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The uncertainties of four-dimensional computed tomography (4DCT), also called as residual motion artefacts (RMA), induced from irregular respiratory patterns can degrade the quality of overall radiotherapy. This study aims to quantify and reduce those uncertainties. A comparative study on quantitative indicators for RMA was performed, and based on this, we proposed a new 4DCT sorting method that is applicable without disrupting the current clinical workflow. In addition to the default phase sorting strategy, both additional amplitude information from external surrogates and the quantitative metric for RMA, investigated in this study, were introduced. The comparison of quantitative indicators and the performance of the proposed sorting method were evaluated via 10 cases of breath-hold (BH) CT and 30 cases of 4DCT. It was confirmed that N-RMSD (normalised root-mean-square-deviation) was best matched to the visual standards of our institute's regime, manual sorting method, and could accurately represent RMA. The performance of the proposed method to reduce 4DCT uncertainties was improved by about 18.8% in the averaged value of N-RMSD compared to the default phase sorting method. To the best of our knowledge, this is the first study that evaluates RMA indicators using both BHCT and 4DCT with visual-criteria-based manual sorting and proposes an improved 4DCT sorting strategy based on them., Competing Interests: The authors have declared that no competing interests exist.

Purpose: More than half of patients with bile duct cancer (BDC) develop recurrence even after curative resection. Recurrent BDC has a poor prognosis, and no optimal treatment modality has been established. We therefore analyzed our experience on the survival outcomes of radiation therapy (RT) for recurrent extrahepatic bile duct cancer (EHBDC)., Patients and Methods: We retrospectively analyzed the records of patients with recurrent EHBDC who underwent concurrent chemoradiation therapy (CCRT) or RT alone at our institution between January 2001 and June 2015. Freedom from locoregional progression (FFLP), progression-free survival (PFS), and overall survival (OS) were assessed, and univariate and multivariate analyses were performed to identify the prognostic factors., Results: A total of 76 patients were included in the analysis. The median OS was 16 months and the rates of 2-year FFLP, PFS, and OS were 61%, 25%, and 33%, respectively. Among the evaluable patients, the first site of failure was the locoregional area in 16 patients, distant metastasis in 27, and both sites in 8. On univariate analysis, disease-free interval (p = 0.012) and concurrent chemotherapy (p = 0.040) were found as significant prognostic factors for OS. One patient with CCRT developed a grade 3 hematologic toxicity, and two patients experienced late grade 3 toxicities including duodenal ulcer bleeding and obstruction., Conclusions: RT for recurrent EHBDC showed favorable survival and local control with limited treatment-related toxicities. Considering that the most common pattern of failure was distant metastasis, further studies on the optimal scheme of chemotherapy and RT are warranted., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Stereotactic body radiation therapy (SBRT) is a promising treatment modality for locally advanced pancreatic cancer (LAPC). We evaluated the clinical outcomes of SBRT in patients with LAPC., Patients and Methods: We retrospectively analyzed the medical records of patients with LAPC who underwent SBRT at our institution between April 2011 and July 2016. Fiducial markers were implanted using endoscopic ultrasound guidance one week prior to 4-dimensional computed tomography (CT) simulation and daily cone beam CT was used for image guidance. Patients received volumetric modulated arc therapy or intensity modulated radiotherapy using respiratory gating technique. A median dose of 28 Gy (range, 24-36 Gy) was given over four consecutive fractions delivered within one week. Survival outcomes including freedom from local disease progression (FFLP), progression-free survival (PFS), and overall survival (OS) were analyzed. Acute and late toxicities related to SBRT were assessed., Results: A total of 95 patients with LAPC were analyzed, 52 of which (54.7%) had pancreatic head cancers. Most (94.7%) had received gemcitabine-based chemotherapy. The 1-year FFLP rate was 80.1%. Median OS and PFS were 16.7 months and 10.2 months, respectively; the 1-year OS and PFS rates were 67.4% and 42.9%, respectively. Among 79 patients who experienced failure, the sites of first failures were isolated local progressions in 12 patients (15.2%), distant metastasis in 55 patients (69.6%), and both in 12 patients (15.2%). Seven patients (7.4%) were able to undergo surgical resection after SBRT and four had margin-negative resections. Three patients (3.2%) had grade 3 nausea/vomiting during SBRT, and late grade 3 toxicity was observed in another three patients., Conclusions: LAPC patients who received chemotherapy and SBRT had favorable FFLP and OS with minimal treatment-related toxicity. The most common pattern of failure was distant metastasis, which warrants further studies on the optimal scheme of chemotherapy and SBRT., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To develop a 4D dose reconstruction method and to evaluate the delivered dose in respiratory-gated volumetric modulated arc therapy (VMAT)., Materials and Methods: A total 112 treatment sessions of gated VMAT for 30 stereotactic body radiotherapy (SBRT) patients (10 lung, 10 liver, and 10 pancreas) were evaluated. For respiratory-gated SBRT, 4DCT was acquired, and the CT data at the end-exhale phase was used for a VMAT plan. The delivered dose was reconstructed using a patient's respiratory motion and machine motion acquired during the beam delivery. The machine motion was obtained from the treatment log file, while the target position was estimated from an external respiratory marker position. The target position was divided into 1-mm position bins, and sub-beams with beam isocenters corresponding to each position bin were created in a motion mimicking plan, reflecting motion data including MLC leaf positions and gantry angle and target position data during beam treatment. The reconstructed 4D dose was compared with the dose of the original plan using these dosimetric parameters; the maximum dose (Dmax) and mean dose (Dmean) of gross target volume (GTV) or organs at risk (spinal cord, esophagus, heart, duodenum, kidney, spinal cord, and stomach). The minimum dose (Dmin) to GTV was also calculated to verify cold spots in tumors., Results: There was no significant difference of dose parameters regard to the GTV in all tumors. For the liver cases, there were significant differences in the Dmax of duodenum (-4.2 ± 1.4%), stomach (-3.5 ± 4.2%), left kidney (-4.1 ± 2.8%), and right kidney (-3.2 ± 1.3%), and in the Dmean of duodenum (-3.8 ± 1.4%), stomach (-3.9 ± 2.2%), left kidney (-3.1 ± 2.8%), and right kidney (-4.1 ± 2.6%). For the pancreas cases, there were significant differences in the Dmax of stomach (2.1 ± 3.0%), and in the Dmean of liver (1.5 ± 0.6%), duodenum (-1.0 ± 1.4%), stomach (2.1 ± 1.6%), and right kidney (-1.3 ± 0.9%). The average gamma pass rates were 97.6 ± 4.8% for lung cases, 99.6 ± 0.5% for liver cases, and 99.5 ± 0.5% for pancreas cases. Most cases showed insignificant dose variation, with gamma pass rates higher than 98%, except for two lung cases with gamma pass rates of 86.9% and 90.6%. The low gamma pass rates showed larger global motion ranges resulting from the baseline shift during beam delivery., Conclusion: The actual delivered dose in thoracic and abdominal VMAT under breathing motion was verified by 4D dose reconstruction using typical treatment equipment and software. The proposed method provides a verification method for the actual delivered dose and could be a dosimetric verification QA tool for radiation treatment under various respiratory management techniques., Competing Interests: The authors have declared that no competing interests exist.

[This corrects the article DOI: 10.1371/journal.pone.0191075.].

Plants have attracted attention as bio-drug production platforms because of their economical and safety benefits. The preliminary efficacy of ZMapp, a cocktail of antibodies produced in N. benthamiana (Nicotiana benthamiana L.), suggested plants may serve as a platform for antibody production. However, because the amino acid sequences of the Fab fragment are diverse and differences in post-transcriptional processes between animals and plants remain to be elucidated, it is necessary to confirm functional equivalence of plant-produced antibodies to the original antibody. In this study, Obinutuzumab, a third generation anti-CD20 antibody, was produced in N. benthamiana leaves (plant-obinutuzumab) and compared to the original antibody produced in glyco-engineered Chinese hamster ovary (CHO) cells (CHO-obinutuzumab). Two forms (with or without an HDEL tag) were generated and antibody yields were compared. The HDEL-tagged form was more highly expressed than the non-HDEL-tagged form which was cleaved in the N-terminus. To determine the equivalence in functions of the Fab region between the two forms, we compared the CD20 binding affinities and direct binding induced cell death of a CD20-positive B cells. Both forms showed similar CD20 binding affinities and direct cell death of B cell. The results suggested that plant-obinutuzumab was equivalent to CHO-obinutuzumab in CD20 binding, cell aggregation, and direct cell death via binding. Therefore, our findings suggest that Obinutuzumab is a promising biosimilar candidate that can be produced efficiently in plants.

Objective: Stereotactic body radiation therapy (SBRT) for the treatment of a malignancy in the liver requires the perilesional implantation of fiducial markers for lesion detection. The purpose of this study is to evaluate the efficacy and safety of ultrasound (US) -guided marker implantation for SBRT., Methods: We retrospectively reviewed 299, US-guided, intrahepatic fiducial markers implanted in 101 patients between November 2013 and September 2014. SBRT-planning CT images were analyzed to determine the technical success of the implantation, the mean distance between the tumor margin and the marker, with the ideal location of fiducials defined as the distance between a marker and a tumor less than 3 cm and the distance between markers greater than 2 cm according to the tumor conspicuity seen on gray-scale US and the artifact obscuring tumor margins. We also evaluated procedure-related major and minor complications., Results: Technical success was achieved in 291 (97.3%) fiducial marker implantations. The mean distance between the tumor and the marker was 3.1 cm (S.D., 2.1 cm; range, 0-9.5 cm). Of 101 patients, 72 lesions (71.3%, 2.2 ± 1.0 cm; range, 0-3.0 cm) had fiducial markers located in an ideal location. The ideal location of fiducials was more common in visible lesions than in poorly conspicuous lesions (90.2% vs. 52.0%, P < 0.001). Seventeen markers (5.8%) developed beam-hardening artifacts obscuring the tumor margins. There were no major complications, although 12 patients (11.9%) developed minor complications., Conclusions: US-guided implantation of fiducial markers in the liver is an effective and safe procedure with only rare complications.

Purpose: To assess the potential dosimetric benefits associated with the CyberKnife (CK) tumor tracking capability, wherein an extra margin for respiratory tumor motion is not required, when compared to respiratory-gated volumetric-modulated arc therapy (VMAT) for hepatocellular carcinoma (HCC)., Methods: Twenty-nine HCC patients previously treated with double-arc VMAT were enrolled. In each VMAT plan, the individual internal target volume (ITV) margin around the tumor was determined by measuring its motion over 30-70% of respiratory phases using four-dimensional computed tomography, followed by a 5-mm isotropic margin for the planning target volume (PTV). For each VMAT plan, two CK plans were generated using the original (CKoriginal, ITV included) and modified PTVs (CKmodified, ITV excluded) for comparison. In each case, the CKoriginal and CKmodified plans were compared to the original VMAT plan in terms of the dosimetric parameters including the conformity index (CI), PTV coverage (CO), organs at risk (OAR) doses, and normal liver tissue sparing., Results: The original PTVs with median 24 cc (range, 9-65 cc) were significantly reduced to median 12 cc (range, 5-41 cc) in the CKmodified plans. Statistically significant differences in plan qualities were observed between the VMAT and the CK plans: mean CI, 1.05 in VMAT vs. 1.17 in both CK plans (p < 0.001); and mean CO, 93.0% in VMAT vs. 96.6% in CKoriginal and 96.9% in CKmodified (p < 0.001). The average volume of normal liver tissue receiving > 15 Gy was significantly decreased in the CKmodified plan, as compared to that in the VMAT and CKoriginal plans, by 1.75- and 1.61-fold, respectively., Conclusions: The tumor tracking capability of the CK system can significantly decrease the volume of normal liver tissue receiving > 15 Gy, while maintaining high precision in target localization, conformity, tumor coverage, and dose sparing of the OAR. Therefore, it can be a valuable SBRT option, particularly for HCC patients with poor liver function., Competing Interests: The authors declare that no competing interests exist.

Although the adrenal glands are not common sites of metastasis from hepatocellular carcinoma (HCC), this metastasis can be met in patients with advanced HCC in some clinical settings. However, the effectiveness of radiotherapy against such metastases is unclear. Therefore, we performed the present multi-institutional study to investigate tumor response, overall survival (OS), treatment-related toxicity, and prognostic factors after radiotherapy. We retrospectively reviewed 134 patients who completed a planned radiotherapy for their adrenal metastases. Complete response was noted in 6 (4.3%), partial response in 48 (34.0%), and stable disease in 78 patients (55.3%). The median OS was 12.8 months, and the 1-, 2-, and 5-year OS rates were 53.1%, 23.9%, and 9.3%, respectively. Grade 3 anorexia occurred in 2 patients, grade 3 diarrhea in 1, and grade 3 fatigue in 1. Multivariate analyses revealed that the following factors had significant effects on OS: controlled intrahepatic tumor; controlled extrahepatic metastasis; and Child-Pugh class A. Although patients with adrenal metastasis from HCC had poor OS, radiotherapy provided an objective response rate of 38.3% and disease stability of 93.6%, with minimal adverse events. Therefore, radiotherapy for these patients could represent a good treatment modality, especially for patients with controlled intrahepatic tumors, controlled extrahepatic metastasis, and good hepatic function.

Background and Aim: To investigate the value of changes in alpha-fetoprotein (AFP) levels for the prediction of radiologic response and survival outcomes in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) who received combined treatment of 3-dimensional conformal radiotherapy (3D-CRT) and transarterial chemoembolization (TACE)., Methods: A database of 154 HCC patients with PVTT and elevated AFP levels (>20 ng/mL) treated with 3D-CRT and TACE as an initial treatment between August 2002 and August 2008 was retrospectively reviewed. AFP levels were determined 1 month after radiotherapy, and AFP response was defined as an AFP level reduction of >20% from the initial level. Radiologic response, overall survival (OS), and progression-free survival (PFS) rates were compared between AFP responders and non-responders. Propensity-score based matching analysis was performed to minimize the effect of potential confounding bias., Results: The median follow-up period was 11.1 months (range, 3.1-82.7 months). In the propensity-score matching cohort (92 pairs), a best radiologic response of CR or PR occurred in more AFP responders than AFP non-responders (41.3% vs. 10.9%, p < 0.001). OS and PFS were also longer in AFP responders than in non-responders (median OS 13.2 months vs. 5.6 months, p < 0.001; median PFS 8.7 months vs. 3.5 months, p < 0.001)., Conclusions: AFP response is a significant predictive factor for radiologic response. Furthermore, AFP response is significant for OS and PFS outcomes. AFP evaluation after combined radiotherapy and TACE appears to be a useful predictor of clinical outcomes in HCC patients with PVTT.

Purpose: To evaluate temporal changes in contrast enhancement patterns of non-tumorous hepatic parenchyma with a focus on arterial hypervascularity on multiphase computed tomography (CT) in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT)., Methods: We retrospectively identified 61 patients who had undergone multiphase contrast-enhanced CT at one, three, and six months after SBRT. Irradiated versus non-irradiated liver parenchyma was delineated by cross-correlation with the dose-volume histogram of SBRT plan. Serial changes in the contrast enhancement patterns of the irradiated versus non-irradiated liver parenchyma were evaluated by two abdominal radiologists in consensus. We compared the frequency of the contrast enhancement patterns according to the follow-up period using the Fisher-Freeman-Halton exact test., Results: The irradiated non-tumorous hepatic parenchyma showed that the prevalence of arterial hypervascularity increased during the follow-up period (P<.01): 11.5% (7/61) in one, 45.9% (28/61) in three, and 54.1% (33/61) in six months. Contrast wash-out on the delayed phase was uncommon: 1.6% (1/61) in one, 3.3% (2/61) in three, and 0% in six months., Conclusion: The incidence of arterial hypervascularity of the irradiated hepatic parenchyma gradually increased until six months after SBRT, which could interfere with the accurate evaluation of treatment response. The lack of wash-out on the delayed phase in the hypervascular area would distinguish SBRT-related change from residual/recurred HCC.

Background: Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment., Materials and Methods: A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT., Results: The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients' survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%)., Conclusions: SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.