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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.

PurposeThis study aimed to evaluate the dosimetric accuracy of respiratory gated volumetric modulated arc therapy (VMAT) for lung stereotactic body radiation therapy (SBRT) under simulation conditions similar to the actual clinical situation using patient-specific lung phantoms and realistic target movements.MethodsSix heterogeneous lung phantoms were fabricated using a 3D-printer (3DISON, ROKIT, Seoul, Korea) to be dosimetrically equivalent to actual target regions of lung SBRT cases treated via gated VMAT. They were designed to move realistically via a motion device (QUASAR, Modus Medical Devices, Canada). Using the lung phantoms and a homogeneous phantom (model 500-3315, Modus Medical Devices), film dosimetry was performed with and without respiratory gating for VMAT delivery (TrueBeam STx; Varian Medical Systems, Palo Alto, CA, USA). The measured results were analyzed with the gamma passing rates (GPRs) of 2%/1 mm criteria, by comparing with the calculated dose via the AXB and AAA algorithms of the Eclipse Treatment Planning System (version 10.0.28; Varian Medical Systems).ResultsGPRs were greater than the acceptance criteria 80% for all film measurements with the stationary and homogeneous phantoms in conventional QAs. Regardless of the heterogeneity of phantoms, there were no significant differences (p > 0.05) in GPRs obtained with and without target motions; the statistical significance (p = 0.031) was presented between both algorithms under the utilization of heterogeneous phantoms.ConclusionsDosimetric verification with heterogeneous patient-specific lung phantoms could be successfully implemented as the evaluation method for gated VMAT delivery. In addition, it could be dosimetrically confirmed that the AXB algorithm improved the dose calculation accuracy under patient-specific simulations using 3D printed lung phantoms.

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).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.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.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.

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).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.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).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.

Genomic changes frequently occur in cancer cells during tumorigenesis from normal cells. Using the Illumina Human NS-12 single-nucleotide polymorphism (SNP) chip to screen for gene copy number changes in primary hepatocellular carcinomas (HCCs), we initially detected amplification of 35 genes from four genomic regions (1q21-41, 6p21.2-24.1, 7p13 and 8q13-23). By integrated screening of these genes for both DNA copy number and gene expression in HCC and colorectal cancer, we selected CENPF (centromere protein F/mitosin), GMNN (geminin, DNA replication inhibitor), CDK13 (cyclin-dependent kinase 13), and FAM82B (family with sequence similarity 82, member B) as common cancer genes. Each gene exhibited an amplification frequency of ~30% (range, 20-50%) in primary HCC (n = 57) and colorectal cancer (n = 12), as well as in a panel of human cancer cell lines (n = 70). Clonogenic and invasion assays of NIH3T3 cells transfected with each of the four amplified genes showed that CENPF, GMNN, and CDK13 were highly oncogenic whereas FAM82B was not. Interestingly, the oncogenic activity of these genes (excluding FAM82B) was highly correlated with gene-copy numbers in tumor samples (correlation coefficient, r>0.423), indicating that amplifications of CENPF, GMNN, and CDK13 genes are tightly linked and coincident in tumors. Furthermore, we confirmed that CDK13 gene copy number was significantly associated with clinical onset age in patients with HCC (P = 0.0037). Taken together, our results suggest that coincidently amplified CDK13, GMNN, and CENPF genes can play a role as common cancer-driver genes in human cancers.

[This corrects the article DOI: 10.1371/journal.pone.0193321.].

Acral melanoma is the most common type of melanoma in Asians, and usually results in a poor prognosis due to late diagnosis. We applied a convolutional neural network to dermoscopy images of acral melanoma and benign nevi on the hands and feet and evaluated its usefulness for the early diagnosis of these conditions.A total of 724 dermoscopy images comprising acral melanoma (350 images from 81 patients) and benign nevi (374 images from 194 patients), and confirmed by histopathological examination, were analyzed in this study. To perform the 2-fold cross validation, we split them into two mutually exclusive subsets: half of the total image dataset was selected for training and the rest for testing, and we calculated the accuracy of diagnosis comparing it with the dermatologist's and non-expert's evaluation.The accuracy (percentage of true positive and true negative from all images) of the convolutional neural network was 83.51% and 80.23%, which was higher than the non-expert's evaluation (67.84%, 62.71%) and close to that of the expert (81.08%, 81.64%). Moreover, the convolutional neural network showed area-under-the-curve values like 0.8, 0.84 and Youden's index like 0.6795, 0.6073, which were similar score with the expert.Although further data analysis is necessary to improve their accuracy, convolutional neural networks would be helpful to detect acral melanoma from dermoscopy images of the hands and feet.

OBJECTIVES:A prospective, multicenter, randomized, double-blind, placebo-controlled trial evaluated the effects of naftopidil 75 mg for medical expulsive therapy for a single ureter stone. MATERIALS AND METHODS:Patients diagnosed with a ureter stone were prescribed aceclofenac 100 mg or a combined medication of tramadol 37.5 mg and acetaminophen 325 mg. Patients then randomly received either naftopidil 75 mg or placebo. Primary endpoint was the stone passage rate at 14 days after medication. RESULTS:The 150 patients enrolled in 6 institutions randomly received either naftopidil (n = 75) or placebo (n = 75). The percentages of ureter stone passed spontaneously 14 days after medication was 60.9% in the naftopidil group and 53.3% in the placebo group. Stone-free rates and the total use of analgesics showed no significant differences between the two groups. Stone-free rates at 14 days after medication were decreased when maximal stone size was increased: 39.4% (≥ 5 mm), 15.5% (≥ 6 mm), and 7.0% (≥ 7 mm). CONCLUSIONS:The use of naftopidil 75 mg once daily was not effective in increasing spontaneous stone passage rates or reducing analgesic use. The maximal stone size < 6 mm and the follow-up for two weeks would be appropriate for applying medical expulsive therapy to patients with a single ureter stone.

Significant functional impairment of the hand is commonly observed in stroke survivors. Our previous studies suggested that the inability to modulate muscle coordination patterns according to task requirements may be substantial after stroke, but these limitations have not been examined directly. In this study, we aimed to characterize post-stroke impairment in the ability to modulate muscle coordination patterns across tasks and its correlation with hand impairment. Fourteen stroke survivors, divided into a group with severe hand impairment (8 subjects) and a group with moderate hand impairment (6 subjects) according to their clinical functionality score, participated in the experiment. Another four neurologically intact subjects participated in the experiment to serve as a point of comparison. Activation patterns of nine hand and wrist muscles were recorded using surface electromyography while the subjects performed six isometric tasks. Patterns of covariation in muscle activations across tasks, i.e., muscle modules, were extracted from the muscle activation data. Our results showed that the degree of reduction in the inter-task separation of the multi-muscle activation patterns was indicative of the clinical functionality score of the subjects (mean value = 26.2 for severely impaired subjects, 38.1 for moderately impaired subjects). The values for moderately impaired subjects were much closer to those of the impaired subjects (mean value = 46.1). The number of muscle modules extracted from the muscle activation patterns of a subject across six tasks, which represents the degree of motor complexity, was found to be correlated with the clinical functionality score (R = 0.68). Greater impairment was also associated with a change in the muscle module patterns themselves, with greater muscle coactivation. A substantial reduction in the degrees-of-freedom of the multi-muscle coordination post-stroke was apparent, and the extent of the reduction, assessed by the stated metrics, was strongly associated with the level of clinical impairment.