• Journal of Life Science
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• v.34 no.7
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• pp.443-452
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• 2024

This study aimed to examine the influence of 3,6-anhydroxygalactose (L-AHG) on the pro-inflammatory M1 polarization and pro-inflammatory responses observed in the RAW264.7 mouse macrophage cell line following stimulation with lipopolysaccharides (LPS). L-AHG exhibited a significant and dose-dependent inhibition of inducible nitric oxide synthase (iNOS) expression, a hallmark of M1 polarization, and subsequent NO production in LPS-stimulated RAW264.7 cells. Furthermore, the LPS-induced upregulation of cyclooxygenase-2 (COX-2), which drives the production of prostaglandin E2, an inflammatory mediator, was also inhibited by L-AHG. L-AHG did not affect the LPS-triggered Toll-like receptor 4 (TLR4)-mediated pro-inflammatory signaling pathway, which culminated in the activation of transforming growth factor-β-activated kinase 1 (TAK1). However, it was observed to inhibit the generation of reactive oxugen species (ROS) in a dose-dependent manner, as well as the TAK1-driven activation of JNK and p38 MAPK. Given that the active p38 MAPK is known to contribute to the assembly of active nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes the intracellular generation of pro-inflammatory ROS in LPS-stimulated macrophages, the dose-dependent reduction in the LPS-induced ROS generation by L-AHG may be mainly due to the prevention of TAK1-driven activation of p38 MAPK. Together, these results demonstrate that the L-AHG-mediated inhibition of the TAK1-JNK/p38 MAPK activation phase of the pro-inflammatory signaling pathway in LPS-stimulated RAW264.7 cells by L-AHG represents a promising mechanism for suppressing M1 polarization and pro-inflammatory responses in macrophages.

• Journal of the Korean Society of Radiology
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• v.82 no.5
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• pp.1207-1217
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• 2021

Purpose To evaluate the safety and efficacy of ultrasound-guided percutaneous core needle biopsy (USPCB) of pancreatic and peripancreatic lesions adjacent to critical vessels. Materials and Methods Data were collected retrospectively from 162 patients who underwent USPCB of the pancreas (n = 98), the peripancreatic area adjacent to the portal vein, the paraaortic area adjacent to pancreatic uncinate (n = 34), and lesions on the third duodenal portion (n = 30) during a 10-year period. An automated biopsy gun with an 18-gauge needle was used for biopsies under US guidance. The USPCB results were compared with those of the final follow-up imaging performed postoperatively. The diagnostic accuracy and major complication rate of the USPCB were calculated. Multiple factors were evaluated for the prediction of successful biopsies using univariate and multivariate analyses. Results The histopathologic diagnosis from USPCB was correct in 149 (92%) patients. The major complication rate was 3%. Four cases of mesenteric hematomas and one intramural hematoma of the duodenum occurred during the study period. The following factors were significantly associated with successful biopsies: a transmesenteric biopsy route rather than a transgastric or transenteric route; good visualization of targets; and evaluation of the entire US pathway. In addition, the number of biopsies required was less when the biopsy was successful. Conclusion USPCB demonstrated high diagnostic accuracy and a low complication rate for the histopathologic diagnosis of pancreatic and peripancreatic lesions adjacent to critical vessels.

• Tuberculosis and Respiratory Diseases
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• v.44 no.4
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• pp.871-888
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• 1997

Background : It is now thought that the earliest manifestation of idiopathic pulmonary fibrosis is alveolitis, that is, an accumulation of inflammatory and immune effector cells within alveolar walls and spaces. Inflammatory cells including alveolar macrophages and resident normal pulmonary tissue cells participate through the release of many variable mediators such as inflammatory growth factors and cytokines, which contribute to tissue damage and finally cause chronic pulmonary inflammation and fibrosis. This study was performed to investigate the source and distribution pattern of transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), platelet derived growth factor(PDGF), basic fibroblast growth factor(bFGF), interleukin 1(IL-1), interleukin 6(IL-6), tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and the role of these mediators on bleomycin(BLM)-induced pulmonary injury and fibrosis in rats. Method : Wistar rats were divided into three groups(control group, BLM treated group, BLM and vitamine E treated group). Animals were sacrificed periodically at 1, 2, 3, 4, 5, 7, 14, 21, 28 days after saline or BLM administration. The effects were compared to the results of bronchoalveolar lavage fluid analysis, light microscopic findings, immunohistochemical stains for six different mediators(TGF-${\beta}_1$, PDGF, bFGF, IL-1, IL-6 and TNF-$\alpha$) and mRNA in situ hybridization for TGF-${\beta}_1$. Results : IL-1 and IL-6 are maximally expressed at postbleomycin 1~7th day which are mainly produced by neutrophils and bronchiolar epithelium. It is thought that they induce recruitment of inflammatory cells at the injury site. The expression of IL-1 and IL-6 at the bronchiolar epithelium within 7th day is an indirect evidence of contribution of bronchiolar epithelial cells to promote and maintain the inflammatory and immune responses adjacent to the airways. TNF-$\alpha$ is mainly produced by neutrophils and bronchiolar epithelial cells during 1~5th day, alveolar macrophages during 7~28th day. At the earlier period, TNF-$\alpha$ causes recruitment of inflammatory cells at the injury site and later stimulates pulmonary fibrosis. The main secreting cells of TGF-${\beta}_1$ are alveolar macrophages and bronchiolar epithelium and the target is pulmonary fibroblasts and extracellular matrix. TGF-${\beta}_1$ and PDGF stimulate proliferation of pulmonary fibroblasts and TGF-${\beta}_1$ and bFGF incite the fibroblasts to produce extracellular matrix. The vitamine E and BLM treated group shows few positive cells(p<0.05). Conclusion : After endothelial and epithelial injury, the neutrophils and bronchiolar epithelium secrete IL-1, IL-6, TNF-$\alpha$ which induce infiltration of many neutrophils. It is thought that variable enzymes and $O_2$ radicals released by these neutrophils cause destruction of normal lung architecture and progression of pulmonary fibrosis. At the 7~28th day, TGF-${\beta}_1$, PDGF, bFGF, TNF-$\alpha$ secreted by alveolar macrophages sting pulmonary fibroblasts into proliferating with increased production of extracellular matrix and finally, they make progression of pulmonary fibrosis. TNF-$\alpha$ compares quite important with TGF-${\beta}_1$ to cause pulmonary fibrosis. Vitamine E seems to decrease the extent of BLM induced pulmonary fibrosis.

• Nuclear Medicine and Molecular Imaging
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• v.42 no.3
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• pp.235-245
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• 2008

Purpose: The HSV1-tk gene has been extensively studied as a type of reporter gene. In hepatocellular carcinoma (HCC), only a small proportion of patients are eligible for surgical resection and there is limitation in palliative options. Therefore, there is a need for the development of new treatment modalities and gene therapy is a leading candidate. In the present study, we investigated the usefulness of substrate, 2'-fluoro-2'-deoxy-1-${\beta}$-D-arabino-furanosyi-5-[$^{124/125}I$]iodo- uracil ([$I^{124/125}I$]FIAU) as a non-invasive imaging agent for HSV1-tk gene therapy in hepatoma model using small animal PET. Material and Methods: With the Morris hepatoma MCA cell line and MCA-tk cell line which was transduced with the HSV1-tk gene, in vitro uptake and correlation study between [$^{125}I$]FIAU uptake according to increasing numeric count of percentage of MCA-tk cell were performed. The biodistribution data and small animal PET images with [$^{124}I$]FIAU were obtained with Balb/c-nude mice bearing both MCA and MCA-tk tumors. Results:, Specific accumulation of [[$^{125}I$]FIAU was observed in MCA-tk cells but uptake was low in MCA cells. Uptake in MCA-tk cells was 15 times higher than that of MCA cells at 480 min. [$^{125}I$]FIAU uptake was linearly correlated (R2 =0.964, p =0.01) with increasing percentage of MCA-tk numeric cell count. Biodistribution results showed that [$^{125}I$]FIAU was mainly excreted via the renal system in the early phase. Ratios of MCA-tk tumor to blood acting were 10, 41, and 641 at 1 h, 4 h, and 24 h post-injection, respectively. The maximum ratio of MCA-tk to MCA tumor was 192.7 at 24 h. Ratios of MCA-tk tumor to liver were 13.8, 66.8, and 588.3 at 1 h, 4 h, and 24 h, respectively. On small animal PET, [$^{124}I$]FIAU accumulated in substantial higher levels in MCA-tk tumor and liver than MCA tumor. Conclusion: FIAU shows selective accumulation to HSV1-tk expressing hepatoma cell tumors with minimal uptake in normal liver. Therefore, radiolabelled FIAU is expected to be a useful substrate for non-invasive imaging of HSV1-tk gene therapy and therapeutic response monitoring of HCC.

• Radiation Oncology Journal
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• v.20 no.1
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• pp.41-52
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• 2002

Purpose : 3D conformal radiotherapy, the optimum dose delivered to the tumor and provided the risk of normal tissue unless marginal miss, was restricted by organ motion. For tumors in the thorax and abdomen, the planning target volume (PTV) is decided including the margin for movement of tumor volumes during treatment due to patients breathing. We designed the respiratory gating radiotherapy device (RGRD) for using during CT simulation, dose planning and beam delivery at identical breathing period conditions. Using RGRD, reducing the treatment margin for organ (thorax or abdomen) motion due to breathing and improve dose distribution for 3D conformal radiotherapy. Materials and Methods : The internal organ motion data for lung cancer patients were obtained by examining the diaphragm in the supine position to find the position dependency. We made a respiratory gating radiotherapy device (RGRD) that is composed of a strip band, drug sensor, micro switch, and a connected on-off switch in a LINAC control box. During same breathing period by RGRD, spiral CT scan, virtual simulation, and 3D dose planing for lung cancer patients were peformed, without an extended PTV margin for free breathing, and then the dose was delivered at the same positions. We calculated effective volumes and normal tissue complication probabilities (NTCP) using dose volume histograms for normal lung, and analyzed changes in doses associated with selected NTCP levels and tumor control probabilities (TCP) at these new dose levels. The effects of 3D conformal radiotherapy by RGRD were evaluated with DVH (Dose Volume Histogram), TCP, NTCP and dose statistics. Results : The average movement of a diaphragm was 1.5 cm in the supine position when patients breathed freely. Depending on the location of the tumor, the magnitude of the PTV margin needs to be extended from 1 cm to 3 cm, which can greatly increase normal tissue irradiation, and hence, results in increase of the normal tissue complications probabiliy. Simple and precise RGRD is very easy to setup on patients and is sensitive to length variation (+2 mm), it also delivers on-off information to patients and the LINAC machine. We evaluated the treatment plans of patients who had received conformal partial organ lung irradiation for the treatment of thorax malignancies. Using RGRD, the PTV margin by free breathing can be reduced about 2 cm for moving organs by breathing. TCP values are almost the same values $(4\~5\%\;increased)$ for lung cancer regardless of increasing the PTV margin to 2.0 cm but NTCP values are rapidly increased $(50\~70\%\;increased)$ for upon extending PTV margins by 2.0 cm. Conclusion : Internal organ motion due to breathing can be reduced effectively using our simple RGRD. This method can be used in clinical treatments to reduce organ motion induced margin, thereby reducing normal tissue irradiation. Using treatment planning software, the dose to normal tissues was analyzed by comparing dose statistics with and without RGRD. Potential benefits of radiotherapy derived from reduction or elimination of planning target volume (PTV) margins associated with patient breathing through the evaluation of the lung cancer patients treated with 3D conformal radiotherapy.

• Radiation Oncology Journal
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• v.29 no.2
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• pp.91-98
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• 2011

Purpose: To assess the usefulness of implanted fiducial markers in the setup of hypofractionated radiotherapy for prostate cancer patients by comparing a fiducial marker matched setup with a pelvic bone match. Materials and Methods: Four prostate cancer patients treated with definitive hypofractionated radiotherapy between September 2009 and August 2010 were enrolled in this study. Three gold fiducial markers were implanted into the prostate and through the rectum under ultrasound guidance around a week before radiotherapy. Glycerin enemas were given prior to each radiotherapy planning CT and every radiotherapy session. Hypofractionated radiotherapy was planned for a total dose of 59.5 Gy in daily 3.5 Gy with using the Novalis system. Orthogonal kV X-rays were taken before radiotherapy. Treatment positions were adjusted according to the results from the fusion of the fiducial markers on digitally reconstructed radiographs of a radiotherapy plan with those on orthogonal kV X-rays. When the difference in the coordinates from the fiducial marker fusion was less than 1 mm, the patient position was approved for radiotherapy. A virtual bone matching was carried out at the fiducial marker matched position, and then a setup difference between the fiducial marker matching and bone matching was evaluated. Results: Three patients received a planned 17-fractionated radiotherapy and the rest underwent 16 fractionations. The setup error of the fiducial marker matching was $0.94{\pm}0.62$ mm (range, 0.09 to 3.01 mm; median, 0.81 mm), and the means of the lateral, craniocaudal, and anteroposterior errors were $0.39{\pm}0.34$ mm, $0.46{\pm}0.34$ mm, and $0.57{\pm}0.59$ mm, respectively. The setup error of the pelvic bony matching was $3.15{\pm}2.03$ mm (range, 0.25 to 8.23 mm; median, 2.95 mm), and the error of craniocaudal direction ($2.29{\pm}1.95$ mm) was significantly larger than those of anteroposterior ($1.73{\pm}1.31$ mm) and lateral directions ($0.45{\pm}0.37$ mm), respectively (p<0.05). Incidences of over 3 mm and 5 mm in setup difference among the fractionations were 1.5% and 0% in the fiducial marker matching, respectively, and 49.3% and 17.9% in the pelvic bone matching, respectively. Conclusion: The more precise setup of hypofractionated radiotherapy for prostate cancer patients is feasible with the implanted fiducial marker matching compared with the pelvic bony matching. Therefore, a less marginal expansion of planning target volume produces less radiation exposure to adjacent normal tissues, which could ultimately make hypofractionated radiotherapy safer.

• Tuberculosis and Respiratory Diseases
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• v.45 no.3
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• pp.553-564
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• 1998

Background: The immediate hoot response to LPS is the production of proinflammatory cytokines that act as intercellular mediators in inflammatory reactions, including acute lung injury. These "early response" cytokines transmit signals from recognition cells to target or effector cells. This host response is further amplified by the expression of leukocyte chemoattractants, growth factors, and adhesion molecules, resulting in an array of proinflammatory events. This experiment was performed to define the lung origin of proinflammatory cytokines, such as TNF-$\alpha$, IL 6 in early periods of endotoxin induced acute lung injury (ALI). Method: The healthy male Sprague-Dawley, weighted 150 - 250g, were divided into saline control (NC) and endotoxemia-induced ALI (ETX-), and leukopenic endotoxemia-induced ALI (CPA-ETX-Group) which was induced by cyclophosphamide, 70 mg/kg i.p. injection. Acute lung injury was evoked by LPS, 5 mg/kg, intravenously administered. Bronchoalveolar lavage was performed at 0, 3, 6 h after LPS-treated to estimate the influx of phagocytes and concentration of total protein, and cytokines as TNF-$\alpha$ and IL 6 by a bioassy using MIT method. We also examined the localization of TNF-$\alpha$ and IL 6 protein in endotoxemia-challenged lung tissue by immunohistochemical stain (IH). Results: The total cell, macrophage and PMN count in BALF were elavated in ETX group compared to NC(p<0.05). In CPA-ETX group, total cell and macrophage count in BALF were not changed compared to NC. but PMN count was markedly reduced and it took part in less than 0.1 % of total BAL cells (p<0.01). The protein concentration in BALF were significantly increased in ETX and CPA-ETX group Compared to NC (p<0.05), but there was significant difference between ETX- and CPA-ETX group only at 6 h (p<0.05). This observation suggested that even if PMNs are involved in the pathogenesis of acute lung injury, their role cannot be viewed as essential The concentration of TNF-$\alpha$ and IL 6 in BALF was significantly increased in the ETX- and CPA-ETX group compared to NC. There was no difference between ETX- and CPA-ETX group. In IH, anti-TNF-$\alpha$- and anti-IL 6 antibody was strongly localized at interstitial monocytes and alveolar macrophages in endotoxemia-challenged lung tissue. From above point of view, activated alveolar macrophage/monocyte considered as a prominent source of proinflammatory cytokines in endotoxemia-challenged lung injury. Conclusion: The prominent source of proinflammatory cytokines in early periods of endotoxemia-induced lung injury will be the activated resident macrophages like an alveolar macrophage and interstitial monocytes. The pulmonary macrophage/monocyte will impact the initiation and continuance of lung injury without PMNs's certain inflammatory role, particularly in endotoxemia-induced acute lung injury.

• The Journal of Korean Society for Radiation Therapy
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• v.24 no.2
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• pp.123-135
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• 2012

Purpose: It is essential to minimize the movement of tumor due to respiratory movement at the time of respiration controlled radiotherapy of non-small cell lung cancer patient. Accordingly, this Study aims to evaluate the usefulness of restricted respiratory period by comparing and analyzing the treatment plans that apply free and restricted respiration period respectively. Materials and Methods: After having conducted training on 9 non-small cell lung cancer patients (tumor n=10) from April to December 2011 by using 'signal monitored-breathing (guided- breathing)' method for the 'free respiratory period' measured on the basis of the regular respiratory period of the patents and 'restricted respiratory period' that was intentionally reduced, total of 10 CT images for each of the respiration phases were acquired by carrying out 4D CT for treatment planning purpose by using RPM and 4-dimensional computed tomography simulator. Visual gross tumor volume (GTV) and internal target volume (ITV) that each of the observer 1 and observer 2 has set were measured and compared on the CT image of each respiratory interval. Moreover, the amplitude of movement of tumor was measured by measuring the center of mass (COM) at the phase of 0% which is the end-inspiration (EI) and at the phase of 50% which is the end-exhalation (EE). In addition, both observers established treatment plan that applied the 2 respiratory periods, and mean dose to normal lung (MDTNL) was compared and analyzed through dose-volume histogram (DVH). Moreover, normal tissue complication probability (NTCP) of the normal lung volume was compared by using dose-volume histogram analysis program (DVH analyzer v.1) and statistical analysis was performed in order to carry out quantitative evaluation of the measured data. Results: As the result of the analysis of the treatment plan that applied the 'restricted respiratory period' of the observer 1 and observer 2, there was reduction rate of 38.75% in the 3-dimensional direction movement of the tumor in comparison to the 'free respiratory period' in the case of the observer 1, while there reduction rate was 41.10% in the case of the observer 2. The results of measurement and comparison of the volumes, GTV and ITV, there was reduction rate of $14.96{\pm}9.44%$ for observer 1 and $19.86{\pm}10.62%$ for observer 2 in the case of GTV, while there was reduction rate of $8.91{\pm}5.91%$ for observer 1 and $15.52{\pm}9.01%$ for observer 2 in the case of ITV. The results of analysis and comparison of MDTNL and NTCP illustrated the reduction rate of MDTNL $3.98{\pm}5.62%$ for observer 1 and $7.62{\pm}10.29%$ for observer 2 in the case of MDTNL, while there was reduction rate of $21.70{\pm}28.27%$ for observer 1 and $37.83{\pm}49.93%$ for observer 2 in the case of NTCP. In addition, the results of analysis of correlation between the resultant values of the 2 observers, while there was significant difference between the observers for the 'free respiratory period', there was no significantly different reduction rates between the observers for 'restricted respiratory period. Conclusion: It was possible to verify the usefulness and appropriateness of 'restricted respiratory period' at the time of respiration controlled radiotherapy on non-small cell lung cancer patient as the treatment plan that applied 'restricted respiratory period' illustrated relative reduction in the evaluation factors in comparison to the 'free respiratory period.

• The Journal of Korean Society for Radiation Therapy
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• v.25 no.1
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• pp.1-8
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• 2013

Purpose: A selection of proper energy in treatment planning is very important because of having different dose distribution in body as photon energy. In generally, the low energy photon has been used in intensity-modulated radiation therapy (IMRT) for head and neck (H&N) cancer. The aim of this study was to evaluate the effect of partially used high energy photon at posterior oblique fields on IMRT plan for H&N cancer. Materials and Methods: The study was carried out on 10 patients (nasopharyngeal cancer 5, tonsilar cancer 5) treated with IMRT in Seoul National University Bundang Hospital. CT images were acquired 3 mm of thickness in the same condition and the treatment plan was performed by Eclipse (Ver.7.1, Varian, Palo Alto, USA). Two plans were generated under same planing objectives, dose volume constraints, and eight fields setting: (1) The low energy plan (LEP) created using 6 MV beam alone, (2) the partially used high energy plan (PHEP) created partially using 15 MV beam at two posterior oblique fields with deeper penetration depths, while 6 MV beam was used at the rest of fields. The plans for LEP and PHEP were compared in terms of coverage, conformity index (CI) and homogeneity index (HI) for planning target volume (PTV). For organs at risk (OARs), $D_{mean}$ and $D_{50%}$ were analyzed on both parotid glands and $D_{max}$, $D_{1%}$ for spinal cord were analyzed. Integral dose (ID) and total monitor unit (MU) were compared as addition parameters. For the comparing dose to normal tissue of posterior neck, the posterior-normal tissue volume (P-NTV) was set on the patients respectively. The $D_{mean}$, $V_{20Gy}$ and $V_{25Gy}$ for P-NTV were evaluated by using dose volume histogram (DVH). Results: The dose distributions were similar with regard to coverage, CI and HI for PTV between the LEP and PHEP. No evident difference was observed in the spinal cord. However, the $D_{mean}$, $D_{50%}$ for both parotid gland were slightly reduced by 0.6%, 0.7% in PHEP. The ID was reduced by 1.1% in PHEP, and total MU for PHEP was 1.8% lower than that for LEP. In the P-NTV, the $D_{mean}$, $V_{20Gy}$ and $V_{25Gy}$ of the PHEP were 1.6%, 1.8% and 2.9% lower than those of LEP. Conclusion: Dose to some OARs and a normal tissue, total monitor unit were reduced in IMRT plan with partially used high energy photon. Although these reduction are unclear how have a clinical benefit to patient, application of the partially used high energy photon could improve the overall plan quality of IMRT for head and neck cancer.

• Progress in Medical Physics
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• v.27 no.2
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• pp.64-71
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• 2016

We develop a manufacture procedure for the production of a patient specific customized bolus (PSCB) using a 3D printer (3DP). The dosimetric accuracy of the 3D-PSCB is evaluated for electron beam therapy. In order to cover the required planning target volume (PTV), we select the proper electron beam energy and the field size through initial dose calculation using a treatment planning system. The PSCB is delineated based on the initial dose distribution. The dose calculation is repeated after applying the PSCB. We iteratively fine-tune the PSCB shape until the plan quality is sufficient to meet the required clinical criteria. Then the contour data of the PSCB is transferred to an in-house conversion software through the DICOMRT protocol. This contour data is converted into the 3DP data format, STereoLithography data format and then printed using a 3DP. Two virtual patients, having concave and convex shapes, were generated with a virtual PTV and an organ at risk (OAR). Then, two corresponding electron treatment plans with and without a PSCB were generated to evaluate the dosimetric effect of the PSCB. The dosimetric characteristics and dose volume histograms for the PTV and OAR are compared in both plans. Film dosimetry is performed to verify the dosimetric accuracy of the 3D-PSCB. The calculated planar dose distribution is compared to that measured using film dosimetry taken from the beam central axis. We compare the percent depth dose curve and gamma analysis (the dose difference is 3%, and the distance to agreement is 3 mm) results. No significant difference in the PTV dose is observed in the plan with the PSCB compared to that without the PSCB. The maximum, minimum, and mean doses of the OAR in the plan with the PSCB were significantly reduced by 9.7%, 36.6%, and 28.3%, respectively, compared to those in the plan without the PSCB. By applying the PSCB, the OAR volumes receiving 90% and 80% of the prescribed dose were reduced from $14.40cm^3$ to $0.1cm^3$ and from $42.6cm^3$ to $3.7cm^3$, respectively, in comparison to that without using the PSCB. The gamma pass rates of the concave and convex plans were 95% and 98%, respectively. A new procedure of the fabrication of a PSCB is developed using a 3DP. We confirm the usefulness and dosimetric accuracy of the 3D-PSCB for the clinical use. Thus, rapidly advancing 3DP technology is able to ease and expand clinical implementation of the PSCB.