Improving radiomics reproducibility using deep learning-based image conversion of CT reconstruction algorithms in hepatocellular carcinoma patients.

OBJECTIVES: CT reconstruction algorithms affect radiomics reproducibility. In this study, we evaluate the effect of deep learning-based image conversion on CT reconstruction algorithms. METHODS: This study included 78 hepatocellular carcinoma (HCC) patients who underwent four-phase liver CTs comprising non-contrast, late arterial (LAP), portal venous (PVP), and delayed phase (DP), reconstructed using both filtered back projection (FBP) and advanced modeled iterative reconstruction (ADMIRE). PVP images were used to train a convolutional neural network (CNN) model to convert images from FBP to ADMIRE and vice versa. LAP, PVP, and DP images were used for validation and testing. Radiomic features were extracted for each patient with a semi-automatic segmentation tool. We used concordance correlation coefficients (CCCs) to evaluate the radiomics reproducibility for original FBP (oFBP) vs. original ADMIRE (oADMIRE), oFBP vs. converted FBP (cFBP), and oADMIRE vs. converted ADMIRE (cADMIRE). RESULTS: In the test group including 30 patients, the CCC and proportion of reproducible features (CCC ≥ 0.85) for oFBP vs. oADMIRE were 0.65 and 32.9% (524/1595) for LAP, 0.65 and 35.9% (573/1595) for PVP, and 0.69 and 43.8% (699/1595) for DP. For oFBP vs. cFBP, the values increased to 0.92 and 83.9% (1339/1595) for LAP, 0.89 and 71.0% (1133/1595) for PVP, and 0.90 and 79.7% (1271/1595) for DP. Similarly, for oADMIRE vs. cADMIRE, the values increased to 0.87 and 68.1% (1086/1595) for LAP, 0.91 and 82.1% (1309/1595) for PVP, and 0.89 and 76.2% (1216/1595) for DP. CONCLUSIONS: CNN-based image conversion between CT reconstruction algorithms improved the radiomics reproducibility of HCCs. CLINICAL RELEVANCE STATEMENT: This study demonstrates that using a CNN-based image conversion technique significantly improves the reproducibility of radiomic features in HCCs, highlighting its potential for enhancing radiomics research in HCC patients. KEY POINTS: Radiomics reproducibility of HCC was improved via CNN-based image conversion between two different CT reconstruction algorithms. This is the first clinical study to demonstrate improvements across a range of radiomic features in HCC patients. This study promotes the reproducibility and generalizability of different CT reconstruction algorithms in radiomics research.

Sex-dependent different clinicopathological characterization of Epstein-Barr virus-associated gastric carcinoma: a large-scale study.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5-16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. METHODS: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV-ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. RESULTS: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan-Meier survival curve. However, this effect was evident only in males. CONCLUSIONS: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females.

Comparison of Muscle Regeneration Effects at Different Melittin Concentrations in Rabbit Atrophied Muscle.

This research aimed to explore the healing impacts of Melittin treatment on gastrocnemius muscle wasting caused by immobilization with a cast in rabbits. Twenty-four rabbits were randomly allocated to four groups. The procedures included different injections: 0.2 mL of normal saline to Group 1 (G1-NS); 4 µg/kg of Melittin to Group 2 (G2-4 µg/kg Melittin); 20 µg/kg of Melittin to Group 3 (G3-20 µg/kg Melittin); and 100 µg/kg of Melittin to Group 4 (G4-100 µg/kg Melittin). Ultrasound was used to guide the injections into the rabbits' atrophied calf muscles following two weeks of immobilization via casting. Clinical measurements, including the length of the calf, the compound muscle action potential (CMAP) of the tibial nerve, and the gastrocnemius muscle thickness, were assessed. Additionally, cross-sectional slices of gastrocnemius muscle fibers were examined, and immunohistochemistry and Western blot analyses were performed following two weeks of therapy. The mean regenerative changes, as indicated by clinical parameters, in Group 4 were significantly more pronounced than in the other groups (p < 0.05). Furthermore, the cross-sectional area of the gastrocnemius muscle fibers and immunohistochemical indicators in Group 4 exceeded those in the remaining groups (p < 0.05). Western blot analysis also showed a more significant presence of anti-inflammatory and angiogenic cytokines in Group 4 compared to the others (p < 0.05). Melittin therapy at a higher dosage can more efficiently activate regeneration in atrophied gastrocnemius muscle compared to lower doses of Melittin or normal saline.

Transcriptional Changes in Radiation-Induced Lung Injury: A Comparative Analysis of Two Radiation Doses for Preclinical Research.

In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury.

The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis.

BACKGROUND: Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. METHODS: We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. RESULTS: HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. CONCLUSIONS: Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.

Early Prediction of Radiation-Induced Pulmonary Fibrosis Using Gastrin-Releasing Peptide Receptor-Targeted PET Imaging.

Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe, [64Cu]Cu-NODAGA-galacto-bombesin (BBN), an analogue peptide of GRP. In this study, we evaluated the usefulness of [64Cu]Cu-NODAGA-galacto-BBN for the early prediction of RIPF. We prepared RIPF mice and acquired PET/CT images of [18F]F-FDG and [64Cu]Cu-NODAGA-galacto-BBN at 0, 2, 5, and 11 weeks after irradiation (n = 3-10). We confirmed that [64Cu]Cu-NODAGA-galacto-BBN targets GRPR in irradiated RAW 264.7 cells. In addition, we examined whether [64Cu]Cu-NODAGA-galacto-BBN monitors the therapeutic efficacy in RIPF mice (n = 4). As a result, the lung uptake ratio (irradiated-to-normal) of [64Cu]Cu-NODAGA-galacto-BBN was the highest at 2 weeks, followed by its decrease at 5 and 11 weeks after irradiation, which matched with the expression of GRPR and was more accurately predicted than [18F]F-FDG. These uptake results were also confirmed by the cell uptake assay. Furthermore, [64Cu]Cu-NODAGA-galacto-BBN could monitor the therapeutic efficacy of pirfenidone in RIPF mice. We conclude that [64Cu]Cu-NODAGA-galacto-BBN is a novel PET imaging probe for the early prediction of RIPF-targeting GRPR expressed during the inflammatory response.

Polydeoxyribonucleotide and Shock Wave Therapy Sequence Efficacy in Regenerating Immobilized Rabbit Calf Muscles.

This study primarily aimed to investigate the combined effects of polydeoxyribonucleotide (PDRN) and extracorporeal shock wave therapy (ESWT) sequences on the regenerative processes in atrophied animal muscles. Thirty male New Zealand rabbits, aged 12 weeks, were divided into five groups: normal saline (Group 1), PDRN (Group 2), ESWT (Group 3), PDRN injection before ESWT (Group 4), and PDRN injection after ESWT (Group 5). After 2 weeks of cast immobilization, the respective treatments were administered to the atrophied calf muscles. Radial ESWT was performed twice weekly. Calf circumference, tibial nerve compound muscle action potential (CMAP), and gastrocnemius (GCM) muscle thickness after 2 weeks of treatment were evaluated. Histological and immunohistochemical staining, as well as Western blot analysis, were conducted 2 weeks post-treatment. Staining intensity and extent were assessed using semi-quantitative scores. Groups 4 and 5 demonstrated significantly greater calf muscle circumference, GCM muscle thickness, tibial nerve CMAP, and GCM muscle fiber cross-sectional area (type I, type II, and total) than the remaining three groups (p < 0.05), while they did not differ significantly in these parameters. Groups 2 and 3 showed higher values for all the mentioned parameters than Group 1 (p < 0.05). Group 4 had the greatest ratio of vascular endothelial growth factor (VEGF) to platelet endothelial cell adhesion molecule-1 (PECAM-1) in the GCM muscle fibers compared to the other four groups (p < 0.05). Western blot analysis revealed significantly higher expression of angiogenesis cytokines in Groups 4 and 5 than in the other groups (p < 0.05). The combination of ESWT and PDRN injection demonstrated superior regenerative efficacy for atrophied calf muscle tissue in rabbit models compared to these techniques alone or saline. In particular, administering ESWT after PDRN injection yielded the most favorable outcomes in specific parameters.

NXC736 Attenuates Radiation-Induced Lung Fibrosis via Regulating NLRP3/IL-1ß Signaling Pathway.

Radiation-induced lung fibrosis (RILF) is a common complication of radiotherapy in lung cancer. However, to date no effective treatment has been developed for this condition. NXC736 is a novel small-molecule compound that inhibits NLRP3, but its effect on RILF is unknown. NLRP3 activation is an important trigger for the development of RILF. Thus, we aimed to evaluate the therapeutic effect of NXC736 on lung fibrosis inhibition using a RILF animal model and to elucidate its molecular signaling pathway. The left lungs of mice were irradiated with a single dose of 75 Gy. We observed that NXC736 treatment inhibited collagen deposition and inflammatory cell infiltration in irradiated mouse lung tissues. The damaged lung volume, evaluated by magnetic resonance imaging, was lower in NXC736-treated mice than in irradiated mice. NXC736-treated mice exhibited significant changes in lung function parameters. NXC736 inhibited inflammasome activation by interfering with the NLRP3-ASC-cleaved caspase-1 interaction, thereby reducing the expression of IL-1ß and blocking the fibrotic pathway. In addition, NXC736 treatment reduced the expression of epithelial-mesenchymal transition markers such as α-SMA, vimentin, and twist by blocking the Smad 2,3,4 signaling pathway. These data suggested that NXC736 is a potent therapeutic agent against RILF.

Efferocytosis and enhanced FPR2 expression following apoptotic cell instillation attenuate radiation-induced lung inflammation and fibrosis.

Lung inflammation and fibrosis are common side effects of radiotherapy that can lead to serious reduction in the quality of life of patients. However, no effective treatment is available, and the mechanisms underlying its pathophysiology are poorly understood. Irradiation increases formyl peptide receptor 2 (FPR2) expression in lung tissue, and FPR2 agonists are known to promote the uptake of apoptosis cells, referred to as efferocytosis that is a hallmark of the resolution of inflammation. Herein, in a mouse model of radiation-induced lung injury (RILI), efferocytosis was induced by injecting apoptotic cells into the lung through the trachea, and its correlation with FPR expression and the effect of efferocytosis and FPR expression on RILI were assessed. Interestingly, when apoptotic cells were injected into the lung, the radiation-induced increase in FPR2 expression was further amplified. In the mouse model of RILI, apoptotic cell instillation reduced the volume of the damaged lung and prevented the decrease in lung function. Additionally, the expression of inflammatory cytokines, fibrosis-related markers, and oxidative stress-related markers was reduced by apoptotic cell instillation. Co-administration of apoptotic Jurkat cells and WRW4, the FPR2 antagonist, reversed these effects. These findings suggest that efferocytosis induced by apoptotic cell instillation and enhanced FPR2 expression attenuate RILI, thereby alleviating lung inflammation and fibrosis.

Adrenal Nodules Detected at Staging CT in Patients with Resectable Gastric Cancers Have a Low Incidence of Malignancy.

Background Guidelines recommending additional imaging for adrenal nodules lack relevant epidemiologic evidence. Purpose To measure the prevalence of adrenal nodules detected at staging CT in patients with potentially resectable gastric cancer and the proportion of patients with malignant nodules among them. Materials and Methods This retrospective study included 10 250 consecutive patients (median age, 63 years; interquartile range, 53-71 years; 6884 men) who underwent staging CT and had potentially resectable gastric cancer in a tertiary center (May 2003 to December 2018). All 10 250 CT studies were retrospectively reviewed, and patients with adrenal nodules (or thickening ≥10 mm) were identified to measure the prevalence of adrenal nodules. Among patients with adrenal nodules, the per-patient proportions of malignant nodules, adrenal metastasis from gastric cancer, and additional adrenal examinations were measured. A secondary analysis was performed by using data from the original CT reports. The same metrics that were used in the retrospective review were assessed. Results The prevalence of adrenal nodules was 4.5% (95% CI: 4.1, 4.9; 462 of 10 250). The proportions of malignant nodules and adrenal metastasis from gastric cancer were 0.4% ( 95% CI: 0.1, 1.6; two of 462) and 0% (95% CI: 0.0, 0.8; 0 of 462), respectively. A total of 27% of the patients (95% CI: 23, 31; 123 of 462) underwent additional adrenal examination. According to original CT reports, the prevalence of adrenal nodules and the proportions of malignant nodules, adrenal metastases from gastric cancer, and additional adrenal examination were 2.7% (95% CI: 2.4, 3.0; 272 of 10 250), 0.7% (95% CI: 0.1, 2.6; two of 272), 0% (95% CI: 0.0, 1.4; 0 of 272), and 42.6% (95% CI: 36.7, 48.8; 116 of 272), respectively. Conclusion Although adrenal nodules were detected frequently on staging CT images of patients with otherwise resectable gastric cancer, these nodules were rarely malignant. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Baumgarten in this issue.

Safety and Efficacy of Intraperitoneal Paclitaxel Plus Intravenous Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) for Gastric Cancer with Peritoneal Metastasis.

BACKGROUND: Peritoneal metastasis (PM) remains a major obstacle in the treatment of stage IV gastric cancer. This is a dose-escalation study of intraperitoneal (IP) paclitaxel combined with intravenous (IV) fluorouracil, leucovorin, and oxaliplatin (FOLFOX) to determine the recommended phase II dose in gastric cancer patients. METHODS: Patients with gastric adenocarcinoma and PM were enrolled. The recommended phase II dose of IP paclitaxel was determined using the standard "3 + 3" dose escalation with planned doses ranging from 40 to 100 mg/m2. IV FOLFOX was administered on the same day (oxaliplatin 100 mg/m2 (day 1), leucovorin 100 mg/m2 (day 1), fluorouracil 2,400 mg/m2 over 46 hours (day 1)). Both IP and IV regimens were repeated every 2 weeks. RESULTS: Among the 13 patients, there was no DLT at 40 and 60 mg/m2. Two patients had grade 3 febrile neutropenia at 80 mg/m2, and the recommended phase II dose was 60 mg/m2. Other patients underwent IP paclitaxel and FOLFOX without serious adverse events. Seven patients underwent second-look diagnostic laparoscopy, and the average change in PCI score was -7.0 ± 9.7. Conversion surgery rate was 23.1% (n = 3). The median overall survival was 16.6 months (95% confidence interval, 16.6-N/A), and progression-free survival was 9.6 months (95% confidence interval, 4.7-N/A). All adverse events were tolerable and manageable. CONCLUSIONS: The biweekly regimen of IP paclitaxel and FOLFOX is safe and the recommended dose of IP paclitaxel for a phase II trial is 60 mg/m2.

Incidence of malignancy in adrenal nodules detected on staging CTs of patients with potentially resectable colorectal cancer.

OBJECTIVE: To measure the prevalence of adrenal nodules detected on staging CT in patients with resectable colorectal cancer, and the proportion of patients with malignant nodules among them. METHODS: This retrospective study included 6474 patients (median age, 65; interquartile range, 56-73; 3902 men) who underwent staging CT for colorectal cancer between May 2003 and December 2018. The patients had potentially resectable colorectal cancer, including resectable hepatic or pulmonary metastases. Through retrospective CT image review, patients with adrenal nodules were identified for the prevalence of adrenal nodule. Among patients with adrenal nodules, per-patient proportions of malignant nodules, adrenal metastasis from colorectal cancer, and additional adrenal examinations (biopsy or imaging tests) were measured. A secondary analysis was performed using data from the official CT reports. RESULTS: The prevalence of adrenal nodules was 5.6% (363 of 6474; 95% CI: 5.1, 6.2). The proportions of malignant nodules and adrenal metastasis from colorectal cancer were 0.8% (3 of 363; 0.2, 2.4) and 0.3% (1 of 363; 0.0, 1.5), respectively. 6.1% (22 of 363; 3.8, 9.0) of the patients underwent additional adrenal examination. According to official CT reports, the prevalence of adrenal nodules and proportions of malignant nodules, adrenal metastasis from colorectal cancer, and additional adrenal examination were 1.9% (125 of 6474; 1.6, 2.3), 1.6% (2 of 125; 0.2, 5.7), 0% (0 of 125; 0.0, 2.9), and 10.4% (1 of 125; 5.7, 17.1), respectively. CONCLUSION: Adrenal nodules detected in staging CTs in patients with otherwise resectable colorectal cancers are rarely malignant. KEY POINTS: • Among 6474 patients who underwent staging CT and had potentially resectable colorectal cancer, 363 had adrenal nodules (≥ 10 mm) detected in retrospective CT image review. • Three out of the 363 patients with adrenal nodules detected on staging CT had malignant adrenal nodules, one of whom had metastasis from colorectal cancer.

Dose reduction potential of vendor-agnostic deep learning model in comparison with deep learning-based image reconstruction algorithm on CT: a phantom study.

OBJECTIVES: To compare the dose reduction potential (DRP) of a vendor-agnostic deep learning model (DLM, ClariCT.AI) with that of a vendor-specific deep learning-based image reconstruction algorithm (DLR, TrueFidelity™). METHODS: Computed tomography (CT) images of a multi-sized image quality phantom (Mercury v4.0) were acquired under six radiation dose levels (0.48/0.97/1.93/3.87/7.74/15.47 mGy) and were reconstructed using filtered back projection (FBP) and three strength levels of the DLR (low/medium/high). The FBP images were denoised using the DLM. For all DLM and DLR images, the detectability index (d') (a task-based detection performance metric) was obtained, under various combinations of three target sizes (10/5/1 mm), five inlets (CT value difference with the background; -895/50/90/335/1000 HU), five phantom diameters (36/31/26/21/16 cm), and six radiation dose levels. Dose reduction potential (DRP) measures the dose reduction made by using DLM or DLR, while yielding d' equivalent to that of FBP at full dose. RESULTS: The DRPs of the DLM, DLR-low, DLR-medium, and DLR-high were 86% (81-88%), 60% (46-67%), 76% (60-81%), and 87% (78-92%), respectively. For 10-mm targets, the DRP of the DLM (87%) was higher than that of all DLR algorithms (58-86%). However, for smaller targets (5 mm/1 mm), the DRPs of the DLR-high (89/88%) were greater than those of the DLM (87/84%). CONCLUSION: The dose reduction potential of the vendor-agnostic DLM was shown to be comparable to that of the vendor-specific DLR at high strength and superior to those of the DLRs at medium and low strengths. KEY POINTS: • DRP of the vendor-agnostic model was comparable to that of high-strength vendor-specific model and superior to those of medium- and low-strength models. • Under various radiation dose levels, the deep learning model shows higher detectability indexes compared to FBP.

Tumor resectability and response on CT following neoadjuvant therapy for pancreatic cancer: inter-observer agreement study.

OBJECTIVES: First, to measure inter-observer agreement regarding tumor resectability and response, and second, to measure diagnostic performance in predicting negative resection margin, on re-staging CTs of patients who received neoadjuvant therapy for pancreatic cancer. METHODS: This retrospective study included patients who received neoadjuvant therapy for borderline resectable pancreatic cancer from 2017 to 2020. Six readers independently evaluated initial staging and re-staging CT images. They categorized the resectability on re-staging CT based on the NCCN guideline, and evaluated tumor response to neoadjuvant therapy according to our proposed criteria on a 5-grade scale. For inter-observer agreement, Gwet's agreement coefficients were used. A crossed random effect model was used to pool the sensitivity and specificity of six readers in predicting negative resection margin. RESULTS: Seventy-seven patients with the median age of 66 (59-70) were included. The pooled agreement for tumor resectability was 0.64 (95% CI, 0.56-0.71) for differentiating the three categories, and 0.84 (0.77-0.91) for differentiating resectable or borderline resectable cancer vs. unresectable cancer. Agreement for tumor response grade was 0.89 (0.85-0.92). The pooled sensitivity and specificity for predicting negative resection margin were 48% (43-52%) and 61% (57-64%), respectively, when only "resectable" on re-staging CT was considered as index test positive. When either "resectable"' or "borderline resectable" was considered as positive, the pooled sensitivity and specificity were 91% (89-94%) and 5% (4-6%), respectively. CONCLUSION: CT can be used reliably with a high inter-observer agreement in selecting candidates for surgery after neoadjuvant therapy of pancreatic cancer. KEY POINTS: • On CT following neoadjuvant therapy of pancreatic cancer, six readers showed high agreement in differentiating resectable or borderline resectable vs. unresectable cancer (Gwet's coefficient, 0.84). • Inter-observer agreement was also high for our proposed tumor response grade (Gwet's coefficient, 0.89). • Specificity was very low (5%) while sensitivity was high (91%) when either resectable or borderline resectable cancer on re-staging CT was considered as predictive of negative resection margin status.

2-Methoxyestradiol Inhibits Radiation-Induced Skin Injuries.

Radiation-induced skin injury (RISI) is a main side effect of radiotherapy for cancer patients, with vascular damage being a common pathogenesis of acute and chronic RISI. Despite the severity of RISI, there are few treatments for it that are in clinical use. 2-Methoxyestradiol (2-ME) has been reported to regulate the radiation-induced vascular endothelial-to-mesenchymal transition. Thus, we investigated 2-ME as a potent anti-cancer and hypoxia-inducible factor 1 alpha (HIF-1α) inhibitor drug that prevents RISI by targeting HIF-1α. 2-ME treatment prior to and post irradiation inhibited RISI on the skin of C57/BL6 mice. 2-ME also reduced radiation-induced inflammation, skin thickness, and vascular fibrosis. In particular, post-treatment with 2-ME after irradiation repaired the damaged vessels on the irradiated dermal skin, inhibiting endothelial HIF-1α expression. In addition to the increase in vascular density, post-treatment with 2-ME showed fibrotic changes in residual vessels with SMA+CD31+ on the irradiated skin. Furthermore, 2-ME significantly inhibited fibrotic changes and accumulated DNA damage in irradiated human dermal microvascular endothelial cells. Therefore, we suggest that 2-ME may be a potent therapeutic agent for RISI.

Deep learning-based denoising algorithm in comparison to iterative reconstruction and filtered back projection: a 12-reader phantom study.

OBJECTIVES: (1) To compare low-contrast detectability of a deep learning-based denoising algorithm (DLA) with ADMIRE and FBP, and (2) to compare image quality parameters of DLA with those of reconstruction methods from two different CT vendors (ADMIRE, IMR, and FBP). MATERIALS AND METHODS: Using abdominal CT images of 100 patients reconstructed via ADMIRE and FBP, we trained DLA by feeding FBP images as input and ADMIRE images as the ground truth. To measure the low-contrast detectability, the randomized repeat scans of Catphan® phantom were performed under various conditions of radiation exposures. Twelve radiologists evaluated the presence/absence of a target on a five-point confidence scale. The multi-reader multi-case area under the receiver operating characteristic curve (AUC) was calculated, and non-inferiority tests were performed. Using American College of Radiology CT accreditation phantom, contrast-to-noise ratio, target transfer function, noise magnitude, and detectability index (d') of DLA, ADMIRE, IMR, and FBPs were computed. RESULTS: The AUC of DLA in low-contrast detectability was non-inferior to that of ADMIRE (p < .001) and superior to that of FBP (p < .001). DLA improved the image quality in terms of all physical measurements compared to FBPs from both CT vendors and showed profiles of physical measurements similar to those of ADMIRE. CONCLUSIONS: The low-contrast detectability of the proposed deep learning-based denoising algorithm was non-inferior to that of ADMIRE and superior to that of FBP. The DLA could successfully improve image quality compared with FBP while showing the similar physical profiles of ADMIRE. KEY POINTS: • Low-contrast detectability in the images denoised using the deep learning algorithm was non-inferior to that in the images reconstructed using standard algorithms. • The proposed deep learning algorithm showed similar profiles of physical measurements to advanced iterative reconstruction algorithm (ADMIRE).

Deep learning-based algorithm to detect primary hepatic malignancy in multiphase CT of patients at high risk for HCC.

OBJECTIVES: To develop and evaluate a deep learning-based model capable of detecting primary hepatic malignancies in multiphase CT images of patients at high risk for hepatocellular carcinoma (HCC). METHODS: A total of 1350 multiphase CT scans of 1280 hepatic malignancies (1202 HCCs and 78 non-HCCs) in 1320 patients at high risk for HCC were retrospectively analyzed. Following the delineation of the focal hepatic lesions according to reference standards, the CT scans were categorized randomly into the training (568 scans), tuning (193 scans), and test (589 scans) sets. Multiphase CT information was subjected to multichannel integration, and livers were automatically segmented before model development. A deep learning-based model capable of detecting malignancies was developed using a mask region-based convolutional neural network. The thresholds of the prediction score and the intersection over union were determined on the tuning set corresponding to the highest sensitivity with < 5 false-positive cases per CT scan. The sensitivity and the number of false-positives of the proposed model on the test set were calculated. Potential causes of false-negatives and false-positives on the test set were analyzed. RESULTS: This model exhibited a sensitivity of 84.8% with 4.80 false-positives per CT scan on the test set. The most frequent potential causes of false-negatives and false-positives were determined to be atypical enhancement patterns for HCC (71.7%) and registration/segmentation errors (42.7%), respectively. CONCLUSIONS: The proposed deep learning-based model developed to automatically detect primary hepatic malignancies exhibited an 84.8% of sensitivity with 4.80 false-positives per CT scan in the test set. KEY POINTS: • Image processing, including multichannel integration of multiphase CT and automatic liver segmentation, enabled the application of a deep learning-based model to detect primary hepatic malignancy. • Our model exhibited a sensitivity of 84.8% with a false-positive rate of 4.80 per CT scan.

Different effects of p53 protein overexpression on the survival of gastric cancer patients according to Lauren histologic classification: a retrospective study.

BACKGROUND: Inactivation of TP53, a tumor suppressor gene, is associated with the development of several malignancies, including gastric cancer (GC). The present study aimed to evaluate the correlation between the overexpression of p53 and survival in different Lauren-type GCs. METHODS: From May 2003 to December 2019, 3608 GC patients treated endoscopically or surgically at the Seoul National University Bundang Hospital were enrolled for the study. Immunohistochemical staining for p53 was performed on all endoscopic and surgical gastric specimens. Clinicopathologic characteristics with Lauren classification, survival rate, and cancer recurrence were analyzed according to p53 overexpression. RESULTS: Among 3608 GC patients, p53 overexpression was seen in 1334 patients (37%). p53 overexpression was associated with lower depth of invasion (P = 0.026) and Early gastric cancer (P = 0.044) in intestinal-type GC, and with advanced TNM stage (P < 0.001) and Advanced gastric cancer (P < 0.001) in diffuse-type GC. The overall survival (OS) and GC-specific survival (GCSS) were significantly lower in p53 overexpression positive patients. This significance was more pronounced and enhanced in the diffuse-type GC and was absent in the intestinal-type GC. In multivariate analyses, p53 overexpression was associated with poor OS in both subtypes of GC and cancer recurrence in diffuse-type GC. (OS in intestinal-type: adjusted hazard ratio [aHR] = 1.423, P = 0.022; OS in diffuse-type: aHR = 1.401 P = 0.035; cancer recurrence in diffuse-type: aHR = 1.502, P = 0.039). CONCLUSION: p53 overexpression was associated with poor prognosis in GC, especially in diffuse-type. In addition, p53 overexpression was associated with early stage disease in intestinal-type GC and with advanced stage disease in diffuse-type GC.

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; P = .01) and MRI features including well-defined margin (odds ratio, 5.5; P = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; P < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; P < .001), and restricted diffusion (odds ratio, 1.9; P = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Motosugi in this issue.

Arctigenin induces necroptosis through mitochondrial dysfunction with CCN1 upregulation in prostate cancer cells under lactic acidosis.

Arctigenin, a mitochondrial complex I inhibitor, has been identified as a potential anti-tumor agent, but the involved mechanism still remains elusive. Herein, we studied the underlying mechanism(s) of action of arctigenin on acidity-tolerant prostate cancer PC-3AcT cells in the lactic acid-containing medium. At concentration showing no toxicity on normal prostate epithelial RWPE-1 and HPrEC cells, arctigenin alone or in combination with docetaxel induced significant cytotoxicity in PC-3AcT cells compared to parental PC-3 cells. With arctigenin treatment, reactive oxygen species (ROS) levels, annexin V-PE positive fractions, sub-G0/G1 peak in cell cycle analysis, mitochondrial membrane depolarization, and cell communication network factor 1 (CCN1) levels were increased, while cellular ATP content and phospho (p)-Akt level were decreased. Pretreatment with ROS scavenger N-acetylcysteine effectively reversed the series of phenomena caused by arctigenin, suggesting that ROS served as upstream molecules of arctigenin-driven cytotoxicity. Meanwhile, arctigenin increased the levels of p-receptor-interacting serine/threonine-protein kinase 3 (p-RIP3) and p-mixed lineage kinase domain-like pseudokinase (p-MLKL) as necroptosis mediators, and pretreatment with necroptosis inhibitor necrostatin-1 restored their levels and cell viability. Treatment of spheroids with arctigenin resulted in necroptotic cell death, which was prevented by N-acetylcysteine. The siRNA-based knockdown of CCN1 suppressed the levels of MLKL, B-cell lymphoma 2 (Bcl-2), and induced myeloid leukemia cell differentiation (Mcl-1) with increased cleavage of Bcl-2-associated X (Bax) and caspase-3. Collectively, these results provide new insights into the molecular mechanisms underlying arctigenin-induced cytotoxicity, and support arctigenin as a potential therapeutic agent for targeting non-Warburg phenotype through induction of necroptosis via ROS-mediated mitochondrial damage and CCN1 upregulation.