The N-Degron Pathway Mediates ER-phagy.

The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.

Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-ß Production.

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-ß in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.

Establishment of a patient-specific avatar organoid model derived from EUS-guided fine-needle biopsy for timely clinical application in pancreatic ductal adenocarcinoma (with video).

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate among tumors. At the time of diagnosis, more than 80% of PDACs are considered to be surgically unresectable, and there is an unmet need for treatment options in these inoperable PDACs. This study aimed to establish a patient-derived organoid (PDO) platform from EUS-guided fine-needle biopsy (EUS-FNB) collected at diagnosis and to determine its clinical applicability for the timely treatment of unresectable PDAC. METHODS: Patients with suspected PDAC were prospectively enrolled at the Samsung Medical Center from 2015 to 2019. PDAC tissues were acquired by means of EUS-FNB to establish PDAC PDOs, which were comprehensively analyzed for histology, genomic sequencing, and high-throughput screening (HTS) drug sensitivity test. RESULTS: PDAC PDOs were established with a success rate of 83.2% (94/113). It took approximately 3 weeks from acquiring minimal EUS-FNB specimens to generating sufficient PDAC PDOs for the simultaneous HTS drug sensitivity test and genomic sequencing. The high concordance between PDAC tissues and matched PDOs was confirmed, and whole-exome sequencing revealed the increased detection of genetic alterations in PDOs compared with EUS-FNB tissues. The HTS drug sensitivity test showed clinical correlation between the ex vivo PDO response and the actual chemotherapeutic response of the study patients in the real world (13 out of 15 cases). In addition, whole-transcriptome sequencing identified candidate genes associated with nab-paclitaxel resistance, such as ITGB7, ANPEP, and ST3GAL1. CONCLUSIONS: This PDAC PDO platform allows several therapeutic drugs to be tested within a short time window and opens the possibility for timely personalized medicine as a "patient avatar model" in clinical practice.

The N-terminal cysteine is a dual sensor of oxygen and oxidative stress.

Cellular homeostasis requires the sensing of and adaptation to intracellular oxygen (O2) and reactive oxygen species (ROS). The Arg/N-degron pathway targets proteins that bear destabilizing N-terminal residues for degradation by the proteasome or via autophagy. Under normoxic conditions, the N-terminal Cys (Nt-Cys) residues of specific substrates can be oxidized by dioxygenases such as plant cysteine oxidases and cysteamine (2-aminoethanethiol) dioxygenases and arginylated by ATE1 R-transferases to generate Arg-CysO2(H) (R-CO2). Proteins bearing the R-CO2 N-degron are targeted via Lys48 (K48)-linked ubiquitylation by UBR1/UBR2 N-recognins for proteasomal degradation. During acute hypoxia, such proteins are partially stabilized, owing to decreased Nt-Cys oxidation. Here, we show that if hypoxia is prolonged, the Nt-Cys of regulatory proteins can be chemically oxidized by ROS to generate Arg-CysO3(H) (R-CO3), a lysosomal N-degron. The resulting R-CO3 is bound by KCMF1, a N-recognin that induces K63-linked ubiquitylation, followed by K27-linked ubiquitylation by the noncanonical N-recognin UBR4. Autophagic targeting of Cys/N-degron substrates is mediated by the autophagic N-recognin p62/SQTSM-1/Sequestosome-1 through recognition of K27/K63-linked ubiquitin (Ub) chains. This Cys/N-degron-dependent reprogramming in the proteolytic flux is important for cellular homeostasis under both chronic hypoxia and oxidative stress. A small-compound ligand of p62 is cytoprotective under oxidative stress through its ability to accelerate proteolytic flux of K27/K63-ubiquitylated Cys/N-degron substrates. Our results suggest that the Nt-Cys of conditional Cys/N-degron substrates acts as an acceptor of O2 to maintain both O2 and ROS homeostasis and modulates half-lives of substrates through either the proteasome or lysosome by reprogramming of their Ub codes.

Calcium pyrophosphate crystal deposition with rotator cuff tear-A case report.

Calcium pyrophosphate dihydrate (CPPD) deposition disease is an inflammatory arthritis induced by calcium pyrophosphate (CPP) crystals and clinically it is called pseudogout. It usually deposits in articular cartilage and in periarticular soft tissues. But no cases of pseudogout in the rotator cuff without cartilage deposition or destruction have been reported so far. We present a case of a 57-year-old woman who was diagnosed as pseudogout with rotator cuff tear.

Vinpocetine, a phosphodiesterase 1 inhibitor, mitigates atopic dermatitis-like skin inflammation.

Atopic dermatitis (AD) is the most common inflammatory pruritic skin disease worldwide, characterized by the infiltration of multiple pathogenic T lymphocytes and histological symptoms such as epidermal and dermal thickening. This study aims to investigate the effect of vinpocetine (Vinp; a phosphodiesterase 1 inhibitor) on a 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD-like model. DNCB (1%) was administered on day 1 in the AD model. Subsequently, from day 14 onward, mice in each group (Vinp-treated groups: 1 mg/kg and 2 mg/kg and dexamethasone- treated group: 2 mg/kg) were administered 100 µl of a specific drug daily, whereas 0.2% DNCB was administered every other day for 30 min over 14 days. The Vinp-treated groups showed improved Eczema Area and Severity Index scores and trans-epidermal water loss, indicating the efficacy of Vinp in improving AD and enhancing skin barrier function. Histological analysis further confirmed the reduction in hyperplasia of the epidermis and the infiltration of inflammatory cells, including macrophages, eosinophils, and mast cells, with Vinp treatment. Moreover, Vinp reduced serum concentrations of IgE, interleukin (IL)-6, IL-13, and monocyte chemotactic protein-1. The mRNA levels of IL-1ß, IL-6, Thymic stromal lymphopoietin, and transforming growth factor-beta (TGF-ß) were reduced by Vinp treatment. Reduction of TGF-ß protein by Vinp in skin tissue was also observed. Collectively, our results underscore the effectiveness of Vinp in mitigating DNCB-induced AD by modulating the expression of various biomarkers. Consequently, Vinp is a promising therapeutic candidate for treating AD.

Genetic influences on alcohol flushing in East Asian populations.

BACKGROUND: Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. METHODS: We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. RESULTS: We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). CONCLUSION: This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.

Use of imaging prediction model for omission of axillary surgery in early-stage breast cancer patients.

PURPOSE: To develop a prediction model incorporating clinicopathological information, US, and MRI to diagnose axillary lymph node (LN) metastasis with acceptable false negative rate (FNR) in patients with early stage, clinically node-negative breast cancers. METHODS: In this single center retrospective study, the inclusion criteria comprised women with clinical T1 or T2 and N0 breast cancers who underwent preoperative US and MRI between January 2017 and July 2018. Patients were temporally divided into the development and validation cohorts. Clinicopathological information, US, and MRI findings were collected. Two prediction models (US model and combined US and MRI model) were created using logistic regression analysis from the development cohort. FNRs of the two models were compared using the McNemar test. RESULTS: A total of 964 women comprised the development (603 women, 54 ± 11 years) and validation (361 women, 53 ± 10 years) cohorts with 107 (18%) and 77 (21%) axillary LN metastases in each cohort, respectively. The US model consisted of tumor size and morphology of LN on US. The combined US and MRI model consisted of asymmetry of LN number, long diameter of LN, tumor type, and multiplicity of breast cancers on MRI, in addition to tumor size and morphology of LN on US. The combined model showed significantly lower FNR than the US model in both development (5% vs. 32%, P < .001) and validation (9% vs. 35%, P < .001) cohorts. CONCLUSION: Our prediction model combining US and MRI characteristics of index cancer and LN lowered FNR compared to using US alone, and could potentially lead to avoid unnecessary SLNB in early stage, clinically node-negative breast cancers.

Beyond Breast Density: Risk Measures for Breast Cancer in Multiple Imaging Modalities.

Breast density is an independent risk factor for breast cancer. In digital mammography and digital breast tomosynthesis, breast density is assessed visually using the four-category scale developed by the American College of Radiology Breast Imaging Reporting and Data System (5th edition as of November 2022). Epidemiologically based risk models, such as the Tyrer-Cuzick model (version 8), demonstrate superior modeling performance when mammographic density is incorporated. Beyond just density, a separate mammographic measure of breast cancer risk is parenchymal textural complexity. With advancements in radiomics and deep learning, mammographic textural patterns can be assessed quantitatively and incorporated into risk models. Other supplemental screening modalities, such as breast US and MRI, offer independent risk measures complementary to those derived from mammography. Breast US allows the two components of fibroglandular tissue (stromal and glandular) to be visualized separately in a manner that is not possible with mammography. A higher glandular component at screening breast US is associated with higher risk. With MRI, a higher background parenchymal enhancement of the fibroglandular tissue has also emerged as an imaging marker for risk assessment. Imaging markers observed at mammography, US, and MRI are powerful tools in refining breast cancer risk prediction, beyond mammographic density alone.

Background Parenchymal Enhancement at Postoperative Surveillance Breast MRI: Association with Future Second Breast Cancer Risk.

Background Background parenchymal enhancement (BPE) is a known risk factor for breast cancer. However, studies on the association between BPE and second breast cancer risk are still lacking. Purpose To investigate whether BPE at surveillance breast MRI is associated with subsequent second breast cancer risk in women with a personal history of breast cancer. Materials and Methods A retrospective search of the imaging database of an academic medical center identified consecutive surveillance breast MRI examinations performed between January 2008 and December 2017 in women who underwent surgery for primary breast cancer and had no prior diagnosis of second breast cancer. BPE at surveillance breast MRI was qualitatively assessed using a four-category classification of minimal, mild, moderate, or marked. Future second breast cancer was defined as ipsilateral breast tumor recurrence or contralateral breast cancer diagnosed at least 1 year after each surveillance breast MRI examination. Factors associated with future second breast cancer risk were evaluated using the multivariable Fine-Gray subdistribution hazard model. Results Among the 2668 women (mean age at baseline surveillance breast MRI, 49 years ± 8 [SD]), 109 developed a second breast cancer (49 ipsilateral, 58 contralateral, and two ipsilateral and contralateral) at a median follow-up of 5.8 years. Mild, moderate, or marked BPE at surveillance breast MRI (hazard ratio [HR], 2.1 [95% CI: 1.4, 3.1]; P < .001), young age (<45 years) at initial breast cancer diagnosis (HR, 3.4 [95% CI: 1.7, 6.4]; P < .001), positive results from a BRCA1/2 genetic test (HR, 6.5 [95% CI: 3.5, 12.0]; P < .001), and negative hormone receptor expression in the initial breast cancer (HR, 1.6 [95% CI: 1.1, 2.6]; P = .02) were independently associated with an increased risk of future second breast cancer. Conclusion Background parenchymal enhancement at surveillance breast MRI was associated with future second breast cancer risk in women with a personal history of breast cancer. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Niell in this issue.

Antiinflammatory effect of the ethanolic extract of Korean native herb Potentilla rugulosa Nakai in Bisphenol-a-stimulated A549 cells.

Potentilla rugulosa Nakai (P. rugulosa) is a perennial herb in the Rosaceae family and found in the Korean mountains. Previously, our findings demonstrated that P. rugulosa contains numerous polyphenols and flavonoids exhibiting important antioxidant and anti-obesity bioactivities. Bisphenol A (BPA) is a xenoestrogen that was shown to produce pulmonary inflammation in humans. However, the mechanisms underlying BPA-induced inflammation remain to be determined. The aim of this study was to examine whether ethanolic extract of P. rugulosa exerted an inhibitory effect on BPA-induced inflammation utilizing an adenocarcinoma human alveolar basal epithelial cell line A549. The P. rugulosa extract inhibited BPA-mediated cytotoxicity by reducing levels of reactive oxygen species (ROS). Further, P. rugulosa extract suppressed the upregulation of various pro-inflammatory mediators induced by activation of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, inhibition of the NF-κB and MAPK signaling pathways by P. rugulosa extract was found to occur via decrease in the transcriptional activity of NF-κB. Further, blockade of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) was noted. Thus, our findings suggest that the ethanolic extract of P. rugulosa may act as a natural anti-inflammatory therapeutic agent.

Comparative study of young-old and old-old people using functional evaluation, gait characteristics, and cardiopulmonary metabolic energy consumption.

BACKGROUND: Walking is an important factor in daily life. Among older adults, gait function declines with age. In contrast to the many studies revealing gait differences between young adults and older adults, few studies have further divided older adults into groups. The purpose of this study was to subdivide an older adult population by age to identify age-related differences in functional evaluation, gait characteristics and cardiopulmonary metabolic energy consumption while walking. METHODS: This was a cross-sectional study of 62 old adult participants who were classified into two age groups of 31 participants each as follows: young-old (65-74 years) and old-old (75-84 years) group. Physical functions, activities of daily living, mood state, cognitive function, quality of life, and fall efficacy were evaluated using the Short Physical Performance Battery (SPPB), Four-square Step Test (FSST), Timed Up and Go Test (TUG), Korean Version of the Modified Barthel Index, Geriatric Depression Scale (GDS), Korean Mini-mental State Examination, EuroQol-5 Dimensions (EQ-5D) questionnaire, and the Korean version of the Fall Efficacy Scale. A three-dimensional motion capture system (Kestrel Digital RealTime System®; Motion Analysis Corporation, Santa Rosa, CA, USA) and two force plates (TF-4060-B; Tec Gihan, Kyoto, Japan) were used to investigate spatiotemporal gait parameters (velocity, cadence, stride length, stride width, step length, single support, stance phase, and swing phase), kinematic variables (hip, knee, and ankle joint angles), and kinetic variables (hip, knee, and ankle joint moment and power) of gait. A portable cardiopulmonary metabolic system (K5; Cosmed, Rome, Italy) was used to measure cardiopulmonary energy consumption. RESULTS: The old-old group showed significantly lower SPPB, FSST, TUG, GDS-SF, and EQ-5D scores (p < 0.05). Among spatiotemporal gait parameters, velocity, stride length, and step length were significantly lower in the old-old group than in the young-old group (p < 0.05). Among the kinematic variables, the knee joint flexion angles during initial contact and terminal swing phase were significantly higher in the old-old than the young-old group (P < 0.05). The old-old group also showed a significantly lower ankle joint plantarflexion angle during the pre- and initial swing phases (P < 0.05). Among the kinetic variables, the hip joint flexion moment and knee joint absorption power in the pre-swing phase were significantly lower in the old-old than the young-old group (P < 0.05). CONCLUSION: This study demonstrated that participants 75-84 years of age had less functional gaits than their young-old counterparts (65-74 years old). As the walking pace of old-old people diminishes, driving strength to move ahead and pressure on the knee joint also tend to decrease together with stride length. These differences in gait characteristics according to age among older adults could improve our understanding of how aging causes variations in gait that increase the risk of falls. Older adults of different ages may require customized intervention plans, such as gait training methods, to prevent age-related falls. TRIAL REGISTRATION: Clinical trials registration information: ClinicalTrials.gov Identifier: NCT04723927 (26/01/2021).

Diffusion-weighted Breast MRI in Prediction of Upstaging in Women with Biopsy-proven Ductal Carcinoma in Situ.

Background Accurate preoperative prediction of upstaging in women with biopsy-proven ductal carcinoma in situ (DCIS) is important for surgical planning, but published models using predictive MRI features remain lacking. Purpose To develop and validate a predictive model based on preoperative breast MRI to predict upstaging in women with biopsy-proven DCIS and to select high-risk women who may benefit from sentinel lymph node biopsy at initial surgery. Materials and methods Consecutive women with biopsy-proven DCIS who underwent preoperative 3.0-T breast MRI including dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) and who underwent surgery between June 2019 and March 2020 were retrospectively identified (development set) from an academic medical center. The apparent diffusion coefficients of lesions from DWI, lesion size and morphologic features on DCE MRI scans, mammographic findings, age, symptoms, biopsy method, and DCIS grade at biopsy were collected. The presence of invasive cancer and axillary metastases was determined with surgical pathology. A predictive model for upstaging was developed by using multivariable logistic regression and validated in a subsequent prospective internal validation set recruited between July 2020 and April 2021. Results Fifty-seven (41%) of 140 women (mean age, 53 years ± 11 [SD]) in the development set and 43 (41%) of 105 women (mean age, 53 years ± 10) in the validation set were upstaged after surgery. The predictive model combining DWI and clinical-pathologic factors showed the areas under the receiver operating characteristic curve at 0.87 (95% CI: 0.80, 0.92) in the development set and 0.76 (95% CI: 0.67, 0.84) in the validation set. The predicted probability of invasive cancer showed good interobserver agreement (intraclass correlation coefficient, 0.79); the positive predictive value was 85% (28 of 33), and the negative predictive value was 92% (22 of 24). Conclusion A predictive model based on diffusion-weighted breast MRI identified women at high risk of upstaging. © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Baltzer in this issue. An earlier incorrect version appeared online. This article was corrected on July 7, 2022.

US Evaluation of Axillary Lymphadenopathy Following COVID-19 Vaccination: A Prospective Longitudinal Study.

Background Both temporal changes in imaging characteristics of lymphadenopathy on US scans after COVID-19 vaccination and expected duration of radiologically evident lymphadenopathy remain uncertain. Purpose To longitudinally evaluate COVID-19 vaccine-associated lymphadenopathy on axillary US scans at various time intervals in both messenger (mRNA) and vector vaccine recipients. Materials and Methods This prospective cohort study was conducted between March 2021 and January 2022. The participants were asymptomatic women without breast cancer who had received COVID-19 vaccination. Serial follow-up US was performed in women with lymphadenopathy. The following variables were assessed: cortical thickness, number of lymph nodes, morphologic characteristics, and Doppler signal. Temporal changes in cortical thickness and number of lymph nodes during follow-up were assessed using a linear mixed model. Results Ninety-one women with lymphadenopathy in the vaccinated arm had undergone a total of 215 serial US examinations (mean age, 44 years ± 13 [SD]). Fifty-one participants had received a vector vaccine (ChAdOx1 nCoV-19 vaccine) and 40 had received an mRNA vaccine (BNT162b2 vaccine [n = 37] and mRNA-1273 vaccine [n = 3]). Three of the 91 women were lost to follow-up; thus, 88 women underwent serial US. Complete resolution of axillary lymphadenopathy was observed at a median of 6 weeks after vaccination (range, 4-7 weeks) in 26% of women (23 of 88). Among 49 women with follow-up US at a median of 12 weeks after vaccination (range, 8-14 weeks), persistent lymphadenopathy was observed in 25 (51%). During the follow-up period, the cortical thickness gradually decreased (P < .001) over time regardless of vaccine type; however, values were higher in recipients of the mRNA vaccine than in recipients of the vector vaccine (P = .02). Conclusion COVID-19 vaccine-associated axillary lymphadenopathy frequently persisted for more than 6 weeks on US scans. Lymphadenopathy should be interpreted considering vaccine type and time elapsed since vaccination. Follow-up US examination at least 12 weeks after vaccination may be reasonable, particularly for recipients of the messenger RNA vaccine. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Moy and Kim in this issue.

Abbreviated Screening MRI for Women with a History of Breast Cancer: Comparison with Full-Protocol Breast MRI.

Background Few studies have compared abbreviated breast MRI with full-protocol MRI in women with a personal history of breast cancer (PHBC), and they have not adjusted for confounding variables. Purpose To compare abbreviated breast MRI with full-protocol MRI in women with PHBC by using propensity score matching to adjust for confounding variables. Materials and Methods In this single-center retrospective study, women with PHBC who underwent full-protocol MRI (January 2008-August 2017) or abbreviated MRI (September 2017-April 2019) were identified. With use of a propensity score-matched cohort, screening performances were compared between the two MRI groups with the McNemar test or a propensity score-adjusted generalized estimating equation. The coprimary analyses were sensitivity and specificity. The secondary analyses were the cancer detection rate, interval cancer rate, positive predictive value for biopsies performed (PPV3), and Breast Imaging Reporting and Data System (BI-RADS) category 3 short-term follow-up rate. Results There were 726 women allocated to each MRI group (mean age ± SD, 50 years ± 8 for both groups). Abbreviated MRI and full-protocol MRI showed comparable sensitivity (15 of 15 cancers [100%; 95% CI: 78, 100] vs nine of 13 cancers [69%; 95% CI: 39, 91], respectively; P = .17). Abbreviated MRI showed higher specificity than full-protocol MRI (660 of 711 examinations [93%; 95% CI: 91, 95] vs 612 of 713 examinations [86%; 95% CI: 83, 88], respectively; P < .001). The cancer detection rate (21 vs 12 per 1000 examinations), interval cancer rate (0 vs five per 1000 examinations), and PPV3 (61% [14 of 23 examinations] vs 41% [nine of 22 examinations]) were comparable (all P < .05). The BI-RADS category 3 short-term follow-up rate of abbreviated MRI was less than half that of full-protocol MRI (5% [36 of 726 examinations] vs 12% [84 of 726 examinations], respectively; P < .001). Ninety-three percent (14 of 15) of cancers detected at abbreviated MRI were node-negative T1-invasive cancers (n = 6) or ductal carcinoma in situ (n = 8). Conclusion Abbreviated breast MRI showed comparable sensitivity and superior specificity to full-protocol MRI in breast cancer detection in women with a personal history of breast cancer. © RSNA, 2022 Online supplemental material is available for this article.

Microcalcifications and Peritumoral Edema Predict Survival Outcome in Luminal Breast Cancer Treated with Neoadjuvant Chemotherapy.

Background Little is known regarding findings at imaging associated with survival in patients with luminal breast cancer treated with neoadjuvant chemotherapy (NAC). Purpose To determine the relationship between imaging (MRI, US, and mammography) and clinical-pathologic variables in predicting distant metastasis-free survival (DMFS) and overall survival (OS) in patients with luminal breast cancer treated with NAC. Materials and Methods In this retrospective study, consecutive women with luminal breast cancer who underwent NAC followed by surgery were identified from the breast cancer registries of two hospitals. Women from one hospital between January 2003 and July 2015 were classified into the development cohort, and women from the other hospital between January 2007 and July 2015 were classified into the validation cohort. MRI scans, US scans, and mammograms before and after NAC (hereafter, referred to as pre- and post-NAC, respectively) and clinical-pathologic data were reviewed. Peritumoral edema was defined as the water-like high signal intensity surrounding the tumor on T2-weighted MRI scans. The prediction model was developed in the development cohort by using Cox regression and then tested in the validation cohort. Results The development cohort consisted of 318 women (68 distant metastases, 54 deaths) and the validation cohort consisted of 165 women (37 distant metastases, 14 deaths) (median age, 46 years in both cohorts). Post-NAC MRI peritumoral edema, age younger than 40 years, clinical N2 or N3, and lymphovascular invasion were associated with worse DMFS (all, P < .05). Pre-NAC mammographic microcalcifications, post-NAC MRI peritumoral edema, age older than 60 years, and clinical T3 or T4 were associated with worse OS (all, P < .05). The prediction model showed good discrimination ability (C index, 0.67-0.75 for DMFS and 0.70-0.77 for OS) and stratified prognosis into low-risk and high-risk groups (10-year DMFS rates, 79% vs 21%, respectively; and 10-year OS rates, 95%-96% vs 63%-67%, respectively) in the validation cohort. Conclusion MRI features and clinical-pathologic variables were identified that were associated with prolonged survival of patients with luminal breast cancer treated with neoadjuvant chemotherapy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kataoka in this issue.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Prediction of axillary nodal burden in patients with invasive lobular carcinoma using MRI.

PURPOSE: To investigate clinical and imaging features associated with a high nodal burden (≥ 3 metastatic lymph nodes [LNs]) and compare diagnostic performance of US and MRI in patients with invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). METHODS: Retrospective search revealed 239 patients with ILC and 999 with IDC who underwent preoperative US and MRI between January 2016 and June 2019. Patients with ILC were propensity-score-matched with patients with IDC. Univariate and multivariate logistic regression analyses were performed to determine factors associated with ≥ 3 metastatic LNs. RESULTS: 412 patients (206 ILC and 206 IDC) were evaluated. Of all patients with ILC, 27.2% (56/206) were node-positive and 7.8% (16/206) showed a high nodal burden. In multivariate analysis, the clinical N stage was the only independent factor associated with a high nodal burden in patients with IDC (odds ratio [OR] 6.24; 95% confidence interval [CI] 1.57-24.73; P = 0.009), but not in patients with ILC. Increased cortical thickness with loss of fatty hilum on US was associated with a high nodal burden in patients with ILC (OR 58.40; 95% CI 5.09-669.71; P = 0.001) and IDC (OR 24.14; 95% CI 3.52-165.37; P = 0.001), while suspicious LN findings at MRI were independently associated with a high nodal burden in ILC only (OR 13.94; 95% CI 2.61-74.39; P = 0.002). CONCLUSION: In patients with ILC, MRI findings of suspicious LNs were helpful to predict a high nodal disease burden.

Factors Affecting Pathologic Complete Response Following Neoadjuvant Chemotherapy in Breast Cancer: Development and Validation of a Predictive Nomogram.

Background There is an increasing need to develop a more accurate prediction model for pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer. Purpose To develop a nomogram based on MRI and clinical-pathologic variables to predict pCR. Materials and Methods In this single-center retrospective study, consecutive women with stage II-III breast cancer who underwent NAC followed by surgery between January 2011 and December 2017 were considered for inclusion. The women were divided into a development cohort between January 2011 and September 2015 and a validation cohort between October 2015 and December 2017. Clinical-pathologic data were collected, and mammograms and MRI scans obtained before and after NAC were analyzed. Logistic regression analyses were performed to identify independent variables associated with pCR in the development cohort from which the nomogram was created. Nomogram performance was assessed with the area under the receiver operating characteristic curve (AUC) and calibration slope. Results A total of 359 women (mean age, 49 years ± 10 [standard deviation]) were in the development cohort and 351 (49 years ± 10) in the validation cohort. Hormone receptor negativity (odds ratio [OR], 3.1; 95% CI: 1.4, 7.1; P = .006), high Ki-67 index (OR, 1.05; 95% CI: 1.03, 1.07; P < .001), and post-NAC MRI variables, including small tumor size (OR, 0.6; 95% CI: 0.4, 0.9; P = .03), low lesion-to-background parenchymal signal enhancement ratio (OR, 0.2; 95% CI: 0.1, 0.6; P = .004), and absence of enhancement in the tumor bed (OR, 3.8; 95% CI: 1.4, 10.5; P = .009) were independently associated with pCR. The nomogram incorporating these variables showed good discrimination (AUC, 0.90; 95% CI: 0.86, 0.94) and calibration abilities (calibration slope, 0.91; 95% CI: 0.69, 1.13) in the independent validation cohort. Conclusion A nomogram incorporating hormone receptor status, Ki-67 index, and MRI variables showed good discrimination and calibration abilities in predicting pathologic complete response. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Imbriaco and Ponsiglione in this issue.

Glandular Tissue Component and Breast Cancer Risk in Mammographically Dense Breasts at Screening Breast US.

Background Breast density at mammography is an established risk factor for breast cancer, but it cannot be used to distinguish between glandular and fibrous tissue. Purpose To evaluate the association between the glandular tissue component (GTC) at screening breast US and the risk of future breast cancer in women with dense breasts and the association between the GTC and lobular involution. Materials and Methods Screening breast US examinations performed in women with no prior history of breast cancer and with dense breasts with negative findings from mammography from January 2012 to December 2015 were retrospectively identified. The GTC was reported as being minimal, mild, moderate, or marked at the time of the US examination. In women who had benign breast biopsy results, the degree of lobular involution in normal background tissue was categorized as not present, mild, moderate, or complete. The GTC-related breast cancer risk in women with a cancer diagnosis or follow-up after 6 months was estimated by using Cox proportional hazards regression. Cumulative logistic regression was used to evaluate the association between the GTC and lobular involution. Results Among 8483 women (mean age, 49 years ± 8 [standard deviation]), 137 developed breast cancer over a median follow-up time of 5.3 years. Compared with a minimal or mild GTC, a moderate or marked GTC was associated with an increased cancer risk (hazard ratio, 1.5; 95% CI: 1.05, 2.1; P = .03) after adjusting for age and breast density. The GTC had an inverse association with lobular involution; women with no, mild, or moderate involution had greater odds (odds ratios of 4.9 [95% CI: 1.5, 16.6], 2.6 [95% CI: 0.95, 7.2], and 1.8 [95% CI: 0.7, 4.6], respectively) of a moderate or marked GTC than those with complete involution (P = .004). Conclusion The glandular tissue component was independently associated with the future breast cancer risk in women with dense breasts and reflects the lobular involution. It should be considered for risk stratification during screening breast US. © RSNA, 2021 Online supplemental material is available for this article.