Feasibility of identifying proliferative active bone marrow with fat fraction MRI and multi-energy CT.

Objective.Active bone marrow (ABM) can serve as both an organ at risk and a target in external beam radiotherapy.18F-fluorothymidine (FLT) PET is the current gold standard for identifying proliferative ABM but it is not approved for human use, and PET scanners are not always available to radiotherapy clinics. Identifying ABM through other, more accessible imaging modalities will allow more patients to receive treatment specific to their ABM distribution. Multi-energy CT (MECT) and fat-fraction MRI (FFMRI) show promise in their ability to characterize bone marrow adiposity, but these methods require validation for identifying proliferative ABM.Approach.Six swine subjects were imaged using FFMRI, fast-kVp switching (FKS) MECT and sequential-scanning (SS) MECT to identify ABM volumes relative to FLT PET-derived ABM volumes. ABM was contoured on FLT PET images as the region within the bone marrow with a SUV above the mean. Bone marrow was then contoured on the FFMRI and MECT images, and thresholds were applied within these contours to determine which threshold produced the best agreement with the FLT PET determined ABM contour. Agreement between contours was measured using the Dice similarity coefficient (DSC).Main results.FFMRI produced the best estimate of the PET ABM contour. Compared to FLT PET ABM volumes, the FFMRI, SS MECT and FKS MECT ABM contours produced average peak DSC of 0.722 ± 0.080, 0.619 ± 0.070, and 0.464 ± 0.080, respectively. The ABM volume was overestimated by 40.51%, 97.63%, and 140.13% by FFMRI, SS MECT and FKS MECT, respectively.Significance.This study explored the ability of FFMRI and MECT to identify the proliferative relative to ABM defined by FLT PET. Of the methods investigated, FFMRI emerged as the most accurate approximation to FLT PET-derived active marrow contour, demonstrating superior performance by both DSC and volume comparison metrics. Both FFMRI and SS MECT show promise for providing patient-specific ABM treatments.

Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer.

Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo. METHODS: [77Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [76Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [76/77Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human. RESULTS: The maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC50) was measured as 0.17 (95 % CI: 0.13-0.24) nM and 0.46 (0.13-0.24) nM for PARP(+) and PARP(-) expressing cell lines, respectively. The EC50 was 0.27 (0.21-0.36) nM and 0.30 (0.22-0.41) nM for BRCA1(-) and BRCA1(+) expressing cell lines, respectively. When measuring the EC50 as a function of cellular activity uptake and nuclear dose, the EC50 ranges from 0.020 to 0.039 Bq/cell and 3.3-9.2 Gy, respectively. Excretion through the hepatobiliary and renal pathways were observed in mice, with liver uptake of 2.3 ± 0.4 %ID/g after 48 h, contributing to estimated absorbed dose values in mice of 19.3 ± 0.3 mGy/MBq and 290 ± 10 mGy/MBq for [77Br]RD1 and [76Br]RD1, respectively. CONCLUSION: [77Br]RD1 cytotoxicity was dependent on PARP expression and independent of BRCA1 status. The in vitro results suggest that [77Br]RD1 cytotoxicity is driven by the targeted Meitner-Auger electron (MAe) radiotherapeutic effect of the agent. Further studies investigating the theranostic potential, organ dose, and tumor uptake of [76/77Br]RD1 are warranted.

Anterior Interosseous Nerve to Ulnar Nerve Transfer: A Systematic Review.

Background: Ulnar nerve injuries, especially high (proximal forearm) injuries, result in poor functional recovery. Peripheral nerve transfers have recently become a popular technique to augment nerve repairs and reduce the reinnervation distance before distal motor endplates irreversibly degenerate, leading to incomplete recovery. Objectives: To systematically review and analyse the recent literature regarding anterior interosseous nerve (AIN) to ulnar nerve transfers, including demographics, indications, outcomes, and complications. Methods: A search was performed using PubMed, MEDLINE, EMBASE, CINAHL, Scopus, and Cochrane databases using the keywords ulnar nerve, ulnar nerve injury, ulnar motor nerve, anterior interosseous nerve, anterior interosseous, AIN, nerve transfer, and end-to-side using a 3-component search along with the Boolean operators 'AND' and 'OR'. Results: A total of 341 studies were retrieved using the search criteria. Sixteen studies met the inclusion criteria including 12 retrospective case series, 3 retrospective cohort studies, and a single randomised control trial. Nine studies involved supercharged end-to-side transfer (SETS), 6 involved end-to-end transfer (ETE), and only 1 study compared results between SETS and ETE transfers. A total of 269 patients underwent nerve transfers. In the ETE subgroup, the average time to nerve transfer was 7 months, with a mean follow-up period of 24.5 months. Post-procedure, 100% (37/37) patients recovered intrinsic function of BMRC ≥1, and the average recovery time was 3.6 months. A total of 85% of patients recovered intrinsic function of BMRC ≥3. In the SETS group, the average time to nerve transfer was 2.5 months. The average follow-up in this cohort was 13.2 months. About 93% (145/156) recovered the intrinsic function of BMRC ≥1, and the average time to recovery was 7 months. About 75% of patients recovered the intrinsic function of BMRC ≥3 in their first dorsal interossei. Conclusion: AIN to ulnar nerve transfer carries low morbidity, and there is low quality evidence to suggest recovery of intrinsic muscle function compared with conventional primary repair techniques. The supercharged end-to-side transfer (SETS) seems to be more favourable compared with end-to-side transfer. Outcome measurements are highly variable amongst studies, making standardisation difficult. Results of further trials are highly anticipated in this exciting field of peripheral nerve surgery.

Thromboelastography in Microsurgical Reconstruction: A Systematic Review.

The aim of this review was to identify studies that used thromboelastography (TEG) or rotational thromboelastometry (ROTEM) in microsurgical free flap reconstruction and analyse whether it is a useful adjunct at predicting and identifying thrombotic complications. A search was conducted using the MEDLINE database using the keywords "thromboelastogram", "TEG", "thromboelastography", "free flaps" and "free tissue transfer" using a two-component search with the Boolean operators "OR" and "AND". Eight studies were retrieved using the search criteria. Seven studies met the inclusion criteria, and a further study was found citing several articles from the initial search. Combined, there were 528 patients who underwent 600 free flaps. A total of 10.3% (62) arterial and venous thromboses were reported in the studies, and the combined flap failure rate was 5.2% (26). A total of 67% (4/6) of the studies supported the use of TEG as a predictive tool to detect thromboses, including three retrospective case series and one prospective cohort, which were all statistically significant. There is low-quality evidence (level IV) that a pre-operative TEG and functional fibrinogen to platelet ratio of ≥42 can identify patients at risk of adverse post-operative thrombotic events following free flap surgery; however, further validation is required. Higher quality, standardised prospective or randomised control trials are required to further evaluate the predictive value of TEG. As a pre-operative screening tool, TEG can help to detect pathological changes in coagulation, aid in the transfusion of blood products, target anticoagulation therapy and predict possible adverse events aiding to further reduce patient morbidity.

Pressure related injuries: A burning issue?

INTRODUCTION: To the majority of health care professionals, burns present as a challenging and potentially distracting diagnosis. Because of their perceived complexity, they often eclipse other medical problems which can often be life threatening. Pressure related injuries, in rare instances can mimic and be mistaken for full thickness burns. Long lies may cause pressure necrosis of decubitus areas and compartment syndrome of vulnerable areas. Compartment syndrome, is a surgical emergency requiring prompt diagnosis and intervention. It may be missed in the context of a long lie after a collapse and maybe detrimental to patients' prognosis. METHODS: We reviewed cases referred to our Burns unit in the last four months to find cases of pressure related injuries referred as burn wounds. Furthermore, we also performed a literature search to find any similar cases to ours. RESULTS: Two cases, with acute pressure related injuries from long lies had been mistaken for burn wounds, were referred to our unit in the last four months. In one case a missed compartment syndrome resulted in a below elbow amputation. CONCLUSION: Pattern analysis and recognition are very important diagnostic tools in medicine. Detailed history taking and examination cannot be emphasised enough. Training both emergency departments and plastic surgeons in recognising long lie related injuries will decrease possible associated dangers such as missing a compartment syndrome.

Concurrent Monte Carlo transport and fluence optimization with fluence adjusting scalable transport Monte Carlo.

PURPOSE: The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and "4π" delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship within a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of "concurrent" Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. METHODS: The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. RESULTS: The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7-8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. CONCLUSIONS: This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead.

Initial characterization of a gel patch dosimeter for in vivo dosimetry.

In vivo dosimetry is a greatly underutilized tool for patient safety in clinical external beam radiotherapy treatments, despite being recommended by several national and international organizations (AAPM, ICRU, IAEA, NACP). The reasons for this underutilization mostly relate to the feasibility and cost of in vivo dosimetry methods. Due to the increase in the number of beam angles and dose per fraction in modern treatments, there is a compelling need for a novel dosimeter that is robust and affordable while able to operate properly in these complex conditions. This work presents a gel patch dosimeter as a novel method of in vivo dosimetry. DEFGEL, a 6% T normoxic polyacrylamide gel, was injected into 1 cm thick acrylic molds to create 1 cm thick small cylindrical patch dosimeters. To evaluate the change in optical density due to radiation induced polymerization, dosimeters were scanned before and after irradiation using an in-house developed laser densitometer. The dose-responses of three separate batches of gel were evaluated and compared to check for linearity and repeatability. The response development time was evaluated to ensure that the patch dosimeter could be high throughput. Additionally, the potential of this system to be used as an in vivo dosimeter was tested with a clinically relevant end-to-end in vivo phantom test. All irradiations were performed with a Varian Clinac 21EX at the University of Wisconsin Medical Radiation Research Center (UWMRRC). The dose-response of all three batches of gel was found to be linear within the range of 2-20 Gy. At doses below 0.5 Gy the statistical uncertainties were prohibitively large to make quantitative assessments of the results. The three batches demonstrated good repeatability in the range of 2 Gy to up to 10 Gy, with only slight variations in response at higher doses. For low doses the dosimeter fully developed within an hour while at higher doses they fully developed within four hours. During the in vivo phantom test the predicted patch absorbed dose was 4.23 Gy while the readout dose was evaluated to be 4.37 Gy, which corresponds to a 3.2% discrepancy. The dosimeter and densitometer pairing shows promise as an in vivo dosimetry system, especially for hypofractionated or MRI-guided radiotherapy treatments where higher doses are prescribed.

Monte Carlo simulations of patient dose perturbations in rotational-type radiotherapy due to a transverse magnetic field: a tomotherapy investigation.

PURPOSE: Several groups are exploring the integration of magnetic resonance (MR) image guidance with radiotherapy to reduce tumor position uncertainty during photon radiotherapy. The therapeutic gain from reducing tumor position uncertainty using intrafraction MR imaging during radiotherapy could be partially offset if the negative effects of magnetic field-induced dose perturbations are not appreciated or accounted for. The authors hypothesize that a more rotationally symmetric modality such as helical tomotherapy will permit a systematic mediation of these dose perturbations. This investigation offers a unique look at the dose perturbations due to homogeneous transverse magnetic field during the delivery of Tomotherapy(®) Treatment System plans under varying degrees of rotational beamlet symmetry. METHODS: The authors accurately reproduced treatment plan beamlet and patient configurations using the Monte Carlo code geant4. This code has a thoroughly benchmarked electromagnetic particle transport physics package well-suited for the radiotherapy energy regime. The three approved clinical treatment plans for this study were for a prostate, head and neck, and lung treatment. The dose heterogeneity index metric was used to quantify the effect of the dose perturbations to the target volumes. RESULTS: The authors demonstrate the ability to reproduce the clinical dose-volume histograms (DVH) to within 4% dose agreement at each DVH point for the target volumes and most planning structures, and therefore, are able to confidently examine the effects of transverse magnetic fields on the plans. The authors investigated field strengths of 0.35, 0.7, 1, 1.5, and 3 T. Changes to the dose heterogeneity index of 0.1% were seen in the prostate and head and neck case, reflecting negligible dose perturbations to the target volumes, a change from 5.5% to 20.1% was observed with the lung case. CONCLUSIONS: This study demonstrated that the effect of external magnetic fields can be mitigated by exploiting a more rotationally symmetric treatment modality.

Consistency evaluation between EGSnrc and Geant4 charged particle transport in an equilibrium magnetic field.

Following the proposal by several groups to integrate magnetic resonance imaging (MRI) with radiation therapy, much attention has been afforded to examining the impact of strong (on the order of a Tesla) transverse magnetic fields on photon dose distributions. The effect of the magnetic field on dose distributions must be considered in order to take full advantage of the benefits of real-time intra-fraction imaging. In this investigation, we compared the handling of particle transport in magnetic fields between two Monte Carlo codes, EGSnrc and Geant4, to analyze various aspects of their electromagnetic transport algorithms; both codes are well-benchmarked for medical physics applications in the absence of magnetic fields. A water-air-water slab phantom and a water-lung-water slab phantom were used to highlight dose perturbations near high- and low-density interfaces. We have implemented a method of calculating the Lorentz force in EGSnrc based on theoretical models in literature, and show very good consistency between the two Monte Carlo codes. This investigation further demonstrates the importance of accurate dosimetry for MRI-guided radiation therapy (MRIgRT), and facilitates the integration of a ViewRay MRIgRT system in the University of Wisconsin-Madison's Radiation Oncology Department.

Comparison of MCNPX and Geant4 proton energy deposition predictions for clinical use.

Several different Monte Carlo codes are currently being used at proton therapy centers to improve upon dose predictions over standard methods using analytical or semi-empirical dose algorithms. There is a need to better ascertain the differences between proton dose predictions from different available Monte Carlo codes. In this investigation Geant4 and MCNPX, the two most-utilized Monte Carlo codes for proton therapy applications, were used to predict energy deposition distributions in a variety of geometries, comprising simple water phantoms, water phantoms with complex inserts and in a voxelized geometry based on clinical CT data. The Gamma analysis was used to evaluate the differences of the predictions between the codes. The results show that in all the cases the agreement was better than clinical acceptance criteria.

The development, validation and application of a multi-detector CT (MDCT) scanner model for assessing organ doses to the pregnant patient and the fetus using Monte Carlo simulations.

The latest multiple-detector technologies have further increased the popularity of x-ray CT as a diagnostic imaging modality. There is a continuing need to assess the potential radiation risk associated with such rapidly evolving multi-detector CT (MDCT) modalities and scanning protocols. This need can be met by the use of CT source models that are integrated with patient computational phantoms for organ dose calculations. Based on this purpose, this work developed and validated an MDCT scanner using the Monte Carlo method, and meanwhile the pregnant patient phantoms were integrated into the MDCT scanner model for assessment of the dose to the fetus as well as doses to the organs or tissues of the pregnant patient phantom. A Monte Carlo code, MCNPX, was used to simulate the x-ray source including the energy spectrum, filter and scan trajectory. Detailed CT scanner components were specified using an iterative trial-and-error procedure for a GE LightSpeed CT scanner. The scanner model was validated by comparing simulated results against measured CTDI values and dose profiles reported in the literature. The source movement along the helical trajectory was simulated using the pitch of 0.9375 and 1.375, respectively. The validated scanner model was then integrated with phantoms of a pregnant patient in three different gestational periods to calculate organ doses. It was found that the dose to the fetus of the 3 month pregnant patient phantom was 0.13 mGy/100 mAs and 0.57 mGy/100 mAs from the chest and kidney scan, respectively. For the chest scan of the 6 month patient phantom and the 9 month patient phantom, the fetal doses were 0.21 mGy/100 mAs and 0.26 mGy/100 mAs, respectively. The paper also discusses how these fetal dose values can be used to evaluate imaging procedures and to assess risk using recommendations of the report from AAPM Task Group 36. This work demonstrates the ability of modeling and validating an MDCT scanner by the Monte Carlo method, as well as assessing fetal and organ doses by combining the MDCT scanner model and the pregnant patient phantom.