been used. AIM: The aim of this study was to design a new margin formula that would cover the space occupied by an oropharyngeal clinical target volume (CTV) with ±5-degree rotation around the spine in order to reduce the pharyngeal constrictors overlap with PTV compared to an isotropic expanded PTV. METHODS: We retrospectively evaluated 20 volumetric-modulated arc therapy (VMAT) plans. In order to perform an off-axis rotation, a hypothetical point was placed through the center of the cervical spinal canal and the image was then rotated around the longitudinal axis ±5 degrees. This created a new set of CTVs that were combined to form the new rotational PTV. The overlap between the pharyngeal constrictor muscles (PCMs) and both PTVs was then evaluated. RESULTS: The new rotational PTV causes reduction in the superior PCM overlap in the base of tongue (BOT) lesions compared to tonsillar lesion, 57.8% vs 25.8%, P = 0.01, as well as middle PCM overlap, 73% vs 49%, P = 0.04. Average percent change for PTV volume and overlap with the superior, middle, and inferior PCMs are as followed: -19%, -37%, -59.4%, and -45.2. The smallest isotropic expansion that covers the new rotational PTV was between 3 and 5mm with the average tumor center shift of 0.49 cm. CONCLUSION: This new rotational PTV causes significant reduction of the overlap volume between PCMs and PTVs in order to spare the PCMs compared to isotropic expanded PTV.

On the Computation of Mean and Variance of Spatial Displacements.

This paper studies the problem of computing an average (or mean) displacement from a set of given spatial displacements using three types of parametric representations: Euler angles and translation vectors, unit quaternions and translation vectors, and dual quaternions. It is shown that the use of Euclidean norm in the space of unit quaternions reduces the problem to that of computing the mean for each quaternion component separately and independently. While the resulting algorithm is simple, a change in the sign of a unit quaternion could lead to an incorrect result. A novel kinematic measure based on dual quaternions is introduced to capture the separation between two spatial displacements. This kinematic measure is used to define the variance of a set of displacements, which is then used to formulate a constrained least squares minimization problem. It is shown that the problem decomposes into that of finding the optimal translation vector and the optimal unit quaternion. The former is simply the centroid of the set of translation vectors and the latter is obtained as the eigenvector corresponding to the least eigenvalue of a 4 × 4 positive definite symmetric matrix. In addition, it is found that the weight factor used in combining rotations and translations in the formulation does not play a role in the final outcome. Examples are provided to show the comparisons of these methods.

On the Construction of Confidence Regions for Uncertain Planar Displacements.

This paper studies the statistical concept of confidence region for a set of uncertain planar displacements with a certain level of confidence or probabilities. Three different representations of planar displacements are compared in this context and it is shown that the most commonly used representation based on the coordinates of the moving frame is the least effective. The other two methods, namely the exponential coordinates and planar quaternions, are equally effective in capturing the group structure of SE(2). However, the former relies on the exponential map to parameterize an element of SE(2), while the latter uses a quadratic map, which is often more advantageous computationally. This paper focus on the use of planar quaternions to develop a method for computing the confidence region for a given set of uncertain planar displacements. Principal component analysis (PCA) is another tool used in our study to capture the dominant direction of movements. To demonstrate the effectiveness of our approach, we compare it to an existing method called rotational and translational confidence limit (RTCL). Our examples show that the planar quaternion formulation leads to a swept volume that is more compact and more effective than the RTCL method, especially in cases when off-axis rotation is present.

Constructing Kinematic Confidence Regions With Double Quaternions.

A spatial displacement as an element of SE ( 3 ) can be approximated by a 4D rotation, which is an element of SO ( 4 ) . In this way, the problem of constructing confidence regions of uncertain spatial displacements may be studied as that of constructing confidence ellipsoids in SO ( 4 ) . In this light, a double-quaternion formulation of kinematic confidence regions is presented that approximately preserve the geometry of SE ( 3 ) . Examples are provided to demonstrate the efficacy of this approach in comparison with the dual-quaternion formulation.

SHAPE DEPENDENT MOTION INTERPOLANTS FOR PLANAR OBJECTS.

Kinematics is most commonly about the motion of unbounded spaces. This paper deals with the kinematics of bounded shapes in a plane. This paper studies the problem of motion interpolation of a planar object with its shape taken into consideration. It applies and extends a shape dependent distance measure between two positions in the context of motion interpolation. Instead of using a fixed reference frame, a shape-dependent inertia frame of reference is used for formulating the distance between positions of a rigid object in a plane. The resulting distance function is then decomposed in two orthogonal directions and is used to formulate an interpolating function for the distance functions in these two directions. This leads to a shape dependent interpolation of translational components of a planar motion. In difference to the original concept of Kazerounian and Rastegar that comes with a shape dependent measure of the angular motion, it is assumed in this paper that the angular motion is shape independent as the angular metric is dimensionless. The resulting distance measure is not only a combination of translation and rotation parameters but also depends on the area moments of inertia of the object. It derives the explicit expressions for decomposing the shape dependent distance in two orthogonal directions, which is then used to obtain shape dependent motion interpolants in these directions. The resulting interpolants have similarities to the well-known spherical linear interpolants widely used in computer graphics in that they are defined using sinusoidal functions instead of linear interpolation in Euclidean space. The path of the interpolating motion can be adjusted by different choice of shape parameters. Examples are provided to illustrate the effect of object shapes on the resulting interpolating motions.

On the Construction of Kinematic Confidence Ellipsoids for Uncertain Spatial Displacements.

This paper deals with the problem of estimating confidence regions of a set of uncertain spatial displacements for a given level of confidence or probabilities. While a direct application of the commonly used statistic methods to the coordinates of the moving frame is straight-forward, it is also the least effective in that it grossly overestimate the confidence region. Based on the dual-quaternion representation, this paper introduces the notion of the kinematic confidence ellipsoids as an alternative to the existing method called rotation and translation confidence limit (RTCL). An example is provided to demonstrate how the kinematic confidence ellipsoids can be computed.

On the mean and variance of planar displacements.

This paper studies the problem of computing the mean (or the average displacement) and variance of a set of planar displacements. It presents three parametric representations of a planar displacement and studies how they influence the computations of means and variances. In particular, it advocates the use of the kinematic concept of relative displacements rather than simple difference in kinematic parameters in formulating the variance and for computing the mean of planar displacements. It is shown that the optimal average displacement is obtained by combining planar-quaternion representation with the concept of relative displacements. Examples are provided to illustrate the advantages of the latter approach.

Dose prescription and reporting in stereotactic body radiotherapy: A multi-institutional study.

BACKGROUND AND PURPOSE: Radiation dose prescriptions are foundational for optimizing treatment efficacy and limiting treatment-related toxicity. We sought to assess the lack of standardization of SBRT dose prescriptions across institutions. MATERIALS & METHODS: Dosimetric data from 1298 patients from 9 academic institutions treated with IMRT and VMAT were collected. Dose parameters D100, D98, D95, D50, and D2 were used to assess dosimetric variability. RESULTS: Disease sites included lung (48.3 %) followed by liver (29.7 %), prostate (7.5 %), spine (6.8 %), brain (4.1 %), and pancreas (2.5 %). The PTV volume in lung varied widely with bimodality into two main groups (22.0-28.7 cm3) and (48.0-67.1 cm3). A hot spot ranging from 120-150 % was noted in nearly half of the patients, with significant variation across institutions. A D50 ≥ 110 % was found in nearly half of the institutions. There was significant dosimetric variation across institutions. CONCLUSIONS: The SBRT prescriptions in the literature or in treatment guidelines currently lack nuance and hence there is significant variation in dose prescriptions across academic institutions. These findings add greater importance to the identification of dose parameters associated with improved clinical outcome comparisons as we move towards more hypofractionated treatments. There is a need for standardized reporting to help institutions in adapting treatment protocols based on the outcome of clinical trials. Dosimetric parameters are subsequently needed for uniformity and thereby standardizing planning guidelines to maximize efficacy, mitigate toxicity, and reduce treatment disparities are urgently needed.

ON THE COMPUTATION OF THE AVERAGE OF SPATIAL DISPLACEMENTS.

Many applications in biomechanics and medical imaging call for the analysis of the kinematic errors in a group of patients statistically using the average displacement and the standard deviations from the average. This paper studies the problem of computing the average displacement from a set of given spatial displacements using three types of parametric representations: Euler angles and translation vectors, unit quaternions and translation vectors, and dual quaternions. It has been shown that the use of Euclidean norm in the space of unit quaternions reduces the problem to that of computing the average for each quaternion component separately and independently. While the resulting algorithm is simple, the change of the sign of a unit quaternion could lead to an incorrect result. A novel kinematic measure based on dual quaternions is introduced to capture the separation between two spatial displacement. This kinematic measure is then used to formulate a constrained least squares minimization problem. It has been shown that the problem decomposes into that of finding the optimal translation vector and the optimal unit quaternion. The former is simply the centroid of the set of given translation vectors and the latter can be obtained as the eigenvector corresponding to the least eigenvalue of a 4 × 4 positive definite symmetric matrix. It is found that the weight factor used in combining rotations and translations in the formulation does not play a role in the final outcome. Examples are provided to show the comparisons of these methods.

On the Computation of the Average of Planar Displacements.

In this paper, we present four parametric representations of a planar displacements and studied the problem of how to compute the average displacement from a set of given planar displacements using these representations. It has been shown that the optimal average displacement is obtained by using planar quaternions and the concept of relative displacements. Examples are provided to show the comparisons of these methods.

Fistuloscopy in the management of pediatric pilonidal sinus disease / Sinus pilonidalis fisztuloszkópos kezelése gyermekekben.

Összefoglaló. Bevezetés: A sinus pilonidalis nehezen kezelheto, sok szövodménnyel és recidívával járó betegség. A legtöbb mutéti eljárás többnapos kórházi kezelést, munkából vagy iskolából való hiányzást követel. Célkituzés: Munkánk célja, hogy a PEPSiT- (pediatric endoscopic pilonidal sinus treatment) mutétek eredményességét vizsgálja. Módszer: Intézetünkben 2019-2020-ban PEPSiT-mutéten átesett, 18 év alatti betegeket válogattunk be a vizsgálatba. Kizártuk a cisztoszkóppal operált és kontrollra nem jelentkezo betegeket. A szövodmények, recidívák számát, a kórházi tartózkodás hosszát, a sebgyógyulás és a hétköznapi aktivitáshoz való visszatérés idejét vizsgáltuk. Eredmények: Betegeink többsége fiú (24 fiú, 4 lány), átlagéletkoruk 15,6 év volt. 28 betegen 31 PEPSiT-beavatkozást végeztünk (3 re-PEPSiT), 6 recidíva, 1 sebgennyedés alakult ki. A betegek egy része egynapos ellátás keretében, míg a többség egy éjszaka bentfekvés után tért haza (1,74 nap ápolási ido). A hétköznapi aktivitáshoz 1,37 nap után tértek vissza, a gyógyulási ido 5,9 hét volt átlagosan. Megbeszélés: A PEPSiT-beavatkozás minimálisan invazív lehetoség, igen rövid kórházi tartózkodással. A betegek hamar térnek vissza a szokott aktivitásukhoz, a korábbi sipolyon kívül újabb mutéti seb nem alakul ki. A recidívaarány hasonló az egyéb technikákéhoz. Következtetés: A PEPSiT-beavatkozás jól alkalmazható, a recidívaarány csökkentése fontos. Orv Hetil. 2021; 162(43): 1740-1743. INTRODUCTION: The treatment of pilonidal disease is often challenging, due to frequent recurrences and adverse events. Most operative treatments require a lengthy hospital stay, and absence from school or work. OBJECTIVE: We aimed towards assessing the effectivity of PEPSiT (pediatric endoscopic pilonidal sinus treatment). METHOD: In this study, we included patients subjected to PEPSiT from 2019 to 2020 between ages 0-18 years. Patients operated via cystoscope and patients who did not attend follow-up examinations were excluded. Adverse events, recurrences, length of hospital stay, wound healing time and return to everyday activity were assessed. RESULTS: The majority of our patients were male (24 male, 4 female), the mean age was 15.6 years. 31 PEPSiT operations were recorded on 28 patients (3 were redo surgeries). 6 recurrences and 1 wound suppuration were documented. Some patients were treated within the confines of one-day surgery, while most of them stayed one night (mean length of stay was 1.74 days). Return to everyday activity was an average 1.37 days, and mean wound healing time was 5.9 weeks. DISCUSSION: PEPSiT is a minimally invasive operative approach with a very short hospital stay. Patients return to everyday activity faster. New operative scarring does not happen apart from the preexisting fistula opening. Recurrence rate is similar to that of other treatment techniques. CONCLUSION: PEPSiT technique is applicable, however, reduction of the recurrence rate is important. Orv Hetil. 2021; 162(43): 1740-1743.

Impact of Lung Parenchymal-Only Failure on Overall Survival in Early-Stage Lung Cancer Patients Treated With Stereotactic Ablative Radiotherapy.

INTRODUCTION: The impact of lung parenchymal-only failure on patient survival after stereotactic ablative body radiotherapy (SABR) for early-stage non-small-cell lung cancer (NSCLC) remains unclear. PATIENTS AND METHODS: The study population included 481 patients with early-stage NSCLC who were treated with 3- to 5-fraction SABR between 2000 and 2016. The primary study objective was to assess the impact of out-of-field lung parenchymal-only failure (OLPF) on overall survival (OS). RESULTS: At a median follow-up of 5.9 years, the median OS was 2.7 years for all patients. Patients with OLPF did not have a significantly different OS compared to patients without failure (P = .0952, median OS 4.1 years with failure vs. 2.6 years never failure). Analysis in a 1:1 propensity score-matched cohort for Karnofsky performance status, comorbidity score, and smoking status showed no differences in OS between patients without failure and those with OLPF (P = .8). In subgroup analyses exploring the impact of time of failure on OS, patients with OLPF 6 months or more after diagnosis did not have significantly different OS compared to those without failure, when accounting for immortal time bias (P = .3, median OS 4.3 years vs. 3.5 years never failure). Only 7 patients in our data set experienced failure within 6 months of treatment, of which only 4 were confirmed to be true failures; therefore, limited data are available in our cohort on the impact of OLPF for ≤ 6 months on OS. CONCLUSION: OLPF after SABR for early-stage NSCLC does not appear to adversely affect OS, especially if occurring at least 6 months after SABR. More studies are needed to understand if OLPF within 6 months of SABR is associated with adverse OS. These data are useful when discussing prognosis of lung parenchymal failures after initial SABR.

Risk factors for symptomatic radiation pneumonitis after stereotactic body radiation therapy (SBRT) in patients with non-small cell lung cancer.

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) can be a potential fatal toxicity of stereotactic body radiation therapy (SBRT) for medically inoperable non-small cell lung cancer (NSCLC). This study aimed to examine the risk factors that predict RP and explore dosimetric tolerance for safe practice in a large institutional series of NSCLC patients. MATERIALS AND METHODS: Patients with early-stage and locally recurrent NSCLC who received lung SBRT between 2002 and 2015 formed the study population. The primary endpoint was grade 2 or above radiation pneumonitis (RP2). Lungs were re-contoured consistently by one radiation oncologist according to the RTOG atlas for organs at risk. Dosimetric factors were computed consistently with exclusion of gross tumor volume of either ipsilateral, contralateral, or total lungs. RESULTS: A total of 339 patients were eligible. With a median follow-up of 47 months, RP2 was recorded in 10% patients. History of respiratory comorbidity, previous thoracic radiation, right lung location, mean lung doses of total or ipsilateral lung, and total lung volume receiving 20 Gy were all significantly associated with the risk of RP2. The dosimetric parameters of contralateral lung, including mean dose and volume receiving more than 5, 10, and 20 Gy, were not significantly associated with RP2 (ps > 0.05). A model of combining significant clinical and dosimetric factors had a predictive accuracy AUC of 0.76. According to this model, RP2 can be limited to <10% should the patient have no previous lung radiation and the mean dose of total and ipsilateral lungs be kept less than 6 Gy and 20 Gy, respectively. CONCLUSION: Dosimetric factors of total or ipsilateral lung together with important clinical factors were significant risk factors for symptomatic radiation pneumonitis after SBRT. Constraining mean lung dose can limit clinically significant lung toxicity.

A DUAL QUATERNION BASED METHOD FOR ESTIMATING MARGINS FOR PLANNING TARGET VOLUMES IN RADIOTHERAPY.

This objective of this paper is to develop a dual quaternion based method for estimating target volumes in radiation therapy for head and neck cancer. Inaccuracies in radiation targeting are responsible for incidental exposure of healthy adjacent tissues, causing significant morbidity and mortality. This paper focuses on inaccuracies incurred when a tumor is displaced during treatment. To address this problem, the clinical target must be expanded to cover the region through which the tumor might move. The resulting expanded target is known as the Planning Target Volume (PTV). In the current practice, the rotational components of displacements are neglected, producing planning target volumes that either miss the true target motion or are larger than needed to cover the target path. By using the dual quaternion based kinematic formulation, this paper represents and captures both translational and rotational inaccuracies. It then presents a framework for calculating the PTV swept out by the target as it shifts within its range of translations and rotations.

Exploiting tumor position differences between deep inspiration and expiration in lung stereotactic body radiation therapy planning.

PURPOSE: We demonstrate proof of principle that normal tissue doses can be greatly reduced in lung stereotactic body radiation therapy (SBRT) for mobile tumors, if the delivered dose is split between opposite respiratory states. METHODS: Patients that underwent 5 fraction lung SBRT at our institution and had deep inspiration breath hold (DIBH) and free breathing 4D computed tomography scans were included. Volumetric modulated arc therapy plans were generated on both respiratory phases and a third composite plan was generated delivering half the dose using the DIBH plan and the other half using the expiratory phase plan for each fraction. Computed tomography scans for the composite plan were fused based on ribs adjacent to the tumor to evaluate the dose volume histogram of critical structures. RESULTS: Four patients with 4 total tumors had requisite planning scans available. Tumor size was between 0.7 to 2.9 cm and tumor movement 1.4 to 2.9 cm. Median reduction in the chest wall (CW) V30Gy for the composite plan was 74.6% (range 33.7 to 100%), 76.9% (range 32.9 to 100%), and 89.3% (range 69.5 to 100%) compared to the DIBH, expiration phase, and free breathing plans, respectively. Median reduction in CW maximum dose for the composite plan was 23.3% (range 0.27% to 46.4%), 23.5% (range 3.2 to 48.2%), and 23.4% (range 0.27% to 48.4%) compared to the DIBH, expiration phase, and free breathing plans, respectively. Greater reduction in CW maximum dose was observed when patients had no overlap in planning target volumes between DIBH and expiration phases (median reduction 43.9% for no overlap vs 2.7% with overlap). Between all plans, lung V20Gy absolute differences were within 1.3%. For 2 of 4 patients, the composite plan met constraints for 3 fraction SBRT, while standard plans did not. CONCLUSIONS: We conclude that composite DIBH-expiration SBRT planning has the potential to improve organ at risk sparing.