Discovery of novel 1H-benzo[d]imidazole-4,7-dione based transglutaminase 2 inhibitors as p53 stabilizing anticancer agents in renal cell carcinoma.

Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the ß-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the ß-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.

Artificial intelligence assistance for women who had spot compression view: reducing recall rates for digital mammography.

BACKGROUND: Mammography yields inevitable recall for indeterminate findings that need to be confirmed with additional views. PURPOSE: To explore whether the artificial intelligence (AI) algorithm for mammography can reduce false-positive recall in patients who undergo the spot compression view. MATERIAL AND METHODS: From January to December 2017, 236 breasts from 225 women who underwent the spot compression view due to focal asymmetry, mass, or architectural distortion on standard digital mammography were included. Three readers who were blinded to the study purpose, patient information, previous mammograms, following spot compression views, and any clinical or pathologic reports retrospectively reviewed 236 standard mammograms and determined the necessity of patient recall and the probability of malignancy per breast, first without and then with AI assistance. The performances of AI and the readers were evaluated with the recall rate, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. RESULTS: Among 236 examinations, 8 (3.4%) were cancers and 228 (96.6%) were benign. The recall rates of all three readers significantly decreased with AI assistance (P < 0.05). The reader-averaged recall rates significantly decreased with AI assistance regardless of breast composition (fatty breasts: 32.7% to 24.1%m P = 0.002; dense breasts: 33.6% to 21.2%, P < 0.001). The reader-averaged AUC increased with AI assistance and was comparable to that of standalone AI (0.835 vs. 0.895; P = 0.234). The reader-averaged specificity (71.2% to 79.8%, P < 0.001) and accuracy (71.3% to 79.7%, P < 0.001) significantly improved with AI assistance. CONCLUSION: AI assistance significantly reduced false-positive recall without compromising cancer detection in women with focal asymmetry, mass, or architectural distortion on standard digital mammography regardless of mammographic breast density.

US, Mammography, and Histopathologic Evaluation to Identify Low Nuclear Grade Ductal Carcinoma in Situ.

Background Low nuclear grade ductal carcinoma in situ (DCIS) identified at biopsy can be upgraded to intermediate to high nuclear grade DCIS at surgery. Methods that confirm low nuclear grade are needed to consider nonsurgical approaches for these patients. Purpose To develop a preoperative model to identify low nuclear grade DCIS and to evaluate factors associated with low nuclear grade DCIS at biopsy that was not upgraded to intermediate to high nuclear grade DCIS at surgery. Materials and Methods In this retrospective study, 470 women (median age, 50 years; interquartile range, 44-58 years) with 477 pure DCIS lesions at surgical histopathologic evaluation were included (January 2010 to December 2015). Patients were divided into the training set (n = 330) or validation set (n = 147) to develop a preoperative model to identify low nuclear grade DCIS. Features at US (mass, nonmass) and at mammography (morphologic characteristics, distribution of microcalcification) were reviewed. The upgrade rate of low nuclear grade DCIS was calculated, and multivariable regression was used to evaluate factors for associations with low nuclear grade DCIS that was not upgraded later. Results A preoperative model that included lesions manifesting as a mass at US without microcalcification and no comedonecrosis at biopsy was used to identify low nuclear grade DCIS, with a high area under the receiver operating characteristic curve of 0.97 (95% CI: 0.94, 1.00) in the validation set. The upgrade rate of low nuclear grade DCIS at biopsy was 38.8% (50 of 129). Ki-67 positivity (odds ratio, 0.04; 95% CI: 0.0003, 0.43; P = .005) was inversely associated with constant low nuclear grade DCIS. Conclusion The upgrade rate of low nuclear grade ductal carcinoma in situ (DCIS) at biopsy to intermediate to high nuclear grade DCIS at surgery occurred in more than a third of patients; low nuclear grade DCIS at final histopathologic evaluation could be identified if the mass was viewed at US without microcalcifications and had no comedonecrosis at histopathologic evaluation of biopsy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Rahbar in this issue. An earlier incorrect version appeared online. This article was corrected on April 14, 2022.

Mammographic Surveillance After Breast-Conserving Therapy: Impact of Digital Breast Tomosynthesis and Artificial Intelligence-Based Computer-Aided Detection.

BACKGROUND. Postoperative mammograms present interpretive challenges due to postoperative distortion and hematomas. The application of digital breast tomosyn-thesis (DBT) and artificial intelligence-based computer-aided detection (AI-CAD) after breast-conserving therapy (BCT) has not been widely investigated. OBJECTIVE. The purpose of our study was to assess the impact of additional DBT or AI-CAD on recall rate and diagnostic performance in women undergoing mammographic surveillance after BCT. METHODS. This retrospective study included 314 women (mean age, 53.3 ± 10.6 [SD] years; four with bilateral breast cancer) who underwent BCT followed by DBT (mean interval from surgery to DBT, 15.2 ± 15.4 months). Three breast radiologists independently reviewed images in three sessions: digital mammography (DM), DM with DBT (DM plus DBT), and DM with AI-CAD (DM plus AI-CAD). Recall rates and diagnostic performance were compared between DM, DM plus DBT, and DM plus AI-CAD using the readers' mean results. RESULTS. Of the 314 women, six breast recurrences (three ipsilateral and three contralateral) had developed at the time of surveillance mammography. The ipsilateral breast recall rate was lower for DM plus AI-CAD (1.9%) than for DM (11.2%) or DM plus DBT (4.1%) (p < .001). The contralateral breast recall rate was significantly lower for DM plus AI-CAD (1.5%, p < .001) than for DM (6.6%) but for not DM plus DBT (2.7%, p = .08). In the ipsilateral breast, accuracy was higher for DM plus AI-CAD (97.0%) than for DM (88.5%) or DM plus DBT (94.8%) (p < .05); specificity was higher for DM plus AI-CAD (98.3%) than for DM (89.3%) or DM plus DBT (96.1%) (p < .05); sensitivity was significantly lower for DM plus AI-CAD (22.2%) than for DM (66.7%, p = .03) but not DM plus DBT (22.2%, p > .99). In the contralateral breast, accuracy was significantly higher for DM plus AI-CAD (97.1%) than for DM (92.5%, p < .001) but not DM plus DBT (96.1%, p = .25); specificity was significantly higher for DM plus AI-CAD (98.6%) than for DM (93.7%, p < .001) but not DM plus DBT (97.5%) (p = .09); sensitivity was not different between DM (33.3%), DM plus DBT (22.2%), and DM plus AI-CAD (11.1%) (p > .05). CONCLUSION. After BCT, adjunct DBT or AI-CAD reduced recall rates and improved accuracy in the ipsilateral and contralateral breasts compared with DM. In the ipsilateral breast, the addition of AI-CAD resulted in a lower recall rate and higher accuracy than the addition of DBT. CLINICAL IMPACT. AI-CAD may help address the challenges of interpreting post-BCT surveillance mammograms.

Outcomes Following Negative Screening MRI Results in Korean Women with a Personal History of Breast Cancer: Implications for the Next MRI Interval.

Background There are limited data on outcomes following screening breast MRI in women with a personal history of breast cancer (PHBC). Purpose To investigate outcomes and factors associated with subsequent cancers following a negative screening MRI study in women with a PHBC. Materials and Methods Consecutive women with a PHBC and a negative prevalence screening breast MRI result between August 2014 and December 2016 were retrospectively identified. Inclusion criteria were prevalence screening MRI performed as part of routine surveillance protocol (1-3 years after treatment) and follow-up data for at least 12 months. The incidence and characteristics of subsequent cancers were reviewed. Logistic regression analysis was used to investigate associations between clinical-pathologic characteristics and subsequent cancers. Performance metrics were compared among screening MRI, mammography, and US. Results A total of 993 women (mean age ± standard deviation, 53 years ± 10) were evaluated. Ten second in-breast cancers (ie, ipsilateral or contralateral) occurred at a median interval of 31.8 months (range, 13.3-44.8 months) after MRI, of which eight (80%) were ductal carcinoma in situ (DCIS) or node-negative T1 cancers. Only one node-negative T1mi (tumor ≤1 mm) second in-breast cancer visible on a mammogram was detected within 24 months of MRI. Of second in-breast cancers, 40% (four of 10) were detected only at subsequent screening MRI, which was performed a median of 30.5 months after negative prevalence screening MRI. Ten local-regional recurrences occurred at a median interval of 16.9 months (range, 6-35 months). Previous treatment for DCIS was associated with second in-breast cancers (odds ratio, 3.73; 95% CI: 1.04, 13.38; P = .04). In 1048 women who underwent prevalence screening MRI (including all Breast Imaging Reporting and Data System categories), MRI showed a lower abnormal interpretation rate and higher specificity than mammography or US (P < .001 for all). Conclusion After a negative screening MRI result, 90% of subsequent cancers were detected at intervals longer than 24 months and there was a low second in-breast cancer rate (1%). © RSNA, 2021 Supplemental material is available for this article. See also the editorial by Chang in this issue.

Interval Cancers after Negative Supplemental Screening Breast MRI Results in Women with a Personal History of Breast Cancer.

Background There are few interval cancer studies of incident screening MRI for women with a personal history of breast cancer (PHBC). Purpose To evaluate the performance measures of screening breast MRI in women with a PHBC across multiple rounds and to identify subgroups who might be more at risk for interval cancer. Materials and Methods Between January 2008 and March 2019, consecutive screening breast MRI studies for women who had undergone breast-conserving surgery because of breast cancer were retrospectively identified. Inclusion criteria were negative or benign findings at mammography with US, availability of at least 1 year of follow-up data, and examinations having been performed within 12 months after the initial cancer surgery. Performance measures were calculated for each round. Multivariable logistic regression analysis was performed to determine factors associated with the risk of interval cancer. Results Among the 6603 MRI examinations for 2809 women (median age, 47 years; interquartile range, 42-53 years), the cancer detection rate was 8.3 per 1000 screening examinations (55 of 6603 examinations) and the interval cancer rate was 1.5 per 1000 screening examinations (10 of 6603 examinations). The sensitivity and specificity were 85% (55 of 65 examinations; 95% CI: 76, 93) and 88.3% (5775 of 6538 examinations; 95% CI: 87.6, 89.1), respectively. At multivariable analysis, interval cancers were associated with a first-degree family history of breast cancer (odds ratio [OR], 5.4; 95% CI: 1.3, 22.5; P = .02), estrogen receptor- and progesterone receptor-negative primary cancers (OR, 3.6; 95% CI: 1.1, 12.2; P = .04), and moderate or marked background parenchymal enhancement (OR, 10.8; 95% CI: 3.3, 35.7; P < .001). Conclusion Performance of screening breast MRI in women with a personal history of breast cancer was sustained across multiple rounds, and a first-degree family history of breast cancer, estrogen receptor- and progesterone receptor-negative primary cancers, and moderate or marked background parenchymal enhancement at MRI were independently associated with the risk of developing interval cancers. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Slanetz in this issue.

Chronological Trends of Breast Ductal Carcinoma In Situ: Clinical, Radiologic, and Pathologic Perspectives.

BACKGROUND: Because no prior studies have evaluated the chronological trends of ductal carcinoma in situ (DCIS) despite the increasing number of surgeries performed for DCIS, this study analyzed how the clinical, radiologic, and pathologic characteristics of DCIS changed during a 10-year period. METHODS: Of 7123 patients who underwent primary breast cancer surgery at a single institution from 2006 to 2015, 792 patients with pure DCIS were included in this study. The chronological trends of age, symptoms, method for detecting either mammography or ultrasonography, tumor size, nuclear grade, comedonecrosis, and molecular markers were calculated using Poisson regression for all patients and asymptomatic patients. RESULTS: During 10 years, DCIS surgery rates significantly increased (p < 0.001). Despite the high percentage of DCIS detected on mammography, the detection rate for DCIS by mammography significantly decreased (97.3% in 2006 to 67.6% in 2015; p = 0.025), whereas the detection rate by ultrasound significantly increased (2.7% to 31.0%; p < 0.001). Conservation surgery rates (odds ratio [OR], 1.058), low-to-intermediate nuclear grade rates (OR, 1.069), and the absence of comedonecrosis (OR, 1.104) significantly increased over time (all p < 0.05). Estrogen receptor (ER) negativity (OR, 0.935) and human epidermal growth factor receptor 2 (HER2) positivity rates (OR, 0.953) significantly decreased (all p < 0.05). The same trends were observed for the 613 asymptomatic patients. CONCLUSION: The rate of DCIS detected on ultrasound only significantly increased during 10 years. Low-to-intermediate nuclear grade rates significantly increased, whereas ER negativity and HER2 positivity rates significantly decreased during the same period. These findings suggest that DCIS detected on screening ultrasound is less aggressive than DCIS detected on mammography.

Combining radiomics with ultrasound-based risk stratification systems for thyroid nodules: an approach for improving performance.

OBJECTIVES: To develop a radiomics score using ultrasound images to predict thyroid malignancy and to investigate its potential as a complementary tool to improve the performance of risk stratification systems. METHODS: We retrospectively included consecutive patients who underwent fine-needle aspiration (FNA) for thyroid nodules that were cytopathologically diagnosed as benign or malignant. Nodules were randomly assigned to a training and test set (8:2 ratio). A radiomics score was developed from the training set, and cutoff values based on the maximum Youden index (Rad_maxY) and for 5%, 10%, and 20% predicted malignancy risk (Rad_5%, Rad_10%, Rad_20%, respectively) were applied to the test set. The performances of the American College of Radiology (ACR) and the American Thyroid Association (ATA) guidelines were compared with the combined performances of the guidelines and radiomics score with interpretations from expert and nonexpert readers. RESULTS: A total of 1624 thyroid nodules from 1609 patients (mean age, 50.1 years [range, 18-90 years]) were included. The radiomics score yielded an AUC of 0.85 (95% CI: 0.83, 0.87) in the training set and 0.75 (95% CI: 0.69, 0.81) in the test set (Rad_maxY). When the radiomics score was combined with the ACR or ATA guidelines (Rad_5%), all readers showed increased specificity, accuracy, and PPV and decreased unnecessary FNA rates (all p < .05), with no difference in sensitivity (p > .05). CONCLUSION: Radiomics help predict thyroid malignancy and improve specificity, accuracy, PPV, and unnecessary FNA rate while maintaining the sensitivity of the ACR and ATA guidelines for both expert and nonexpert readers. KEY POINTS: • The radiomics score yielded an AUC of 0.85 and 0.75 in the training and test set, respectively. • For all readers, combining a 5% predicted malignancy risk cutoff for the radiomics score with the ACR and ATA guidelines significantly increased specificity, accuracy, and PPV and decreased unnecessary FNA rates, with no decrease in sensitivity. • Radiomics can help predict malignancy in thyroid nodules in combination with risk stratification systems, by improving specificity, accuracy, and PPV and unnecessary FNA rates while maintaining sensitivity for both expert and nonexpert readers.

Persimmon leaf extract protects mice from atopic dermatitis by inhibiting T cell activation via regulation of the JNK pathway.

Persimmon leaf extracts (PLE) have been widely used as a traditional medicine in East Asian countries. The effects of persimmon leaves, including antioxidant, antiinflammatory, hypotensive, and anti-allergy effects, have been investigated; however, there is little evidence on the inhibition of T cell activation in vitro and effects on T cell-related diseases, such as atopic dermatitis (AD), in vivo by persimmon leaves. PLE (50 µg/mL) effectively attenuated the mRNA levels of IL-2 in Jurkat T cells stimulated with PMA/A23187 and Staphylococcus enterotoxin E-loaded Raji B cells without causing cytotoxicity. In Jurkat T cells stimulated with PMA/A23187, treatment with 50 µg/mL PLE blocked the translocation of p65 and IκBα degradation. Moreover, the JNK signaling pathway in Jurkat T cells stimulated with PMA/A23187 was affected by treatment with PLE. The oral administration of PLE markedly attenuated AD manifestations in mice, including ear thickness, IgE levels, and lymph node sizes. These results indicate PLE significantly blocked T cell activation via NF-κB signaling and the JNK pathway. This suggests underlying mechanisms of PLE involving the control of effector cytokines produced by activated T cells in ear tissue and lymph nodes, as well as the infiltration of mast cells and the therapeutic potential of AD.

Inhibitory Effect of LGS and ODE Isolated from the Twigs of Syringa oblata subsp. dilatata on RANKL-Induced Osteoclastogenesis in Macrophage Cells.

Osteoblasts and osteoclasts play a pivotal role in maintaining bone homeostasis, of which excessive bone resorption by osteoclasts can cause osteoporosis and various bone diseases. However, current osteoporosis treatments have many side effects, and research on new treatments that can replace these treatments is ongoing. Therefore, in this study, the roles of ligustroside (LGS) and oleoside dimethylester (ODE), a natural product-derived compound isolated from Syringa oblata subsp. dilatata as a novel, natural product-derived osteoporosis treatments were investigated. In the results of this study, LGS and ODE inhibited the differentiation of receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced RAW264.7 cells into osteoclasts without cytotoxicity, and down-regulated the activity of TRAP, a specific biomarker of osteoclasts. In addition, it inhibited bone resorption and actin ring formation, which are important functions and features of osteoclasts. Also, the effects of LGS and ODE on the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and phosphoinositide 3-kinases (PI3K)/ protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathways that play important roles in osteoclast differentiation were evaluated. In the results, LGS and ODE downregulated the phosphorylation of RANKL-induced MAPK and PI3K/Akt/mTOR proteins in a concentration-dependent manner, translocation of NF-κB into the nucleus was inhibited. As a result, the compounds LGS and ODE isolated from S. oblate subsp. dilatata effectively regulated the differentiation of RANKL-induced osteoclasts and inhibited the phosphorylation of signaling pathways that play a pivotal role in osteoclast differentiation. Therefore, these results suggest the possibility of LGS and ODE as new natural product treatments for bone diseases caused by excessive osteoclasts.

Comparing recall rates following implementation of digital breast tomosynthesis to synthetic 2D images and digital mammography on women with breast-conserving surgery.

OBJECTIVES: To evaluate the recall rates of digital mammography (DM) and synthetic images after adding digital breast tomosynthesis (DBT) in patients with breast-conserving surgery. METHODS: From November 2015 to April 2017, 229 women with breast-conserving surgery due to breast cancer who underwent DBT after surgery were included (mean interval, 12.9 ± 1.4 months). All women underwent combo-mode DBT examinations including full-field DM, tomosynthesis, and reconstructed synthetic 2D images. Three board-certified breast radiologists reviewed the images sequentially: synthetic 2D+DBT and, 1 month later, DM and then DM+DBT. Recall rates and the abnormality type causing the recall were calculated and compared for each mammographic modality and breast density. RESULTS: Of the 229 patients included, 230 mammography images were reviewed. One patient (0.4%) developed locoregional recurrences during follow-up (mean duration, 25.8 ± 4.5 months). Recall rates for synthetic 2D+DBT were significantly lower than for DM alone (4.1% (2.6-6.2) vs. 11.6% (9.2-14.5), respectively; p < 0.001). Recall rates did not differ between synthetic 2D+DBT and DM+DBT (4.1% (2.6-6.2) vs. 2.9% (1.9-4.5), respectively; p = 0.234). Recall rates of synthetic 2D+DBT and DM+DBT were significantly lower than those of DM alone, regardless of mammographic breast density (all p < 0.05, respectively). CONCLUSION: Adding DBT to synthetic 2D images or DM shows significant reduction in recall rates compared with DM alone for women who undergo breast-conserving surgery for breast cancer, regardless of mammographic density. KEY POINTS: • Recall rates for synthetic 2D+DBT were significantly lower than those of DM alone (4.1% (2.6-6.2) vs. 11.6% (9.2-14.5), respectively; p < 0.001). • No significant differences were seen in recall rates between synthetic 2D+DBT and DM+DBT (4.1 (2.6-6.2) vs. 2.9 (1.9-4.5), respectively; p = 0.234). • Reader-averaged recall rates after adding DBT to synthetic 2D or DM were significantly lower than those of DM alone, regardless of mammographic breast density (all p < 0.05, respectively).

Significance of Radial Margin in Patients Undergoing Complete Mesocolic Excision for Colon Cancer.

BACKGROUND: Comparable to circumferential resection margin in rectal cancer, radial margin is a potential prognostic factor in colon cancer that has just begun to be studied. No previous studies have investigated the influence of radial margin in the context of complete mesocolic excision. OBJECTIVE: This study aimed to examine the impact of radial margin on oncologic outcomes after complete mesocolic excision for colon cancer. DESIGN: We retrospectively reviewed patients with stage I to III colon cancer who underwent curative resection from October 2010 to March 2013. SETTINGS: This study was conducted using the prospective colorectal cancer registry of Severance hospital. PATIENTS: A total of 834 consecutive patients who underwent complete mesocolic excision for colon adenocarcinoma were included. INTERVENTIONS: We assigned patients into 3 groups according to radial margin distance: group A, radial margin ≥2.0 mm; group B, 1.0 ≤ radial margin < 2.0 mm; group C, radial margin <1 mm. MAIN OUTCOMES AND MEASURES: Overall survival and disease-free survival were estimated. RESULTS: On adjusted Cox regression analysis, only group C was predictive of reduced overall survival (HR, 1.90; 95% CI, 1.11-3.25; p = 0.018) and disease-free survival (HR, 1.93; 95% CI, 1.28-2.89; p = 0.001). We thereby defined radial margin threatening as radial margin <1 mm. Postoperative 5-fluorouracil (HR, 0.86; 95% CI, 0.35-2.10; p = 0.743) and FOLFOX (HR, 1.23; 95% CI, 0.57-2.64; p = 0.581) chemotherapy did not affect disease-free survival in patients with radial margin threatening. LIMITATIONS: This study has the limitations inherent in all retrospective, single-institution studies. CONCLUSIONS: Even with complete mesocolic excision, radial margin <1 mm was an independent predictor of survival and recurrence. This finding suggests that special efforts for obtaining a clear radial margin may be necessary in locally advanced colon cancer. See Video Abstract at http://links.lww.com/DCR/B125. IMPORTANCIA DEL MARGEN RADIAL EN PACIENTES SOMETIDOS A ESCISIÓN MESOCÓLICA COMPLETA PARA CÁNCER DEL COLON: Comparable al margen de resección circunferencial en cáncer rectal, el margen radial en cáncer de colon, es un factor pronóstico potencial, que recientemente comienza a estudiarse. Ningún estudio previo ha investigado la influencia del margen radial, en el contexto de la escisión mesocólica completa.Examinar en cáncer de colon, el impacto del margen radial en los resultados oncológicos, después de la escisión mesocólica completa.Revisión retrospectiva de pacientes con cáncer de colon en estadio I-III, sometidos a resección curativa de octubre 2010 a marzo 2013.Este estudio se realizó utilizando un registro prospectivo de cáncer colorrectal del hospital Severance.Se incluyeron un total de 834 pacientes consecutivos con adenocarcinoma de colon, sometidos a escisión mesocólica completa. Dividimos a los pacientes en 3 grupos según la distancia del margen radial: grupo A, margen radial ≥ 2.0 mm; grupo B, 1.0 ≤ margen radial <2.0 mm; grupo C, margen radial <1 mm.Se estimó la supervivencia general y la supervivencia libre de enfermedad.En el análisis de regresión de Cox ajustado, solo el grupo C fue predictivo de supervivencia global reducida (HR, 1.90; IC 95%, 1.11-3.25; p = 0.018) y supervivencia libre de enfermedad (HR, 1.93; IC 95%, 1.28-2.89; p = 0.001). Definimos como margen radial amenazante, un margen radial <1 mm. La quimioterapia posoperatoria con 5-FU (HR, 0,86; IC 95%, 0,35-2,10; p = 0.743) y FOLFOX (HR, 1,23; IC 95%, 0,57-2,64; p = 0,581), no afectó la supervivencia libre de enfermedad en pacientes con riesgo de margen radial.Este estudio tiene limitaciones inherentes a todos los estudios retrospectivos de una sola institución.Aun con la escisión mesocólica completa, el margen radial <1 mm fue un predictor independiente de supervivencia y recurrencia. Este hallazgo sugiere que pueden ser necesarios esfuerzos especiales para obtener un claro margen radial, en cáncer de colon localmente avanzado. Consulte Video Resumen en http://links.lww.com/DCR/B125.

Inhibitory Effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside on RANKL-Induced Osteoclast Differentiation and ROS Generation in Macrophages.

In bone homeostasis, bone loss due to excessive osteoclasts and inflammation or osteolysis in the bone formation process cause bone diseases such as osteoporosis. Suppressing the accompanying oxidative stress such as ROS in this process is an important treatment strategy for bone disease. Therefore, in this study, the effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside (BAG), an arylbutanoid glycoside isolated from Betula platyphylla var. japonica was investigated in RANKL-induced RAW264.7 cells and LPS-stimulated MC3E3-T1 cells. BAG inhibited the activity of TRAP, an important marker of osteoclast differentiation and F-actin ring formation, which has osteospecific structure. In addition, the protein and gene levels were suppressed of integrin ß3 and CCL4, which play an important role in the osteoclast-induced bone resorption and migration of osteoclasts, and inhibited the production of ROS and restored the expression of antioxidant enzymes such as SOD and CAT lost by RANKL. The inhibitory effect of BAG on osteoclast differentiation and ROS production appears to be due to the inhibition of MAPKs phosphorylation and NF-κß translocation, which play a major role in osteoclast differentiation. In addition, BAG inhibited ROS generated by LPS and effectively restores the mineralization of lost osteoblasts, thereby showing the effect of bone formation in the inflammatory situation accompanying bone loss by excessive osteoclasts, suggesting its potential as a new natural product-derived bone disease treatment.

Comparison of synthetic and digital mammography with digital breast tomosynthesis or alone for the detection and classification of microcalcifications.

OBJECTIVE: To compare the performance of synthetic mammography (SM) and digital mammography (DM) with digital breast tomosynthesis (DBT) or alone for the evaluation of microcalcifications. METHODS: This retrospective study includes 198 mammography cases, all with DM, SM, and DBT images, from January to October 2013. Three radiologists interpreted images and recorded the presence of microcalcifications and their conspicuity scores and final BI-RADS categories (1, 2, 3, 4a, 4b, 4c, 5). Readers' area under the ROC curves (AUCs) were analyzed for SM plus DBT vs. DM plus DBT and SM alone vs. DM alone using the BI-RADS categories for the overall group and dense breast subgroup. RESULTS: Conspicuity scores of detected microcalcifications were neither significantly different between SM and DM with DBT nor alone (p>0.05). In predicting malignancy of detected microcalcifications, no significant difference was found between readers' AUCs for SM and DM with DBT or alone in the overall group or dense breast subgroup (p>0.05). CONCLUSIONS: Diagnostic performances of SM and DM for the evaluation of microcalcifications are not significantly different, whether performed with DBT or alone. KEY POINTS: • In DBT-imaging, SM and DM show comparable performances when evaluating microcalcifications. • For BI-RADS classification of microcalcifications, SM and DM show similar AUCs. • DBT with SM may be sufficient for diagnosing microcalcifications, without DM.

Clinicopathological and biomolecular characteristics of stage IIB/IIC and stage IIIA colon cancer: Insight into the survival paradox.

BACKGROUND: A survival paradox of stage IIB/IIC and IIIA colon cancer has been consistently observed throughout revisions of the TNM system. This study aimed to understand this paradox with clinicopathological and molecular differences. METHODS: Clinicopathological characteristics of patients with pathologically confirmed stage IIB/IIC or IIIA colon cancer were retrospectively reviewed from a database. Publicly available molecular data were retrieved, and intrinsic subtypes were identified and subjected to gene sets enrichment analysis (GSEA). RESULTS: Among the 159 patients included in the clinicopathological analysis, those at stage IIB/IIC had worse 3-year disease-free and overall survival than those at stage IIIA (59.3% vs 91.7%, P < 0.001 and 82.7% vs 98.5%, P < 0.001, respectively), even after adjusting for confounding factors. Data of 95 patients were retrieved from public databases, demonstrating a higher frequency of the microsatellite instable subtype in stage IIB/IIC. The consensus molecular subtype distribution pattern differed between the groups. The GSEA further suggested the protumor inflammatory reaction might be more prominent in stage IIB/IIC. CONCLUSIONS: The survival paradox in colon cancer was confirmed and appears to be a multifactorial phenomenon not attributed to a single clinicopathologic factor. However, the greater molecular heterogeneity in stage IIB/IIC could contribute to the poor prognosis.

Preoperative Axillary US in Early-Stage Breast Cancer: Potential to Prevent Unnecessary Axillary Lymph Node Dissection.

Purpose To evaluate the value of preoperative axillary ultrasonography (US) for preventing unnecessary axillary lymph node dissection after sentinel lymph node (SLN) biopsy in a large series of patients with early-stage breast cancers treated with both breast-conserving surgery and SLN biopsy. Materials and Methods From March 2009 to February 2013, 1802 patients who underwent breast-conserving surgery for clinical T1-2/N0 cancers and SLN biopsy with or without axillary lymph node dissection were included. Preoperative axillary US results and clinical-pathologic variables were compared according to the status of non-SLN metastasis. Multivariate logistic regression analysis was performed to find factors associated with non-SLN metastasis. Results Of 1802 patients, 397 (22.0%) underwent axillary lymph node dissection due to positive SLN biopsy and 76 (4.2%) had non-SLN metastasis at final histopathologic examination. Patients with non-SLN metastasis were younger and showed positive axilla at US and clinical T2 stage more frequently (P < .05). At multivariate analysis, positive axilla at US (P = .001), clinical T2 stage (P = .005), and lymphovascular invasion (P < .001) were significantly associated with non-SLN metastasis. Among 1284 patients with negative axilla at US and clinical T1 stage cancer, 1254 (97.7%) did not have non-SLN metastasis and 30 (2.3%) had non-SLN metastasis. Conclusion Preoperative axillary US results and clinical T stage are associated with the status of non-SLN metastasis in patients with early breast cancer. The results of this study suggest that preoperative axillary US can help select patients at minimal risk of non-SLN metastasis, for whom axillary lymph node dissection can be omitted. © RSNA, 2018 Online supplemental material is available for this article.

Comparison of Ultrasound Elastography and Color Doppler Ultrasonography for Distinguishing Small Triple-Negative Breast Cancer From Fibroadenoma.

OBJECTIVES: To compare the performance of ultrasound elastography and color Doppler ultrasonography (US) in distinguishing small, oval, or round triple-negative breast cancer from fibroadenoma and the influence on the further management decision at US. METHODS: In total, 131 biopsy-proven oval or round fibroadenomas (n = 68) and triple-negative breast cancers (n = 63) smaller than 2 cm were included. Three blinded readers assessed the images from US, elastography, and color Doppler imaging according to the Breast Imaging Reporting and Data System lexicon independently. Interobserver agreement was assessed, and sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve values for each data set were compared. Pathologic results were reference standards. RESULTS: The interobserver agreements were excellent (intraclass correlation coefficients, 0.856 for US, 0.948 for elastography, and 0.864 for color Doppler). The specificity and accuracy of US with elastography were increased compared with US alone or US with Doppler imaging without statistically significant differences in sensitivity. The average area under the curve for US with elastography (0.869) was increased compared with US alone (0.650) or US with color Doppler (0.576). CONCLUSIONS: Elastography is more useful than color Doppler imaging for distinguishing small, oval, or round triple-negative breast cancer from fibroadenoma, and elastography can help avoid biopsy of benign masses.

Assessment of TSPO in a Rat Experimental Autoimmune Myocarditis Model: A Comparison Study between [18F]Fluoromethyl-PBR28 and [18F]CB251.

Overexpression of the 18-kDa translocator protein (TSPO) is closely linked to inflammatory responses in the heart, including myocarditis, which can lead to myocardial necrosis. In vivo assessment of inflammatory responses has enabled the precise diagnosis of myocarditis to improve clinical outcomes. Here, we evaluated TSPO overexpression in a rat model of experimental autoimmune myocarditis (EAM) compared to healthy rats using two TSPO radiotracers, [18F]fluoromethyl-PBR28 ([18F]1) and [18F]CB251 ([18F]2). All radiolabeling methods were successfully applied to an automated module for the reproducible preparation of TSPO radiotracers. Both radiotracers were directly compared in an EAM rat model, as well as in healthy rats to determine whether either radiotracer provides a more promising assessment of in vivo TSPO overexpression. [18F]2 provided more specific TSPO-uptake in the heart of the EAM rats (1.32-fold that of the heart-to-lung uptake ratio versus healthy controls), while [18F]1 did not show a significant difference between the two groups. Histopathological characterization revealed that a prominent positron emission tomography (PET) signal of [18F]2 in the EAM rats corresponded to the presence of a higher density of TSPO compared to the healthy controls. These results suggest that the imidazole[1,2-a]pyridine-based radiotracer [18F]2 is a sensitive tool for noninvasively diagnosing myocarditis related to inflammation of the heart muscle by assessing abnormal TSPO expression.

Additional diagnostic value of shear-wave elastography and color Doppler US for evaluation of breast non-mass lesions detected at B-mode US.

OBJECTIVE: To evaluate the diagnostic value of shear-wave elastography (SWE) and colour Doppler ultrasound (US) for evaluation of breast non-mass lesions (NMLs) detected by B-mode US. METHODS: This retrospective study enrolled 116 NMLs (42 benign, 74 malignant). For each lesion, B-mode US, SWE and colour Doppler US were performed. Mean elasticity (E mean), maximum elasticity (E max) and vascularity were assessed by SWE and Doppler US. Diagnostic performances of B-mode US, SWE and Doppler US were calculated to differentiate benign and malignant NMLs. RESULTS: In benign NMLs, average E mean and E max were lower, and low vascularity (no flow or only one vessel flow) was more frequent (P < 0.001). When BI-RADS category 4a NMLs were downgraded to category 3 with 'E mean of 85.1 kPa or less' and/or 'low vascularity', specificities increased (69.0-90.5 %; P < 0.001), without significant loss in sensitivities (97.3-100 %). When these 4a NMLs were downgraded by the combination of SWE and Doppler US, all downgraded NMLs (59.3 %, 19/32) were confirmed as benign. CONCLUSIONS: Addition of SWE and colour Doppler US to B-mode US improved diagnostic performances in differentiating benign and malignant NMLs. This study suggests that the combination of SWE and colour Doppler may help patients with BI-RADS category 4a NMLs avoid unnecessary biopsies. KEY POINTS: • B-mode US features of malignant and benign NMLs may overlap. • SWE and colour Doppler provides useful information about breast NMLs. • SWE and colour Doppler may decrease unnecessary biopsies of breast NMLs.