Mixed-Methods Study to Predict Upstaging of DCIS to Invasive Disease on Mammography.

BACKGROUND. The incidence of ductal carcinoma in situ (DCIS) has steadily increased, as have concerns regarding overtreatment. Active surveillance is a novel treatment strategy that avoids surgical excision, but identifying patients with occult invasive disease who should be excluded from active surveillance is challenging. Radiologists are not typically expected to predict the upstaging of DCIS to invasive disease, though they might be trained to perform this task. OBJECTIVE. The purpose of this study was to determine whether a mixed-methods two-stage observer study can improve radiologists' ability to predict upstaging of DCIS to invasive disease on mammography. METHODS. All cases of DCIS calcifications that underwent stereotactic biopsy between 2010 and 2015 were identified. Two cohorts were randomly generated, each containing 150 cases (120 pure DCIS cases and 30 DCIS cases upstaged to invasive disease at surgery). Nine breast radiologists reviewed the mammograms in the first cohort in a blinded fashion and scored the probability of upstaging to invasive disease. The radiologists then reviewed the cases and results collectively in a focus group to develop consensus criteria that could improve their ability to predict upstaging. The radiologists reviewed the mammograms from the second cohort in a blinded fashion and again scored the probability of upstaging. Statistical analysis compared the performances between rounds 1 and 2. RESULTS. The mean AUC for reader performance in predicting upstaging in round 1 was 0.623 (range, 0.514-0.684). In the focus group, radiologists agreed that upstaging was better predicted when an associated mass, asymmetry, or architectural distortion was present; when densely packed calcifications extended over a larger area; and when the most suspicious features were focused on rather than the most common features. Additionally, radiologists agreed that BI-RADS descriptors do not adequately characterize risk of invasion, and that microinvasive disease and smaller areas of DCIS will have poor prediction estimates. Reader performance significantly improved in round 2 (mean AUC, 0.765; range, 0.617-0.852; p = .045). CONCLUSION. A mixed-methods two-stage observer study identified factors that helped radiologists significantly improve their ability to predict upstaging of DCIS to invasive disease. CLINICAL IMPACT. Breast radiologists can be trained to better predict upstaging of DCIS to invasive disease, which may facilitate discussions with patients and referring providers.

Machine learning-based prediction of future breast cancer using algorithmically measured background parenchymal enhancement on high-risk screening MRI.

BACKGROUND: Preliminary work has demonstrated that background parenchymal enhancement (BPE) assessed by radiologists is predictive of future breast cancer in women undergoing high-risk screening MRI. Algorithmically assessed measures of BPE offer a more precise and reproducible means of measuring BPE than human readers and thus might improve the predictive performance of future cancer development. PURPOSE: To determine if algorithmically extracted imaging features of BPE on screening breast MRI in high-risk women are associated with subsequent development of cancer. STUDY TYPE: Case-control study. POPULATION: In all, 133 women at high risk for developing breast cancer; 46 of these patients developed breast cancer subsequently over a follow-up period of 2 years. FIELD STRENGTH/SEQUENCE: 5 T or 3.0 T T1 -weighted precontrast fat-saturated and nonfat-saturated sequences and postcontrast nonfat-saturated sequences. ASSESSMENT: Automatic features of BPE were extracted with a computer algorithm. Subjective BPE scores from five breast radiologists (blinded to clinical outcomes) were also available. STATISTICAL TESTS: Leave-one-out crossvalidation for a multivariate logistic regression model developed using the automatic features and receiver operating characteristic (ROC) analysis were performed to calculate the area under the curve (AUC). Comparison of automatic features and subjective features was performed using a generalized regression model and the P-value was obtained. Odds ratios for automatic and subjective features were compared. RESULTS: The multivariate model discriminated patients who developed cancer from the patients who did not, with an AUC of 0.70 (95% confidence interval: 0.60-0.79, P < 0.001). The imaging features remained independently predictive of subsequent development of cancer (P < 0.003) when compared with the subjective BPE assessment of the readers. DATA CONCLUSION: Automatically extracted BPE measurements may potentially be used to further stratify risk in patients undergoing high-risk screening MRI. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019;50:456-464.

A machine learning approach to radiogenomics of breast cancer: a study of 922 subjects and 529 DCE-MRI features.

BACKGROUND: Recent studies showed preliminary data on associations of MRI-based imaging phenotypes of breast tumours with breast cancer molecular, genomic, and related characteristics. In this study, we present a comprehensive analysis of this relationship. METHODS: We analysed a set of 922 patients with invasive breast cancer and pre-operative MRI. The MRIs were analysed by a computer algorithm to extract 529 features of the tumour and the surrounding tissue. Machine-learning-based models based on the imaging features were trained using a portion of the data (461 patients) to predict the following molecular, genomic, and proliferation characteristics: tumour surrogate molecular subtype, oestrogen receptor, progesterone receptor and human epidermal growth factor status, as well as a tumour proliferation marker (Ki-67). Trained models were evaluated on the set of the remaining 461 patients. RESULTS: Multivariate models were predictive of Luminal A subtype with AUC = 0.697 (95% CI: 0.647-0.746, p < .0001), triple negative breast cancer with AUC = 0.654 (95% CI: 0.589-0.727, p < .0001), ER status with AUC = 0.649 (95% CI: 0.591-0.705, p < .001), and PR status with AUC = 0.622 (95% CI: 0.569-0.674, p < .0001). Associations between individual features and subtypes we also found. CONCLUSIONS: There is a moderate association between tumour molecular biomarkers and algorithmically assessed imaging features.

Positive and negative mood following imaging-guided core needle breast biopsy and receipt of biopsy results.

Positive and negative mood are independent psychological responses to stressful events. Negative mood negatively impacts well-being and co-occurring positive mood leads to improved adjustment. Women undergoing core needle breast biopsies (CNB) experience distress during CNB and awaiting results; however, influences of mood are not well known. This longitudinal study examines psychosocial and biopsy- and spirituality-related factors associated with mood in patients day of CNB and one week after receiving results. Ninety women undergoing CNB completed questionnaires on psychosocial factors (chronic stress, social support), biopsy experiences (pain, radiologist communication), and spirituality (peace, meaning, faith) day of CNB. Measures of positive and negative mood were completed day of CNB and one week after receiving results (benign n = 50; abnormal n = 25). Multiple linear regression analyses were conducted. Greater positive mood correlated with greater peace (ß = .25, p = .02) day of CNB. Lower negative mood correlated with greater peace (ß = -.29, p = .004) and there was a trend for a relationship with less pain during CNB (ß = .19, p = .07). For patients with benign results, day of CNB positive mood predicted positive mood post-results (ß = .31, p = .03) and only chronic stress predicted negative mood (ß = .33, p = .03). For women with abnormal results, greater meaning day of CNB predicted lower negative mood post-results (ß = -.45, p = .03). Meaning and peace may be important for women undergoing CNB and receiving abnormal results.

Mucosal Th17 cell function is altered during HIV infection and is an independent predictor of systemic immune activation.

Mucosal Th17 cells maintain the gut epithelial barrier and prevent invasion by luminal bacteria through a delicate balance of immunosuppressive and proinflammatory functions. HIV infection is characterized by mucosal Th17 depletion, microbial translocation, and immune activation. Therefore, we assessed the function of blood and sigmoid Th17 cells during both early and chronic HIV infection, as well as the impact of short- and long-term antiretroviral therapy. Th17 cells were defined as IL-17a(+) CD4 T cells, and their functional capacity was assessed by the coproduction of the inflammatory cytokines IL-22, TNF-α, and IFN-γ, as well as the immunoregulatory cytokine IL-10. Gut Th17 cells had a much greater capacity to produce proinflammatory cytokines than did those from the blood, but this capacity was dramatically reduced from the earliest stages of HIV infection. Immunoregulatory skewing of mucosal Th17 cell function, characterized by an increased IL-10/TNF-α ratio, was uniquely seen during early HIV infection and was independently associated with reduced systemic immune activation. Antiretroviral therapy rapidly restored mucosal Th17 cell numbers; however, normalization of mucosal Th17 function, microbial translocation, and mucosal/systemic immune activation was much delayed. These findings emphasize that strategies to preserve or to more rapidly restore mucosal Th17 function may have important therapeutic benefit.

The role of SHIP in the development and activation of mouse mucosal and connective tissue mast cells.

Although SHIP is a well-established suppressor of IgE plus Ag-induced degranulation and cytokine production in bone marrow-derived mast cells (BMMCs), little is known about its role in connective tissue (CTMCs) or mucosal (MMCs) mast cells. In this study, we compared SHIP's role in the development as well as the IgE plus Ag and TLR-induced activation of CTMCs, MMCs, and BMMCs and found that SHIP delays the maturation of all three mast cell subsets and, surprisingly, that it is a positive regulator of IgE-induced BMMC survival. We also found that SHIP represses IgE plus Ag-induced degranulation of all three mast cell subsets and that TLR agonists do not trigger their degranulation, whether SHIP is present or not, nor do they enhance IgE plus Ag-induced degranulation. In terms of cytokine production, we found that in MMCs and BMMCs, which are poor producers of TLR-induced cytokines, SHIP is a potent negative regulator of IgE plus Ag-induced IL-6 and TNF-α production. Surprisingly, however, in splenic or peritoneal derived CTMCs, which are poor producers of IgE plus Ag-induced cytokines, SHIP is a potent positive regulator of TLR-induced cytokine production. Lastly, cell signaling and cytokine production studies with and without LY294002, wortmannin, and PI3Kα inhibitor-2, as well as with PI3K p85α(-/-) BMMCs and CTMCs, are consistent with SHIP positively regulating TLR-induced cytokine production via an adaptor-mediated pathway while negatively regulating IgE plus Ag-induced cytokine production by repressing the PI3K pathway.

Effect of antiretroviral therapy on HIV reservoirs in elite controllers.

Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in the absence of antiretroviral therapy (ART). However, precise frequencies of CD4(+) T cells carrying replication-competent HIV and/or the dynamics of the infectious viral reservoirs in response to initiation and discontinuation of ART in elite controllers are unknown. We show that the size of the pool of CD4(+) T cells harboring infectious HIV diminished significantly after initiation of ART and rebounded to baseline upon cessation of therapy. Our data provide compelling evidence that persistent viral replication occurs in untreated elite controllers even in the absence of detectable plasma viremia.

A molecular mechanism underlying the neural-specific defect in torsinA mutant mice.

A striking but poorly understood feature of many diseases is the unique involvement of neural tissue. One example is the CNS-specific disorder DYT1 dystonia, caused by a 3-bp deletion ("DeltaE") in the widely expressed gene TOR1A. Disease mutant knockin mice (Tor1a(DeltaE/DeltaE)) exhibit disrupted nuclear membranes selectively in neurons, mimicking the tissue specificity of the human disease and providing a model system in which to dissect the mechanisms underlying neural selectivity. Our in vivo studies demonstrate that lamina-associated polypeptide 1 (LAP1) and torsinB function with torsinA to maintain normal nuclear membrane morphology. Moreover, we show that nonneuronal cells express dramatically higher levels of torsinB and that RNAi-mediated depletion of torsinB (but not other torsin family members) causes nuclear membrane abnormalities in Tor1a(DeltaE/DeltaE) nonneuronal cells. The Tor1a(DeltaE/DeltaE) neural selective phenotype therefore arises because high levels of torsinB protect nonneuronal cells from the consequences of torsinA dysfunction, demonstrating how tissue specificity may result from differential susceptibility of cell types to insults that disrupt ubiquitous biological pathways.

Corrigendum: Translating the observed differences in interleukin-6 levels between some antiretroviral regimens into potential long-term risk of serious non-AIDS events: A modeling study.

[This corrects the article DOI: 10.3389/fimmu.2022.976564.].

Using the BI-RADS lexicon in a restrictive form of double reading as a strategy for minimizing screening mammography recall rates.

OBJECTIVE: The purpose of this article is to determine the potential reduction in screening recall rates by strictly following standardized BI-RADS lexicon for lesions seen on screening mammography. MATERIALS AND METHODS: Of 3084 consecutive mammograms performed at our screening facilities, 345 women with 437 lesions were recalled for additional imaging and constituted our study population. Three radiologists retrospectively classified lesions using the standard BI-RADS lexicon and assigned each to one of four groups: group A, the finding met criteria for recall by the BI-RADS lexicon; group B, the finding did not meet strict BI-RADS criteria for recall but was sufficiently indeterminate to warrant recall by the majority of the study panel; group C, the finding was classifiable by the BI-RADS lexicon but was not recalled because it was benign or stable; and group D, the questioned finding was not considered an abnormality by our study panel. Recall rates and the cancer detection rate were determined. The adjusted recall rate was calculated for lesions considered appropriate for recall (group A), and the reduction in the recall rate was determined. RESULTS: Nineteen malignancies were detected in our recalled population, for a cancer detection rate of 0.65%. All 19 malignancies were lesions considered appropriate for recall (group A). If only group A lesions had been recalled, the recall rate would have decreased from 11.4% to 6.2%, representing a 46% reduction in recalls without affecting the cancer detection rate. CONCLUSION: Using the BI-RADS lexicon as a decision-making aid may help adjust thresholds for recalling indeterminate or suspicious lesions and reduce recall rates from screening mammography.

SHIP is required for dendritic cell maturation.

Although several groups have investigated the role of SHIP in macrophage (M) development and function, SHIP's contribution to the generation, maturation, and innate immune activation of dendritic cells (DCs) is poorly understood. We show herein that SHIP negatively regulates the generation of DCs from bone marrow precursors in vitro and in vivo, as illustrated by the enhanced expansion of DCs from SHIP(-/-) GM-CSF cultures, as well as increased numbers of DCs in the spleens of SHIP-deficient mice. Interestingly, however, these SHIP(-/-) DCs display a relatively immature phenotype and secrete substantially lower levels of IL-12 after TLR ligand stimulation than wild type DCs. This, in turn, leads to a dramatically reduced stimulation of Ag-specific T cell proliferation and Th1 cell responses in vitro and in vivo. This immature phenotype of SHIP(-/-) DCs could be reversed with the PI3K inhibitors LY294002 and wortmannin, suggesting that SHIP promotes DC maturation by reducing the levels of the PI3K second messenger phosphatidylinositol-3,4,5-trisphosphate. These results are consistent with SHIP being a negative regulator of GM-CSF-derived DC generation but a positive regulator of GM-CSF-derived DC maturation and function.

Healthcare resource utilization and costs associated with renal, bone and cardiovascular comorbidities among persons living with HIV compared to the general population in Quebec, Canada.

There is limited understanding on healthcare utilization and costs of age-related comorbidities such as cardiovascular, bone and renal disease/disorder in people living with human immunodeficiency virus, so we compared comorbidity prevalence and associated healthcare utilization and costs. Through the Quebec health insurance database, people living with human immunodeficiency virus on antiretroviral therapy for ≥6 months from January 2006 to June 2012 were categorized by their comorbidity status using International Classification of Diseases (ICD)-9 codes, and controls without human immunodeficiency virus diagnosis or antiretroviral therapy use were age and gender matched. We compared healthcare utilization and costs. A total of 3,905 people living with human immunodeficiency virus and 11,715 control individuals were included. The mean age of people living with human immunodeficiency virus was 45.3 years and 77.3% were men. Prevalence of comorbidities was higher and occurred earlier in people living with human immunodeficiency virus and increased with older age regardless of human immunodeficiency virus status. Interestingly, bone comorbidity was high (37%) and 5-fold greater in people living with human immunodeficiency virus <20 years than the controls. Polypharmacy and comorbidity scores were greater in people living with human immunodeficiency virus than controls (p<0.01), as were cardiovascular, bone and renal comorbidities (40.3%, 26.0% and 5.5%, respectively; p<0.01). People living with human immunodeficiency virus had higher healthcare utilization and costs than controls largely due to longer hospital stays and prescriptions. Mean total healthcare cost/person/year for people living with human immunodeficiency virus was CAD$6,248 and was highest for those with renal disease (CAD$19,617). Comorbidities in people living with human immunodeficiency virus are more prevalent, occur earlier and incur a higher burden on the healthcare system; earlier screening and improved preventative and management strategies may reduce the burden to people living with human immunodeficiency virus and to the healthcare system.

Randomized, Blinded, Placebo-Controlled Trial of De Simone Formulation Probiotic During HIV-Associated Suboptimal CD4+ T Cell Recovery.

OBJECTIVE: To assess whether probiotic supplementation may reduce disease-linked systemic immune activation in people living with HIV with the immunologic nonresponder phenotype. DESIGN: Phase 2b, randomized, double-blind, placebo-controlled pilot trial. METHODS: HIV-positive individuals with blood CD4+ T-cell counts <350/mm3 despite viral suppression were randomized to 2:1 to receive De Simone Formulation Probiotic (DSFP; "Visbiome" commercially) or placebo for 48 weeks; target enrollment was 36 patients. The primary endpoint was the change in blood CD8+ T-cell coexpression of human leukocyte antigen-DR isotype and CD38 ("CD8 activation"). Secondary endpoints included biomarkers of inflammation, immune reconstitution, bacterial translocation, and gut permeability. Adjusted linear regression and linear mixed regression methods evaluated the differences between study arms from baseline to week 48. Study monitoring was performed by the CIHR Canadian HIV Trials Network Data Safety Monitoring Committee. RESULTS: Nineteen patients received DSFP, whereas 10 received placebo. One probiotic arm patient withdrew early. Blood CD8 activation increased 0.82 percentage points (pp) in the probiotic arm (95% confidence interval: -1.23 to 2.87;) and decreased by 2.06 pp in the placebo arm (-4.81 to 0.70; between arms P = 0.097). CD4+ T-cell activation (%HLA-DR+) decreased in the placebo arm [-3.79 pp (-7.32 to -0.26)] but increased in the probiotic arm [1.64 (-0.98 to 4.26); between arms P = 0.018]. No differences were observed in plasma or urine biomarkers of inflammation or microbial translocation. CONCLUSIONS: Blood immune activation markers in immunologic nonresponder individuals on effective antiretroviral treatment were not reduced by supplementation with DSFP; CD4+ T-cell activation may have been increased.

Cross-sectional comparison of age- and gender-related comorbidities in people living with HIV in Canada.

Because antiretroviral therapy (ART) is allowing people living with human immunodeficiency virus (PLWH) to survive longer, they are developing more age-related comorbidities. We evaluated the effects of age and gender on the burden of age-related comorbidities among PLWH. In this retrospective real-world study, de-identified data were extracted from the medical charts of 2000 HIV-positive adults on ART across 10 sites in Canada. The prevalence of age-related comorbidities was determined in 6 age subgroups (<30, 30-39, 40-49, 50-59, 60-69, and ≥70 years). The effects of gender on these comorbidities were also examined. Risks of cardiovascular disease and chronic kidney disease (CKD) were calculated using the Framingham and D:A:D equations. Most persons were White (68%), male (87%), and virologically suppressed (94%). The mean age was 50.3 years (57% aged ≥50 years), and mean CD4+ T-cell count was 616 cells/mm3. The most common comorbidities were neuropsychiatric symptoms (61%), overweight/obesity (43%), liver disease (37%), and dyslipidemia (37%). The mean number of comorbidities increased across age subgroups (P < .001). Across all age subgroups, the prevalence of hypertension (P = .04), dyslipidemia (P = .04), CKD (P = .03), bone fragility (P = .03), and depression (P = .02) differed between males and females. Both age (P < .001) and gender (P < .001) impacted cardiovascular disease and CKD risk. Age and gender influenced the burden, types, and risks of age-related comorbidities in PLWH in this Canadian cohort. These comorbidities should be diagnosed and treated in routine clinical practice.

Translating the observed differences in interleukin-6 levels between some antiretroviral regimens into potential long-term risk of serious non-AIDS events: A modeling study.

Introduction: Variable levels of systemic inflammation are observed in people with HIV (PWH), but the clinical significance of differences among antiretroviral therapy (ART) regimens on associated levels of inflammatory markers is unclear. Based on data from previous epidemiologic studies that defined the predicted change in risk of serious non-AIDS events (SNAEs)/death by changes in interleukin-6 (IL-6) and D-dimer, we modeled the effects of differences in these markers between specific ART regimens on the long-term risk of clinical outcomes. Methods: We used a Markov model to compare the risk of SNAEs/death with differences in IL-6 and D-dimer levels associated with remaining on specific three-drug regimens versus switching to specific two-drug ART regimens over 5 years of treatment. We used IL-6 and D-dimer data based on trajectories over time from the randomized TANGO and observational AIR studies. Age at model entry was set at 39 years. The primary endpoint was the number needed to treat for one additional SNAE/death. Results: Over 144 weeks, PWH on one of the three-drug regimens studied were predicted to spend 22% more time in the low IL-6 quartile and 13% less time in the high IL-6 quartile compared with those on one of the two-drug regimens. Over 144 weeks, the predicted mean number of SNAEs/deaths per 100 PWH was 5.6 for a three-drug regimen associated with lower IL-6 levels versus 6.8 for a two-drug regimen associated with higher IL-6 levels. The number needed to treat for one additional SNAE/death among PWH receiving a two-drug versus three-drug regimen for 240 weeks was 43. Approximately 2,900 participants would be required for a 240-week clinical study to evaluate the accuracy of the model. Conclusions: Our Markov model suggests that higher IL-6 levels associated with switching from specific three- to two- drug ART regimens may be associated with an increase in the risk of SNAEs/death. Clinical studies are warranted to confirm or refute these results.

Targeting trastuzumab-resistant breast cancer cells with a lentivirus engineered to bind antibodies that recognize HER-2.

Targeting HER-2 over-expressing breast cancer cells with trastuzumab has resulted in significant improvements in both disease-free and overall survival rates. However, despite a favorable initial response, some cancer cells become resistant and develop into fatal metastatic disease. Here we report that we can specifically target HER-2 over-expressing and trastuzumab-resistant breast cancer cells by using an engineered lentivirus which has trastuzumab bound to its envelope. In vitro, this lentiviral construct mediated both the expression of reporter genes, such as enhanced green fluorescent protein (EGFP) and firefly luciferase, as well as the therapeutic gene, herpes thymidine kinase (hTK), in HER-2 over-expressing cells. Subsequent application of the pro-drug ganciclovir selectively killed breast cancer cells in which lentivirus mediated expression of hTK. In vivo, we successfully targeted the expression of firefly luciferase to trastuzumab-resistant breast cancer tumors established in nude mice. Furthermore, we found that systemic administration of trastuzumab-bound lentivirus led to expression of EGFP in circulating trastuzumab-resistant breast cancer cells. In conclusion, HER-2 over-expressing breast cancer cells resistant to trastuzumab can be targeted for selective gene expression and destruction by viruses with envelope-proteins engineered to bind to this antibody.

Comparative performance of multiview stereoscopic and mammographic display modalities for breast lesion detection.

PURPOSE: Mammography is known to be one of the most difficult radiographic exams to interpret. Mammography has important limitations, including the superposition of normal tissue that can obscure a mass, chance alignment of normal tissue to mimic a true lesion and the inability to derive volumetric information. It has been shown that stereomammography can overcome these deficiencies by showing that layers of normal tissue lay at different depths. If standard stereomammography (i.e., a single stereoscopic pair consisting of two projection images) can significantly improve lesion detection, how will multiview stereoscopy (MVS), where many projection images are used, compare to mammography? The aim of this study was to assess the relative performance of MVS compared to mammography for breast mass detection. METHODS: The MVS image sets consisted of the 25 raw projection images acquired over an arc of approximately 45 degrees using a Siemens prototype breast tomosynthesis system. The mammograms were acquired using a commercial Siemens FFDM system. The raw data were taken from both of these systems for 27 cases and realistic simulated mass lesions were added to duplicates of the 27 images at the same local contrast. The images with lesions (27 mammography and 27 MVS) and the images without lesions (27 mammography and 27 MVS) were then postprocessed to provide comparable and representative image appearance across the two modalities. All 108 image sets were shown to five full-time breast imaging radiologists in random order on a state-of-the-art stereoscopic display. The observers were asked to give a confidence rating for each image (0 for lesion definitely not present, 100 for lesion definitely present). The ratings were then compiled and processed using ROC and variance analysis. RESULTS: The mean AUC for the five observers was 0.614 +/- 0.055 for mammography and 0.778 +/- 0.052 for multiview stereoscopy. The difference of 0.164 +/- 0.065 was statistically significant with a p-value of 0.0148. CONCLUSIONS: The differences in the AUCs and the p-value suggest that multiview stereoscopy has a statistically significant advantage over mammography in the detection of simulated breast masses. This highlights the dominance of anatomical noise compared to quantum noise for breast mass detection. It also shows that significant lesion detection can be achieved with MVS without any of the artifacts associated with tomosynthesis.

Predicting Upstaging of DCIS to Invasive Disease: Radiologists's Predictive Performance.

RATIONALE AND OBJECTIVES: The purpose of this study is to quantify breast radiologists' performance at predicting occult invasive disease when ductal carcinoma in situ (DCIS) presents as calcifications on mammography and to identify imaging and histopathological features that are associated with radiologists' performance. MATERIALS AND METHODS: Mammographically detected calcifications that were initially diagnosed as DCIS on core biopsy and underwent definitive surgical excision between 2010 and 2015 were identified. Thirty cases of suspicious calcifications upstaged to invasive ductal carcinoma and 120 cases of DCIS confirmed at the time of definitive surgery were randomly selected. Nuclear grade, estrogen and progesterone receptor status, patient age, calcification long axis length, and breast density were collected. Ten breast radiologists who were blinded to all clinical and pathology data independently reviewed all cases and estimated the likelihood that the DCIS would be upstaged to invasive disease at surgical excision. Subgroup analysis was performed based on nuclear grade, long axis length, breast density and after exclusion of microinvasive disease. RESULTS: Reader performance to predict upstaging ranged from an area under the receiver operating characteristic curve (AUC) of 0.541-0.684 with a mean AUC of 0.620 (95%CI: 0.489-0.751). Performances improved for lesions smaller than 2 cm (AUC: 0.676 vs 0.500; p = 0.002). The exclusion of microinvasive cases also improved performance (AUC: 0.651 vs 0.620; p = 0.005). There was no difference in performance based on breast density (p = 0.850) or nuclear grade (p = 0.270) CONCLUSION: Radiologists were able to predict invasive disease better than chance, particularly for smaller DCIS lesions (<2 cm) and after the exclusion of microinvasive disease.

Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope.

An enigmatic feature of many genetic diseases is that mutations in widely expressed genes cause tissue-specific illness. One example is DYT1 dystonia, a neurodevelopmental disease caused by an in-frame deletion (Deltagag) in the gene encoding torsinA. Here we show that neurons from both torsinA null (Tor1a(-/-)) and homozygous disease mutant "knockin" mice (Tor1a(Deltagag/Deltagag)) contain severely abnormal nuclear membranes, although non-neuronal cell types appear normal. These membrane abnormalities develop in postmigratory embryonic neurons and subsequently worsen with further neuronal maturation, a finding evocative of the developmental dependence of DYT1 dystonia. These observations demonstrate that neurons have a unique requirement for nuclear envelope localized torsinA function and suggest that loss of this activity is a key molecular event in the pathogenesis of DYT1 dystonia.

Relationship between Background Parenchymal Enhancement on High-risk Screening MRI and Future Breast Cancer Risk.

RATIONALE AND OBJECTIVES: To determine if background parenchymal enhancement (BPE) on screening breast magnetic resonance imaging (MRI) in high-risk women correlates with future cancer. MATERIALS AND METHODS: All screening breast MRIs (n = 1039) in high-risk women at our institution from August 1, 2004, to July 30, 2013, were identified. Sixty-one patients who subsequently developed breast cancer were matched 1:2 by age and high-risk indication with patients who did not develop breast cancer (n = 122). Five fellowship-trained breast radiologists independently recorded the BPE. The median reader BPE for each case was calculated and compared between the cancer and control cohorts. RESULTS: Cancer cohort patients were high-risk because of a history of radiation therapy (10%, 6 of 61), high-risk lesion (18%, 11 of 61), or breast cancer (30%, 18 of 61); BRCA mutation (18%, 11 of 61); or family history (25%, 15 of 61). Subsequent malignancies were invasive ductal carcinoma (64%, 39 of 61), ductal carcinoma in situ (30%, 18 of 61) and invasive lobular carcinoma (7%, 4of 61). BPE was significantly higher in the cancer cohort than in the control cohort (P = 0.01). Women with mild, moderate, or marked BPE were 2.5 times more likely to develop breast cancer than women with minimal BPE (odds ratio = 2.5, 95% confidence interval: 1.3-4.8, P = .005). There was fair interreader agreement (κ = 0.39). CONCLUSIONS: High-risk women with greater than minimal BPE at screening MRI have increased risk of future breast cancer.