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Background Pharmacokinetics (PK) of docetaxel is characterized by high inter‐individual variability (IIV). While covariate models that explain the PK variability of docetaxel exist, not much is known about the effects of genetic variations on docetaxel disposition. Methods Fifty patients with head and neck or prostate cancer were enrolled of whom two patients withdrew consent before the start of the study. Docetaxel was administered at either 50 or 75 mg/m2 as intravenous infusion over 1 h. One pharmacogenetic sample and a series of PK samples, either intensive (N = 5; 13 samples each) or sparse (N = 43; 6 samples each), were collected from each patient. Docetaxel levels were estimated using a validated HPLC method. Polymorphic loci on the Absorption, Distribution, Metabolism, and Elimination (ADME) genes were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Results Docetaxel PK was well characterized by a three‐compartment model. Clearance (Cl) was found to be 18 L/h with an IIV of 45.3%. None of the genetic variants showed significant covariate effect on the Cl of docetaxel. Patients with abnormal alanine aminotransferase (ALT) were found to have 25% lower Cl as compared to patients with normal ALT values. However, the covariate effect could not be established in the final model possibly due to lack of adequate number of patients with abnormal ALT. Conclusion Genetic polymorphisms in the ADME gene do not explain the IIV in PK of docetaxel. However, patients with abnormal liver function might require dose reduction. Clinical trial registration: Not applicable since participants in this study received treatment that was standard of care., The study aims to explain the inter‐individual variability in the pharmacokinetics of docetaxel using a population pharmacokinetic approach. Our results conclusively exclude pharmacogenetic variants as a significant covariate, while recommending dose modification for patients with hepatic impairment.

Background Data on rate, risk factors, and consequences of early reoperation after liver transplantation are still limited. Study design Single-center retrospective analysis of data of 428 patients, who underwent liver transplantation in period between January 2009 and December 2014. Univariate and multivariate analysis were used to study the risk factors of early reoperation and its impact on graft survival. Results Of 428 patients, 74 (17.3%) underwent early reoperation. Of them, 46 (62.2%) underwent reoperation within the first week and 28 (37.8%) underwent reoperation later than 1 week after transplantation. With multivariate analysis, significant risk factors of early reoperation included pretransplant ICU admission, previous abdominal surgery and diabetes. Early reoperation itself was not found to be an independent predictor of graft loss. However, early reoperation later than 7 days from transplant was found to be independent predictor of graft loss (odds ratio [OR] = 5.125; 95% CI, 1.358-19.552; P = .016). In our series, other independent predictors of graft loss were MELD score (P = .010) and operative time (P = .048). Conclusions This analysis demonstrates that early reoperations later than a week appear to negatively impact the graft survival. The timing of early reoperation should be a focus of additional studies.

The mechanisms that regulate the complex physiological task of photoreceptor outer segment assembly remain an enigma. One limiting factor in revealing the mechanism(s) by which this process is modulated is that not all of the role players who participate in this process are known. The purpose of this study was to determine some of the retinal proteins that likely play a critical role in regulating photoreceptor outer segment assembly. To do so, we analyzed and compared the proteome map of tadpole Xenopus laevis retinal pigment epithelium (RPE)-supported retinas containing organized outer segments with that of RPE-deprived retinas containing disorganized outer segments. Solubilized proteins were labeled with CyDye fluors followed by multiplexed two-dimensional separation. The intensity of protein spots and comparison of proteome maps was performed using DeCyder software. Identification of differentially regulated proteins was determined using nanoLC-ESI-MS/MS analysis. We found a total of 27 protein spots, 21 of which were unique proteins, which were differentially expressed in retinas with disorganized outer segments. We predict that in the absence of the RPE, oxidative stress initiates an unfolded protein response. Subsequently, downregulation of several candidate Müller glial cell proteins may explain the inability of photoreceptors to properly fold their outer segment membranes. In this study, we have used identification and bioinformatics assessment of proteins that are differentially expressed in retinas with disorganized outer segments as a first step in determining probable key molecules involved in regulating photoreceptor outer segment assembly.

Purpose: Evaluation of KODAK RT2000 CR System for its practical use in replacing portal localization films. Methods: Patient setup verification is critical to accurately deliver a prescribed dose to a patient. We use portal film imaging on some of our old machines. KODAK RT2000 CR System was recently evaluated to replace the conventional portal films with digital imaging. Rando phantom was used to test the functionality and accuracy of the Kodak CR system. A treatment plan was generated using the CTimages of the Rando phantom; the plan was then exported to Siemens PRIMUS via ARIA. Portalimages were taken using KODAK photostimulable phosphor (PSP) system. The PSP system was read by scanning the phosphor using KODAK CR System. These digitized images were exported to Varian ARIA RT Chart and evaluated in Offline Review for registration of DRRs with the digital portalimage. DRRs from the treatment planning system and digital portalimages from KODAK CR System were matched and differences between the planned set‐up and the in‐room set‐up of phantom were measured with tools in Offline Review. Shifts in lateral, longitudinal and vertical directions along with tilt angle were obtained to finally register the DRRs with the digital portalimages. Results: We converted our old film‐based portalimaging system into a digital portalimaging system. These digital images can be shared across a network. A digital imaging system provides easy access through ARIA network for physician's approval of portalimages. Conclusions: We successfully integrated four different multi‐vendor modalities (Odyssey TPS from Optivus, Siemen's Primus, Varian ARIA and KODAK CR System) to develop a portal digital imaging system. The system increases accuracy of treatment, offers flexibility of offline review by a physician, and thus makes the whole process more efficient.

Purpose: Accurate, patient‐specific anatomical information is a prerequisite for successful radiation therapy planning and delivery to the tumor, while minimizing dose to surrounding tissues. A new FPDI system (XRD 1640, Perkin Elmer) was installed and commissioned replacing a CCD and mirror‐based digital imager (DI, Optivus). The details of the tests performed during the commissioning will be presented. Methods and Materials: Rando phantom is used for testing patient orientation in the imager. A RMI magnification plate and a radio‐opaque ruler are used to measure the magnification factor of the imaging system. A black‐hole phantom along with a line‐pair phantom, aluminum and copper plates are used to measure the image quality. To test the alignment of two sources (x‐ray and proton), the x‐rays and proton beam double‐exposure (one x‐ray and one proton) was done on two cross‐wires (one in the aperture and one in front of FPDI) at four cardinal angles. To test the drift of the nozzle, the same test (with two double‐exposures) was done for nozzle at fully extended and fully retracted positions and at different gantry angles. Results: FPDI requires low x‐ray energy settings (90 kVp, 20–40 mAs) for collecting images of similar quality when compared to the previous imager (105 kVp, 250 mAs). The acceptance test showed the maximum high‐contrast spatial visibility (resolution) of 0.8 line pairs per mm and the maximum low‐contrast visibility (resolution) of 0.5 mm diameter circular objects. The images obtained from double‐exposure as well as two double‐exposures showed the coincidence within 1 mm. The FPDI images obtained from Rando phantom depicted differences to the images of exported DRRs, which enabled the correct adjustment of the phantom alignment and orientation. Conclusion: When compared to the previous imager, FPDI provides a sharper image for locating the landmarks for patient alignment with less exposure to the patient.

Purpose: To evaluate the planned dose accuracy of whole breast irradiation using field‐in‐field technique by comparing with 2D array detector measurements and Monte Carlo simulations. Methods: The ion chamber based Octavius 2D‐array detector (PTW, Freiburg, Germany) was used to measure the absolute dose and dose distributions of tangential field‐in‐field breast irradiation. A commercially available treatment planning system (Eclipse V10.0, Varian, Palo Alto CA USA) was used to calculate the absolute dose and dose distributions. Phantom geometry was simplified for the measurements and for Monte Carlo simulations, but its size and shape were similar to typical breast. The dose accuracy of the treatment planning system was evaluated and the desirable points for monitor unit calculation were recommended based on the results of the study. Results: The discrepancy between measured and planned dose distribution depended on the location of the monitor unit calculation point. The differences were larger when monitor unit calculation point was closer to the irradiated edges of phantom. The doses calculated by the treatment planning system near the center of the irradiated field were about 2% higher than measured doses. There was good agreement between the measured doses and those predicted by Monte Carlo methods. Conclusion: Because of inadequate treatment of scatter in the irradiation of breast with tangential ports, the dose predictions by a treatment planning system do not always agree with the actual measurements. The treatment planning algorithm evaluated in this study over‐compensates for the loss of scatter in tangential ports glancing the sloping surface of a typical breast. The choice of the prescription point can have significant effect on the dose prediction and the actual dose delivered. Keeping the prescription point away from the field edges will help improve the agreement between the calculated and measured dose.

Purpose: To determine the cross calibration factors which can predict more accurate dose distribution for fixed beam IMRT QA using Octavius phantom. Methods: The ion chamber based Octavius 2D‐array detector (PTW, Freiburg, Germany) is a step in the right direction to measure the absolute dose and dose distribution for patient specific IMRT QA. However, the directional dependency of this detector made it less than desirable for angle dependent IMRT QA. We evaluated the new Octavius system (PTW, Freiburg, Germany) for angle dependent IMRT QA which compensates the response due to directional dependency. The system is designed for full arc VMAT QA, but does not always work for the discrete angle IMRT QA due to non‐averaging of errors caused by directional dependence of detectors. The proposed method uses correction factors for each gantry angle. The dose for a 10cm × 10cm open field for each gantry angle was calculated by treatment planning system and measured using the Octavius phantom. The correction factors were determined at each gantry angle and the dose distribution was renormalized at each angle using correction factors. Results: The discrepancy between measured and planned dose per monitor unit depended on the gantry angle and were in the range of +−4% using the PTW method. Using our method, uncertainty due to the detector angle dependency was eliminated. Conclusions: The new method removes the angle dependency of ion chamber based 2D array detector for the fixed beam IMRT QA. It provides fast, accurate and more realistic results for angle dependent IMRT QA.

Purpose: To investigate the response of electronic portal imaging device(EPID) in integration mode for intensity modulated beams including step‐ and‐shoot (SS) and sliding window (SW) deliveries. Methods: We evaluated EPID dose response measurements of open, SS, and SW irradiations. We designed three beams using 6MV x‐rays with 10×10 cm2 field size. For the SS irradiation, two MLC leaves with 0.5 cm opening outside 10 × 10 cm2 were discontinuously moved by 10 cm during each segmental irradiation among ten segments of the entire delivery. For the SW beam, the same MLC leaves were continuously moved by 10 cm ten times during the delivery. The employment of the same open beam area ensures the same dose irradiation by the three. Monitor units were varied. We additionally investigated the dose linearity of EPID response. We used EPID‐ADU1000 operated with IAS3 system for the integrated acquisition. Results: The SS delivery showed a deviation greater than 2% from the open beam, if a segment employed less than 10 MUs. If it employed greater than 10 MUs, then a deviation less than 1% was observed. The SW delivery showed a maximum deviation of 1.4% at the lowest MU. The open beam irradiation showed linearity within 0.8%, the SW irradiation 1.2%, and the SS irradiation 1.7%. Conclusions: The SS delivery is associated with a greater error than the SW delivery due to beam instability at the start of acquisition and reading loss during MLC movement. Using large monitor units greater than 10 MUs/segment can minimize the deviation for the SS delivery from open beam. The linearity of EPID response to dose was better with the SW delivery than the SS delivery. This study will help understand dosimetric response of EPID for the SS delivery. This study was in part supported by Varian Medical Systems, Inc.

Purpose: To compare treatment plans on select complex cases using IMRT and protons involving patch‐field technique Methods: IMRT is used to treat tumors adjacent to critical structures. This is achieved by a dose optimizing algorithm that creates field segments using MLC and modulating the photon fluence to treat different parts of the tumor and conformally avoiding nearby critical structures. Proton beams offer an alternate way to treat such tumors and avoid critical structures. Properties of proton beams important to treatment planning are the ease with which a proton beam can be stopped at the desired depth in a medium as well as its sharp distal dose fall off near the end of the range. In a patch‐field proton beam arrangement a shoot through beam is used to treat majority of the tumor and a patching beam treats remaining tumor near the critical structures. The patching beam stops distally on the lateral edge of the shoot through beam. The weighting and the distal overlap between the shoot‐through and the patching beams are optimized to conformally cover the entire tumor. Here we are comparing treatment plans for different tumor sites using IMRT and proton beams involving patch‐field arrangements. Results: The isodose distributions and dose volume histograms (DVH) were compared between the two treatment modalities. Both IMRT and proton plans do a good job of conformally irradiating the tumor. But overall, proton plans do a better job of sparing the critical structures. One clear advantage of proton beams is the avoidance of low dose to normal tissues surrounding the tumor leading to a lower integral dose Conclusions: Complex tumors surrounding critical structures can be treated effectively with IMRT or proton beams. But protons are more effective in sparing critical structures and they give lower dose to normal tissues than IMRT.

Purpose: To describe a technique for partial breast irradiation with proton beam radiotherapy.Method and Materials: A breast patient post lumpectomy is fitted with a special brassiere to reproducibly support the ipsilateral breast while compressing the contralateral breast. The patient then lies prone in a PVC half cylindrical pipe, supported from shoulder up and below the abdomen by foam bead cushions. The air from the cushions is evacuated resulting in rigid immobilization. The breast area is then immobilized with a urethane based foaming agent producing custom immobilization of the ipsilateral breast. Next, the patient undergoes a treatment planningCT scan of the thorax. The physician contours the tumor bed to include surgical clips and then contours organs at risk. A 3D conformal treatment plan is then developed. For every treatment, the patient is fitted with the treatment brassiere, and positioned prone in the custom immobilization device. Orthogonal and treatment angle diagnostic x‐ray images are taken prior to treatment and are compared with the treatment planning DRRs to reproduce the treatment position according to the plan. The titanium clips are used in the alignment process. At least two fields are treated each day delivering a daily dose of 4.0 cobalt Gray equivalent, and a total dose of 40 cobalt Gray equivalent in 10 fractions. Results: 60 patients have been treated so far. Immobilization procedure is highly reproducible. A comparison with a photon plan demonstrates the clear advantage of a protontreatment to spare the organs at risk, including a significant decrease in skindose.Conclusion: The immobilization procedure provides an accurate and reproducible breast positioning, and minimizes respiratory motion. The procedure has been well tolerated by most patients treated so far. Protons provide significant normal tissue sparing as compared to photontreatments and the clinical results look encouraging.

Purpose: To illustrate the use of patch field arrangements to treat geometrically complex tumors with proton beams. Method and Materials: One very important property of a high‐energy proton beam is the ease with which it can be stopped at a desired depth in a medium and the sharp distal dose fall‐off near the end of range. This leads to the creation of straightforward beam arrangements to treat very complex tumor shapes. One variation of these beam arrangements is the patch field arrangement. These patch field arrangements are a powerful tool in proton therapy planning. A geometrically complex tumor, e.g., one wrapped around a critical structure, can be treated by a patch field arrangement in which one beam, called a shoot‐through beam, irradiates a part of the tumor. Patching another beam from a different direction and distally stopping this beam on the lateral edge of the shoot‐through beam irradiates the tumor not treated by the shoot‐through beam. We will show how proton patch fields can be used to treat complex clinical cases. Results: We present two plans showing the use of proton patch fields to treat two clinical cases. These cases demonstrate the simplicity of the patch field beam arrangements and the ease with which critical structures can be conformally spared and tumors can be fully irradiated. In addition, these beam arrangements are quite simple to set up clinically. Conclusion: In any clinical practice, one is frequently faced with difficult cases in which tumors, because of their proximity to critical structures, can neither be fully resected nor can they be safely treated with conventional radiation.Proton irradiation, because of its superior dosimetric characteristics, offers treatment options for such cases.