Intercostal Nerve Blockade with Exparel® Results in Lower Opioid Usage during the First 24 Hours after Video-Assisted Thorascopic Surgery.

Liposomal bupivacaine (LipoB) provides prolonged local anesthetic effects and has seen usage in several fields of surgery. We review our experience using LipoB intraoperatively for intercostal nerve blocks after video-assisted throacoscopic surgery (VATS). A retrospective, single-center review was conducted for patients undergoing VATS from August 2012 to December 2014. Patients those who received LipoB as an intercostal nerve block were compared with patients who received blocks with standard bupivacaine. Opiate amounts used within the first six hours and then subsequent 18, 48, and 72 hours were converted into morphine equivalents for comparison. Forty-seven patients met inclusion criteria: 21 receiving LipoB intercostal nerve block and 26 controls. Groups were similar for age, diabetes, hypertension, chronic kidney disease, body mass index and American Society of Anesthesiologists scores. The LipoB group had a larger portion of males (P < 0.02). Postoperatively, morphine equivalent usage was significantly less in the LipoB group compared with the standard bupivacaine within the first six hours after surgery (15.62 vs 52.41, P = 0.001) and in the subsequent 18 hours (28.98 vs 65.17, P = 0.01). After the first 24 hours there was not a significant difference in opiate usage between the two groups. There was no difference in length of stay between the two groups. In our study group of VATS patients, an intercostal nerve block with LipoB significantly reduced the usage of postoperative opioids in the first 24 hours only when compared with standard bupivacaine.

The MapCHECK Measurement Uncertainty function and its effect on planar dose pass rates.

Our study aimed to quantify the effect of the Measurement Uncertainty function on planar dosimetry pass rates, as measured and analyzed with the Sun Nuclear Corporation MapCHECK 2 array and its associated software. This optional function is toggled in the program preferences of the software (though turned on by default upon installation), and automatically increases the dose difference tolerance defined by the user for each planar dose comparison. Dose planes from 109 static-gantry IMRT fields and 40 VMAT arcs, of varying modulation complexity, were measured at 5 cm water-equivalent depth in the MapCHECK 2 diode array, and respective calculated dose planes were exported from a commercial treatment planning system. Planar dose comparison pass rates were calculated within the Sun Nuclear Corporation analytic software using a number of calculation parameters, including Measurement Uncertainty on and off. By varying the percent difference (%Diff) criterion for similar analyses performed with Measurement Uncertainty turned off, an effective %Diff criterion was defined for each field/arc corresponding to the pass rate achieved with Measurement Uncertainty turned on. On average, the Measurement Uncertainty function increases the user-defined %Diff criterion by 0.8%-1.1% for 3%/3 mm analysis, depending on plan type and calculation technique (corresponding to an average change in pass rate of 1.0%-3.5%, and a maximum change of 8.7%). At the 2%/2 mm level, the Measurement Uncertainty function increases the user-defined %Diff criterion by 0.7%-1.2% on average, again depending on plan type and calculation technique (corresponding to an average change in pass rate of 3.5%-8.1%, and a maximum change of 14.2%). The largest increases in pass rate due to the Measurement Uncertainty function are generally seen with poorly matched planar dose comparisons, while the function has a notably smaller effect as pass rates approach 100%. The Measurement Uncertainty function, then, may substantially increase the pass rates for planar dose comparisons. Meanwhile, the types of uncertainties incorporated into the function (and their associated quantitative estimates, as described in the software user's manual) may not be an accurate estimation of actual measurement uncertainty, depending on the user's measurement conditions. Pass rates listed in published reports, comparisons between institutions or simply separate workstations, or comparisons with the calculation methods of other vendors, should clearly indicate whether or not the Measurement Uncertainty function is used, since it has the potential to substantially inflate pass rates for typical IMRT and VMAT dose planes.

Evaluation of fluence-based dose delivery incorporating the spatial variation of dosimetric leaf gap (DLG).

The Eclipse treatment planning system uses a single dosimetric leaf gap (DLG) value to retract all multileaf collimator leaf positions during dose calculation to model the rounded leaf ends. This study evaluates the dosimetric impact of the 2D variation of DLG on clinical treatment plans based on their degree of fluence modulation. In-house software was developed to retrospectively apply the 2D variation of DLG to 61 clinically treated VMAT plans, as well as to several test plans. The level of modulation of the VMAT cases were determined by calculating their modulation complexity score (MCS). Dose measurements were done using the MapCHECK device at a depth of 5.0 cm for plans with and without the 2D DLG correction. Measurements were compared against predicted dose planes from the TPS using absolute 3%/3 mm and 2%/2 mm gamma criteria for test plans and for VMAT cases, respectively. The gamma pass rate for the 2 mm, 4 mm, and 6 mm sweep test plans increased by 23.2%, 28.7%, and 26.0%, respectively, when the measurements were corrected with 2D variation of DLG. The clinical anal VMAT cases, which had very high MLC modulation, showed the most improvement. The majority of the improvement occurred for doses created by the 1.0 cm width leaves for both the test plans and the VMAT cases. The gamma pass rates for the highly modulated head and neck (H&N) cases, moderately modulated prostate and esophageal cases, and minimally modulated brain cases improved only slightly when corrected with 2D variation of DLG. This is because these cases did not employ the 1.0 cm width leaves for dose calculation and delivery. These data suggest that, at the very least, the TPS plans with highly modulated fluences created by the 1.0 cm fields require 2D DLG correction. Incorporating the 2D variation of DLG for the highly modulated clinical treatment plans improves their planar dose gamma pass rates, especially for fields employing the outer 1.0 cm width MLC leaves. This is because there are differences in DLG between the true DLG exhibited by the 1.0 cm width outer leaves and the constant DLG value modeled by the TPS for dose calculation.

TBI lung dose comparisons using bilateral and anteroposterior delivery techniques and tissue density corrections.

This study compares lung dose distributions for two common techniques of total body photon irradiation (TBI) at extended source-to-surface distance calculated with, and without, tissue density correction (TDC). Lung dose correction factors as a function of lateral thorax separation are approximated for bilateral opposed TBI (supine), similar to those published for anteroposterior-posteroanterior (AP-PA) techniques in AAPM Report 17 (i.e., Task Group 29). 3D treatment plans were created retrospectively for 24 patients treated with bilateral TBI, and for whom CT data had been acquired from the head to the lower leg. These plans included bilateral opposed and AP-PA techniques- each with and without - TDC, using source-to-axis distance of 377 cm and largest possible field size. On average, bilateral TBI requires 40% more monitor units than AP-PA TBI due to increased separation (26% more for 23 MV). Calculation of midline thorax dose without TDC leads to dose underestimation of 17% on average (standard deviation, 4%) for bilateral 6 MV TBI, and 11% on average (standard deviation, 3%) for 23 MV. Lung dose correction factors (CF) are calculated as the ratio of midlung dose (with TDC) to midline thorax dose (without TDC). Bilateral CF generally increases with patient separation, though with high variability due to individual uniqueness of anatomy. Bilateral CF are 5% (standard deviation, 4%) higher than the same corrections calculated for AP-PA TBI in the 6 MV case, and 4% higher (standard deviation, 2%) for 23 MV. The maximum lung dose is much higher with bilateral TBI (up to 40% higher than prescribed, depending on patient anatomy) due to the absence of arm tissue blocking the anterior chest. Dose calculations for bilateral TBI without TDC are incorrect by up to 24% in the thorax for 6 MV and up to 16% for 23 MV. Bilateral lung CF may be calculated as 1.05 times the values published in Table 6 of AAPM Report 17, though a larger patient pool is necessary to better quantify this trend. Bolus or customized shielding will reduce lung maximum dose in the anterior thorax.

Spatial variation of dosimetric leaf gap and its impact on dose delivery.

PURPOSE: During dose calculation, the Eclipse treatment planning system (TPS) retracts the multileaf collimator (MLC) leaf positions by half of the dosimetric leaf gap (DLG) value (measured at central axis) for all leaf positions in a dynamic MLC plan to accurately model the rounded leaf ends. The aim of this study is to map the variation of DLG along the travel path of each MLC leaf pair and quantify how this variation impacts delivered dose. METHODS: 6 MV DLG values were measured for all MLC leaf pairs in increments of 1.0 cm (from the line intersecting the CAX and perpendicular to MLC motion) to 13.0 cm off axis distance at dmax. The measurements were performed on two Varian linear accelerators, both employing the Millennium 120-leaf MLCs. The measurements were performed at several locations in the beam with both a Sun Nuclear MapCHECK device and a PTW pinpoint ion chamber. RESULTS: The measured DLGs for the middle 40 MLC leaf pairs (each 0.5 cm width) at positions along a line through the CAX and perpendicular to MLC leaf travel direction were very similar, varying maximally by only 0.2 mm. The outer 20 MLC leaf pairs (each 1.0 cm width) have much lower DLG values, about 0.3-0.5 mm lower than the central MLC leaf pair, at their respective central line position. Overall, the mean and the maximum variation between the 0.5 cm width leaves and the 1.0 cm width leaf pairs are 0.32 and 0.65 mm, respectively. CONCLUSIONS: The spatial variation in DLG is caused by the variation of intraleaf transmission through MLC leaves. Fluences centered on the CAX would not be affected since DLG does not vary; but any fluences residing significantly off axis with narrow sweeping leaves may exhibit significant dose differences. This is due to the fact that there are differences in DLG between the true DLG exhibited by the 1.0 cm width outer leaves and the constant DLG value utilized by the TPS for dose calculation. Since there are large differences in DLG between the 0.5 cm width leaf pairs and 1.0 cm width leaf pairs, there is a need to correct the TPS plans, especially those with high modulation (narrow dynamic MLC gap), with 2D variation of DLG.

EPID dosimetry for pretreatment quality assurance with two commercial systems.

This study compares the EPID dosimetry algorithms of two commercial systems for pretreatment QA, and analyzes dosimetric measurements made with each system alongside the results obtained with a standard diode array. 126 IMRT fields are examined with both EPID dosimetry systems (EPIDose by Sun Nuclear Corporation, Melbourne FL, and Portal Dosimetry by Varian Medical Systems, Palo Alto CA) and the diode array, MapCHECK (also by Sun Nuclear Corporation). Twenty-six VMAT arcs of varying modulation complexity are examined with the EPIDose and MapCHECK systems. Optimization and commissioning testing of the EPIDose physics model is detailed. Each EPID IMRT QA system is tested for sensitivity to critical TPS beam model errors. Absolute dose gamma evaluation (3%, 3 mm, 10% threshold, global normalization to the maximum measured dose) yields similar results (within 1%-2%) for all three dosimetry modalities, except in the case of off-axis breast tangents. For these off-axis fields, the Portal Dosimetry system does not adequately model EPID response, though a previously-published correction algorithm improves performance. Both MapCHECK and EPIDose are found to yield good results for VMAT QA, though limitations are discussed. Both the Portal Dosimetry and EPIDose algorithms, though distinctly different, yield similar results for the majority of clinical IMRT cases, in close agreement with a standard diode array. Portal dose image prediction may overlook errors in beam modeling beyond the calculation of the actual fluence, while MapCHECK and EPIDose include verification of the dose calculation algorithm, albeit in simplified phantom conditions (and with limited data density in the case of the MapCHECK detector). Unlike the commercial Portal Dosimetry package, the EPIDose algorithm (when sufficiently optimized) allows accurate analysis of EPID response for off-axis, asymmetric fields, and for orthogonal VMAT QA. Other forms of QA are necessary to supplement the limitations of the Portal Vision Dosimetry system.

Statistical variability and confidence intervals for planar dose QA pass rates.

PURPOSE: The most common metric for comparing measured to calculated dose, such as for pretreatment quality assurance of intensity-modulated photon fields, is a pass rate (%) generated using percent difference (%Diff), distance-to-agreement (DTA), or some combination of the two (e.g., gamma evaluation). For many dosimeters, the grid of analyzed points corresponds to an array with a low areal density of point detectors. In these cases, the pass rates for any given comparison criteria are not absolute but exhibit statistical variability that is a function, in part, on the detector sampling geometry. In this work, the authors analyze the statistics of various methods commonly used to calculate pass rates and propose methods for establishing confidence intervals for pass rates obtained with low-density arrays. METHODS: Dose planes were acquired for 25 prostate and 79 head and neck intensity-modulated fields via diode array and electronic portal imaging device (EPID), and matching calculated dose planes were created via a commercial treatment planning system. Pass rates for each dose plane pair (both centered to the beam central axis) were calculated with several common comparison methods: %Diff/DTA composite analysis and gamma evaluation, using absolute dose comparison with both local and global normalization. Specialized software was designed to selectively sample the measured EPID response (very high data density) down to discrete points to simulate low-density measurements. The software was used to realign the simulated detector grid at many simulated positions with respect to the beam central axis, thereby altering the low-density sampled grid. Simulations were repeated with 100 positional iterations using a 1 detector/cm(2) uniform grid, a 2 detector/cm(2) uniform grid, and similar random detector grids. For each simulation, %/DTA composite pass rates were calculated with various %Diff/DTA criteria and for both local and global %Diff normalization techniques. RESULTS: For the prostate and head/neck cases studied, the pass rates obtained with gamma analysis of high density dose planes were 2%-5% higher than respective %/DTA composite analysis on average (ranging as high as 11%), depending on tolerances and normalization. Meanwhile, the pass rates obtained via local normalization were 2%-12% lower than with global maximum normalization on average (ranging as high as 27%), depending on tolerances and calculation method. Repositioning of simulated low-density sampled grids leads to a distribution of possible pass rates for each measured/calculated dose plane pair. These distributions can be predicted using a binomial distribution in order to establish confidence intervals that depend largely on the sampling density and the observed pass rate (i.e., the degree of difference between measured and calculated dose). These results can be extended to apply to 3D arrays of detectors, as well. CONCLUSIONS: Dose plane QA analysis can be greatly affected by choice of calculation metric and user-defined parameters, and so all pass rates should be reported with a complete description of calculation method. Pass rates for low-density arrays are subject to statistical uncertainty (vs. the high-density pass rate), but these sampling errors can be modeled using statistical confidence intervals derived from the sampled pass rate and detector density. Thus, pass rates for low-density array measurements should be accompanied by a confidence interval indicating the uncertainty of each pass rate.

Effects of long-term progesterone exposure on porcine uterine gene expression: progesterone alone does not induce secreted phosphoprotein 1 (osteopontin) in glandular epithelium.

Pigs experience significant conceptus loss near mid-gestation, correlating with increasing glandular epithelial (GE) development and secretory activity. Secreted phosphoprotein 1 (SPP1, osteopontin) increases in GE between days 30 and 40 of pregnancy and is expressed in the GE of day 90 pseudopregnant pigs, suggesting that progesterone (P(4)) from corpora lutea is responsible for induction of SPP1 in GE. In this study, pigs were ovariectomized and treated daily with P(4) to assess effects of 40 days of P(4) exposure on SPP1, P(4) receptor (PGR), uteroferrin (ACP5), and fibroblast growth factor 7 (FGF7) expression in porcine endometria. PGR mRNA decreased in pigs injected with P(4) compared with pigs injected with corn oil (CO), and PGRs were downregulated in the luminal epithelium (LE) and GE. ACP5 mRNA increased in pigs injected with P(4) compared with pigs injected with CO, and ACP5 was induced in the GE of P(4)-treated pigs. FGF7 mRNA increased in pigs injected with P(4) compared with pigs injected with CO, and FGF7 was induced in the LE and GE of P(4)-treated pigs. SPP1 mRNA was not different between pigs injected with P(4) compared with pigs injected with CO, and SPP1 was not present in the GE of P(4)-treated pigs. Therefore, long-term P(4), in the absence of ovarian and/or conceptus factors, does not induce SPP1 expression in GE. We hypothesize that a servomechanism involving sequential effects of multiple hormones and cytokines, similar to those for sheep and humans, is required for GE differentiation and function, including the synthesis and secretion of SPP1.

Effects of long-term progesterone on developmental and functional aspects of porcine uterine epithelia and vasculature: progesterone alone does not support development of uterine glands comparable to that of pregnancy.

In pigs, endometrial functions are regulated primarily by progesterone and placental factors including estrogen. Progesterone levels are high throughout pregnancy to stimulate and maintain secretion of histotroph from uterine epithelia necessary for growth, implantation, placentation, and development of the conceptus (embryo and its extra-embryonic membranes). This study determined effects of long-term progesterone on development and histoarchitecture of endometrial luminal epithelium (LE), glandular epithelium (GE), and vasculature in pigs. Pigs were ovariectomized during diestrus (day 12), and then received daily injections of either corn oil or progesterone for 28 days. Prolonged progesterone treatment resulted in increased weight and length of the uterine horns, and thickness of the endometrium and myometrium. Hyperplasia and hypertrophy of GE were not evident, but LE cell height increased, suggesting elevated secretory activity. Although GE development was deficient, progesterone supported increased endometrial angiogenesis comparable to that of pregnancy. Progesterone also supported alterations to the apical and basolateral domains of LE and GE. Dolichos biflorus agglutinin lectin binding and α(v) integrin were downregulated at the apical surfaces of LE and GE. Claudin-4, α(2)ß(1) integrin, and vimentin were increased at basolateral surfaces, whereas occludins-1 and -2, claudin-3, and E-cadherin were unaffected by progesterone treatment indicating structurally competent trans-epithelial adhesion and tight junctional complexes. Collectively, the results suggest that progesterone affects LE, GE, and vascular development and histoarchitecture, but in the absence of ovarian or placental factors, it does not support development of GE comparable to pregnancy. Furthermore, LE and vascular development are highly responsive to the effects of progesterone.

Cathepsin B, cathepsin L, and cystatin C in the porcine uterus and placenta: potential roles in endometrial/placental remodeling and in fluid-phase transport of proteins secreted by uterine epithelia across placental areolae.

Cathepsins (CTSB and CTSL1) and their inhibitor, cystatin C (CST3), remodel uterine endometrium and placenta for transport of gases, micronutrients, and macromolecules essential for development and growth of the conceptus (embryo/fetus and placental membranes). We examined the temporal/spatial control of expression for CTSB, CTSL1, and CST3 mRNAs in endometria and placentae of pigs using three developmental models: 1) pigs were hysterectomized during the estrous cycle or pregnancy; 2) cyclic pigs were injected with estrogen to induce pseudopregnancy and were hysterectomized; and 3) pigs were ovariectomized, injected with progesterone, and hysterectomized. The abundance of CTSB, CTSL1, and CST3 mRNAs increased in endometrial epithelia during pregnancy and in response to exogenous progesterone but not estrogen. CST3 was also expressed in cells scattered within the stratum compactum stroma. Progesterone decreased epithelial but increased stromal compartment expression of CST3. CTSB increased in all chorionic epithelia, but CTSL1 was limited to chorionic epithelia that form areolae to absorb secretions from uterine glands. Based on the placental and endometrial distribution of CTSL1, we examined expression in the neonatal enterocytes known to transport immunoglobulins from colostrum. CTSL1 was also expressed in enterocytes of intestine from neonatal piglets. Therefore, CTSL1 is expressed by endometrial epithelia, placental areolae, and neonatal intestine, and it may function in the transport of macromolecules across these epithelia. Our results support the idea that reciprocal interactions between CSTL1, CTSB, and CST3 may be required to remodel endometrial and placental tissues for close apposition between maternal and fetal vasculatures and to facilitate transplacental transport of gases, micronutrients (amino acids, glucose), and macromolecules (proteins). Cysteine proteases and their inhibitors may also specifically modify proteins for successful utilization and fluid-phase transport across uterine, placental, and neonatal gut epithelia.

A fully electronic intensity-modulated radiation therapy quality assurance (IMRT QA) process implemented in a network comprised of independent treatment planning, record and verify, and delivery systems.

BACKGROUND: The purpose of this study is to implement an electronic method to perform and analyze intensity-modulated radiation therapy quality assurance (IMRT QA) using an aSi megavoltage electronic portal imaging device in a network comprised of independent treatment planning, record and verify (R&V), and delivery systems. METHODS: A verification plan was generated in the treatment planning system using the actual treatment plan of a patient. After exporting the treatment fields to the R&V system, the fields were delivered in QA mode with the aSi imager deployed. The resulting dosimetric images are automatically stored in a DICOM-RT format in the delivery system treatment console computer. The relative dose density images are subsequently pushed to the R&V system. The absolute dose images are then transferred electronically from the treatment console computer to the treatment planning system and imported into the verification plan in the dosimetry work space for further analysis. Screen shots of the gamma evaluation and isodose comparison are imported into the R&V system as an electronic file (e.g. PDF) to be reviewed prior to initiation of patient treatment. A relative dose image predicted by the treatment planning system can also be sent to the R&V system to be compared with the relative dose density image measured with the aSi imager. RESULTS: Our department does not have integrated planning, R&V, and delivery systems. In spite of this, we are able to fully implement a paperless and filmless IMRT QA process, allowing subsequent analysis and approval to be more efficient, while the QA document is directly attached to its specific patient chart in the R&V system in electronic form. The calculated and measured relative dose images can be compared electronically within the R&V system to analyze the density differences and ensure proper dose delivery to patients. CONCLUSIONS: In the absence of an integrated planning, verifying, and delivery system, we have shown that it is nevertheless possible to develop a completely electronic IMRT QA process.

An effective correction algorithm for off-axis portal dosimetry errors.

Portal dosimetric images acquired for IMRT pretreatment verification show dose errors of up to 15% near the detector edges as compared to dose predictions calculated by a treatment planning system for these off-axis regions. A method is proposed to account for these off-axis effects by precisely correcting the off-axis output factors, which calibrate the imager for absolute dose. Using this method, agreement between the predicted and the measured doses improves by up to 15% for fields near the detector edges, resulting in passing rate improvements of as much as 60% for gamma evaluation of 3 mm, 3% within the collimator jaws.

Stanniocalcin 1 is a luminal epithelial marker for implantation in pigs regulated by progesterone and estradiol.

Stanniocalcin 1 (STC1) is a glycoprotein that decreases calcium and increases phosphate in cells/tissues. This investigation examined endocrine regulation of STC1 in endometria of pigs during the estrous cycle and pregnancy. STC1 mRNA was present exclusively in luminal epithelium (LE) between d 12 and 15 of the estrous cycle, increased between d 12 and d 20, and was not detectable by d 30 of pregnancy. STC1 protein was also detected in uterine flushings. To determine effects of estrogen and progesterone, pigs were ovariectomized and treated with these hormones alone or together. Progesterone, but not estrogen, induced STC1 in LE. Cotreatment with progesterone and estrogen further stimulated STC1 over progesterone alone. To determine effects of pseudopregnancy, nonpregnant gilts were given daily injections of estradiol benzoate from d 11 to d 14. STC1 was not expressed in LE on d 90 of pseudopregnancy, suggesting that the estradiol given to induce pseudopregnancy and/or long-term exposure to progesterone are required for down-regulation of STC1. To determine effects of long-term progesterone, without effects of estradiol, pigs were ovariectomized on d 12, given daily injections of progesterone through d 39, and hysterectomized on d 40 after estrus. STC1 was expressed in LE of progesterone-treated pigs, suggesting that estrogen is involved in down-regulation of STC1. We conclude that STC1 is induced in LE by progesterone and further stimulated by estrogen, and its down-regulation in LE by d 25 likely requires exposure of the progestinized uterus to estrogen. The temporal and cell type-specific expression of STC1 makes this gene a unique marker for implantation in pigs.