Evaluation of the performance of both machine learning models using PET and CT radiomics for predicting recurrence following lung stereotactic body radiation therapy: A single-institutional study.

PURPOSE: Predicting recurrence following stereotactic body radiotherapy (SBRT) for non-small cell lung cancer provides important information for the feasibility of the individualized radiotherapy and allows to select the appropriate treatment strategy based on the risk of recurrence. In this study, we evaluated the performance of both machine learning models using positron emission tomography (PET) and computed tomography (CT) radiomic features for predicting recurrence after SBRT. METHODS: Planning CT and PET images of 82 non-small cell lung cancer patients who performed SBRT at our hospital were used. First, tumors were delineated on each CT and PET of each patient, and 111 unique radiomic features were extracted, respectively. Next, the 10 features were selected using three different feature selection algorithms, respectively. Recurrence prediction models based on the selected features and four different machine learning algorithms were developed, respectively. Finally, we compared the predictive performance of each model for each recurrence pattern using the mean area under the curve (AUC) calculated following the 0.632+ bootstrap method. RESULTS: The highest performance for local recurrence, regional lymph node metastasis, and distant metastasis were observed in models using Support vector machine with PET features (mean AUC = 0.646), Naive Bayes with PET features (mean AUC = 0.611), and Support vector machine with CT features (mean AUC = 0.645), respectively. CONCLUSIONS: We comprehensively evaluated the performance of prediction model developed for recurrence following SBRT. The model in this study would provide information to predict the recurrence pattern and assist in making treatment strategies.

Development of a phantom for assessing the precision of setup in skin mark-less surface-guided radiotherapy.

BACKGROUND: Surface-guided radiotherapy (SGRT) is adopted by several institutions; however, reports on the phantoms used to assess the precision of the SGRT setup are limited. PURPOSE: The purpose of this study was to develop a phantom to verify the accuracy of the irradiation position during skin mark-less SGRT. METHODS: An acrylonitrile butadiene styrene (ABS) plastic cube phantom with a diameter of 150 mm on each side containing a dummy target of 15 mm and two types of body surface-shaped phantoms (breast/face shape) that could be attached to the cube phantom were fabricated. Films can be inserted on four sides of the cubic phantom (left, right, anterior and posterior), and the center of radiation can be calculated by irradiating the dummy target with orthogonal MV beams. Three types of SGRT using a VOXELAN-HEV600M (Electronics Research&Development Corporation, Okayama, Japan) were evaluated using this phantom: (i) SGRTCT-a SGRT set-up based solely on a computed tomography (CT)-reference image. (ii) SGRTCT + CBCT-a method where cone beam computed tomography (CBCT) matching was performed after SGRTCT. (iii) SGRTScan-a resetup technique using a scan reference image obtained after completing the (ii) step. RESULTS: Both the breast and face phantoms were recognized in the SGRT system without problems. SGRTScan ensure precision within 1 mm/1° for breast and face verification, respectively. All SGRT methods showed comparable rotational accuracies with no significant disparities. CONCLUSIONS: The developed phantom was useful for verifying the accuracy of skin mark-less SGRT position matching. The SGRTScan demonstrated the feasibility of achieving skin-mark less SGRT with high accuracy, with deviations of less than 1 mm. Additional research is necessary to evaluate the suitability of the developed phantoms for use in various facilities and systems. This phantom could be used for postal surveys in the future.

The Ki67 index evaluation of pancreatic neuroendocrine tumors using 3D immunohistochemistry in small tissue specimens.

BACKGROUND: /Objectives: This study aimed to evaluate the usefulness of three-dimensional (3D) immunohistochemistry for the Ki67 index of small tissue specimens of pancreatic neuroendocrine tumor (PanNET). METHODS: Clinicopathological materials from 17 patients with PanNET who underwent surgical resection at Jichi Medical University Hospital were analyzed. We compared the Ki67 index of endoscopic ultrasonography-fine-needle aspiration biopsy (EUS-FNAB) specimens, surgical specimens, and small tissue specimens hollowed from paraffin blocks of surgical specimens that were substituted for EUS-FNAB specimens ("sub-FNAB"). The sub-FNAB specimens were optically cleared using LUCID (IlLUmination of Cleared organs to IDentify target molecules) and analyzed using 3D immunohistochemistry. RESULTS: The median Ki67 index in FNAB, sub-FNAB, and surgical specimens with conventional immunohistochemistry were 1.2% (0.7-5.0), 2.0% (0.5-14.6), and 5.4% (1.0-19.4), respectively. The median Ki67 index in sub-FNAB specimens with tissue clearing was calculated separately using the total number of cells on multiple images ("multiple slice"), with the image of the fewest positive cells ("coldspot"), and with the image of most positive cells ("hotspot"), which were 2.7% (0.2-8.2), 0.8% (0-4.8), and 5.5% (2.3-12.4), respectively. PanNET grade evaluated for the hotspot of the surgical specimens was significantly more consistent with those of the hotspot than multiple images of sub-FNAB specimens (16/17 vs. 10/17, p = 0.015). Hotspot evaluation using 3D immunohistochemistry of the sub-FNAB specimens showed agreement with the assessment of the surgical specimens (Kappa coefficient: 0.82). CONCLUSIONS: Tissue clearing and 3D immunohistochemistry for the Ki67 index can potentially improve the preoperative evaluation of EUS-FNAB specimens of PanNET in routine clinical practice.

Development of a dynamic motion platform with two independent drive systems for radiotherapy.

BACKGROUND: There are some motion platforms for radiotherapy quality assurance. However, no platform with two drive systems that can move along three axes is available. PURPOSE: The purpose of this study is to develop a dynamic motion platform with two drive systems capable of three-axis motion and to evaluate its motion performance. METHODS: The developed moving platform had two drive systems that use the same equipment. Each axis of the platform used can support a maximum load of 10 kg. The motors for moving the platform in each direction are capable of a drive stroke up to 40 mm. The drive speed is 30 mm/s at maximum load fluctuation. To evaluate the static positional accuracy of this system with an arbitrary input movement, the XYZ position of each axis was measured using a coordinate measuring machine operating from 0 to 40 mm at 10 mm intervals. In addition, the accuracy of dynamic motion was verified with Sine waveform inputs of different patterns to the three axes for approximately 60 s, and they were compared with the resulting detected signals by SyncTrax. RESULTS: The two drive systems were successfully operated on three axes by using independent control systems. For static position, the accuracies were within 0.2 mm, 0.05 mm, and 0.14 mm for lateral, longitudinal, and vertical directions, respectively. For dynamic motion, the mean absolute errors in the X, Y, and Z axes between the platform inputs and SyncTrax detected signals were 0.14 ± 0.10 mm, 0.16 ± 0.12 mm, and 0.16 ± 0.11 mm, respectively. CONCLUSIONS: A new dynamic platform for radiation therapy with two drive systems capable of three-axis motion was developed, and the positional accuracy of the drive axes was confirmed to be less than 0.2 mm.

Evaluation of computed tomography metal artifact and CyberKnife fiducial recognition for novel size fiducial markers.

PURPOSE: This study aimed to compare fiducial markers used in CyberKnife treatment in terms of metal artifact intensity observed in CT images and fiducial recognition in the CyberKnife system affected by patient body thickness and type of marker. METHODS: Five markers, ACCULOC 0.9 mm × 3 mm, Ball type Gold Anchor (GA) 0.28 mm × 10 mm, 0.28 mm × 20 mm, and novel size GA 0.4 mm × 10 mm, 0.4 mm × 20 mm were evaluated. To evaluate metal artifacts of CT images, two types of CT images of water-equivalent gels with each marker were acquired using Aquilion LB CT scanner, one applied SEMAR (SEMAR-on) and the other did not apply this technique (SEMAR-off). The evaluation metric of artifact intensity (MSD ) which represents a variation of CT values were compared for each marker. Next, 5, 15, and 20 cm thickness of Tough Water (TW) was placed on the gel under the condition of overlapping the vertebral phantom in the Target Locating System, and the live image of each marker was acquired to compare fiducial recognition. RESULTS: The mean MSD of SEMAR-off was 78.80, 74.50, 97.25, 83.29, and 149.64 HU for ACCULOC, GA0.28 mm × 10 mm, 20 mm, and 0.40 mm × 10 mm, 20 mm, respectively. In the same manner, that of SEMAR-on was 23.52, 20.26, 26.76, 24.89, and 33.96 HU, respectively. Fiducial recognition decreased in the order of 5, 15, and 20 cm thickness, and GA 0.4 × 20 mm showed the best recognition at thickness of 20 cm TW. CONCLUSIONS: We demonstrated the potential to reduce metal artifacts in the CT image to the same level for all the markers we evaluated by applying SEMAR. Additionally, the fiducial recognition of each marker may vary depending on the thickness of the patient's body. Particularly, we showed that GA 0.40 × 20 mm may have more optimal recognition for CyberKnife treatment in cases of high bodily thickness in comparison to the other markers.

Reproducibility of deep inspiration breath-hold technique for left-side breast cancer with respiratory monitoring device, Abches.

PURPOSE: This study aimed to evaluate the reproducibility of deep inspiration breath-hold (DIBH) using a respiratory control device, Abches, in patients with left-sided breast cancer. MATERIAL AND METHODS: Abches comprises a main body, an indicator panel, and two fulcrums, one each on the chest and abdomen. Forty left side breast cancer patients treated with DIBH using abches were enrolled in this study. For all patients, CT images were taken three times to confirm the target position inside the body and to check the breath-hold reproducibility. Three anatomical points on the nipple, sternum, and heart were selected as measurement points on CT images. After measuring the coordinates, breath-hold reproducibility was defined as the mean of the absolute difference in the coordinates between the three CT images. The maximum differences were also investigated. In addition, the dice similarity coefficient (DSC) was calculated to examine the displacement of the heart volume in detail. Moreover, digitally reconstructed radiographs (DRRs) and linac graphs (LGs) were used to measure the positional accuracy of the chest and heart. RESULTS: The reproducibility in all patients was within 0.75 mm for the nipple, 0.78 mm for the sternum, and 2.18 mm for the heart in each direction. Similarly, the maximum displacements for all patients were within 1.90 mm, 1.69 mm, and 4.75 mm, respectively, in each direction. For heart volume, the average DSC for all cases was 0.93 ± 0.01. The differences between the DRR and LG images were 1.70 ± 1.10 mm and 2.10 ± 1.60 mm, for the chest and heart, respectively. CONCLUSION: Our study showed that DIBH using Abches can be performed with good target reproducibility of less than 3 mm with proper breath-hold practice, whereas the heartbeat-derived reproducibility of the cardiac position is poor and needs to be monitored carefully during treatment simulation.

Quantification of image quality of intra-fractional cone-beam computed tomography for arc irradiation with various imaging condition.

BACKGROUND: 3-dimensional intra-cone beam computed tomography (intra-CBCT ) could be a potentially powerful tool for use with arc irradiation such as volumetric modulated arc therapy. The aim of the study was to evaluate the image quality of intra-cone beam computed tomography (intra-CBCT ) for arc irradiation with various imaging condition. MATERIALS AND METHODS: Two types of intra-CBCT imaging techniques were evaluated - intra-fractional CBCT with flattening filtered (FF) beam (intra-FF CBCT ) and that with flattening filter free (FFF) beam (intra-FFF CBCT ). For the intra-MV beams, four different field sizes (2 cm × 2 cm, 5 cm × 5 cm, 10 cm × 10 cm, and 20 cm × 20 cm) were used with dose rates of 500 MU/min and 1600 MU/min, for 6 MV FF and 6 MV FFF, respectively. For all image acquisitions, two rotation angles (full-arc and half-arc) were investigated. Thereafter, the linearity, contrast-to-noise ratio (CNR), and uniformity index (UI) of intra-CBCT image were compared with those of conventional CBCT image. RESULTS: All acquisition conditions had good linearity of the CT value (R2 > 0.99). For CNR, the change rates from conventional CBCT ranged from 0.6-33.7% for a 2 cm × 2 cm beam, whereas that for a 20 cm × 20 cm beam ranged from 62.7-82.3%. Similarly, the UI increased from 1.5% to 7.0% as the field size increased. CONCLUSION: Quality of intra-CBCT image was affected by the field size and acquisition angle. Image quality of intra-CBCT was worse than that of conventional CBCT, but it was better under a smaller field and wider correction angle and would be acceptable for clinical use.

Effect of a hydrogel spacer on the intrafractional prostate motion during CyberKnife treatment for prostate cancer.

The purpose of this study was to evaluate the effect of a hydrogel spacer on intrafractional prostate motion during CyberKnife treatment. The retrospective study enrolled 24 patients (with the hydrogel spacer = 12, without the hydrogel spacer = 12) with two fiducial markers. Regarding intrafractional prostate motion, the offset values (mm) of three axes (X-axis; superior [+] to inferior [-], Y-axis; right [+] to left [-], Z-axis; posterior [+] to anterior [-]) obtained from fiducial markers position between a digitally reconstructed radiographs images and live images in the Target Locating System were used, and extracted from generated log files. The mean values of the offset and each standard deviation were calculated for each patient, and both the groups were compared. For all the patients, a total of 2204 offset values and timestamps (without the hydrogel spacer group: 1065, with the hydrogel spacer group: 1139) were recorded for the X-, Y-, and Z-axes, respectively. The offset values (mean ± standard deviation) for the X-, Y-, and Z-axes were -0.04 ± 0.92 mm, -0.03 ± 0.97 mm (P = 0.66), 0.02 ± 0.51, -0.02 ± 0.49 mm (P = 0.50), and 0.56 ± 0.97 mm, 0.34 ± 1.07 mm (P = 0.14), in patients inserted without or with the hydrogel spacer, respectively. There was no effect of a hydrogel spacer on the intrafractional prostate motion in the three axes during CyberKnife treatment for prostate cancer.

Evaluation of the target dose coverage of stereotactic body radiotherapy for lung cancer using helical tomotherapy: A dynamic phantom study.

AIM: To evaluate the target dose coverage for lung stereotactic body radiotherapy (SBRT) using helical tomotherapy (HT) with the internal tumor volume (ITV) margin settings adjusted according to the degree of tumor motion. BACKGROUND: Lung SBRT with HT may cause a dosimetric error when the target motion is large. MATERIALS AND METHODS: Two lung SBRT plans were created using a tomotherapy planning station. Using these original plans, five plans with different ITV margins (4.0-20.0 mm for superior-inferior [SI] dimension) were generated. To evaluate the effects of respiratory motion on HT, an original dynamic motion phantom was developed. The respiratory wave of a healthy volunteer was used for dynamic motion as the typical tumor respiratory motion. Five patterns of motion amplitude that corresponded to five ITV margin sizes and three breathing cycles of 7, 14, and 28 breaths per minute were used. We evaluated the target dose change between a static delivery and a dynamic delivery with each motion pattern. RESULTS: The target dose difference increased as the tumor size decreased and as the tumor motion increased. Although a target dose difference of <5 % was observed at ≤10 mm of tumor motion for each condition, a maximum difference of -9.94 % ± 7.10 % was observed in cases of small tumors with 20 mm of tumor motion under slow respiration. CONCLUSIONS: Minimizing respiratory movement is recommended as much as possible for lung SBRT with HT, especially for cases involving small tumors.

Comparison of CT artifacts and image recognition of various fiducial markers including two types of thinner fiducial markers for CyberKnife treatment.

AIM: The aim of the study was to evaluate computed tomography (CT) artifacts and image recognition of the CyberKnife system. Regarding fiducial markers, VISICOIL of 0.5 mm × 5.0 mm and 0.75 mm × 5.0 mm, ball-shaped Gold Anchor (GA) of 0.28 mm × 10 mm and 0.28 mm × 20 mm, were compared with the standard cylinder marker of 0.9 mm × 3.0 mm (ACCULOC). BACKGROUND: Recently, various kinds of commercial fiducial markers have been available in CyberKnife treatment. MATERIALS AND METHODS: The CT images of a water equivalent gel with each fiducial marker were acquired for the evaluation of CT artifacts. The evaluation was performed using the standard deviation of Hounsfield Unit (HU) value for a rectangle region near the fiducial marker. Then, to evaluate the image recognition, each fiducial marker was located to overlap in the target locating system (TLS) for the two sites; the vertebral bone and the pubic bone. RESULTS: For CT artifacts, the standard deviations of the VISICOIL of 0.5 mm × 5.0 mm was the smallest. The image recognition of four fiducial markers had a value close to the standard cylinder marker and was feasible for common use, but was slightly poorer when using GA of 0.28 mm × 10 mm in the dynamic conditions. CONCLUSION: Our results indicated that VISICOIL 0.5 × 5.0 mm and the GAs can be used nearly always for CyberKnife treatment in spite of their much thinner needles than those of cylinder types.

Absence of H3F3A mutation in a subset of malignant giant cell tumor of bone.

Giant cell tumor of bone typically involves the epiphysis of the long bones of skeletally mature patients. It is genetically characterized by highly recurrent and specific mutations of the H3F3A gene, which encodes histone H3.3. The most common mutation H3F3A G34W can readily be detected by a recently developed mutation-specific antibody. Giant cell tumor of bone rarely transforms to a sarcoma (malignant giant cell tumor of bone), which has not been genetically characterized in detail. We studied seven clinicopathologically defined malignant giant cell tumors, as well as two H3F3A-mutant bone sarcomas without giant cell tumor histology using a combination of clinicopathological, immunohistochemical, and molecular methods (Sanger sequencing + pyrosequencing or next generation sequencing). The cases included five men and four women, with a median age at initial diagnosis of 27 years. The two H3F3A G34W-positive sarcomas without giant cell tumor histology involved the subarticular epiphyseal sites, suggesting relatedness with giant cell tumor of bone. In two of the seven clinicopathologically defined malignant giant cell tumor cases, the sarcoma tissue showed the H3F3A G34W mutation. However, in the remaining five cases, in contrast to their associated H3F3A G34W-mutant giant cell tumor, the sarcoma lacked the H3F3A G34W mutation, either entirely or sub-clonally in the samples tested. This discordant mutation status was confirmed in all instances by immunohistochemistry and sequencing. A FISH analysis suggested that the absence of the H3F3A G34W mutation may be related to deletion of the H3F3A gene. Therefore, we have demonstrated that H3F3A G34W mutation, a critical driver in giant cell tumor, is absent in a subset of malignant giant cell tumor of bone. This novel recurrent phenomenon has potential biological and diagnostic implications, and further study is required to better characterize this progression pathway and understand its mechanism.

Remnant pancreatic volume as an indicator of poor prognosis in pancreatic cancer patients after resection.

BACKGROUND: Remnant pancreatic volume (RPV) is a well-known marker for short-term outcomes in pancreatic cancer patients after resection. However, in terms of the long-term outcomes, the significance of the RPV value remains unclear. Here, we address whether the RPV value is a predictor of the long-term outcomes in pancreatic cancer patients after resection by comparing various cancer-, patient-, and surgery-related prognostic factors and systemic inflammatory response markers in a retrospective cohort. METHODS: The RPV was measured on a three-dimensional (3D) image, revealing the actual pancreatic parenchymal remnant volume. Ninety-one patients who underwent pancreaticoduodenectomy were retrospectively enrolled. We divided the cohort into high- and low-RPV groups based on a cut-off value (>31.5 cm3, n = 66 and ≤31.5 cm3, n = 25, respectively). The median survival times (MSTs) were compared between the two groups. Using multivariate analysis, the RPV and other well-known prognostic factors were independently assessed. RESULTS: The MSTs (days) were significantly different between the two groups (high, 823 vs. low, 482, p = 0.001). Multivariate analysis identified the RPV (≤31.5 cm3) (hazard ratio [HR], 2.015; p = 0.011), lymph node metastasis (HR, 8.415; p = 0.002), lack of adjuvant chemotherapy (HR, 5.352; p < 0.001), stage III/IV disease (HR, 2.352; p = 0.029), and pathological fibrosis (HR, 1.771; p = 0.031) as independent prognostic factors. CONCLUSIONS: The present study suggests that the RPV value is also useful for predicting long-term outcomes in pancreatic cancer patients after resection.

Comparison of MLC error sensitivity of various commercial devices for VMAT pre-treatment quality assurance.

The purpose of this study was to compare the MLC error sensitivity of various measurement devices for VMAT pre-treatment quality assurance (QA). This study used four QA devices (Scandidos Delta4, PTW 2D-array, iRT systems IQM, and PTW Farmer chamber). Nine retrospective VMAT plans were used and nine MLC error plans were generated for all nine original VMAT plans. The IQM and Farmer chamber were evaluated using the cumulative signal difference between the baseline and error-induced measurements. In addition, to investigate the sensitivity of the Delta4 device and the 2D-array, global gamma analysis (1%/1, 2%/2, and 3%/3 mm), dose difference (1%, 2%, and 3%) were used between the baseline and error-induced measurements. Some deviations of the MLC error sensitivity for the evaluation metrics and MLC error ranges were observed. For the two ionization devices, the sensitivity of the IQM was significantly better than that of the Farmer chamber (P < 0.01) while both devices had good linearly correlation between the cumulative signal difference and the magnitude of MLC errors. The pass rates decreased as the magnitude of the MLC error increased for both Delta4 and 2D-array. However, the small MLC error for small aperture sizes, such as for lung SBRT, could not be detected using the loosest gamma criteria (3%/3 mm). Our results indicate that DD could be more useful than gamma analysis for daily MLC QA, and that a large-area ionization chamber has a greater advantage for detecting systematic MLC error because of the large sensitive volume, while the other devices could not detect this error for some cases with a small range of MLC error.

Protecting liver sinusoidal endothelial cells suppresses apoptosis in acute liver damage.

AIM: Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. METHODS: Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. RESULTS: Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group. CONCLUSION: Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure.

Donor cell leukemia with bone marrow necrosis.

A 60-year-old man with myelodysplastic syndrome underwent allogeneic transplantation of female umbilical cord blood in 2010 and sustained a complete remission. He experienced severe pain in his left hip joint and was admitted to the orthopedic surgery division of our institution in February 2015. After admission, he was suspected to have hemophagocytic syndrome (HPS) and was thus transferred to the hematology division. Bone marrow aspiration revealed hyper-cellular marrow filled with abnormal collapsed cells, consistent with bone marrow necrosis (BMN). As there was no evidence of infection, collagen disease, or occult cancer, he was diagnosed with HPS of unknown origin and treated with dexamethasone, cyclosporine A, and etoposide according to the HLH-2004 protocol. Although his general condition and laboratory findings showed amelioration, morphologically abnormal cells appeared in peripheral blood two weeks after treatment. Bone marrow aspiration showed BMN with increased abnormal cells, positive for CD117 and MPO. Sex chromosome FISH analysis revealed donor chimerism and cytogenetic analysis showed 46XX, +1, der (1;7) (q10;q10). He was diagnosed with donor cell leukemia (DCL) and received salvage chemotherapy. However, he died because of severe pneumonia and sepsis without neutrophil recovery at day 68. We herein report this rare case of DCL with BMN.

Sphingosine 1-phosphate has anti-apoptotic effect on liver sinusoidal endothelial cells and proliferative effect on hepatocytes in a paracrine manner in human.

AIM: Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite released from erythrocytes and platelets, and is a potent stimulus for endothelial cell proliferation. However, the role of S1P on human liver sinusoidal endothelial cells (LSEC) remains unclear. The proliferation and inhibition of apoptosis in LSEC are involved in the promotion of liver regeneration and the suppression of liver injury after liver resection and transplantation. The aim of this study is to investigate the role of S1P on human LSEC and the interaction between S1P and LSEC in hepatocyte proliferation in vitro. METHODS: Immortalized human LSEC were used. LSEC were cultured with S1P, and the cell proliferation, anti-apoptosis, signal transductions and production of cytokines and growth factors were subsequently examined. To investigate the interaction between S1P and LSEC in hepatocyte proliferation, primary human hepatocytes were cultured with the supernatants of LSEC with and without S1P. DNA synthesis and signal transductions in hepatocytes were examined. RESULTS: S1P induced LSEC proliferation through activation of Akt and extracellular signal-related kinase pathways and suppressed LSEC apoptosis by affecting the expression levels of Bcl-2, Bax and cleaved caspase-3. S1P promoted interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) production in LSEC. The supernatants of LSEC cultured with S1P enhanced hepatocyte DNA synthesis more strongly than the supernatants of LSEC cultured without S1P through activation of the signal transducer and activator of transcription-3 pathway. CONCLUSION: S1P has proliferative and anti-apoptotic effects and promotes the production of IL-6 and VEGF in human LSEC, thereby promoting hepatocyte proliferation.

1,8-Cineole Ameliorates Steatosis of Pten Liver Specific KO Mice via Akt Inactivation.

Hepatocyte-specific Phosphatase and tensin homolog (Pten)-knockout (KO) mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). 1,8-cineole is a monoterpene oxide and it has several biological effects including hepatoprotective effects. In this study we revealed that 1,8-cineole ameliorates NASH of Pten KO mice. Pten KO mice were assigned to a control group without any medication or to a 1,8-cineole group injected with 50 mg/kg i.p. twice per week for eight weeks. At eight weeks, livers from each group were processed to measure triglyceride (TG) content, gene expression analysis, western blot analysis, and histological examination including Oil red O staining. 1,8-cineole ameliorated hepatic steatosis in Pten KO mice, revealed by TG content and Oil red O staining. Moreover, 1,8-cineole downregulated collagen 1a1 expression and improved liver fibrosis. Thus, 1,8-cineole has potential as a candidate to treat NASH by inactivating the Akt/PI3-kinase pathway.

Evaluation of a New Method for CyberKnife Treatment for Central Lung and Mediastinal Tumors by Tracheobronchial Tracking.

BACKGROUND: CyberKnife treatment for central lung tumors and mediastinal tumors can be difficult to perform with marker less. PURPOSE: We aimed to evaluate a novel tracheobronchial-based method (ie, tracheobronchial tracking) for the purpose of minimally invasive CyberKnife treatment for central lung and mediastinal tumors. METHODS: Five verification plans were created using an in-house phantom. Each plan included five irradiation sessions. The reference plan irradiated and tracked the simulated tumor (using the target tracking volume, TTV). Trachea plans tracked the simulated tracheo-bronchus and irradiated the simulated tumor and included two types of subplans: correlated plans in which the displacement of the simulated tracheobronchial and the simulated tumor were correlated, and non-correlated plans in which these factors were not correlated. Moreover, 15 mm and 25 mm TTVs were evaluated for each plan. The sin waveform and the patient's respiratory waveform were prepared as the respiratory model. Evaluations were performed by calculating the dose difference between the radiophotoluminescent glass dosimeter (RPLD)-generated mean dose values (generated by the treatment planning system, TPS) and the actual absorbed RPLD dose. Statistical analyses were performed to evaluate findings for each plan. Correlation and prediction errors were calculated for each axis of each plan using log files to evaluate tracking accuracy. RESULTS: Dose differences were statistically significant only in comparisons with the non-correlated plan. When evaluated using the sin waveform, the mean values for correlation and prediction errors in each axis and for all plans were less than 0.6 mm and 0.1 mm, respectively. In the same manner, they were less than 1.1 mm and 0.2 mm when evaluated using the patient's respiratory waveform. CONCLUSION: Our newly-developed tracheobronchial tracking method would be useful in facilitating minimally invasive CyberKnife treatment in certain cases of central lung and mediastinal tumors.

Long-term experience in quality assurance of on-rail computed tomography systems for image-guided radiotherapy using in-house multifunctional phantoms.

To report the long-term quality assurance (QA) experience of an on-rail computed tomography (CT) system for image-guided radiotherapy using an in-house phantom. An on-rail CT system combining the Elekta Synergy and Canon Aquilion LB was used. The treatment couch was shared by the linear accelerators and CT, and the couch was rotated by 180° when using the on-rail-CT system to ensure that the CT direction was toward the head. All QA analyses were performed by radiation technologists on CBCT or on-rail CT images of the in-house phantom. The CBCT center accuracy from the linac laser, couch rotational accuracy (CBCT center vs. on-rail CT center), horizontal accuracy by CT gantry shift, and remote couch shift accuracy were evaluated. This study reported the QA status of the system during the period 2014-2021. The absolute mean accuracy of couch rotation was 0.4 ± 0.28 mm, 0.44 ± 0.36 mm, and 0.37 ± 0.27 mm in the SI, RL, and AP directions, respectively. Horizontal and remote movement accuracies of the treatment couch were also within 0.5 mm of the absolute mean value. A decrease in the accuracy of couch rotation was also observed due to aging deterioration of related parts caused by the frequent use of couch rotation. The three-dimensional accuracy of on-rail CT systems derived mainly from treatment couches can be maintained within 0.5 mm with appropriate accuracy assurance for at least > 8 years.