Dose to level I and II axillary lymph nodes and lung by tangential field radiation in patients undergoing postmastectomy radiation with tissue expander reconstruction

<p>Abstract</p> <p>Background</p> <p>To define the dosimetric coverage of level I/II axillary volumes and the lung volume irradiated in postmastectomy radiotherapy (PMRT) following tissue expander placement.</p> <p>Methods and Materials</p> <p>Twenty-three patients were identified who had undergone postmastectomy radiotherapy with tangent only fields. All patients had pre-radiation tissue expander placement and expansion. Thirteen patients had bilateral expander reconstruction. The level I/II axillary volumes were contoured using the RTOG contouring atlas. The patient-specific variables of expander volume, superior-to-inferior location of expander, distance between expanders, expander angle and axillary volume were analyzed to determine their relationship to the axillary volume and lung volume dose.</p> <p>Results</p> <p>The mean coverage of the level I/II axillary volume by the 95% isodose line (V_D95%) was 23.9% (range 0.3 - 65.4%). The mean Ipsilateral Lung V_D50%was 8.8% (2.2-20.9). Ipsilateral and contralateral expander volume correlated to Axillary V_D95%in patients with bilateral reconstruction (p = 0.01 and 0.006, respectively) but not those with ipsilateral only reconstruction (p = 0.60). Ipsilateral Lung V_D50%correlated with angle of the expander from midline (p = 0.05).</p> <p>Conclusions</p> <p>In patients undergoing PMRT with tissue expanders, incidental doses delivered by tangents to the axilla, as defined by the RTOG contouring atlas, do not provide adequate coverage. The posterior-superior region of level I and II is the region most commonly underdosed. Axillary volume coverage increased with increasing expander volumes in patients with bilateral reconstruction. Lung dose increased with increasing expander angle from midline. This information should be considered both when placing expanders and when designing PMRT tangent only treatment plans by contouring and targeting the axilla volume when axillary treatment is indicated.</p

Identification of human CD4+ T cell populations with distinct antitumor activity

How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4+ T cell populations to improve durability of solid tumor therapies

Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo.

Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating.We used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine in vivo studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution.Both in vivo studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. In vivo, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 μg/g to 3.0 μg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug.Both computer models and in vivo study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems

Plasma AUC predicts tissue uptake.

<p>Computer simulation results: (A) Systemic plasma concentration of TSL-Dox (i.e. encapsulated Dox). Areas under the curve (AUC’s) are colored/shaded for an ablation heating cycle initiated immediately following a 30 min TSL-Dox infusion (5, 12, and 30 min duration), or following 1 and 2 hours after infusion (12 min duration). (B) Systemic plasma AUC of TSL-Dox correlates with total amount of doxorubicin delivered to the target tissue (R² = 0.97).</p

Drug delivery model overview.

<p>Intravascular temperature-dependent release of Dox from TSL, uptake by interstitium (EES), and cell uptake are simulated. Local temperature and perfusion are fed into the drug delivery model from the heat transfer model.</p

Radial drug concentration profile.

<p>(A) <i>In</i> vivo radial drug concentration profile (see path in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.g005" target="_blank">Fig 5B</a>, averaged over 360°), referenced to the boundary of the visible coagulation zone. Two heated tissue samples each were evaluated for 5 and 12 min ablation, indicated by circles and triangles. There was statistically significant difference between the two groups (5, 12 min) from 2 to 12 mm distance. (B) Radial drug concentration from computer simulation (calculated 30 min after ablation completion). Drug uptake increases approximately linearly with ablation time for both <i>in vivo</i> study and computer model. Most of the drug is delivered to within ~10–15 mm of the ablation zone boundary. Note that the visible coagulation zone indicated by the gray shaded region in (A) and (B) does not represent the tissue region destroyed by heat. The boundary of the kill zone (= ablation zone = region destroyed by heat) is indicated by a dashed line in (B), and extends ~2.2 mm beyond the visible coagulation zone. I.e. there is no viable tissue zone in-between the ablation zone and the region of drug delivery, as may be assumed from Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.g005" target="_blank">5</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.g006" target="_blank">6A</a>.</p

<i>In vivo</i> results.

<p>Grey scale images demonstrate the visible coagulation zone (red dashed line in (A)) after either 12 min (A), or 5 min (C) ablation. The color images show tissue doxorubicin concentration extracted from fluorescence imaging of the same tissue slices after either 12 min (B), or 5 min (D) ablation. The visible coagulation zone is marked by dashed lines in (A) and (B). A radial sample path along which drug concentration profile was calculated is shown in (B). Note these slices are oriented orthogonal to the computer simulation results (dashed line in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.g002" target="_blank">Fig 2B</a>).</p

Heating with multiple RF electrodes.

<p>(A) 3-D computer model results for three-electrode array, where a 12-min ablation was performed with each needle sequentially to emulate clinical treatment of a large tumor by multiple overlapping ablations. Drug delivery is enhanced in tissue regions that were exposed to hyperthermic temperatures by more than one heating cycle, i.e. the areas in-between the RF needles. This observation is clinically relevant, as this preferential delivery may prevent tumor recurrence in untreated tumor regions that remain when sequential ablations are not overlapping. (B) A prior <i>in vivo</i> study demonstrates a similar drug delivery pattern with enhanced uptake in-between electrodes after three sequential ablations (3 x 12 min) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.ref031" target="_blank">31</a>]. Left image shows the visible coagulation zone, right image shows drug fluorescence. This prior study used smaller electrodes (resulting in smaller ablations), and used a ~2.3 times higher TSL-Dox dose (1.43 mg/kg), than the current study, explaining the substantially higher tissue drug concentration. (images in (B) produced base on prior data [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.ref031" target="_blank">31</a>]).</p

Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and <i>in vivo</i>

<div><p>Background</p><p>Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating.</p><p>Methods</p><p>We used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine <i>in vivo</i> studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution.</p><p>Results</p><p>Both <i>in vivo</i> studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. <i>In vivo</i>, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 μg/g to 3.0 μg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug.</p><p>Conclusions</p><p>Both computer models and <i>in vivo</i> study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems.</p></div

Computer model results.

<p>(A) Temperature (left half of figure) and perfusion map (right half of figure) at the end of a 12 min ablation. This perfusion map varied during heating depending on thermal dose (see supporting information, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.s001" target="_blank">S1 File</a>) (B) Temperature at the end of a 12 min ablation (left half of figure), and total tissue doxorubicin concentration 30 min after completion of ablation (right half of figure). The RF heating electrode is located at the center (gray: insulated catheter region; white: active tip region). The dashed line indicates the location where concentration profile is plotted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.g004" target="_blank">Fig 4</a>, and also indicates approximate slice location of <i>in vivo</i> tissue slices in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179131#pone.0179131.g003" target="_blank">Fig 3</a>.</p