Radiologists with and without deep learning-based computer-aided diagnosis: comparison of performance and interobserver agreement for characterizing and diagnosing pulmonary nodules/masses.

OBJECTIVES: To compare the performance of radiologists in characterizing and diagnosing pulmonary nodules/masses with and without deep learning (DL)-based computer-aided diagnosis (CAD). METHODS: We studied a total of 101 nodules/masses detected on CT performed between January and March 2018 at Osaka University Hospital (malignancy: 55 cases). SYNAPSE SAI Viewer V1.4 was used to analyze the nodules/masses. In total, 15 independent radiologists were grouped (n = 5 each) according to their experience: L (< 3 years), M (3-5 years), and H (> 5 years). The likelihoods of 15 characteristics, such as cavitation and calcification, and the diagnosis (malignancy) were evaluated by each radiologist with and without CAD, and the assessment time was recorded. The AUCs compared with the reference standard set by two board-certified chest radiologists were analyzed following the multi-reader multi-case method. Furthermore, interobserver agreement was compared using intraclass correlation coefficients (ICCs). RESULTS: The AUCs for ill-defined boundary, irregular margin, irregular shape, calcification, pleural contact, and malignancy in all 15 radiologists, irregular margin and irregular shape in L and ill-defined boundary and irregular margin in M improved significantly (p < 0.05); no significant improvements were found in H. L showed the greatest increase in the AUC for malignancy (not significant). The ICCs improved in all groups and for nearly all items. The median assessment time was not prolonged by CAD. CONCLUSIONS: DL-based CAD helps radiologists, particularly those with < 5 years of experience, to accurately characterize and diagnose pulmonary nodules/masses, and improves the reproducibility of findings among radiologists. KEY POINTS: • Deep learning-based computer-aided diagnosis improves the accuracy of characterizing nodules/masses and diagnosing malignancy, particularly by radiologists with < 5 years of experience. • Computer-aided diagnosis increases not only the accuracy but also the reproducibility of the findings across radiologists.

Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies.

Intracellular proteins are often targeted by autoantibodies in autoimmune diseases; however, the mechanism through which intracellular molecules are targeted remains unknown. We previously found that several intracellular misfolded proteins are transported to the cell surface by HLA class II molecules and are recognized by autoantibodies in some autoimmune diseases, such as rheumatoid arthritis, antiphospholipid syndrome, and microscopic polyangiitis. Ro52 is an intracellular Fc receptor that is a target antigen for myositis-associated autoantibodies. We analyzed the role of HLA class II molecules in the autoantibody recognition of Ro52. Ro52 alone was not transported to the cell surface by HLA class II molecules; however, it was transported to the cell surface in the presence of both IgG heavy chain and HLA class II molecules to form a Ro52/IgG/HLA-DR complex. The Ro52/IgG/HLA-DR complex was specifically recognized by autoantibodies from some patients with inflammatory myopathies. We then evaluated 120 patients with inflammatory myopathies with four types of myositis-specific antibodies and analyzed the autoantibodies against the Ro52/IgG/HLA-DR complex. The specific antibodies against the Ro52/IgG/HLA-DR complex were detected in 90% and 93% of patients who were positive for anti-MDA5 and anti-ARS antibodies, respectively. In individual patients with these two inflammatory myopathies, changes in serum titers of anti-Ro52/IgG/HLA-DR-specific antibodies were correlated with the levels of KL-6 (R = 0.51 in anti-MDA5 antibody-positive DM patients, R = 0.67 in anti-ARS antibody-positive PM/DM patients with respiratory symptoms) and CK (R = 0.63 in anti-ARS antibody-positive PM/DM patients with muscle symptoms) over time. These results suggest that antibodies against Ro52/IgG/HLA-DR expressed on the cell surface could be involved in the pathogenesis of inflammatory myopathy subgroups.

Claw Toe: Anatomic Guide for Injection of Botulinum Toxin into Foot Muscles.

BACKGROUND: Poor response to injection of botulinum toxin (BoNT) into the flexor digitorum longus (FDL) muscle has been reported especially in patients with claw foot deformity. We previously advocated BoNT injection into the flexor hallucis longus (FHL) muscle in such patients. Here, we determined the functional and anatomical relationships between FHL and FDL. METHODS: Toe flexion pattern was observed during electrical stimulation of FHL and FDL muscles in 31 post-stroke patients with claw-foot deformity treated with BoNT. The FHL and FDL tendon arrangement was also studied in five limbs of three cadavers. RESULTS: Electrical stimulation of the FHL muscle elicited big toe flexion in all 28 cases examined and second toe in 25, but the response was limited to the big toe in 3. FDL muscle stimulation in 29 patients elicited weak big toe flexion in 1 and flexion of four toes (2nd to 5th) in 16 patients. Cadaver studies showed division of the FHL tendon with branches fusing with the FDL tendon in all five limbs examined; none of the tendons was inserted only in the first toe. No branches of the FDL tendon merged with the FHL tendon. CONCLUSION: Our results showed coupling of FHL and FDL tendons in most subjects. Movements of the second and third toes are controlled by both the FDL and FHL muscles. The findings highlight the need for BoNT injection in both the FDL and FHL muscles for the treatment of claw-toe deformity.

Hue selectivity of collinear facilitation.

Collinear facilitation (CF) is the improvement of the detection sensitivity of the target when two high-contrast flanking stimuli (flankers) have the same visual properties. While it is known that CF does not occur between achromatic flanking stimuli and chromatic targets, or vice versa, it remains unclear whether CF occurs when the hue of the target and flankers are different. We measured CF for Gabor stimuli defined in an isoluminant plane using stimuli defined by isoluminant colors along isolated cone-opponent axes and in two diagonal directions. The measured CF varied with the difference in hue between the target and flankers. Moreover, increased thresholds were also observed. These results suggest that CF exhibits hue selectivity and involves a suppression as well as a facilitation component. The hue selectivity profile of these factors infer that the CF cannot be simply explained by the assumption of two independent cone opponent mechanisms.

[Impact of Aperture Shape Controller on Volumetric Modulated Arc Therapy Treatment Planning for Nasopharyngeal Cancer].

PURPOSE: The aperture shape controller (ASC) decreases the complexity of the multi-leaf collimator (MLC) aperture for volumetric modulated arc therapy (VMAT). The purpose of this study was to evaluate the effect of ASC settings on the VMAT plan quality. METHOD: First, VMAT plans were created (ASC=off) for three test patterns of The American Association of Physicists in Medicine (AAPM) Task Group 119 (TG-119) and 20 cases of nasopharyngeal cancer. Next, for these VMAT plans, only the ASC settings were changed from very low (complexity reduction: low) to very high (complexity reduction: high) in five steps, and VMAT plans were created respectively. To evaluate the created VMAT plans per each ASC settings, we analyzed the modulation complexity score (MCSV) and dosimetric parameters for the planning target volume (PTV) and organ at risk (OAR). RESULT: In three test patterns, there were no major dosimetric differences between the VMAT plans. In nasopharyngeal cancer, the mean MCSV were 0.413, 0.325, 0.320, 0.307, 0.303, and 0.272 for very high, high, moderate, low, very low, off settings, respectively. Therefore, the most complex MLC aperture was off, followed by very low, low, moderate, high, and very high. In terms of dosimetric parameters, the VMAT plans created using the very high setting showed an increase of D2% in the PTV and worse OAR sparing than that using other ASC settings. On the other hand, the dosimetric results for the very low to moderate setting obtained similar results to those for the off setting, respectively. CONCLUSION: The ASC was able to decrease the complexity of the MLC aperture according to the setting level. From very low to moderate settings, a plan equivalent to the off setting could be created in terms of dose parameters.

[Impact of DVH Outliers Registered in Knowledge-based Planning on Volumetric Modulated Arc Therapy Treatment Planning for Prostate Cancer].

RapidPlan, a knowledge-based planning software, uses a model library containing the dose-volume histogram (DVH) of previous treatment plans, and it automatically provides optimization objectives based on a trained model to future patients for volumetric modulated arc therapy treatment planning. However, it is unknown how DVH outliers registered in models influence the resulting plans. The purpose of this study was to investigate the effect of DVH outliers on the resulting quality of RapidPlan knowledge-based plans generated for patients with prostate cancer. First, 123 plans for patients with prostate cancer were used to populate the initial model (modelall). Next, modelall-20 and modelall-40 were created by excluding DVH outliers of bladder optimization contours 20 and 40 patients from modelall, respectively. These models were used to create plans for a 20-patient. The plans created using modelall-40 showed reductions of D30% and D50% in the bladder wall dose, and the DVH shape excluding outliers were affected. However, there were no significant differences in monitor units, target doses, or bladder wall doses between each treatment plan. Thus, we have shown that removal of DVH outliers from models does not affect the quality of plans created by the model.

[Influence of Respiratory Phase during Image Acquisition on Prescribed Dose in Image Guided Radiation Therapy Using Implant Marker for Prostate Cancer].

In image guided radiation therapy (IGRT) using implanted fiducial marker by two-dimensional radiography for prostate cancer, temporal positional relationship during treatment between the isocenter and the prostate is changed by respiratory phase at the time of image acquisition. We examined influence of the respiratory phase in the IGRT on dose variation by interplay effect. Intra-fractional prostate motions of patients who were implanted fiducial marker were measured using fluoroscopy, then we reconstructed plans considering for the respiratory phase in IGRT and the respiratory motion during volumetric modulated arc therapy. Averages of the intra-fractional prostate motion in left-right, anterior-posterior and superior-inferior direction were 0.039, 0.49 and 1.6 mm respectively. There was a patient whose intra-fractional prostate motion was larger than 4 mm that was planning target volume margin. By changing the respiratory phase like inspiration, exhalation and dispersing respiratory phase in each fraction, dose variation from original plan became smaller in order of the inspiration, exhalation and dispersion. The largest variations of dose indices in clinical target volume, bladder and rectum were 8.0%, 4.5% and 9.1% respectively when IGRT was done in inspiration. When the IGRT is performed by the same respiratory phase in each fraction, systematic dose variations may occur even if the respiratory phase at the timing of irradiation is changed. By dispersing the respiratory phase in each fraction, the variations in all dose indices were<1% from original plan. We realized that dispersing the respiratory phase in IGRT by each fraction is effective to reduce the dose variation caused by the respiratory phase in IGRT.

Comparison of patient-specific intensity modulated radiation therapy quality assurance for the prostate across multiple institutions.

AIM: To evaluate the success of a patient-specific intensity modulated radiation therapy (IMRT) quality assurance (QA) practice for prostate cancer patients across multiple institutions using a questionnaire survey. BACKGROUND: The IMRT QA practice involves different methods of dose distribution verification and analysis at different institutions. MATERIALS AND METHODS: Two full-arc volumetric modulated arc therapy (VMAT) plan and 7 fixed-gantry IMRT plan with DMLC were used for patient specific QA across 22 institutions. The same computed tomography image and structure set were used for all plans. Each institution recalculated the dose distribution with fixed monitor units and without any modification. Single-point dose measurement with a cylindrical ionization chamber and dose distribution verification with a multi-detector or radiochromic film were performed, according to the QA process at each institution. RESULTS: Twenty-two institutions performed the patient-specific IMRT QA verifications. With a single-point dose measurement at the isocenter, the average difference between the calculated and measured doses was 0.5 ±â€¯1.9%. For the comparison of dose distributions, 18 institutions used a two or three-dimensional array detector, while the others used Gafchromic film. In the γ test with dose difference/distance-to-agreement criteria of 3%-3 mm and 2%-2 mm with a 30% dose threshold, the median gamma pass rates were 99.3% (range: 41.7%-100.0%) and 96.4% (range: 29.4%-100.0%), respectively. CONCLUSION: This survey was an informative trial to understand the verification status of patient-specific IMRT QA measurements for prostate cancer. In most institutions, the point dose measurement and dose distribution differences met the desired criteria.

Relative contributions of low- and high-luminance components to material perception.

Besides specular highlights, image pixels that represent clues to recognizing the object material, such as shading between threads of fabrics, often yield relatively lower luminance in the image. Here, we psychophysically examined how lower and higher luminance components contribute to material perception. We created two types of luminance-modulated images-low- and high-luminance-preserved (LLP and HLP) images-and instructed observers to choose which modified image resulted in a material impression closer to the original. LLP images were created by compressing the luminance contrast of the higher half of the histogram in each original photograph and vice versa. The stimuli were photographs of various samples of stone, wood, leather, and fabric. Although the LLP and HLP images were equally chosen, the choice ratios of the HLP images largely differed across the samples and categories and moderately correlated with the luminance statistics of higher-spatial-frequency sub-bands. These results suggest that either the lower- or higher-luminance components play an important role in material perception, depending on the material category. However, the correlation with sub-band image statistics for stone/wood samples was much weaker than for leather/fabric samples, suggesting that more intricate image characteristics may be involved in evaluating the material impressions of the stone/wood samples.

[Impact of Respiratory Motion on Dose Variation in Radiation Therapy for Glottic Cancer].

In radiation therapy for glottic cancer, respiratory motion of larynx may change the dose variation in the target. The purpose of this study is to measure the respiratory motion of the larynx, and quantify the impact of the motion on the dose variation. This study included 10 patients treated by opposing portal irradiation for glottic cancer. We acquired fluoroscopy and respiratory waveform of the patients simultaneously and formulated the relationship between the displacement of larynx and the respiratory phase. We divided one field into 39 sub-fields on the basis of control points. Dose distributions accounting for the displacement were calculated by shifting isocenter calculated using the formula in every sub-fields. Dose variations of clinical target volume (CTV) were evaluated by subtracting dose distributions with displacement consideration and dose distributions without it. Average amplitude and the maximum amplitude of respiratory motion were 2.5 and 8.7 mm, respectively. Average of mean dose variation in CTV was 0.1% of the prescribed dose, and maximum of local dose variation was 2.0% of the prescribed dose. Hence, it is realized that dose variation in CTV by respiratory motion was slight.

Impact of Jaw Position Accuracy on Dose Variation in Volumetric Modulated Arc Therapy Using Jaw Tracking.

The technique of jaw tracking can be used in volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT). In this technique, jaw tracks apertures of the multi leaf collimator (MLC) during irradiation. It is reported that dose variation is occurred by the changing accuracy of MLC position in VMAT and IMRT. Though jaw moves dynamically in the irradiation by using this technique, the influence of the jaw position accuracy on dose variation is not examined. The purpose of this study is to verify the influence of jaw position accuracy on dose variation in VMAT using jaw tracking. We appended intentional errors on jaw position in digital image communication in medicine-radiation therapy (DICOM-RT) plans created using jaw tracking technique. These plans were irradiated on the phantom that was inserted ion chamber, and we measured dose variation by changing the intentional error. The dose variation in planning target volume (PTV) was enlarged by increasing the error, and agreed with the variation of a collimator scatter factor within 0.03%. In clinical case of oropharyngeal cancer, the maximum dose variations in parotid gland were 0.179% and 1.23% when the errors were 1 mm and 10 mm, respectively. Dose variation in parotid gland was larger than the variation in PTV and spinal cord because of increasing MLC transmission. The dose variation caused by jaw position error was smaller than it caused by MLC position error. So, we can keep the dose error slightly that is related to jaw position error in VMAT by maintaining jaw position accuracy correctly.

Dissociation of equilibrium points for color-discrimination and color-appearance mechanisms in incomplete chromatic adaptation.

We compared the color-discrimination thresholds and supra-threshold color differences (STCDs) obtained in complete chromatic adaptation (gray) and incomplete chromatic adaptation (red). The color-difference profiles were examined by evaluating the perceptual distances between various color pairs using maximum likelihood difference scaling. In the gray condition, the chromaticities corresponding with the smallest threshold and the largest color difference were almost identical. In contrast, in the red condition, they were dissociated. The peaks of the sensitivity functions derived from the color-discrimination thresholds and STCDs along the L-M axis were systematically different between the adaptation conditions. These results suggest that the color signals involved in color discrimination and STCD tasks are controlled by separate mechanisms with different characteristic properties.

[Optimal parameter decision method in VMAT for lung tumors with respiratory motions].

When performing lung cancer treatments using volumetric modulated arc therapy (VMAT) technique, dose error related to respiratory motion of tumors and multi leaf collimator (MLC) movement may occur. The dose error causes daily dose variation in multiple fractionations irradiation. The purpose of this study is to verify the influence of the respiratory motion and the MLC movement on the daily dose variation, and to confirm the feasibility of deciding robust planning parameter against the dose variation. We prepared 5 VMAT plans for imitating lung tumor in thorax dynamic phantom. Dose calculations of these plans were done taking into account the respiratory motions. We examined the relation between dose variation and two parameters that were number of respiration in an arc and MLC gap width. We presented the relationship between the dose variation and each parameters using regression analysis, and we could derive the approximation formula for estimating the dose variation using these parameters. We could estimate dose variation in another VMAT plans using the approximation formula and another plans parameters. By confirming dose variation in planning procedure using this estimation method, we may decide planning parameter taking the dose variation into account. So, we could establish the estimation method to decide adequate planning parameters in VMAT.

Synthesis and biological evaluation of kendomycin and its analogues.

Ansa compounds are gifts from microbes with intriguing molecular structures and highly potent bioactivities. One of the ansa compounds, kendomycin, has an oxa-metacyclophane skeleton with a quinone methide core and a fully substituted tetrahydropyran ring. Beyond a common synthetic strategy for construction of the ansa skeleton (i.e., elongation of an alkyl chain from an aromatic core followed by macrocyclization), we challenged a new method for construction of the ansa skeleton via simultaneous macrocyclization and benzannulation (using an intramolecular Dötz benzannulation). Understanding the reactivity of various Fischer-type ω-alkynyloxy chromium carbene complexes with kendomycin analogue syntheses led to achievement of the total synthesis of kendomycin. Investigations of structure-activity relationships revealed the need for an ansa skeleton for antimicrobial activity. Therefore, we envisage that this intramolecular Dötz benzannulation will enable divergent syntheses of ansa compounds which have important bioactive potential.

[Impact of dynamic parameters on dose delivery accuracy in volumetric modulated arc therapy].

Volumetric modulated arc therapy (VMAT) is an irradiation method in which the multi-leaf collimator (MLC) shape, gantry speed and dose-rate is continuously varied. Gantry speed and dose-rate are treated as specific dynamic parameters (DPs) in VMAT, so there is a need to confirm the influence of DPs on dose distribution. The purpose of this study was to verify the impact of DPs on the accuracy of dose delivery in VMAT. We adopted an irradiation scenario in which DPs were modified from the original plan without making any changes in the dose distribution. We carried out irradiation and measured the dose distributions using a Delta4 diode array phantom, during which we acquired log files that enabled us to calculate DPs. The results showed that dose errors exceeding 1% or geometric errors greater than 1 mm were not produced by modifying the DPs. We were therefore able to verify the impact of DPs on dose delivery accuracy in VMAT.

Translation and Testing the Reliability and Validity of a Japanese Version of the Paternal Antenatal Attachment Scale (PAAS-J).

Background and Purpose: This study aimed to translate and validate a Japanese version of the Paternal Antenatal Attachment Scale (PAAS-J). Methods: The PAAS-J was translated through a pilot study and a survey of fathers with pregnant partners. Results: The survey involved 189 fathers. A confirmatory factor analysis was performed, but the model fit was poor. Therefore, an exploratory factor analysis (EFA) was performed. Based on the results of the EFA, three items with low interitem correlations and factor loadings were deleted, and a 13-item scale consisting of 2 domains was created. Coefficient alpha was .80. The intraclass correlation coefficient of the retest method was .80, confirming its reliability. Conclusions: The PAAS-J was found to be reliable and valid.

Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Myotonic dystrophy type 1 (DM1) is a devastating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene, which subsequently triggers toxic RNA expression and dysregulated splicing. In a preclinical study, we demonstrated that erythromycin reduces the toxicity of abnormal RNA and ameliorates the aberrant splicing and motor phenotype in DM1 model mice. Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at three centres in Japan to translate preclinical findings into practical applications in patients with DM1 by evaluating the safety and efficacy of erythromycin. Between Nov 29, 2019, and Jan 20, 2022, a total of 30 adult patients with DM1 were enrolled and randomly assigned in a 1:2:2 ratio to receive either placebo or erythromycin at two daily doses (500 mg or 800 mg) for 24 weeks. The primary outcome included the safety and tolerability of erythromycin. The secondary efficacy measures included splicing biomarkers, 6-min walk test results, muscle strength, and serum creatinine kinase (CK) values. This trial is registered with the Japan Registry of Clinical Trials, jRCT2051190069. Findings: Treatment-related gastrointestinal symptoms occurred more frequently in the erythromycin group, but all adverse events were mild to moderate and resolved spontaneously. No serious safety concerns were identified. The CK levels from baseline to week 24 decreased in the overall erythromycin group compared with the placebo group (mean change of -6.4 U/L [SD 149] vs +182.8 [SD 228]), although this difference was not statistically significant (p = 0.070). Statistically significant improvements in the overall erythromycin treated groups compared to placebo were seen for two of the eleven splicing biomarkers that were each evaluated in half of the trial sample. These were MBNL1 (p = 0.048) and CACNA1S (p = 0.042). Interpretation: Erythromycin demonstrated favourable safety and tolerability profiles in patients with DM1. A well-powered phase 3 trial is needed to evaluate efficacy, building on the preliminary findings from this study. Funding: Japan Agency for Medical Research and Development.

[A practical procedure to improve the accuracy of radiochromic film dosimetry: a integration with a correction method of uniformity correction and a red/blue correction method].

It has been reported that the light scattering could worsen the accuracy of dose distribution measurement using a radiochromic film. The purpose of this study was to investigate the accuracy of two different films, EDR2 and EBT2, as film dosimetry tools. The effectiveness of a correction method for the non-uniformity caused from EBT2 film and the light scattering was also evaluated. In addition the efficacy of this correction method integrated with the red/blue correction method was assessed. EDR2 and EBT2 films were read using a flatbed charge-coupled device scanner (EPSON 10000G). Dose differences on the axis perpendicular to the scanner lamp movement axis were within 1% with EDR2, but exceeded 3% (Maximum: +8%) with EBT2. The non-uniformity correction method, after a single film exposure, was applied to the readout of the films. A corrected dose distribution data was subsequently created. The correction method showed more than 10%-better pass ratios in dose difference evaluation than when the correction method was not applied. The red/blue correction method resulted in 5%-improvement compared with the standard procedure that employed red color only. The correction method with EBT2 proved to be able to rapidly correct non-uniformity, and has potential for routine clinical IMRT dose verification if the accuracy of EBT2 is required to be similar to that of EDR2. The use of red/blue correction method may improve the accuracy, but we recommend we should use the red/blue correction method carefully and understand the characteristics of EBT2 for red color only and the red/blue correction method.