Simultaneous isolation of hormone receptor-positive breast cancer organoids and fibroblasts reveals stroma-mediated resistance mechanisms.

Recurrent hormone receptor-positive (HR+) breast cancer kills more than 600,000 women annually. Although HR+ breast cancers typically respond well to therapies, approximately 30% of patients relapse. At this stage, the tumors are usually metastatic and incurable. Resistance to therapy, particularly endocrine therapy is typically thought to be tumor intrinsic (e.g., estrogen receptor mutations). However, tumor-extrinsic factors also contribute to resistance. For example, stromal cells, such as cancer-associated fibroblasts (CAFs), residing in the tumor microenvironment, are known to stimulate resistance and disease recurrence. Recurrence in HR+ disease has been difficult to study due to the prolonged clinical course, complex nature of resistance, and lack of appropriate model systems. Existing HR+ models are limited to HR+ cell lines, a few HR+ organoid models, and xenograft models that all lack components of the human stroma. Therefore, there is an urgent need for more clinically relevant models to study the complex nature of recurrent HR+ breast cancer, and the factors contributing to treatment relapse. Here, we present an optimized protocol that allows a high take-rate, and simultaneous propagation of patient-derived organoids (PDOs) and matching CAFs, from primary and metastatic HR+ breast cancers. Our protocol allows for long-term culturing of HR+ PDOs that retain estrogen receptor expression and show responsiveness to hormone therapy. We further show the functional utility of this system by identifying CAF-secreted cytokines, such as growth-regulated oncogene α , as stroma-derived resistance drivers to endocrine therapy in HR+ PDOs.

Comparison of Contrast-enhanced Mammography with MRI Utilizing an Enriched Reader Study: A Breast Cancer Study (CONTRRAST Trial).

Background Despite growing interest in using contrast-enhanced mammography (CEM) for breast cancer screening as an alternative to breast MRI, limited literature is available. Purpose To determine whether CEM is noninferior to breast MRI or abbreviated breast MRI (AB MRI) and superior to two-dimensional mammography in an asymptomatic population simulating those who would present for screening and then undergo diagnostic work-up. Materials and Methods This enriched reader study used CEM and MRI data prospectively collected from asymptomatic individuals at a single institution from December 2014 to March 2020. Case sets were obtained at screening, as part of work-up for a screening-detected finding, or before biopsy of a screening-detected abnormality. All images were anonymized and randomized, and all 12 radiologists interpreted them. For CEM interpretation, readers were first shown low-energy images as a surrogate for digital mammography and asked to give a forced Breast Imaging Reporting and Data System score for up to three abnormalities. The highest score was used as the case score. Readers then reviewed the full CEM examination and scored it similarly. After a minimum 1-month washout, the readers similarly interpreted AB MRI and full MRI examinations. Receiver operating characteristic analysis, powered to test CEM noninferiority to full MRI, was performed. Results The study included 132 case sets (14 negative, 74 benign, and 44 malignant; all female participants; mean age, 54 years ± 12 [SD]). The mean areas under the receiver operating characteristic curve (AUCs) for digital mammography, CEM, AB MRI, and full MRI were 0.79, 0.91, 0.89, and 0.91, respectively. CEM was superior to digital mammography (P < .001). No evidence of a difference in AUC was found between CEM and AB MRI and MRI. Conclusion In an asymptomatic study sample, CEM was noninferior to full MRI and AB MRI and was superior to digital mammography. Clinical trial registration no. NCT03482557 and NCT02275871 © RSNA, 2023 Supplemental material is available for this article.

Enhancement Type at Contrast-enhanced Mammography and Association with Malignancy.

Background Despite the increasing use of contrast-enhanced mammography (CEM), there are limited data on the evaluation of findings on recombined images and the association with malignancy. Purpose To determine the rates of malignancy of enhancement findings on CEM images in the presence or absence of low-energy findings using the Breast Imaging Reporting and Data System (BI-RADS) lexicon developed for mammography and MRI. Materials and Methods All diagnostic CEM examinations performed at one academic institution between December 2015 and December 2019 had low-energy and recombined images retrospectively. Data were independently reviewed by three breast imaging radiologists with 5-25 years of experience using the BI-RADS mammography and MRI lexicon. Outcome was determined with pathologic analysis or 1-year imaging or clinical follow-up. The χ2 and Fisher exact tests were used for analysis. Results A total of 371 diagnostic CEM studies were performed in 371 women (mean age, 54 years ± 11[SD]). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value of enhancement on CEM images was 95% (104 of 109 [95% CI: 90, 98]), 67% (176 of 262 [95% CI: 61, 73]), 55% (104 of 190 [95% CI: 47, 62]), and 97% (176 of 181 [95% CI: 94, 99]), respectively. Among 190 CEM studies with enhancing findings, enhancing lesions were more likely to be malignant when associated with low-energy findings (26% vs 59%, P < .001). Among enhancement types, mass enhancement composed 71% (99 of 140) of all malignancies with PPV of 63% when associated with low-energy findings. Foci, non-mass enhancement, and mass enhancement without low-energy findings had PPV of 6%, 24%, and 38%, respectively. Neither background parenchymal enhancement nor density was associated with enhancement type (P = .19 and P = .28, respectively). Conclusion Mass enhancement on recombined images using CEM was most commonly associated with malignancy, especially when associated with low-energy findings. Enhancement types were more likely to be benign when not associated with low-energy findings; however, they should still be viewed with suspicion, given the high association with malignancy. © RSNA, 2022 Online supplemental material is available for this article.

Palliative care in amyotrophic lateral sclerosis clinics: A survey of NEALS consortium membership.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition managed with a multidisciplinary approach. Palliative care is important for this approach, but there is a lack of recommendations for the role and involvement of palliative medicine (PM) specialists in multidisciplinary ALS care. METHODS: This questionnaire-based survey assessed the state of palliative care in selective sites that are a part of Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS). RESULTS: Twenty-seven percent of the sites included palliative care specialists as a part of their ALS clinics and they were introduced to the patients and family by ALS specialists (75.94%) usually at an advanced stage of ALS. DISCUSSION: Our study when compared with other study results having a similar aim showed that there is a variability in the practice of palliative care specialists in ALS clinics. Having evidence-based guidelines will help in the management of ALS patients more effectively.

Approach to Limb Weakness.

"Approach to limb weakness" provides an overview of the pathways of the motor system and the type of weakness seen with pathology at each level from the cortex to the muscle. This article provides the clinical pearls needed to identify different patterns of weakness and accurately localize the level of weakness. It offers important pointers that help distinguish among the different etiologies of weakness at each level, as well as various diagnostic approaches and treatments of diseases that lead to limb weakness. The diagnoses discussed are meant to be representative and not exhaustive, as a complete differential for each pattern of weakness is beyond the scope of this article.

Factors Associated With Background Parenchymal Enhancement on Contrast-Enhanced Mammography.

OBJECTIVE. The purpose of this study was to determine the relationship between background parenchymal enhancement (BPE) on contrast-enhanced mammography (CEM) and breast tissue density, menstrual status, endocrine therapy, and risk factors for breast cancer and also to evaluate interreader agreement on classification of BPE on CEM. MATERIALS AND METHODS. Five subspecialty-trained breast radiologists independently and blindly graded tissue density (with fatty tissue and scattered fibroglandular tissue classified as nondense tissue and with heterogeneously dense and extremely dense classified as dense tissue) and BPE (with minimal or mild BPE categorized as low BPE and moderate or marked BPE categorized as high BPE) on CEM examinations performed from 2014 to 2018. Electronic medical charts were reviewed for information on menstrual status, endocrine therapy, history of breast surgery, and other risk factors for breast cancer. Comparisons were performed using the Kruskal-Wallis test, Mann-Whitney test, and Spearman rank correlation. Interreader agreement was estimated using the Fleiss kappa test. RESULTS. A total of 202 patients (mean [± SD] age, 54 ± 10 years; range, 25-84 years) underwent CEM. Tissue density was categorized as fatty in two patients (1%), scattered fibroglandular in 67 patients (33%), heterogeneously dense in 117 patients (58%), and extremely dense in 16 patients (8%). Among the 202 patients, BPE was minimal in 77 (38%), mild in 80 (40%), moderate in 31 (15%), and marked in 14 (7%). Dense breasts, younger age, premenopausal status, no history of endocrine therapy, and no history of breast cancer were significantly associated with high BPE. Among premenopausal patients, no association was found between BPE and time from last menstrual period to CEM. Overall interreader agreement on BPE was moderate (κ = 0.41; 95% CI, 0.40-0.42). Interreader agreement on tissue density was substantial (κ = 0.67; 95% CI, 0.66-0.69). CONCLUSION. Women with dense breasts, premenopausal status, and younger age are more likely to have greater BPE. Targeting CEM to the last menstrual period is not indicated.

A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis Screening Among People Living With Human Immunodeficiency Virus.

BACKGROUND: Gene-expression profiles have been reported to distinguish between patients with and without active tuberculosis (TB), but no prior study has been conducted in the context of TB screening. METHODS: We included all the patients (n = 40) with culture-confirmed TB and time-matched controls (n = 80) enrolled between July 2013 and April 2015 in a TB screening study among people living with human immunodeficiency virus (PLHIV) in Kampala, Uganda. We randomly split the patients into training (n = 80) and test (n = 40) datasets. We used the training dataset to derive candidate signatures that consisted of 1 to 5 differentially-expressed transcripts (P ≤ .10) and compared the performance of our candidate signatures with 4 published TB gene-expression signatures, both on the independent test dataset and in 2 external datasets. RESULTS: We identified a novel, 5-transcript signature that met the accuracy thresholds recommended for a TB screening test. On the independent test dataset, our signature had an area under the curve (AUC) of 0.87 (95% confidence interval [CI] 0.72-0.98), with sensitivity of 94% and specificity of 75%. None of the 4 published TB signatures achieved desired accuracy thresholds. Our novel signature performed well in external datasets from both high (AUC 0.81, 95% CI 0.74-0.88) and low (0.81, 95% CI 0.77-0.85) TB burden settings. CONCLUSIONS: We identified the first gene-expression signature for TB screening. Our signature has the potential to be translated into a point-of-care test to facilitate systematic TB screening among PLHIV and other high-risk populations.

Contrast-Enhanced Mammography: A Systematic Guide to Interpretation and Reporting.

OBJECTIVE: The purpose of this article is to discuss the essential steps involved in performing, interpreting, managing, and reporting findings on contrast-enhanced mammography for successful implementation into clinical practice. CONCLUSION: To successfully implement contrast-enhanced mammography into clinical practice, an understanding about the acquisition of images, image interpretation, and reporting of the spectrum of negative, benign, and malignant findings is essential.

Contrast-enhanced Mammography: Current Applications and Future Directions.

Contrast-enhanced mammography (CEM) is a developing modality used for the workup and management of breast cancer. Although diagnostic imaging modalities such as mammography and US have historically been the mainstays of initial breast cancer workup, recent advances in breast MRI have allowed better disease evaluation. However, MRI is not always readily available, can be time consuming, and is contraindicated in certain patients. CEM is an alternative to US and MRI, and it can be used to obtain contrast material-enhanced information and standard mammograms simultaneously. A CEM examination is shorter than that of MRI, and the modalities have similar rates of sensitivity to detect lesions. CEM also costs less than MRI. The authors evaluate clinical uses of CEM and discuss the literature supporting these indications.©RSNA, 2019.

Potential role of abbreviated MRI for breast cancer screening in an academic medical center.

The purpose is to determine whether an abbreviated MRI protocol (ABMR) is ready to be used for breast cancer screening in an academic practice setting. Two hundred and fifty nine breast MRIs from 1/1/2012 to 6/30/2012 were retrospectively reviewed using ABMR (MIP, Pre-contrastT1, single dynamic post-contrastT1, and subtraction). Five breast radiologists (4-28 year-expr) participated in this reader study performed in two phases: Phase1 - radiologist's privy to clinical history but not to comparison imaging. Phase2 - radiologists provided comparison imaging. For phase1, studies were reviewed using three steps: (a) MIP only (positive/negative/intermediate); (b) ABMR (recall/no recall) and (c) With T2 (for changes in recommendations). Radiologist also recorded total time for interpretation. In Phase2 the MRIs coded as "recall" were re-reviewed with available comparison studies, noting changes in final recommendation. The abnormal interpretation rates (AIRs) were calculated for phase1 and phase2 results with comparison to the original full protocol. Of the 259 patients (avg. age-52 years; range 26-78), there were seven cancers (three invasive, three DCIS and one breast lymphoma). Acquisition time for ABMR was 3 minutes, ABMR + T2-8 minutes, and original full protocol 16 minutes. Average MIP was positive or indeterminate in 86% (6/7) and negative in 14% (1/7) cancers. The average AIR for MIP only was 20.8% (sens-77.1%; spec-80.8%. The AIR w/o comparisons was 25.6% (sens-91.4%; spec- 76.2%); however the average AIR decreased in phase 2 with comparisons to 13.7% (sens-91.4%; spec-88.5%). The AIR of the original full protocol read was 16.2% (sens-100%; spec-85.7%). Addition of T2 changed assessment in only 3% (1.2%-6.5%). Avg. read time for ABMR including T2 was 2.5 minutes (1.6-4.0 minutes). ABMR is reliable for breast cancer screening, with acceptable interpretation time and acceptable AIR.

Breast MRI ordering practices in a large health care network.

The purpose of this study was to evaluate providers' ordering practices and perceptions of breast magnetic resonance imaging (MRI) in an academic network in order to better understand and educate a referral base. An online survey was distributed to primary care providers (PCPs) and specialists in our hospital and community practices. Questions included provider demographics, current ordering practices, challenges to ordering, and perceptions about breast MRI. Of 525 ordering providers, 134 responded (26% response rate). Of 134 providers, 57 (42%) order breast MRI in practice. Of those who do not, the most consistent reason was a lack of familiarity with the use of breast MRI (32/77 [42%] of cases). Of 57 cases, 45 (79%) order less than 10 exams annually. The most frequent indication is for high-risk screening (40/47 [84%]). PCPs order fewer breast MRI compared with specialists (P = 0.01). Both PCPs and specialists have mixed perceptions of the clinical utility of breast MRI. However, 30% of all providers are ordering more breast MRI since the enactment of breast density legislation in Massachusetts. Furthermore, 29% report they would order breast MRI more often to screen women with dense breasts if there was a low cost option. Referring provider surveys are useful tools for assessing a radiology practice. Our study suggests a growing clinical interest in breast MRI for screening; however, there is a need for provider education on the clinical utility of breast MRI. Increasing the radiologist's role in targeted educational interventions may help improve awareness and lead to more appropriate utilization of resources.

The Road to Wellness: Engagement Strategies to Help Radiologists Achieve Joy at Work.

Physician wellness is recognized as a critical component of enhancing the quality of health care. An epidemic of symptoms related to stress and burnout among medical professionals, including radiologists, in the workplace is threatening not only health care providers at a personal level but also the entire health care system. In this review, the authors highlight recognized stressors in the contemporary radiology workplace and offer practical suggestions for mitigating burnout, improving professional engagement, and promoting wellness. Thematic goals to focus on include fostering an integrated and harmonious community at work, diminishing workplace detractors, creating opportunities to cultivate positive attitudes and intellect, and implementing effective leadership practices. ©RSNA, 2018.

Indications for biopsy of imaging-detected intramammary and axillary lymph nodes in the absence of concurrent breast cancer.

To evaluate the prevalence of malignancy in imaging-detected abnormal lymph nodes (LNs) in women without concurrent cancer and to identify imaging features predictive of malignancy in this population. This is an IRB-approved study with waived informed consent. We retrospectively reviewed medical records of all image-guided LN FNAs and CNBs performed at our institution from 1/1/08 through 12/31/10. LNs sampled in patients without concurrent breast cancer comprised our study group (SG; n = 77), and with concurrent breast cancer our reference group (RG; n = 124). Blinded to cytology/histology, imaging features of the LNs including size, loss of fatty hilum, and cortical thickness were reviewed. A low/high suspicion category was then assigned based on LN appearance. The prevalence of malignancy in LNs in SG was 6% (5/77) and in RG 52% (64/124; P < .0001). Complete loss of fatty hilum had 100% (5/5) sensitivity, and 100% (56/56) NPV for detecting cancer in SG, compared to 39% (25/64) sensitivity and 61% (60/99) NPV in RG. When a "high suspicion" imaging feature was used as a threshold to biopsy, the sensitivity (5/5) and NPV (45/45) in SG were 100%, and in RG 78% (50/64) and 77% (47/61), respectively. The prevalence of cancer in imaging-detected abnormal LNs in patients without concurrent breast cancer is low. In the absence of concurrent cancer, using highly suspicious features of loss of fatty hilum or cortical thickness ≥ 5 mm as a threshold to biopsy will maintain high sensitivity with lower false-positive biopsy rate.

Proposed biopsy performance benchmarks for MRI based on an audit of a large academic center.

Performance benchmarks exist for mammography (MG); however, performance benchmarks for magnetic resonance imaging (MRI) are not yet fully developed. The purpose of our study was to perform an MRI audit based on established MG and screening MRI benchmarks and to review whether these benchmarks can be applied to an MRI practice. An IRB approved retrospective review of breast MRIs was performed at our center from 1/1/2011 through 12/31/13. For patients with biopsy recommendation, core biopsy and surgical pathology results were reviewed. The data were used to derive mean performance parameter values, including abnormal interpretation rate (AIR), positive predictive value (PPV), cancer detection rate (CDR), percentage of minimal cancers and axillary node negative cancers and compared with MG and screening MRI benchmarks. MRIs were also divided by screening and diagnostic indications to assess for differences in performance benchmarks amongst these two groups. Of the 2455 MRIs performed over 3-years, 1563 were performed for screening indications and 892 for diagnostic indications. With the exception of PPV2 for screening breast MRIs from 2011 to 2013, PPVs were met for our screening and diagnostic populations when compared to the MRI screening benchmarks established by the Breast Imaging Reporting and Data System (BI-RADS) 5 Atlas® . AIR and CDR were lower for screening indications as compared to diagnostic indications. New MRI screening benchmarks can be used for screening MRI audits while the American College of Radiology (ACR) desirable goals for diagnostic MG can be used for diagnostic MRI audits. Our study corroborates established findings regarding differences in AIR and CDR amongst screening versus diagnostic indications.

Surgical upgrade rate of breast atypia to malignancy: An academic center's experience and validation of a predictive model.

Atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS) are commonly seen on breast core needle biopsy (CNB). Many institutions recommend excision of these lesions to exclude malignancy. A retrospective chart review was performed on patients who had ADH, ALH, or LCIS on breast CNB from 1/1/08 to 12/31/10 who subsequently had surgical excision of the biopsy site. Study objectives included determining upgrade to malignancy at surgical excision, identification of predictors of upgrade, and validation of a recently published predictive model. Clinical and demographic factors, pathology, characteristics of the biopsy procedure and visible residual lesion were recorded. T test and chi-squared test were used to identify predictors. Classification tree was used to predict upgrade. 151 patients had mean age of 53 years. The mean maximum lesion size on imaging was 11 mm. The primary atypia was ADH in 63.6%, ALH in 27.8%, and LCIS in 8.6%. 16.6% of patients had upgrade to malignancy, with 72% DCIS and 28% invasive carcinoma. Risk factors for upgrade included maximum lesion size (P = .002) and radiographic presence of residual lesion (P = .001). A predictive model based on these factors had sensitivity 78%, specificity 80% and AUC = 0.88. Validating a published nomogram with our data produced accuracy figures (AUC = 0.65) within published CI of 0.63-0.82. In CNB specimens containing ADH, ALH, or LCIS, initial lesion size and presence of residual lesion are predictors of upgrade to malignancy. A validated model may be helpful in developing patient management strategies.

Clinical Value of Mammography in the Evaluation of Palpable Breast Lumps in Women 30 Years Old and Older.

OBJECTIVE: The purpose of this study was to determine whether mammography adds clinical value in the diagnostic imaging workup of women 30 years old and older who present with palpable breast lumps. MATERIALS AND METHODS: We retrospectively identified the records of all women 30 years old and older who underwent imaging evaluation with mammography and ultrasound for a palpable lump between January 1, 2009, and December 31, 2010. Imaging reports were reviewed for findings related to the lump and for incidental nonpalpable findings. Benign versus malignant outcomes were determined by pathologic analysis or 24-month imaging or clinical follow-up. The contribution of mammography to final diagnosis was assessed on the basis of objective criteria to determine the clinical impact of mammographic findings. RESULTS: The study cohort included 861 patients presenting with 935 palpable lumps. Imaging correlates were reported for 568 of 935 (60.7%) lumps, and imaging findings were negative in 367 of 935 (39.3%). Of the 935 palpable lumps, 858 (91.8%) were benign and 77 (8.2%) were malignant. Mammography added clinical value in the evaluation of 27 of 77 (35.0%) malignant lumps by better delineating extent of disease and in the evaluation of 26 of 858 benign lumps (3.0%) by confirming benignity. Fifty-two of 861 (6.0%) patients had incidental findings that led to a recommendation for biopsy. Twenty-nine of the 52 findings were originally seen with mammography and 23 with ultrasound. Mammography also depicted seven incidental malignancies in nonpalpable areas, and ultrasound depicted one incidental malignancy. CONCLUSION: Adjunct mammography is warranted for evaluation of palpable breast lumps in women 30 years old and older because of the value added to clinical management. In all age cohorts, mammography contributed to delineation of disease extent, detection of incidental malignancies, and confirmation of benign diagnoses.

Imaging Features of Spindle Cell Breast Lesions.

OBJECTIVE: The purpose of our study is to review the clinical presentation, multimodality appearance, and management of the most common benign and malignant spindle cell lesions of the breast. CONCLUSION: Spindle cell lesions of the breast exhibit characteristic features at mammography, ultrasound, and MRI. Although a definitive diagnosis of these lesions cannot be made with diagnostic imaging alone, knowledge of their characteristic imaging features can assist in refining the differential diagnosis and guiding appropriate management.

Prediction of Low versus High Recurrence Scores in Estrogen Receptor-Positive, Lymph Node-Negative Invasive Breast Cancer on the Basis of Radiologic-Pathologic Features: Comparison with Oncotype DX Test Recurrence Scores.

Purpose To review mammographic, ultrasonographic (US), and magnetic resonance (MR) imaging features and pathologic characteristics of estrogen receptor (ER)-positive, lymph node-negative invasive breast cancer and to determine the relationship of these characteristics to Oncotype DX (Genomic Health, Redwood City, Calif) test recurrence scores (ODRS) for breast cancer recurrence. Materials and Methods This institutional review board-approved retrospective study was performed in a single large academic medical center. The study population included patients with ER-positive, lymph node-negative invasive breast cancer who underwent genomic testing from January 1, 2009, to December 31, 2013. Imaging features of the tumor were classified according to the Breast Imaging Reporting and Data System lexicon by breast imagers who were blinded to the ODRS. Mammography was performed in 86% of patients, US was performed in 84%, and MR imaging was performed in 33%, including morphologic and kinetic evaluation. Images from each imaging modality were evaluated. Each imaging finding, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, and tumor grade were then individually correlated with ODRS. Analysis of variance was used to determine differences for each imaging feature. Regression analysis was used to calculate prediction of recurrence on the basis of imaging features combined with histopathologic features. Results The 319 patients had a mean age ± standard deviation of 55 years ± 8.7 (range, 31-82 years). Imaging features with a positive correlation with ODRS included a well-circumscribed oval mass (P = .024) at mammography, vascularity (P = .047) and posterior enhancement (P = .004) at US, and lobulated mass (P = .002) at MR imaging. Recurrence scores were predicted by using these features in combination with PR and HER2 status and tumor grade by using the threshold of more than 30 as a high recurrence score. With a regression tree, there was correlation (r = 0.79) with 89% sensitivity and 83% specificity. Conclusion On the basis of preliminary data, information obtained routinely for breast cancer diagnosis can reliably be used to predict the ODRS with high sensitivity and specificity. (©) RSNA, 2016.