Retrospective dose reconstruction of prostate stereotactic body radiotherapy using cone-beam CT and a log file during VMAT delivery with flattening-filter-free mode.

This study aimed to reconstruct the dose distribution of single fraction of stereotactic body radiotherapy for patients with prostate cancer using cone-beam computed tomography (CBCT) and a log file during volumetric-modulated arc therapy (VMAT) delivery with flattening-filter-free (FFF) mode. Twenty patients with clinically localized prostate cancer were treated with FFF-VMAT, and projection images for in-treatment CBCT (iCBCT) imaging were concomitantly acquired with a log file. A D95 dose of 36.25 Gy in five fractions was prescribed to each planning target volume (PTV) on each treatment planning CT (pCT). Deformed pCT (dCT) was obtained from the iCBCT using a hybrid deformable image registration algorithm. Dose distributions on the dCT were calculated using Pinnacle3 v9.10 by converting the log file data to Pinnacle3 data format using an in-house software. Dose warping was performed by referring to deformation vector fields calculated from pCT and dCT. Reconstructed dose distribution was compared with that of the original plan. Dose differences between the original and reconstructed dose distributions were within 3% at the isocenter and observed in PTV and organ-at-risk (OAR) regions. Differences in OAR regions were relatively larger than those in the PTV, presumably because OARs were more deformed than the PTV. Therefore, our method can be used successfully to reconstruct the dose distributions of one fraction using iCBCT and a log file during FFF-VMAT delivery.

Identification of protein arginine N-methyltransferase 5 (PRMT5) as a novel interacting protein with the tumor suppressor protein RASSF1A.

The candidate tumor suppressor gene RASSF1A (Ras-association domain family 1, isoform A) is inactivated in many types of adult and childhood cancers. However, the mechanisms by which RASSF1A exerts tumor suppressive functions have yet to be elucidated. In this report, we sought to identify candidate proteins that interact with RASSF1A using proteomic screening. Using peptide mass fingerprinting, we identified protein arginine N-methyltransferase 5 (PRMT5), a type II protein arginine N-methyltransferase that monomethylates and symmetrically dimethylates arginine residues, as a novel protein that interacts with RASSF1A. The association between the two proteins was confirmed by co-immunoprecipitation and immunofluorescence staining. Co-expressing RASSF1A and PRMT5 led to a redistribution of PRMT5 from the cytosol to stabilized microtubules, where RASSF1A and PRMT5 became co-localized. Our results demonstrate that PRMT5 translocates to bundled microtubules on stabilization by RASSF1A expression. Our results show that the tumor suppressor RASSF1A interacts with PRMT5 in vivo and in vitro. Notably, this is the first demonstration of RASSF1A-dependent microtubule recruitment of PRMT5, suggesting a novel role for RASSF1A in the anchoring of cytosolic PRMT5 to microtubules.

[Dose reconstruction using respiratory signals and machine parameters during treatment in stereotactic body radiotherapy].

PURPOSE: Volumetric modulated arc therapy (VMAT) is a rotational intensity-modulated radiotherapy (IMRT) technique capable of acquiring projection images during treatment. The purpose of this study was to reconstruct the dose distribution from respiratory signals and machine parameters acquired during stereotactic body radiotherapy (SBRT). METHODS: The treatment plans created for VMAT-SBRT included the constraint of 1 mm/degree in multileaf collimator (MLC) for a moving phantom and three patients with lung tumors. The respiratory signals were derived from projection images acquired during VMAT delivery, while the machine parameters were derived from machine logs. The respiratory signals and machine parameters were then linked along with the gantry angle. With this data, the dose distribution of each respiratory phase was calculated on the planned four-dimensional CT (4D CT). The doses at the isocenter, the point of max dose and the centroid of the target were compared with those of the corresponding plans. RESULTS AND DISCUSSION: In the phantom study, the maximum dose difference between the plan and "in-treatment" results was -0.4% at the centroid of the target. In the patient study, the difference was -1.8 ± 0.4% at the centroid of the target. Dose differences of the evaluated points between 4 and 10 phases were not significant. CONCLUSION: The present method successfully reconstructed the dose distribution using the respiratory signals and machine parameters acquired during treatment. This is a feasible method for verifying the actual dose for a moving target.

[Winston-lutz test and acquisition of flexmap using rotational irradiation].

PURPOSE: IGRT (image guided radiation therapy) is a useful technique for implementing precisely targeted radiation therapy. Quality assurance and quality control (QA/QC) medical linear accelerators with a portal imaging system (electronic portal imaging device: EPID) are the key to ensuring safe IGRT. The Winston-Lutz test (WLT) provides an evaluation of the MV isocenter, which is the intersection of radiation, collimator, and couch isocenters. A flexmap can indicate a displacement of EPID from the beam center axis as a function of gantry angles which can be removed from the images. The purpose of this study was to establish a novel method for simultaneously carrying out WLT and acquiring a flexmap using rotational irradiation. We also observed long-term changes in flexmaps over a period of five months. METHOD: We employed rotational irradiation with a rectangular field (30×30 mm). First, the displacement of EPID from the beam center axis, indicated by the ball bearing (BB) center, was evaluated using an in-house program. The location of the BB center was then modified according to WLT. Second, a second irradiation was used to acquire a flexmap. We performed this examination regularly and evaluated long-term changes in the flexmap. RESULTS AND DISCUSSION: It proved feasible to perform WLT and flexmap measurements using our proposed methods. The precision of WLT using rotational irradiation was 0.1 mm. In flexmap analysis, the maximum displacement from the mean value for each angle was 0.4 mm over five months. CONCLUSION: We have successfully established a novel method of simultaneously carrying out WLT and flexmap acquisition using rotational irradiation. Maximum displacement from the mean in each angle was 0.4 mm over five months.

Individually wide range of renal motion evaluated by four-dimensional computed tomography.

OBJECTIVES: Assessment of physiologic renal motion in order to optimize abdominal intensity-modulated radiation therapy and stereotactic body radiation therapy. METHODS AND MATERIALS: Twenty patients with a median age of 47 years underwent computed tomography simulation and four-dimensional computed tomography acquisition. Thirty-nine kidneys were contoured during ten phases of respiration to estimate renal motion. RESULTS: Kidney motion was not related to age (p = 0.42), sex (p = 0.28), height (p = 0.75), or body weight (p = 0.63). The average +/- standard deviation (SD) of movement of the center of gravity for all subjects was 11.1 +/- 4.8 mm in the cranio-caudal (CC) direction (range, 2.5-20.5 mm), 3.6 +/- 2.1 mm in the anterior-posterior (AP) direction (range, 0.6-8.0 mm), and 1.7 +/- 1.4 mm in the right-left (RL) direction (range, 0.4-5.9 mm). Renal motion strongly correlated with the respiratory phases (r > 0.97 and p < 0.01 in all three directions). CONCLUSIONS: Renal motion was independent of age, sex, height, or body weight. Renal motion in all directions was strongly respiration dependent, but motion in the cranio-caudal direction showed wide individual variation. In a clinical setting, it will be necessary to evaluate renal respiratory motion separately in each individual.

[Multidisciplinary medical care in radiation oncology].

Multidisciplinary medical care is now needed in the clinical setting of cancer treatment. In Japan, radiotherapy technologists and nurses have long played an important role in radiation oncology departments in many hospitals, resulting in spontaneously-arising multidisciplinary medical care teams. Multidisciplinary medical care, in which many medical staff work together on an equal footing, is based on multidisciplinary conferences, interdisciplinary communications, and most of all, doctors' decisions to transfer important daily work to paramedicals. The newly-introduced consultation fee for outpatient radiotherapy is a special charge for radiotherapy patients. To charge this fee, daily observation of patients by technologists or nurses is required, a practice which promotes multidisciplinary medical care in the field of radiation oncology. The number of technologists and nurses who specialize in radiation oncology has been increasing in recent years. When hospitals allow them to devote their specialized knowledge and skills entirely to radiation oncology practice, multidisciplinary medical care will develop within the clinical practice of radiation oncology.

4D registration and 4D verification of lung tumor position for stereotactic volumetric modulated arc therapy using respiratory-correlated cone-beam CT.

We propose a clinical workflow of stereotactic volumetric modulated arc therapy (VMAT) for a lung tumor from planning to tumor position verification using 4D planning computed tomography (CT) and 4D cone-beam CT (CBCT). A 4D CT scanner, an Anzai belt and a BodyFix were employed to obtain 10-phase respiratory-correlated CT data for a lung patient under constrained breathing conditions. A planning target volume (PTV) was defined by adding a 5-mm margin to an internal target volume created from 10 clinical target volumes, each of which was delineated on each of the 10-phase planning CT data. A single-arc VMAT plan was created with a D(95) prescription dose of 50 Gy in four fractions on the maximum exhalation phase CT images. The PTV contours were exported to a kilovoltage CBCT X-ray Volume Imaging (XVI) equipped with a linear accelerator (linac). Immediately before treatment, 10-phase 4D CBCT images were reconstructed leading to animated lung tumor imaging. Initial bone matching was performed between frame-averaged 4D planning CT and frame-averaged 4D CBCT datasets. Subsequently, the imported PTV contours and the animated moving tumor were simultaneously displayed on the XVI monitor, and a manual 4D registration was interactively performed on the monitor until the moving tumor was symmetrically positioned inside the PTV. A VMAT beam was delivered to the patient and during the delivery further 4D CBCT projection data were acquired to verify the tumor position. The entire process was repeated for each fraction. It was confirmed that the moving tumor was positioned inside the PTV during the VMAT delivery.

[Motion analysis of target during stereotactic radiotherapy of lung tumors using volumetric modulated arc therapy].

Volumetric modulated arc therapy (VMAT) is a rotational intensity-modulated radiotherapy (IMRT) technique capable of acquiring projection images for cone-beam computed tomography (CBCT). Respiratory-correlated cone-beam computed tomography, namely 4D-CBCT, serves to assess the displacement of a tumor position between planning and treatment due to organ motion and respiration, and is important for more accurate radiation therapy. On the other hand, recently, a 320-detector row CT scanner, namely 4D-CT, has become available that allows axial volumetric scanning of a 16-cm-long range in a patient without table movement. The goal of our research is to establish a new method of verification during treatment in stereotactic body radiotherapy. In this study, we compare the movement of the tumor between "before treatment" using 4D-CT and "in treatment" using 4D-CBCT. Three patients (55-68 years of age) with lung tumors underwent CT scans for radiotherapy planning using 4D-CT scans to analyze the movement of the tumor before treatment. The patients were treated by VMAT while acquiring projection images. 4D-CBCT datasets were reconstructed from the projection images using in-house programs. The tumor positions in 4D-CT and 4D-CBCT were detected and the movement of the tumor between "before treatment" and "in treatment" was similar. The movement of the tumors during treatment was predictable from 4D-CT before treatment. Furthermore, 4D-CBCT clarified the tumor position during treatment and could reevaluate the actual tumor position and dose distribution. We have successfully shown the movement of the tumor between "before treatment" using 4D-CT and "in treatment" using 4D-CBCT.

[Motion analysis of target in stereotactic radiotherapy of lung tumors using 320-row multidetector CT].

Multi-detector computed tomography (MDCT) has rapidly evolved and is increasingly used for treatment simulation of thoracic and abdominal radiotherapy. A 320-detector row CT scanner has recently become available that allows axial volumetric scanning of a 16-cm-long range in a patient without table movement. Current radiotherapy techniques require a generous margin around the presumed gross tumor volume (GTV) to account for uncertainties such as tumor motion and set up error. Motion analysis is useful to evaluate the internal margin of a moving target due to respiration and to improve therapeutic precision. The purpose of this study is to propose a method using phase-only correlation to automatically detect the target and to assess the motion of the target in numerical phantoms and patients. Free-breathing scans using 320-detector row CT were acquired for 4 patients with lung tumor(s). The proposed method was feasible for motion analysis of all numerical phantoms and patients. The results reproduced the facts that the motion of tumors in the patients varied in orbits during the respiratory cycle and exhibited hysteresis. The maximum distance between peak exhalation and inhalation increased as the tumors approached the diaphragm. The proposed method detected the three-dimensional position of the targets automatically and analyzed the trajectories. The tumor motion due to respiration differed by region and was greatest for the lower lobe.

Verification of in-treatment tumor position using kilovoltage cone-beam computed tomography: a preliminary study.

Three-dimensional tumor position during rotational dose delivery was evaluated by acquiring in-treatment kilovoltage (kV) cone-beam CT (CBCT) to ensure treatment quality. The CBCT projection data of a phantom were acquired during rotational megavoltage (MV) dose delivery up to 6 Gy to evaluate image quality under MV beam irradiation. A lung tumor patient was treated with a total dose of 48 Gy in four fractions, each fraction including seven coplanar and noncoplanar beams, as well as a full-angle rotational beam. Tumor registration was performed between a planning CT image and a CBCT image immediately after patient setup. The patient couch was adjusted according to the registration results, and then the registration was repeated three times: immediately before treatment, during treatment, and immediately after treatment. The phantom image quality of the kV CBCT was not visually degraded up to the rotational MV dose of 6 Gy. Tumor position during rotational dose delivery was verified for the first time using kV CBCT.

Haloperidol is an inhibitor but not substrate for MDR1/P-glycoprotein.

The involvement of the multidrug resistant transporter MDR1/P-glycoprotein in the penetration of haloperidol into the brain and absorption in the intestine was investigated to examine its role in inter/intra-individual variability, using the porcine kidney epithelial cell line LLC-PK(1) and its MDR1-overexpressing transfectant, LLC-GA5-COL150. The inhibitory effect of haloperidol on other MDR1 substrates was also investigated in terms of the optimization of haloperidol-based pharmacotherapy. The transepithelial transport of [(3)H]haloperidol did not differ between the two cell lines, and vinblastine, a typical MDR1 substrate, had no effect on the transport, suggesting that haloperidol is not a substrate for MDR1, and it is unlikely that MDR function affects haloperidol absorption and brain distribution, and thereby the response to haloperidol. However, haloperidol was found to have an inhibitory effect on the MDR1-mediated transport of [(3)H]digoxin and [(3)H]vinblastine with an IC50 value of 7.84+/-0.76 and 3.60+/-0.64 microM, respectively, suggesting that the intestinal absorption, not distribution into the brain, of MDR1 substrate drugs could be altered by the co-administration of haloperidol in the clinical setting, although further clinical studies are needed.

Nucleotide sequence of the p53 cDNA of beluga whale (Delphinapterus leucas).

The cDNA (DNA complementary to RNA) of the p53 gene of the beluga whale (Delphinapterus leucas) was sequenced by the method of 5'- and 3'-rapid amplification of cDNA ends (RACE) with the cDNA made for the RNA obtained from fresh peripheral blood leukocytes isolated from two animals. Primers for the RACE method were synthesized based on the sequence of the DNA of beluga whale corresponding to exon 5 of the human p53 gene, which was determined after amplification of the DNA isolated from the liver from a beluga whale by using a pair of primers for the human sequence. The sequenced cDNA had a 2150-nucleotide length and contained the whole region corresponding to human exons 1 through 11. The reading frame was 1164 bp (base pair) long and began in exon 2 and ended in exon 11, coding for a 387-amino acid protein. The nucleotide sequence of the reading frame showed high similarity over 85% with pig, sheep, cow, and human genes. The similarities with the former two animals at the amino acid level were also more than 85%. Lower similarity of the beluga whale p53 gene was also found with those of lower tetrapods, fish and invertebrates.