Publications by authors named "Naoki Miyamoto"

74 Publications

Diagnosis of visceral pleural invasion using confocal laser endomicroscopy during lung cancer surgery.

J Thorac Dis 2021 Aug;13(8):4742-4752

Department of Thoracic, Endocrine Surgery and Oncology, Tokushima University Graduate School of Biomedical Sciences, Kuramotocho, Tokushima, Japan.

Background: Visceral pleural invasion (VPI) in lung cancer is a significant prognostic factor; however, it is difficult to diagnose preoperatively or intraoperatively. In this study, we examined the possibility of intraoperative diagnosis of VPI using confocal laser endomicroscopy (CLE).

Methods: Among patients with primary lung cancer who underwent surgery between April 2018 and August 2019, those in whom the tumor was in contact with the pleura on chest computed tomography and whose pleural changes were intraoperatively confirmed were enrolled in this study. In the 35 patients who underwent lung resection (6 cases with visceral pleural infiltration), the area where pleural change was noted was observed and a short video was recorded using CLE. Based on the video images, three evaluators determined the defect ratio (0%, 25%, 50%, 75%, and 100%) of the autofluorescence-positive structure. The area under the receiver operating characteristic curve was used to evaluate the diagnostic performance for VPI. In 15 cases (3 cases with VPI), a validation study was performed for intraoperative VPI according to the cutoff value of the defect ratio of the autofluorescence-positive structure.

Results: The areas under the receiver operating characteristic curve for the defect ratio of the autofluorescence-positive structure were 0.86-0.91 for the three readers. Using defect ratio of autofluorescence-positive structure cutoff of ≥50% as predictor of VPI, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 83.3-100.0%, 57.7-73.1%, 35.3-41.7%, 95.0-100.0%, and 75.0-78.1%, respectively, for the three readers. In the validation study, the sensitivity was 100%, the specificity was 83.3%, and the diagnostic accuracy rate was 86.7%.

Conclusions: The diagnosis of VPI through CLE is simple, non-invasive, and has high diagnostic accuracy rates. This method may be applicable for determining surgical procedures.
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http://dx.doi.org/10.21037/jtd-21-137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411182PMC
August 2021

Hypervascularized bronchial arteries as a risk factor for intraoperative bleeding and prolonged surgery.

J Thorac Dis 2021 Aug;13(8):4731-4741

Department of Thoracic, Endocrine Surgery and Oncology, Tokushima University Graduate School of Biomedical Sciences, Kuramotocho, Tokushima, Japan.

Background: The present study investigated whether highly vascularized bronchial arteries affect the intraoperative blood loss and the operative time of video-assisted thoracic surgery (VATS) lobectomy for patients with non-small cell lung cancer. We retrospectively collected data on consecutive pathological stage I to IIIA non-small cell lung cancer patients who underwent VATS lobectomy with systematic lymph node dissection between January 2017 and December 2019. Patients were divided into the following two groups according to bronchial artery diameters on preoperative enhanced contrast computed tomography (CT) findings: ≤2 and >2 mm groups.

Results: Among the 175 patients enrolled, risk factors for intraoperative blood loss >50 mL were being male (P=0.005), a history of smoking (P=0.01), percent forced expiratory volume in 1 s (FEV1.0%) <70% (P=0.012), squamous cell carcinoma (P=0.049), and a bronchial artery diameter >2.0 mm (P<0.001) in the unadjusted analysis, and a bronchial artery diameter >2.0 mm (P<0.001) in the multivariable analysis. Risk factors for an operative time >200 min were being male (P<0.001), a history of smoking (P=0.007), FEV1.0% <70% (P=0.011), squamous cell carcinoma (P=0.046), a bronchial artery diameter >2.0 mm (P<0.001), and experience of surgeon <10 years (P=0.011) in the unadjusted analysis, and being male (P=0.047), a bronchial artery diameter >2.0 mm (P=0.024), and experience of surgeon <10 years (P=0.047) in the multivariable analysis.

Conclusions: Bronchial artery diameter was the most important risk factor of intraoperative bleeding and prolonged operative time during VATS lobectomy.
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http://dx.doi.org/10.21037/jtd-21-616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411168PMC
August 2021

Eribulin improves tumor oxygenation demonstrated by F-DiFA hypoxia imaging, leading to radio-sensitization in human cancer xenograft models.

Eur J Nucl Med Mol Imaging 2021 Sep 1. Epub 2021 Sep 1.

Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.

Purpose: Eribulin, an inhibitor of microtubule dynamics, is known to show antitumor effects through its remodeling activity in the tumor vasculature. However, the extent to which the improvement of tumor hypoxia by eribulin affects radio-sensitivity remains unclear. We utilized 1-(2,2-dihydroxymethyl-3-F-fluoropropyl)-2-nitroimidazole (F-DiFA), a new PET probe for hypoxia, to investigate the effects of eribulin on tumor hypoxia and evaluate the radio-sensitivity during eribulin treatment.

Methods: Mice bearing human breast cancer MDA-MB-231 cells or human lung cancer NCI-H1975 cells were administered a single dose of eribulin. After administration, mice were injected with F-DiFA and pimonidazole, and tumor hypoxia regions were analyzed. For the group that received combined treatment with radiation, F-DiFA PET/CT imaging was performed before tumors were locally X-irradiated. Tumor size was measured every other day after irradiation.

Results: Eribulin significantly reduced F-DiFA accumulation levels in a dose-dependent manner. Furthermore, the reduction in F-DiFA accumulation levels by eribulin was most significant 7 days after treatment. These results were also supported by reduction of the pimonidazole-positive hypoxic region. The combined treatment showed significant retardation of tumor growth in comparison with the control, radiation-alone, and drug-alone groups. Importantly, tumor growth after irradiation was inversely correlated with F-DiFA accumulation.

Conclusion: These results demonstrated that F-DiFA PET/CT clearly detected eribulin-induced tumor oxygenation and that eribulin efficiently enhanced the antitumor activity of radiation by improving tumor oxygenation.
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http://dx.doi.org/10.1007/s00259-021-05544-4DOI Listing
September 2021

First experimental results of gated proton imaging using x-ray fluoroscopy to detect a fiducial marker.

Phys Med Biol 2021 Sep 9;66(18). Epub 2021 Sep 9.

Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan.

Increasing numbers of proton imaging research studies are being conducted for accurate proton range determination in proton therapy treatment planning. However, there is no proton imaging system that deals with motion artifacts. In this study, a gated proton imaging system was developed and the first experimental results of proton radiography (pRG) were obtained for a moving object without motion artifacts. A motion management system using dual x-ray fluoroscopy for detecting a spherical gold fiducial marker was introduced and the proton beam was gated in accordance with the motion of the object. To demonstrate the performance of the gated proton imaging system, gated pRG images of a moving phantom were acquired experimentally, and the motion artifacts clearly were diminished. Also, the factors causing image deteriorations were evaluated focusing on the new gating system developed here, and the main factor was identified as the latency (with a maximum value of 93 ms) between the ideal gating signal according to the actual marker position and the actual gating signal. The possible deterioration due to the latency of the proton imaging system and proton beam irradiation was small owing to appropriate setting of the time structure.
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http://dx.doi.org/10.1088/1361-6560/ac212bDOI Listing
September 2021

Real-time CT image generation based on voxel-by-voxel modeling of internal deformation by utilizing the displacement of fiducial markers.

Med Phys 2021 Jul 14. Epub 2021 Jul 14.

Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido, Japan.

Purpose: To show the feasibility of real-time CT image generation technique utilizing internal fiducial markers that facilitate the evaluation of internal deformation.

Methods: In the proposed method, a linear regression model that can derive internal deformation from the displacement of fiducial markers is built for each voxel in the training process before the treatment session. Marker displacement and internal deformation are derived from the four-dimensional computed tomography (4DCT) dataset. In the treatment session, the three-dimensional deformation vector field is derived according to the marker displacement, which is monitored by the real-time imaging system. The whole CT image can be synthesized by deforming the reference CT image with a deformation vector field in real-time. To show the feasibility of the technique, image synthesis accuracy and tumor localization accuracy were evaluated using the dataset generated by extended NURBS-Based Cardiac-Torso (XCAT) phantom and clinical 4DCT datasets from six patients, containing 10 CT datasets each. In the validation with XCAT phantom, motion range of the tumor in training data and validation data were about 10 and 15 mm, respectively, so as to simulate motion variation between 4DCT acquisition and treatment session. In the validation with patient 4DCT dataset, eight CT datasets from the 4DCT dataset were used in the training process. Two excluded inhale CT datasets can be regarded as the datasets with large deformations more than training dataset. CT images were generated for each respiratory phase using the corresponding marker displacement. Root mean squared error (RMSE), normalized RMSE (NRMSE), and structural similarity index measure (SSIM) between the original CT images and the synthesized CT images were evaluated as the quantitative indices of the accuracy of image synthesis. The accuracy of tumor localization was also evaluated.

Results: In the validation with XCAT phantom, the mean NRMSE, SSIM, and three-dimensional tumor localization error were 7.5 ± 1.1%, 0.95 ± 0.02, and 0.4 ± 0.3 mm, respectively. In the validation with patient 4DCT dataset, the mean RMSE, NRMSE, SSIM, and three-dimensional tumor localization error in six patients were 73.7 ± 19.6 HU, 9.2 ± 2.6%, 0.88 ± 0.04, and 0.8 ± 0.6 mm, respectively. These results suggest that the accuracy of the proposed technique is adequate when the respiratory motion is within the range of the training dataset. In the evaluation with a marker displacement larger than that of the training dataset, the mean RMSE, NRMSE, and tumor localization error were about 100 HU, 13%, and <2.0 mm, respectively, except for one case having large motion variation. The performance of the proposed method was similar to those of previous studies. Processing time to generate the volumetric image was <100 ms.

Conclusion: We have shown the feasibility of the real-time CT image generation technique for volumetric imaging.
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http://dx.doi.org/10.1002/mp.15095DOI Listing
July 2021

Prediction of target position from multiple fiducial markers by partial least squares regression in real-time tumor-tracking radiation therapy.

J Radiat Res 2021 Sep;62(5):926-933

Department of Medical Physics, Hokkaido University Hospital, North 14, West 5, Kita-ku, Sapporo, Hokkaido 060-8648, Japan.

The purpose of this work is to show the usefulness of a prediction method of tumor location based on partial least squares regression (PLSR) using multiple fiducial markers. The trajectory data of respiratory motion of four internal fiducial markers inserted in lungs were used for the analysis. The position of one of the four markers was assumed to be the tumor position and was predicted by other three fiducial markers. Regression coefficients for prediction of the position of the tumor-assumed marker from the fiducial markers' positions is derived by PLSR. The tracking error and the gating error were evaluated assuming two possible variations. First, the variation of the position definition of the tumor and the markers on treatment planning computed tomograhy (CT) images. Second, the intra-fractional anatomical variation which leads the distance change between the tumor and markers during the course of treatment. For comparison, rigid predictions and ordinally multiple linear regression (MLR) predictions were also evaluated. The tracking and gating errors of PLSR prediction were smaller than those of other prediction methods. Ninety-fifth percentile of tracking/gating error in all trials were 3.7/4.1 mm, respectively in PLSR prediction for superior-inferior direction. The results suggested that PLSR prediction was robust to variations, and clinically applicable accuracy could be achievable for targeting tumors.
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http://dx.doi.org/10.1093/jrr/rrab054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438269PMC
September 2021

Fundamental study on quality assurance (QA) procedures for a real-time tumor tracking radiotherapy (RTRT) system from the viewpoint of imaging devices.

J Appl Clin Med Phys 2021 Jul 2;22(7):165-176. Epub 2021 Jun 2.

Department of biomedical science and Engineering, Faculty of Health science, Hokkaido University, Sapporo, Hokkaido, Japan.

Purpose: The real-time tumor tracking radiotherapy (RTRT) system requires periodic quality assurance (QA) and quality control. The goal of this study is to propose QA procedures from the viewpoint of imaging devices in the RTRT system.

Methods: Tracking by the RTRT system (equips two sets of colored image intensifiers (colored I.I.s) fluoroscopy units) for the moving gold-marker (diameter 2.0 mm) in a rotating phantom were performed under various X-ray conditions. To analyze the relationship between fluoroscopic image quality and precision of gold marker coordinate calculation, the standard deviation of the 3D coordinate (σ3D [mm]) of the gold marker, the mean of the pattern recognition score (PRS) and the standard deviation of the distance between rays (DBR) (σDBR [mm]) were evaluated.

Results: When tracking with speed of 10-60 mm/s, σDBR increased, though the mean PRS did not change significantly (p>0.05). On the contrary, the mean PRS increased depending on the integral noise equivalent quanta (∫NEQ) that is an indicator of image quality calculated from the modulation transfer function (MTF) as an indicator of spatial resolution and the noise power spectrum (NPS) as an indicator of noise characteristic.

Conclusion: The indicators of NEQ, MTF, and NPS were useful for managing the tracking accuracy of the RTRT system. We propose observing the change of these indicators as additional QA procedures for each imaging device from the commissioning baseline.
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http://dx.doi.org/10.1002/acm2.13307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292702PMC
July 2021

A CASE OF VAGUS NERVE SCHWANNOMA DIFFICULT TO DISTINGUISH FROM LYMPH NODAL METASTASIS OF ESOPHAGEAL CANCER.

J Med Invest 2021 ;68(1.2):205-208

Department of Thoracic, Endocrine Surgery and Oncology, Tokushima University Graduate School.

In this report, we describe a rare case of vagus nerve schwannoma associated with esophageal cancer. A 70-year-old man visited our hospital complaining of worsening dysphagia. His upper gastrointenstinal endoscopy revealed a mass in the esophagus. A contrast-enhanced chest computed tomography also detected a 15 mm nodule attached to the tracheal membrane. This nodule was diagnosed as a metastatic lymph node. Although the primary tumor reduced after neoadjuvant chemotherapy, the nodule remained intact ; it showed fluorodeoxyglucose accumulation on positron emission tomography. We had a clinical diagnosis of stage III after neoadjuvant chemotherapy and underwent surgery. Intraoperatively, the nodule could not be detached from the right vagus nerve ; therefore, we excised the nodule along with the adjacent vagus nerve. The nodule was pathologically diagnosed as a vagus schwannoma. The nodule was not a regional lymph node metastasis of esophageal cancer. His postoperative course was uneventful, and he is currently undergoing outpatient follow-up without recurrence. J. Med. Invest. 68 : 205-208, February, 2021.
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http://dx.doi.org/10.2152/jmi.68.205DOI Listing
January 2021

Calcification in thymomas can predict invasiveness to surrounding organs.

Thorac Cancer 2021 06 6;12(12):1857-1863. Epub 2021 May 6.

Department of Thoracic, Endocrine Surgery and Oncology, Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan.

Background: Thymomas are the most common type of anterior mediastinal tumors. Calcification is sometimes observed in thymomas using computed tomography (CT), and it is more frequent in invasive thymomas than in noninvasive thymomas. However, the significance of calcification in thymomas remains unknown. This study aimed to evaluate the significance of calcification in thymomas on invasiveness to surrounding organs and investigate the characteristics of thymoma cases with calcification at our institution.

Methods: We included thymoma patients treated at our institution between 2000 and 2016, and evaluated their characteristics, including demographics, calcification on CT, histology, Masaoka stage, and myasthenia gravis status. The patients were categorized into calcification (C) and noncalcification (NC) groups.

Results: Among 51 included patients, 11 (21.6%) had calcification. A higher proportion of group C patients had World Health Organization histological type B2 and B3 tumors (high-risk) than type A, AB, and B1 tumors (low-risk; p = 0.0477). The number of patients with Masaoka stages III and IV were significantly higher in the C group than in the NC group (p < 0.0001). The C group patients had significantly higher rates of invasion to the mediastinal pleura, pericardium, lung, phrenic nerve, and chest wall and pleural dissemination than the NC group patients.

Conclusions: Calcification reflects invasiveness of tumors to surrounding organs and tissues, and may thus predict thymoma stage and histologically high-risk thymomas. Calcification in thymomas may also predict the pathological stage and help decide therapeutic methods and surgical approaches to treat thymomas based on the calcification status according to CT findings.
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http://dx.doi.org/10.1111/1759-7714.13964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201533PMC
June 2021

Validation of dose distribution for liver tumors treated with real-time-image gated spot-scanning proton therapy by log data based dose reconstruction.

J Radiat Res 2021 Jul;62(4):626-633

Department of Medical Physics, Hokkaido University Hospital, North14 West5, Kita-ku, Sapporo, Hokkaido 060-8638, Japan.

In spot scanning proton therapy (SSPT), the spot position relative to the target may fluctuate through tumor motion even when gating the radiation by utilizing a fiducial marker. We have established a procedure that evaluates the delivered dose distribution by utilizing log data on tumor motion and spot information. The purpose of this study is to show the reliability of the dose distributions for liver tumors treated with real-time-image gated SSPT (RGPT). In the evaluation procedure, the delivered spot information and the marker position are synchronized on the basis of log data on the timing of the spot irradiation and fluoroscopic X-ray irradiation. Then a treatment planning system reconstructs the delivered dose distribution. Dose distributions accumulated for all fractions were reconstructed for eight liver cases. The log data were acquired in all 168 fractions for all eight cases. The evaluation was performed for the values of maximum dose, minimum dose, D99, and D5-D95 for the clinical target volumes (CTVs) and mean liver dose (MLD) scaled by the prescribed dose. These dosimetric parameters were statistically compared between the planned dose distribution and the reconstructed dose distribution. The mean difference of the maximum dose was 1.3% (95% confidence interval [CI]: 0.6%-2.1%). Regarding the minimum dose, the mean difference was 0.1% (95% CI: -0.5%-0.7%). The mean differences of D99, D5-D95 and MLD were below 1%. The reliability of dose distributions for liver tumors treated with RGPT-SSPT was shown by the evaluation of the accumulated dose distributions.
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http://dx.doi.org/10.1093/jrr/rrab024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273791PMC
July 2021

Treatment outcomes of stereotactic body radiation therapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinomas.

Hepatol Res 2021 Aug 11;51(8):870-879. Epub 2021 May 11.

Department of Radiation Oncology, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.

Aim: To report the outcomes of stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinoma patients.

Methods: From January 2005 to July 2018, 63 patients with 74 lesions with a maximum diameter ≤52 mm were treated by stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system. No patient with a Child-Pugh Score ≥9 was included, and 85.6% had a score of 5 or 6. Using the biological effective dose (BED) with an α/β ratio of 10 (BED ), the median dose in BED at the reference point was 76.8 Gy (range 60-122.5 Gy). Overall survival (OS) and local control rates were assessed using the Kaplan-Meier method.

Results: With a median follow-up period of 24.6 months (range 0.9-118.4 months), the 1-year and 2-year OS rates were 86.8% (95% confidence interval [95% CI] 75.8-93.3) and 71.1% (57.8-81.6), respectively. The 2-year OS was 89.6% in patients with the baseline modified albumin-bilirubin (mALBI) grade =1, and 61.7% in patients with grade ≥2a. In the multivariate analysis, the mALBI grade (=1 vs. ≥2a) was a significant factor for OS (p = 0.028, 95% CI 1.11-6.18). The 1-year and 2-year local control rates were 100% (100-100%) and 92.0% (77.5-97.5%). The local control rates were significantly higher in the BED ≥100 Gy group than in the BED <100 Gy group (2-year 100% vs. 86.5%, p = 0.049) at the reference point.

Conclusion: This retrospective study of stereotactic body radiotherapy using real-time tumor-tracking radiotherapy for hepatocellular carcinoma showed favorable outcomes with lower incidence of toxicities, especially in patients treated with BED ≥100 Gy to the reference point.
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http://dx.doi.org/10.1111/hepr.13649DOI Listing
August 2021

Cone-beam computed tomography versus computed tomography-guided ultrathin bronchoscopic diagnosis for peripheral pulmonary lesions: A propensity score-matched analysis.

Respirology 2021 05 21;26(5):477-484. Epub 2021 Feb 21.

Department of Thoracic and Endocrine Surgery and Oncology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima, Japan.

Background And Objective: CBCT-guided TBB using a UTB under VBN is a useful method for the diagnosis of peripheral small pulmonary lesions. CBCT-guided TBB using UTB under VBN has been used as an alternative to CT-guided TBB. However, the advantage of CBCT-guided TBB using UTB under VBN over CT-guided TBB is still unknown. This study aimed to compare the diagnostic yield of CT-guided TBB and CBCT-guided TBB using a propensity score-matched analysis.

Methods: Patients with peripheral pulmonary lesions ≤30 mm were included. Lesions whose bronchus could not be determined by CT were excluded. A UTB and biopsy forceps were advanced to the target bronchus under VBN, 2D-fluoroscopy and CT or CBCT. The CT-guided and CBCT-guided groups were matched for their propensity scores based on patient characteristics.

Results: We retrospectively reviewed 93 patients in the CT-guided group and 79 patients in the CBCT-guided group for this study. Furthermore, 48 distinct examination pairs were generated by propensity score matching. In the overall diagnostic yield, the CBCT-guided group showed better results (72.9%) than did the CT-guided group (47.9%) (P = 0.012). The median examination time lasted for 43 (IQR: 37-51) min in the CBCT-guided group and 50 (IQR: 43-62) min in the CT-guided group. The examination time in the CBCT-guided group was significantly shorter than that of the CT-guided group (P = 0.001).

Conclusion: CBCT-guided TBB had a better diagnostic yield and shorter examination time than did CT-guided TBB.
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http://dx.doi.org/10.1111/resp.14016DOI Listing
May 2021

Can computed tomography differentiate adenocarcinoma in situ from minimally invasive adenocarcinoma?

Thorac Cancer 2021 04 17;12(7):1023-1032. Epub 2021 Feb 17.

Department of Thoracic, Endocrine Surgery, and Oncology, Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan.

Background: Given the subtle pathological signs of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), effective differentiation between the two entities is crucial. However, it is difficult to predict these conditions using preoperative computed tomography (CT) imaging. In this study, we investigated whether histological diagnosis of AIS and MIA using quantitative three-dimensional CT imaging analysis could be predicted.

Methods: We retrospectively analyzed the images and histopathological findings of patients with lung cancer who were diagnosed with AIS or MIA between January 2017 and June 2018. We used Synapse Vincent (v. 4.3) (Fujifilm) software to analyze the CT attenuation values and performed a histogram analysis.

Results: There were 22 patients with AIS and 22 with MIA. The ground-glass nodule (GGN) rate was significantly higher in patients with AIS (p < 0.001), whereas the solid volume (p < 0.001) and solid rate (p = 0.001) were significantly higher in those with MIA. The mean (p = 0.002) and maximum (p = 0.025) CT values were significantly higher in patients with MIA. The 25th, 50th, 75th, and 97.5th percentiles (all p < 0.05) for the CT values were significantly higher in patients with MIA.

Conclusions: We demonstrated that quantitative analysis of 3D-CT imaging data using software can help distinguish AIS from MIA. These analyses are useful for guiding decision-making in the surgical management of early lung cancer, as well as subsequent follow-up.
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http://dx.doi.org/10.1111/1759-7714.13838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017252PMC
April 2021

Clinical practice vs. state-of-the-art research and future visions: Report on the 4D treatment planning workshop for particle therapy - Edition 2018 and 2019.

Phys Med 2021 Feb 13;82:54-63. Epub 2021 Feb 13.

Institute of Nuclear Physics Polish Academy of Sciences, PL-31342 Krakow, Poland.

The 4D Treatment Planning Workshop for Particle Therapy, a workshop dedicated to the treatment of moving targets with scanned particle beams, started in 2009 and since then has been organized annually. The mission of the workshop is to create an informal ground for clinical medical physicists, medical physics researchers and medical doctors interested in the development of the 4D technology, protocols and their translation into clinical practice. The 10th and 11th editions of the workshop took place in Sapporo, Japan in 2018 and Krakow, Poland in 2019, respectively. This review report from the Sapporo and Krakow workshops is structured in two parts, according to the workshop programs. The first part comprises clinicians and physicists review of the status of 4D clinical implementations. Corresponding talks were given by speakers from five centers around the world: Maastro Clinic (The Netherlands), University Medical Center Groningen (The Netherlands), MD Anderson Cancer Center (United States), University of Pennsylvania (United States) and The Proton Beam Therapy Center of Hokkaido University Hospital (Japan). The second part is dedicated to novelties in 4D research, i.e. motion modelling, artificial intelligence and new technologies which are currently being investigated in the radiotherapy field.
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http://dx.doi.org/10.1016/j.ejmp.2020.12.013DOI Listing
February 2021

Classifying the destination of right top pulmonary vein in 31 clinical cases.

Gen Thorac Cardiovasc Surg 2021 Aug 14;69(8):1192-1195. Epub 2021 Feb 14.

Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.

Disruption in the flow of blood vessels is of great concern during thoracic surgery. Preoperative 3-dimensional computed tomography facilitates visualization of the exact location and course of blood vessels. The right posterior upper lobe segmental vein, known as the right top pulmonary vein (RTPV), is an anomalous vein beginning at the right upper lobe and running through the posterior surface of the intermediate bronchus. We clinically investigated 31 patients with RTPV who underwent lobectomy or total resection of the right lung in our hospital or related institutions. We classified the final destination of RTPV into four types. The RTPV flowed into the left atrium in 35.5% of cases, superior pulmonary vein in 9.7%, inferior pulmonary vein in 41.9%, and independently into V6 in 12.9%. An RTPV with a diameter ≥ 5 mm was considered a main drainage vein in S2. We should pay attention to the RTPV during right lung lobectomy.
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http://dx.doi.org/10.1007/s11748-021-01604-6DOI Listing
August 2021

Effects of excitation light intensity on parathyroid autofluorescence with a novel near-infrared fluorescence imaging system: two surgical case reports.

Gland Surg 2020 Oct;9(5):1584-1589

Department of Thoracic, Endocrine Surgery, and Oncology, Institute of Health Biosciences, The University of Tokushima, Kuramoto-cho, Tokushima, Japan.

The intraoperative identification and preservation of the parathyroid glands are vital techniques, which are largely dependent on a surgeon's experience. Therefore, a simple and reproducible technique to identify the parathyroid glands during surgery is needed. Parathyroid tissue shows near-infrared (NIR) autofluorescence, which enables the intraoperative identification of the parathyroid gland. We herein present two cases that underwent surgery on the parathyroid glands, which were observed using the NIR fluorescence imaging system LIGHTVISION (Shimazu, Kyoto, Japan). In a case of papillary thyroid carcinoma, the system was adopted to preserve normal parathyroid glands during left hemithyroidectomy. The left lower parathyroid gland was identified using the imaging system under white light; however, its autofluorescence was visualized more clearly with the excitation light of NIR. In a case of primary hyperparathyroidism due to MEN1, the system was adopted to identify and remove all of the parathyroid glands during total parathyroidectomy. The autofluorescence of diseased glands was weaker than that of normal glands, even with the excitation light of NIR. When the parathyroid glands were irradiated with a red laser pointer, the intensity of autofluorescence significantly increased. However, the largest gland, which was pathologically proven to contain strongly proliferating chief cells, did not show autofluorescence. These results suggest that normal or less diseased parathyroid glands, which are generally small and difficult to identify during surgery, showed relatively strong autofluorescence. A stronger excitation light increases the autofluorescence of parathyroid glands, which enhances sensitivity for detecting parathyroid glands during surgery. In conclusion, LIGHTVISION is a useful device to identify parathyroid glands and an additional excitation light of a red laser pointer increases the detection sensitivity.
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http://dx.doi.org/10.21037/gs-20-386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667091PMC
October 2020

The impact of dose delivery time on biological effectiveness in proton irradiation with various biological parameters.

Med Phys 2020 Sep 2;47(9):4644-4655. Epub 2020 Aug 2.

Division of Quantum Science and Engineering, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido, 0608628, Japan.

Purpose: The purpose of this study is to evaluate the sublethal damage (SLD) repair effect in prolonged proton irradiation using the biophysical model with various cell-specific parameters of (α/β) and T (repair half time). At present, most of the model-based studies on protons have focused on acute radiation, neglecting the reduction in biological effectiveness due to SLD repair during the delivery of radiation. Nevertheless, the dose-rate dependency of biological effectiveness may become more important as advanced treatment techniques, such as hypofractionation and respiratory gating, come into clinical practice, as these techniques sometimes require long treatment times. Also, while previous research using the biophysical model revealed a large repair effect with a high physical dose, the dependence of the repair effect on cell-specific parameters has not been evaluated systematically.

Methods: Biological dose [relative biological effectiveness (RBE) × physical dose] calculation with repair included was carried out using the linear energy transfer (LET)-dependent linear-quadratic (LQ) model combined with the theory of dual radiation action (TDRA). First, we extended the dose protraction factor in the LQ model for the arbitrary number of different LET proton irradiations delivered sequentially with arbitrary time lags, referring to the TDRA. Using the LQ model, the decrease in biological dose due to SLD repair was systematically evaluated for spread-out Bragg peak (SOBP) irradiation in a water phantom with the possible ranges of both (α/β) and repair parameters ((α/β)  = 1-15 Gy, T  = 0-90 min). Then, to consider more realistic irradiation conditions, clinical cases of prostate, liver, and lung tumors were examined with the cell-specific parameters for each tumor obtained from the literature. Biological D and biological dose homogeneity coefficient (HC) were calculated for the clinical target volumes (CTVs), assuming dose-rate structures with a total irradiation time of 0-60 min.

Results: The differences in the cell-specific parameters resulted in considerable variation in the repair effect. The biological dose reduction found at the center of the SOBP with 30 min of continuous irradiation varied from 1.13% to 14.4% with a T range of 1-90 min when (α/β) is fixed as 10 Gy. It varied from 2.3% to 6.8% with an (α/β) range of 1-15 Gy for a fixed value of T  = 30 min. The decrease in biological D per 10 min was 2.6, 1.2, and 3.0% for the prostate, liver, and lung tumor cases, respectively. The value of the biological D reduction was neither in the order of (α/β) nor prescribed dose, but both comparably contributed to the repair effect. The variation of HC was within the range of 0.5% for all cases; therefore, the dose distribution was not distorted.

Conclusion: The reduction in biological dose caused by the SLD repair largely depends on the cell-specific parameters in addition to the physical dose. The parameters should be considered carefully in the evaluation of the repair effect in prolonged proton irradiation.
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http://dx.doi.org/10.1002/mp.14381DOI Listing
September 2020

A case of long-term unchanged calcifying fibrous tumor.

Gen Thorac Cardiovasc Surg 2020 Dec 8;68(12):1587-1590. Epub 2020 Jun 8.

Department of Thoracic, Endocrine Surgery and Oncology, Tokushima University Graduate School of Medical Science, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.

A calcifying fibrous tumor (CFT) is a rare benign tumor that may occur in any part of the body. We report the case of an asymptomatic 21-year-old woman with thoracic tumors. Chest computed tomography showed multiple masses in the left costophrenic angle. As we were unable to diagnose the tumor with a CT-guided needle biopsy, we performed a thoracoscopic biopsy. We found smooth multilobulated masses on the pleura and multiple small nodules around the main tumors. Partial resection of the tumor was performed by VATS. Histological examination revealed that the tumor had hypocellular fibrosclerotic tissue and distributed psammomatous calcifications with inflammatory infiltrates. Immunohistochemistry demonstrated that the spindle cells were partially positive for CD34 and CD99, but negative for anaplastic lymphoma kinase-1, smooth muscle actin, BCL-2, STAT6, and S-100 protein. The tumor was diagnosed as CFT. The patient's postoperative recovery was uneventful, and no progression of the lesions was observed during follow-up.
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http://dx.doi.org/10.1007/s11748-020-01396-1DOI Listing
December 2020

Difference in LET-based biological doses between IMPT optimization techniques: Robust and PTV-based optimizations.

J Appl Clin Med Phys 2020 Apr 9;21(4):42-50. Epub 2020 Mar 9.

Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Hokkaido, Japan.

Purpose: While a large amount of experimental data suggest that the proton relative biological effectiveness (RBE) varies with both physical and biological parameters, current commercial treatment planning systems (TPS) use the constant RBE instead of variable RBE models, neglecting the dependence of RBE on the linear energy transfer (LET). To conduct as accurate a clinical evaluation as possible in this circumstance, it is desirable that the dosimetric parameters derived by TPS ( ) are close to the "true" values derived with the variable RBE models ( ). As such, in this study, the closeness of to was compared between planning target volume (PTV)-based and robust plans.

Methods: Intensity-modulated proton therapy (IMPT) treatment plans for two Radiation Therapy Oncology Group (RTOG) phantom cases and four nasopharyngeal cases were created using the PTV-based and robust optimizations, under the assumption of a constant RBE of 1.1. First, the physical dose and dose-averaged LET (LET ) distributions were obtained using the analytical calculation method, based on the pencil beam algorithm. Next, was calculated using three different RBE models. The deviation of from was evaluated with D and D , which have been used as the evaluation indices for clinical target volume (CTV) and organs at risk (OARs), respectively. The influence of the distance between the OAR and CTV on the results was also investigated. As a measure of distance, the closest distance and the overlapped volume histogram were used for the RTOG phantom and nasopharyngeal cases, respectively.

Results: As for the OAR, the deviations of from were always smaller in robust plans than in PTV-based plans in all RBE models. The deviation would tend to increase as the OAR was located closer to the CTV in both optimization techniques. As for the CTV, the deviations of from were comparable between the two optimization techniques, regardless of the distance between the CTV and the OAR.

Conclusion: Robust optimization was found to be more favorable than PTV-based optimization in that the results presented by TPS were closer to the "true" values and that the clinical evaluation based on TPS was more reliable.
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http://dx.doi.org/10.1002/acm2.12844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170293PMC
April 2020

Dynamic gating window technique for the reduction of dosimetric error in respiratory-gated spot-scanning particle therapy: An initial phantom study using patient tumor trajectory data.

J Appl Clin Med Phys 2020 Apr 18;21(4):13-21. Epub 2020 Feb 18.

Division of Quantum Science and Engineering, Faculty of Engineering, Hokkaido University, Sapporo, Japan.

Spot-scanning particle therapy possesses advantages, such as high conformity to the target and efficient energy utilization compared with those of the passive scattering irradiation technique. However, this irradiation technique is sensitive to target motion. In the current clinical situation, some motion management techniques, such as respiratory-gated irradiation, which uses an external or internal surrogate, have been clinically applied. In surrogate-based gating, the size of the gating window is fixed during the treatment in the current treatment system. In this study, we propose a dynamic gating window technique, which optimizes the size of gating window for each spot by considering a possible dosimetric error. The effectiveness of the dynamic gating window technique was evaluated by simulating irradiation using a moving target in a water phantom. In dosimetric characteristics comparison, the dynamic gating window technique exhibited better performance in all evaluation volumes with different effective depths compared with that of the fixed gate approach. The variation of dosimetric characteristics according to the target depth was small in dynamic gate compared to fixed gate. These results suggest that the dynamic gating window technique can maintain an acceptable dose distribution regardless of the target depth. The overall gating efficiency of the dynamic gate was approximately equal or greater than that of the fixed gating window. In dynamic gate, as the target depth becomes shallower, the gating efficiency will be reduced, although dosimetric characteristics will be maintained regardless of the target depth. The results of this study suggest that the proposed gating technique may potentially improve the dose distribution. However, additional evaluations should be undertaken in the future to determine clinical applicability by assuming the specifications of the treatment system and clinical situation.
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http://dx.doi.org/10.1002/acm2.12832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170289PMC
April 2020

The urethral position may shift due to urethral catheter placement in the treatment planning for prostate radiation therapy.

Radiat Oncol 2019 Dec 12;14(1):226. Epub 2019 Dec 12.

Department of Radiation Medical Science and Engineering, Faculty of Medicine, Hokkaido University, North-15, West-7, Kita-Ku, Sapporo, Hokkaido, 060-8638, Japan.

Purpose: To determine the best method to contour the planning organ at risk volume (PRV) for the urethra, this study aimed to investigate the displacement of a Foley catheter in the urethra with a soft and thin guide-wire.

Methods: For each patient, the study used two sets of computed tomography (CT) images for radiation treatment planning (RT-CT): (1) set with a Foley urethral catheter (4.0 mm diameter) plus a guide-wire (0.46 mm diameter) in the first RT-CT and (2) set with a guide-wire alone in the second CT recorded 2 min after the first RT-CT. Using three fiducial markers in the prostate for image fusion, the displacement between the catheter and the guide-wire in the prostatic urethra was calculated. In 155 consecutive patients treated between 2011 and 2017, 5531 slices of RT-CT were evaluated.

Results: Assuming that ≥3.0 mm of difference between the catheter and the guide-wire position was a significant displacement, the urethra with the catheter was displaced significantly from the urethra with the guide-wire alone in > 20% of the RT-CT slices in 23.2% (36/155) of the patients. The number of patients who showed ≥3.0 mm anterior displacement with the catheter in ≥20% RT-CT slices was significantly larger at the superior segment (38/155) than at the middle (14/155) and inferior segments (18/155) of the prostatic urethra (p < 0.0167).

Conclusions: The urethral position with a Foley catheter is different from the urethral position with a thin and soft guide-wire in a significant proportion of the patients. This should be taken into account for the PRV of the urethra to ensure precise radiotherapy such as in urethra-sparing radiotherapy.
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http://dx.doi.org/10.1186/s13014-019-1424-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909476PMC
December 2019

Erastin, a ferroptosis-inducing agent, sensitized cancer cells to X-ray irradiation via glutathione starvation in vitro and in vivo.

PLoS One 2019 4;14(12):e0225931. Epub 2019 Dec 4.

Department of Biomedical Imaging, Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan.

High concentrations of antioxidants in cancer cells are huge obstacle in cancer radiotherapy. Erastin was first discovered as an inducer of iron-dependent cell death called ferroptosis accompanied by antioxidant depletion caused by cystine glutamate antiporter inhibition. Therefore, treatment with erastin is expected to potentially enhance cellular radiosensitivity. In this study, we investigated the influence of treatment with erastin on the radiation efficiency against cancers. The clonogenic ability, glutathione peroxidase 4 (GPX4) expression, and glutathione concentration were evaluated using HeLa and NCI-H1975 adenocarcinoma cell lines treated with erastin and/or X-ray irradiation. For in vivo studies, NCI-H1975 cells were transplanted in the left shoulder of nude mice, and then radiosensitizing effect of erastin and glutathione concentration in the cancer were evaluated. Treatment with erastin induced ferroptosis and decreased the concentration of glutathione and GPX4 protein expression levels in the two tumor cell lines. Moreover, erastin enhanced X-ray irradiation-induced cell death in both human tumor cell lines. Furthermore, erastin treatment of a tumor-transplanted mouse model similarly demonstrated the radiosensitizing effect and decrease in intratumoral glutathione concentration in the in vitro study. In conclusion, our study demonstrated the radiosensitizing effect of erastin on two adenocarcinoma cell lines and the tumor xenograft model accompanied by glutathione depletion, indicating that ferroptosis inducers that reduce glutathione concentration could be applied as a novel cancer therapy in combination with radiotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892486PMC
March 2020

Percutaneous insertion of hepatic fiducial true-spherical markers for real-time adaptive radiotherapy.

Minim Invasive Ther Allied Technol 2020 Dec 13;29(6):334-343. Epub 2019 Sep 13.

Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital, Sapporo, Japan.

This study evaluated the success rate and complications of percutaneous implantation of hepatic fiducial true-spherical gold markers for real-time adaptive radiotherapy (RAR), which constitutes real-time image-guided radiotherapy with gating. We retrospectively evaluated 100 patients who underwent 116 percutaneous intrahepatic implantations of 2-mm-diameter, spherical, gold fiducial markers before RAR from 1999 to 2016, with Seldinger's method. We defined technical success as marker placement at the intended liver parenchyma, without mispositioning, and clinical success as successful tracking of the gold marker and completion of planned RAR. Complications related to marker placement were assessed. The technical success rate for true-spherical gold marker implantation was 92.2% (107/116). Nine of 116 markers migrated (intra-procedurally in seven patients, delayed in two patients). Migration out of the liver ( 4) or intrahepatic vessels ( 5) occurred without complications; these markers were not retrieved. The clinical success rate was 100.0% (115/115). Abdominal pain occurred in 16 patients, fever and hemorrhage in seven patients each, and pneumothorax and nausea in one patient each. No major complications were encountered. Percutaneous transhepatic implantation of true-spherical gold markers for RAR is feasible and can be conducted with a high success rate and low complication rate.
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http://dx.doi.org/10.1080/13645706.2019.1663217DOI Listing
December 2020

Quantitative evaluation of image recognition performance of fiducial markers in real-time tumor-tracking radiation therapy.

Phys Med 2019 Sep 12;65:33-39. Epub 2019 Aug 12.

Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, North 14, West 5, Kita-ku, Sapporo, Hokkaido 060-8648, Japan; Department of Radiation Medicine, Faculty of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan.

Purpose: To quantitatively evaluate and compare the image recognition performance of multiple fiducial markers available in real-time tumor-tracking radiation therapy (RTRT).

Methods: Clinically available markers including sphere shape, coil shape, cylinder shape, line shape, and ball shape (folded line shape) were evaluated in liver and lung models of RTRT. Maximum thickness of the polymethyl metacrylate (PMMA) phantom that could automatically recognize the marker was determined by template-pattern matching. Image registration accuracy of the fiducial marker was determined using liver RTRT model. Lung RTRT was mimicked with an anthropomorphic chest phantom and a one-dimensional motion stage in order to simulate marker motion in heterogeneous fluoroscopic images. The success or failure of marker tracking and image registration accuracy for the lung model were evaluated in the same manner as that for the liver model.

Results: All fiducial markers except for line shape and coil shape of thinner diameter were recognized by the PMMA phantom, which is assumed to have the typical thickness of an abdomen, with two-dimensional image registration accuracy of <2 pixels. Three-dimensional calculation error with the use of real-time stereoscopic fluoroscopy in RTRT was thought to be within 1 mm. In the evaluation using the lung model, the fiducial markers were recognized stably with sufficient accuracy for clinical application. The same was true for the evaluation using the liver model.

Conclusions: The image recognition performance of fiducial markers was quantified and compared. The results presented here may be useful for the selection of fiducial markers.
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http://dx.doi.org/10.1016/j.ejmp.2019.08.004DOI Listing
September 2019

Impact of organ motion on volumetric and dosimetric parameters in stomach lymphomas treated with intensity-modulated radiotherapy.

J Appl Clin Med Phys 2019 Aug 10;20(8):78-86. Epub 2019 Aug 10.

Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.

Purpose: Interplay effects may influence dose distributions to a moving target when using dynamic delivery techniques such as intensity-modulated radiotherapy (IMRT). The aim of this study was to evaluate the impact of organ motion on volumetric and dosimetric parameters in stomach lymphomas treated with IMRT.

Methods: Ten patients who had been treated with IMRT for stomach lymphomas were enrolled. The clinical target volume (CTV) was contoured as the whole stomach. Considering interfractional uncertainty, the internal target volume (ITV) margin was uniformly 1.5 cm to the CTV and then modified based on the 4DCT images in case of the large respiratory motion. The planning target volume (PTV) was created by adding 5 mm to the ITV. The impact of organ motion on the volumetric and dosimetric parameters was evaluated retrospectively (4D simulation). The organ motion was reproduced by shifting the isocenter on the radiation treatment planning system. Several simulation plans were created to test the influence of the beam-on timing in the respiration cycle on the dose distribution. The homogeneity index (HI), volume percentage of stomach covered by the prescribed dose (V ), and D of the CTV were evaluated.

Results: The organ motion was the largest in the superior-inferior direction (10.1 ± 4.5 mm [average ± SD]). Stomach volume in each respiratory phase compared to the mean volume varied approximately within a ± 5% range in most of the patients. The PTV margin was sufficiently large to cover the CTV during the IMRT. There was a significant reduction in V and D but not in HI in the 4D simulation in free-breathing and multiple fractions compared to the clinically-used plan (P < 0.05) suggesting that interplay effects deteriorate the dose distribution. The absolute difference of D was less than 1% of the prescribed dose.

Conclusions: There were significant interplay effects affecting the dose distribution in stomach IMRT. The magnitude of the dose reduction was small when patients were treated on free-breathing and multiple fractions.
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http://dx.doi.org/10.1002/acm2.12681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698764PMC
August 2019

[Effectiveness of Ramucirumab Therapy for Advanced Gastric Cancer after Stent Placement for Esophagogastric Junction Carcinoma Obstruction-A Case Report].

Gan To Kagaku Ryoho 2019 Jun;46(6):1057-1059

Dept. of Surgery, Tokushima Red Cross Hospital.

According to the REGARD and RAINBOW trials, ramucirumab(RAM)was introduced as second-line therapy for advanced or metastatic gastric cancer. Endoscopic metallic stent placement and angiogenesis inhibitor administration carry the risk of gastrointestinal perforation. The outcomes of patients who undergo endoscopic placement of metallic stents during RAM treatment have not yet been fully assessed. A 60's man was diagnosed with advanced esophagogastric junction cancer(por) with Virchow's lymph node metastases. His tumor was classified as cT4a(SE), N1(#1), M1, stage Ⅳ. He received chemotherapy, but the size of the primary tumor and metastases increased. After stenting for gastric outlet obstruction, he received a paclitaxel(PTX)plus RAM regimen as third-line treatment. Because of CTCAE Grade 2 peripheral neuropathy, PTX was discontinued after 10 courses. For 11 months, tumor control without adverse events was maintained. The patient was then switched to CPT-11 as fourth-line treatment.
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June 2019

Real-Time Tumor-Tracking Radiotherapy and General Stereotactic Body Radiotherapy for Adrenal Metastasis in Patients With Oligometastasis.

Technol Cancer Res Treat 2018 01;17:1533033818809983

2 Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.

Background: Precise local radiotherapy for adrenal metastasis can prolong the useful life of patients with oligometastasis. The aim of this retrospective, 2-center study was to establish the safety and effectiveness of real-time tumor-tracking radiotherapy and general stereotactic body radiotherapy in treating patients with adrenal metastatic tumors.

Materials And Methods: Thirteen lesions in 12 patients were treated with real-time tumor-tracking radiotherapy (48 Gy in 8 fractions over 2 weeks) and 8 lesions in 8 patients were treated with general stereotactic body radiotherapy (40-50 Gy in 5-8 fractions over 2 weeks or 60-70 Gy in 10 fractions over 2 weeks). Overall survival rates, local control rates, and adverse effects were analyzed.

Results: The actuarial overall survival rates for all patients at 1 and 2 years were 78.5% and 45.8%, respectively, with a median follow-up of 17.5 months, and the actuarial local control rates for all tumors at 1 and 2 years were 91.7% and 53.0%, respectively, with a median follow-up of 9 months. A complete local tumor response was obtained in 3 tumors treated by real-time tumor-tracking radiotherapy (lung adenocarcinomas with diameters of 35, 40, and 60 mm). There was a statistically significant difference in the local control between the groups treated by real-time tumor-tracking radiotherapy (100% at 1 year) and general stereotactic body radiotherapy (50% at 1 year; P < .001). No late adverse reactions at Grade 2 or higher were reported for either treatment group.

Conclusions: This study showed that although both treatments are safe and effective, the real-time tumor-tracking radiotherapy is more effective than general stereotactic body radiotherapy in local control for adrenal metastasis.
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http://dx.doi.org/10.1177/1533033818809983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259059PMC
January 2018

Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.

Sci Rep 2018 09 10;8(1):13549. Epub 2018 Sep 10.

Divisions of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan.

Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the BCR-ABL protein. Recently, potent degraders against BCR-ABL have been developed by conjugating dasatinib to ligands for E3 ubiquitin ligases. Since the degraders contain the dasatinib moiety, they also inhibit BCR-ABL kinase activity, which complicates our understanding of the impact of BCR-ABL degradation by degraders in CML growth inhibition. To address this issue, we chose DAS-IAP, as a potent BCR-ABL degrader, and developed a structurally related inactive degrader, DAS-meIAP, which inhibits kinase activity but does not degrade the BCR-ABL protein. DAS-IAP showed slightly weaker activity than DAS-meIAP in inhibiting cell growth when CML cells were treated for 48 h. However, DAS-IAP showed sustained growth inhibition even when the drug was removed after short-term treatment, whereas CML cell growth rapidly resumed following removal of DAS-meIAP and dasatinib. Consistently, suppression of BCR-ABL levels and downstream kinase signaling were maintained after DAS-IAP removal, whereas kinase signaling rapidly recovered following removal of DAS-meIAP and dasatinib. These results indicate that BCR-ABL degrader shows more sustained inhibition of CML cell growth than ABL kinase inhibitor.
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http://dx.doi.org/10.1038/s41598-018-31913-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131351PMC
September 2018

An analytical dose-averaged LET calculation algorithm considering the off-axis LET enhancement by secondary protons for spot-scanning proton therapy.

Med Phys 2018 Jul 19;45(7):3404-3416. Epub 2018 Jun 19.

Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, 0608638, Japan.

Purpose: To evaluate the biological effects of proton beams as part of daily clinical routine, fast and accurate calculation of dose-averaged linear energy transfer (LET ) is required. In this study, we have developed the analytical LET calculation method based on the pencil-beam algorithm (PBA) considering the off-axis enhancement by secondary protons. This algorithm (PBA-dLET) was then validated using Monte Carlo simulation (MCS) results.

Methods: In PBA-dLET, LET values were assigned separately for each individual dose kernel based on the PBA. For the dose kernel, we employed a triple Gaussian model which consists of the primary component (protons that undergo the multiple Coulomb scattering) and the halo component (protons that undergo inelastic, nonelastic and elastic nuclear reaction); the primary and halo components were represented by a single Gaussian and the sum of two Gaussian distributions, respectively. Although the previous analytical approaches assumed a constant LET value for the lateral distribution of a pencil beam, the actual LET increases away from the beam axis, because there are more scattered and therefore lower energy protons with higher stopping powers. To reflect this LET behavior, we have assumed that the LETs of primary and halo components can take different values (LET and LET ), which vary only along the depth direction. The values of dual-LET kernels were determined such that the PBA-dLET reproduced the MCS-generated LET distribution in both small and large fields. These values were generated at intervals of 1 mm in depth for 96 energies from 70.2 to 220 MeV and collected in the look-up table. Finally, we compared the LET distributions and mean LET (LET ) values of targets and organs at risk between PBA-dLET and MCS. Both homogeneous phantom and patient geometries (prostate, liver, and lung cases) were used to validate the present method.

Results: In the homogeneous phantom, the LET profiles obtained by the dual-LET kernels agree well with the MCS results except for the low-dose region in the lateral penumbra, where the actual dose was below 10% of the maximum dose. In the patient geometry, the LET profiles calculated with the developed method reproduces MCS with the similar accuracy as in the homogeneous phantom. The maximum differences in LET for each structure between the PBA-dLET and the MCS were 0.06 keV/μm in homogeneous phantoms and 0.08 keV/μm in patient geometries under all tested conditions, respectively.

Conclusions: We confirmed that the dual-LET-kernel model well reproduced the MCS, not only in the homogeneous phantom but also in complex patient geometries. The accuracy of the LET was largely improved from the single-LET-kernel model, especially at the lateral penumbra. The model is expected to be useful, especially for proper recognition of the risk of side effects when the target is next to critical organs.
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http://dx.doi.org/10.1002/mp.12991DOI Listing
July 2018
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