Ultrafast DCE-MRI for discriminating pregnancy-associated breast cancer lesions from lactation related background parenchymal enhancement.

OBJECTIVE: To investigate the utility of ultrafast dynamic-contrast-enhanced (DCE) MRI in visualization and quantitative characterization of pregnancy-associated breast cancer (PABC) and its differentiation from background-parenchymal-enhancement (BPE) among lactating patients. MATERIALS AND METHODS: Twenty-nine lactating participants, including 10 PABC patients and 19 healthy controls, were scanned on 3-T MRI using a conventional DCE protocol interleaved with a golden-angle radial sparse parallel (GRASP) ultrafast sequence for the initial phase. The timing of the visualization of PABC lesions was compared to lactational BPE. Contrast-noise ratio (CNR) was compared between the ultrafast and conventional DCE sequences. The differences in each group's ultrafast-derived kinetic parameters including maximal slope (MS), time to enhancement (TTE), and area under the curve (AUC) were statistically examined using the Mann-Whitney test and receiver operator characteristic (ROC) curve analysis. RESULTS: On ultrafast MRI, breast cancer lesions enhanced earlier than BPE (p < 0.0001), enabling breast cancer visualization freed from lactation BPE. A higher CNR was found for ultrafast acquisitions vs. conventional DCE (p < 0.05). Significant differences in AUC, MS, and TTE values were found between the tumor and BPE (p < 0.05), with ROC-derived AUC of 0.86 ± 0.06, 0.82 ± 0.07, and 0.68 ± 0.08, respectively. The BPE grades of the lactating PABC patients were reduced as compared with the healthy lactating controls (p < 0.005). CONCLUSION: Ultrafast DCE MRI allows BPE-free visualization of lesions, improved tumor conspicuity, and kinetic quantification of breast cancer during lactation. Implementation of this method may assist in the utilization of breast MRI for lactating patients. CLINICAL RELEVANCE: The ultrafast sequence appears to be superior to conventional DCE MRI in the challenging evaluation of the lactating breast. Thus, supporting its possible utilization in the setting of high-risk screening during lactation and the diagnostic workup of PABC. KEY POINTS: • Differences in the enhancement slope of cancer relative to BPE allowed the optimal visualization of PABC lesions on mid-acquisitions of ultrafast DCE, in which the tumor enhanced prior to the background parenchyma. • The conspicuity of PABC lesions on top of the lactation-related BPE was increased using an ultrafast sequence as compared with conventional DCE MRI. • Ultrafast-derived maps provided further characterization and parametric contrast between PABC lesions and lactation-related BPE.

Pacemaker in patients undergoing mammography: A limitation for breast cancer diagnosis?

INTRODUCTION: A pacemaker may affect the utility of a mammogram in several ways. The aim of this study is to summarize our institution's experience with mammograms among patients with a cardiac pacemaker, focusing on the diagnostic workup among patients with a newly diagnosed ipsilateral breast cancer. METHODS: A retrospective search of all mammography reports between January 2011 and April 2021 was conducted for identifying cases of patients with a pacemaker. Demographic and clinical characteristics as well as mammography-derived quality parameters and findings were categorized and statistically compared. RESULTS: The incidence of pacemaker concurrence in mammographic examination, although apparently slightly under-documented, accounted for 0.33% of cases. Population mean age was 71.7 years, and most patients (79%) had a left-sided pacemaker. The pacemaker was much more likely to be projected on the medio-lateral-oblique (96%) than on the cranio-caudal view (10%), on the axilla rather than the breast, and on the retro-pectoral rather than the pre-pectoral region (P < 0.001 for all). Compression force decreased by up to 23.0% (P < 0.001) and breast thickness increased by up to 9.5% (P < 0.001) for the ipsilateral vs. the contralateral side. Among 11 patients with newly diagnosed ipsilateral breast cancer, the pacemaker partially projected on the tumour region in two cases, and significantly obscured the tumour in another two. CONCLUSION: Although rare, the coexistence of a pacemaker in patients undergoing mammography is associated with reduced image quality due to suboptimal breast visualization and reduced compression, and as a result, this may eventually lead to decreased diagnostic efficacy.

MRI can accurately diagnose breast cancer during lactation.

OBJECTIVE: To test the diagnostic performance of breast dynamic contrast-enhanced (DCE) MRI during lactation. MATERIALS AND METHODS: Datasets of 198 lactating patients, including 66 pregnancy-associated breast cancer (PABC) patients and 132 controls, who were scanned by DCE on 1.5-T MRI, were retrospectively evaluated. Six blinded, expert radiologists independently read a single DCE maximal intensity projection (MIP) image for each case and were asked to determine whether malignancy was suspected and the background-parenchymal-enhancement (BPE) grade. Likewise, computer-aided diagnosis CAD MIP images were independently read by the readers. Contrast-to-noise ratio (CNR) analysis was measured and compared among four consecutive acquisitions of DCE subtraction images. RESULTS: For MIP-DCE images, the readers achieved the following means: sensitivity 93.3%, specificity 80.3%, positive-predictive-value 70.4, negative-predictive-value 96.2, and diagnostic accuracy of 84.6%, with a substantial inter-rater agreement (Kappa = 0.673, p value < 0.001). Most false-positive interpretations were attributed to either the MIP presentation, an underlying benign lesion, or an asymmetric appearance due to prior treatments. CAD's derived diagnostic accuracy was similar (p = 0.41). BPE grades were significantly increased in the healthy controls compared to the PABC cohort (p < 0.001). CNR significantly decreased by 11-13% in each of the four post-contrast images (p < 0.001). CONCLUSION: Breast DCE MRI maintains its high efficiency among the lactating population, probably due to a vascular-steal phenomenon, which causes a significant reduction of BPE in cancer cases. Upon validation by prospective, multicenter trials, this study could open up the opportunity for breast MRI to be indicated in the screening and diagnosis of lactating patients, with the aim of facilitating an earlier diagnosis of PABC. KEY POINTS: • A single DCE MIP image was sufficient to reach a mean sensitivity of 93.3% and NPV of 96.2%, to stress the high efficiency of breast MRI during lactation. • Reduction in BPE among PABC patients compared to the lactating controls suggests that several factors, including a possible vascular steal phenomenon, may affect cancer patients. • Reduction in CNR along four consecutive post-contrast acquisitions highlights the differences in breast carcinoma and BPE kinetics and explains the sufficient conspicuity on the first subtracted image.

Breast MRI during pregnancy and lactation: clinical challenges and technical advances.

The breast experiences substantial changes in morphology and function during pregnancy and lactation which affects its imaging properties and may reduce the visibility of a concurrent pathological process. The high incidence of benign gestational-related entities may further add complexity to the clinical and radiological evaluation of the breast during the period. Consequently, pregnancy-associated breast cancer (PABC) is often a delayed diagnosis and carries a poor prognosis. This state-of-the-art pictorial review illustrates how despite currently being underutilized, technical advances and new clinical evidence support the use of unenhanced breast MRI during pregnancy and both unenhanced and dynamic-contrast enhanced (DCE) during lactation, to serve as effective supplementary modalities in the diagnostic work-up of PABC.

A single cell atlas of the human liver tumor microenvironment.

Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA-sequencing and spatial analysis of malignant and adjacent non-malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient-independent expression programs, and reconstruct a ligand-receptor map that highlights recurring tumor-stroma interactions. By combining transcriptomics of laser-capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non-malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.

Diet Diurnally Regulates Small Intestinal Microbiome-Epithelial-Immune Homeostasis and Enteritis.

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.

Endometrial stem cell transplantation in MPTP- exposed primates: an alternative cell source for treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. Cell-replacement therapies have emerged as a promising strategy to slow down or replace neuronal loss. Compared to other stem cell types, endometrium-derived stem cells (EDSCs) are an attractive source of stem cells for cellular therapies because of their ease of collection and vast differentiation potential. Here we demonstrate that endometrium-derived stem cells may be transplanted into an MPTP exposed monkey model of PD. After injection into the striatum, endometrium-derived stem cells engrafted, exhibited neuron-like morphology, expressed tyrosine hydroxylase (TH) and increased the numbers of TH positive cells on the transplanted side and dopamine metabolite concentrations in vivo. Our results suggest that endometrium-derived stem cells may provide a therapeutic benefit in the primate model of PD and may be used in stem cell based therapies.

Migration of cells from experimental endometriosis to the uterine endometrium.

Endometriosis is the estrogen-dependent growth of endometrial tissue outside the uterus. Endometriosis has an effect on the eutopic endometrium; however, the nature of the cellular or molecular signal from the lesion to the uterus is unknown. Here we demonstrate that cells migrate from endometriosis to eutopic endometrium. Experimental endometriosis was established by transplanting endometrial tissue from green fluorescent protein (GFP) mice to the peritoneal cavity of DS-Red mice. Immunofluorescence (IF) identified cells from the ectopic lesions in the uterus. The eutopic endometrial cells were sorted by fluorescence activated cell sorting, and the GFP(+)/DS-Red(-) population was characterized using microarray analysis. The results of cell sorting as well as the array results were confirmed by quantitative PCR and IF. GFP(+)/DS-red(-)/Cd45(-) cells were identified in the eutopic endometrium of mice with experimental endometriois (∼1.8%) and not in controls. Global gene expression profiling of these cells showed absence of leukocyte and increased expression of pan-epithelial markers in the uterine GFP(+) cells. Moreover, GFP(+) cells showed up-regulation of Wnt7A expression and 17 other genes associated with the Wingless pathway. Several genes that are associated with epithelial-to-mesenchymal transition were also highly differentially expressed in GFP(+) cells. IF confirmed the presence of the GFP(+)/CD45(-)/Wnt7a(+)/cytokeritin(+) cells in the endometrium of endometriotic animals, and not in controls. Cells from endometriotic lesions are capable of migrating to the eutopic endometrium. The ectopic expression of Wnt7A suggests a possible mechanism by which ectopic lesions affect the eutopic endometrium and interfere with embryo implantation and fertility.

A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis.

Endometriosis is found in 5-15% of women of reproductive age and is more frequent in relatives of women with the disease. Activation of KRAS results in de novo endometriosis in mice, however, activating KRAS mutations have not been identified in women. We screened 150 women with endometriosis for a polymorphism in a let-7 microRNA (miRNA) binding site in the 3'-UTR of KRAS and detected a KRAS variant allele in 31% of women with endometriosis as opposed to 5% of a large diverse control population. KRAS mRNA and protein expression were increased in cultured endometrial stromal cells of women with the KRAS variant. Increased KRAS protein was due to altered miRNA binding as demonstrated in reporter assays. Endometrial stromal cells from women with the KRAS variant showed increased proliferation and invasion. In a murine model, endometrial xenografts containing the KRAS variant demonstrated increased proliferation and decreased progesterone receptor levels. These findings suggest that an inherited polymorphism of a let-7 miRNA binding site in KRAS leads to abnormal endometrial growth and endometriosis. The LCS6 polymorphism is the first described genetic marker of endometriosis risk.

MicroRNA 135 regulates HOXA10 expression in endometriosis.

CONTEXT: Homeo box A10 (HOXA10) regulates endometrial receptivity and its expression is decreased in women with endometriosis. Although sex steroids regulate HOXA10, these hormones are unaltered in endometriosis. We hypothesized a role for microRNA in the regulation of HOXA10. OBJECTIVE: MicroRNA 135a and -b are small noncoding RNA with predicted targets that include HOXA10. We evaluated miR135a/b expression and HOXA10 regulation in endometrium from subjects with and without endometriosis. DESIGN: The design of the study was the measurement of miR135a/b expression by quantitative PCR and in vitro analysis of HOXA10 regulation. SETTING: The study was conducted at a university medical center. PATIENTS: Patients included 50 controls and 32 women with endometriosis. INTERVENTIONS: Study interventions included endometrial biopsies and in vitro transfection. MAIN OUTCOME MEASURES: miR135a/b and HOXA10 expression were measured in the study. RESULTS: All endometrial samples expressed miR135a and -b. miR135a expression in controls was increased during the proliferative phase, decreased at the time of ovulation, and increased during the luteal phase. Subjects with endometriosis had 3-fold higher expression of miR135a in the proliferative phase than controls. miR135b showed less variation across the menstrual cycle; however, it was significantly increased in women with endometriosis in the proliferative and secretory phases. HOXA10 expression was simultaneously repressed in the endometrium of women with endometriosis. Transfection of endometrial stromal cells with mir135a/b or miR135a/b inhibitors resulted in the altered expression of HOXA10 mRNA and protein. miR135a or -b decreased luciferase expression driven by the HOXA10 3' untranslated region containing the miR135 binding site. miR135a regulation of HOXA10 was absent in MCF-7 cells, demonstrating cell specificity. CONCLUSIONS: HOXA10 was aberrantly regulated in the endometrium of women with endometriosis by both miR135a and miR135b. Increased microRNA expression likely suppresses genes required for implantation.

Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes.

Pancreatic islet cell transplantation is an effective approach to treat type 1 diabetes, however the shortage of cadaveric donors and limitations due to rejection require alternative solutions. Multipotent cells derived from the uterine endometrium have the ability to differentiate into mesodermal and ectodermal cellular lineages, suggesting the existence of mesenchymal stem cells in this tissue. We differentiated human endometrial stromal stem cells (ESSC) into insulin secreting cells using a simple and nontransfection protocol. An in vitro protocol was developed and evaluated by assessing the expression of pan ß-cell markers, followed by confirmation of insulin secretion. PAX4, PDX1, GLUT2, and insulin, were all increased in differentiated cells compared to controls. Differentiated cells secreted insulin in a glucose responsive manner. In a murine model, differentiated cells were injected into the kidney capsules of diabetic mice and human insulin identified in serum. Within 5 weeks blood glucose levels were stabilized in animals transplanted with differentiated cells, however those treated with undifferentiated cells developed progressive hyperglycemia. Mice transplanted with control cells lost weight and developed cataracts while those receiving insulin producing cells did not. Endometrium provides an easily accessible, renewable, and immunologically identical source of stem cells with potential therapeutic applications in diabetes.