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Objectives: The purpose of our study was to assess the chondrogenic potential and the MR signal effects of GadofluorineM-Cy labeled matrix associated stem cell implants (MASI) in pig knee specimen. Materials and Methods: Human mesenchymal stem cells (hMSCs

Rationale and Objectives: To develop and evaluate an AI algorithm that detects breast cancer in MRI scans up to one year before radiologists typically identify it, potentially enhancing early detection in high-risk women., Materials and Methods: A convolutional neural network (CNN) AI model, pre-trained on breast MRI data, was fine-tuned using a retrospective dataset of 3029 MRI scans from 910 patients. These contained 115 cancers that were diagnosed within one year of a negative MRI. The model aimed to identify these cancers, with the goal of predicting cancer development up to one year in advance. The network was fine-tuned and tested with 10-fold cross-validation. Mean age of patients was 52 years (range, 18-88 years), with average follow-up of 4.3 years (range 1-12 years)., Results: The AI detected cancers one year earlier with an area under the ROC curve of 0.72 (0.67-0.76). Retrospective analysis by a radiologist of the top 10% highest risk MRIs as ranked by the AI could have increased early detection by up to 30%. (35/115, CI:22.2-39.7%, 30% sensitivity). A radiologist identified a visual correlate to biopsy-proven cancers in 83 of prior-year MRIs (83/115, CI: 62.1-79.4%). The AI algorithm identified the anatomic region where cancer would be detected in 66 cases (66/115, CI:47.8-66.5%); with both agreeing in 54 cases (54/115, CI:%37.5-56.4%)., Conclusion: This novel AI-aided re-evaluation of "benign" breasts shows promise for improving early breast cancer detection with MRI. As datasets grow and image quality improves, this approach is expected to become even more impactful., Competing Interests: Declaration of Competing Interest All authors declare no financial or non-financial competing interests., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

This work aims to perform a cross-site validation of automated segmentation for breast cancers in MRI and to compare the performance to radiologists. A three-dimensional (3D) U-Net was trained to segment cancers in dynamic contrast-enhanced axial MRIs using a large dataset from Site 1 (n = 15,266; 449 malignant and 14,817 benign). Performance was validated on site-specific test data from this and two additional sites, and common publicly available testing data. Four radiologists from each of the three clinical sites provided two-dimensional (2D) segmentations as ground truth. Segmentation performance did not differ between the network and radiologists on the test data from Sites 1 and 2 or the common public data (median Dice score Site 1, network 0.86 vs. radiologist 0.85, n = 114; Site 2, 0.91 vs. 0.91, n = 50; common: 0.93 vs. 0.90). For Site 3, an affine input layer was fine-tuned using segmentation labels, resulting in comparable performance between the network and radiologist (0.88 vs. 0.89, n = 42). Radiologist performance differed on the common test data, and the network numerically outperformed 11 of the 12 radiologists (median Dice: 0.85-0.94, n = 20). In conclusion, a deep network with a novel supervised harmonization technique matches radiologists' performance in MRI tumor segmentation across clinical sites. We make code and weights publicly available to promote reproducible AI in radiology., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly "silent" in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from in vitro experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of in vitro assays performed in the absence of competing IgG.

Purpose: Mammography, breast ultrasound (US), and US-guided breast biopsy are essential services for breast cancer early detection and diagnosis. This study undertook a comprehensive evaluation to determine population-level access to these services for breast cancer early detection and diagnosis in Nigeria using a previously validated geographic information system (GIS) model., Methods: A comprehensive list of public and private facilities offering mammography, breast US, and US-guided breast biopsy was compiled using publicly available facility data and a survey administered nationally to Nigerian radiologists. All facilities were geolocated. A cost-distance model using open-source population density (GeoData Institute) and road network data (OpenStreetMap) was used to estimate population-level travel time to the nearest facility for mammography, breast US, and US-guided biopsy using GIS software (ArcMAP)., Results: In total, 1,336 facilities in Nigeria provide breast US, of which 47.8% (639 of 1,336) are public facilities, and 218 provide mammography, of which 45.4% (99 of 218) are public facilities. Of the facilities that provide breast US, only 2.5% (33 of 1,336) also provide US-guided breast biopsy. At the national level, 83.1% have access to either US or mammography and 61.7% have access to US-guided breast biopsy within 120 minutes of a continuous one-way travel. There are differences in access to mammography (64.8% v 80.6% with access at 120 minutes) and US-guided breast biopsy (49.0% v 77.1% with access at 120 minutes) between the northern and southern Nigeria and between geopolitical zones., Conclusion: To our knowledge, this is the first comprehensive evaluation of breast cancer detection and diagnostic services in Nigeria, which demonstrates geospatial inequalities in access to mammography and US-guided biopsy. Targeted investment is needed to improve access to these essential cancer care services in the northern region and the North East geopolitical zone.

Background: In Nigeria, breast cancer incidence is rising, late presentation is common, and outcomes are poor. Patient-related factors such as lack of awareness and misperceptions in addition to health system deficiencies such as lack of a clearly defined framework for breast cancer screening and referral are some of the major drivers of this poor outlook. Guidelines for breast cancer screening in high-income countries have limited applicability in low-middle-income countries, hence the need for innovative, resource-compatible strategies to combat the negative trend. This manuscript presents our study protocol which aims to evaluate the impact of a novel breast cancer early detection program developed to address delayed presentation and lack of access to diagnostic and treatment facilities in South-West Nigeria. This entails the use of mobile technology (innovative handheld iBreast Exam [iBE] device, mobile breast ultrasound, and mobile mammography) and patient navigation as interventions at the community level., Methods: The study (ClinicalTrials.gov identifier: NCT05321823) will adopt a randomized two group clinical trial design with one local government area (LGA) serving as an intervention arm and another serving as the control. Both LGAs will receive breast cancer awareness education but only one will receive the interventions. In the intervention arm, asymptomatic (40-70 years) and symptomatic (30-70 years) women will be invited for breast evaluation which will be performed by trained Community Health Nurses using Clinical Breast Exam (CBE), and iBE. Those with positive findings will proceed to imaging using mobile mammography and ultrasound brought to the LGA every month. Symptomatic women with negative findings on CBE and iBE will be scheduled for repeat clinical evaluation on a short-term basis (one month). The Radiologist will obtain core needle biopsies as indicated and transfer them for prompt pathological assessment. Women presenting to the Primary Healthcare Centers in the control LGA will be referred directly to Obafemi Awolowo University Teaching Hospitals Complex as per the current standard of care. Records of all breast cancer cases seen in the two LGAs during the study period will be obtained. The program metrics will include screening participation rate, cancer detection rate, stage at diagnosis, and timeline from detection to initiation of treatment. The stage at diagnosis and timeline from detection to treatment compared between the two LGAs will be used to assess the impact of the intervention. The study is proposed for 2 years; however, a descriptive analysis will be carried out at 1.5 years to evaluate the retention of the study participants., Study Significance: It is anticipated that this study will provide vital data to support wider breast cancer screening efforts in Nigeria., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Despite national and international guidelines, asthma is frequently misdiagnosed, control is poor and unnecessary deaths are far too common. Large scale asthma management programme such as that undertaken in Finland, can improve asthma outcomes. A primary care asthma management quality improvement programme was developed with the support of the British Lung Foundation (now Asthma + Lung UK) and Optimum Patient Care (OPC) Limited. It was delivered and cascaded to all relevant staff at participating practices in three Clinical Commissioning Groups. The programme focussed on improving diagnostic accuracy, management of risk and control, patient self-management and overall asthma control. Patient data were extracted by OPC for the 12 months before (baseline) and after (outcome) the intervention. In the three CCGs, 68 GP practices participated in the programme. Uptake from practices was higher in the CCG that included asthma in its incentivised quality improvement programme. Asthma outcome data were successfully extracted from 64 practices caring for 673,593 patients. Primary outcome (Royal College of Physicians Three Questions [RCP3Q]) data were available in both the baseline and outcome periods for 10,328 patients in whom good asthma control (RCP3Q = 0) increased from 36.0% to 39.2% (p < 0.001) after the intervention. The odds ratio of reporting good asthma control following the intervention was 1.15 (95% CI 1.09-1.22), p < 0.0001. This asthma management programme produced modest but highly statistically significant improvements in asthma outcomes. Key lessons learnt from this small-scale implementation will enable the methodology to be improved to maximise benefit in a larger scale role out., (© 2023. The Author(s).)

Response to immunotherapy across multiple cancer types is approximately 25%, with some tumor types showing increased response rates compared to others (i.e. response rates in melanoma and non-small cell lung cancer (NSCLC) are typically 30-60%). Patients whose tumors are resistant to immunotherapy often lack high levels of pre-existing inflammation in the tumor microenvironment. Increased tumor glycolysis, acting through glucose deprivation and lactic acid accumulation, has been shown to have pleiotropic immune suppressive effects using in-vitro and in-vivo models of disease. To determine whether the immune suppressive effect of tumor glycolysis is observed across human solid tumors, we analyzed glycolytic and immune gene expression patterns in multiple solid malignancies. We found that increased expression of a glycolytic signature was associated with decreased immune infiltration and a more aggressive disease across multiple tumor types. Radiologic and pathologic analysis of untreated estrogen receptor (ER)-negative breast cancers corroborated these observations, and demonstrated that protein expression of glycolytic enzymes correlates positively with glucose uptake and negatively with infiltration of CD3 + and CD8 + lymphocytes. This study reveals an inverse relationship between tumor glycolysis and immune infiltration in a large cohort of multiple solid tumor types., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cohen, Pareja, Socci, Shen, Doane, Schwartz, Khanin, Morris, Sutton and Blasberg.)

Purpose: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping., Methods: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 and HLA, affecting 21 drug-gene pairs, were deposited preemptively in the Mayo electronic health record., Results: For the 13 pharmacogenes of interest, the genomes of 79% of participants carried clinically actionable variants in 3 or more genes, and DNA sequencing identified an average of 3.3 additional conservatively predicted deleterious variants that would not have been evident using genotyping., Conclusion: Implementation of preemptive rather than reactive and sequence-based rather than genotype-based PGx prescribing revealed nearly universal patient applicability and required integrated institution-wide resources to fully realize individualized drug therapy and to show more efficient use of health care resources., Competing Interests: Conflict of Interest Liewei Wang, John Logan Black III, and Richard M. Weinshilboum are cofounders of and stockholders in OneOme, LLC, which was used only to return results to the study participants. Additionally, John Logan Black III and Mayo Clinic Ventures have applied for a patent on the CNVAR software cited in this study as well as the methodology upon which the software is based. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Prognostic information is key to shared decision-making, particularly in life-limiting illness like advanced chronic kidney disease (CKD)., Objective: To understand the prognostic information preferences expressed by older patients with CKD., Design and Participants: Qualitative study of 28 consecutively enrolled patients over 65 years of age with non-dialysis dependent CKD stages 3b-5, receiving care in a multi-disciplinary CKD clinic., Approach: Semi-structured telephone or in-person interviews to explore patients' preference for and perceived value of individualized prognostic information. Interviews were analyzed using inductive content analysis., Key Results: We completed interviews with 28 patients (77.7 ± SD 6.8 years, 69% men). Patients varied in their preference for prognostic information and more were interested in their risk of progression to end-stage kidney disease (ESKD) than in life expectancy. Many conflated ESKD risk with risk of death, perceiving a binary choice between dialysis and quick decline and death. Patients expressed that prognostic information would allow them to plan, take care of important business, and think about their treatment options. Patients were accepting of prognostic uncertainty and imagined leveraging it to nurture hope or motivate them to better manage risk factors. They endorsed the desire to receive prognosis of life expectancy even though it may be hard to accept or difficult to talk about but worried it could create helplessness for other patients in their situation., Conclusion: Most, but not all, patients were interested in prognostic information and could see its value in motivating behavior change and allowing planning. Some patients expressed concern that information on life expectancy might cause depression and hopelessness. Therefore, prognostic information is most appropriate as part of a clinical conversation that fosters shared decision-making and helps patients consider treatment risks, benefits, and burdens in context of their lives., (© 2021. Society of General Internal Medicine.)

Purpose: To develop a deep network architecture that would achieve fully automated radiologist-level segmentation of cancers at breast MRI., Materials and Methods: In this retrospective study, 38 229 examinations (composed of 64 063 individual breast scans from 14 475 patients) were performed in female patients (age range, 12-94 years; mean age, 52 years ± 10 [standard deviation]) who presented between 2002 and 2014 at a single clinical site. A total of 2555 breast cancers were selected that had been segmented on two-dimensional (2D) images by radiologists, as well as 60 108 benign breasts that served as examples of noncancerous tissue; all these were used for model training. For testing, an additional 250 breast cancers were segmented independently on 2D images by four radiologists. Authors selected among several three-dimensional (3D) deep convolutional neural network architectures, input modalities, and harmonization methods. The outcome measure was the Dice score for 2D segmentation, which was compared between the network and radiologists by using the Wilcoxon signed rank test and the two one-sided test procedure., Results: The highest-performing network on the training set was a 3D U-Net with dynamic contrast-enhanced MRI as input and with intensity normalized for each examination. In the test set, the median Dice score of this network was 0.77 (interquartile range, 0.26). The performance of the network was equivalent to that of the radiologists (two one-sided test procedures with radiologist performance of 0.69-0.84 as equivalence bounds, P < .001 for both; n = 250)., Conclusion: When trained on a sufficiently large dataset, the developed 3D U-Net performed as well as fellowship-trained radiologists in detailed 2D segmentation of breast cancers at routine clinical MRI. Keywords: MRI, Breast, Segmentation, Supervised Learning, Convolutional Neural Network (CNN), Deep Learning Algorithms, Machine Learning AlgorithmsPublished under a CC BY 4.0 license. Supplemental material is available for this article., Competing Interests: Disclosures of Conflicts of Interest: L.H. Grant from NIBIB and NIMH through the NIH BRAIN Initiative (R01 EB02157); consulting fee from City College of New York. Y.H. Consulting fee from City College of New York. S.L. No relevant relationships. C.R.S. No relevant relationships. R.L.G. No relevant relationships. I.D.N. Grant from Alfonso Martín Escudero Foundation. A.G.V.B. No relevant relationships. N.O. No relevant relationships. E.S.K. No relevant relationships. D.L. No relevant relationships. D.A. Consulting fee AEAD850301RG4. S.E.W. RSNA Research and Education Foundation grant no. RF1905 (content is solely the responsibility of the authors and does not necessarily represent the official views of the RSNA R&E Foundation). M.H. No relevant relationships. D.F.M. No relevant relationships. K.P. Funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 and the Breast Cancer Research Foundation; ongoing research grants include Digital Hybrid Breast PET/MRI for Enhanced Diagnosis of Breast Cancer (HYPMED) H2020 - Research and Innovation Framework Programme PHC-11-2015 #667211-2, A Body Scan for Cancer Detection using Quantum Technology (CANCERSCAN) H2020-FETOPEN-2018-2019-2020-01 # 828978, Multiparametric 18F-Fluoroestradiol PET/MRI coupled with Radiomics Analysis and Machine Learning for Prediction and Assessment of Response to Neoadjuvant Endocrine Therapy in Patients with Hormone Receptor+/HER2− Invasive Breast Cancer Jubiläumsfonds of the Austrian National Bank # Nr: 18207, Deciphering breast cancer heterogeneity and tackling the hypoxic tumor microenvironment challenge with PET/MRI, MSI and radiomics The Vienna Science and Technology Fund LS19-046, MSKCC 2020 Molecularly Targeted Intra-Operative Imaging Award 07/2020-06/2021, Breast Cancer Research Foundation 06/2019 - 05/2021 PI Mark Robson Co-I, NIH R01 Breast Cancer Intravoxel-Incoherent-Motion MRI Multisite (BRIMM) 09/01/2020-08/30/2025 PI Eric Sigmund Co-I, NIH R01 subaward: Abbreviated Non-Contrast-Enhanced MRI for Breast Cancer Screening 09/01/2023-08/31/2025 PI Brian Hargreaves; payment for lectures, service on speakers bureaus and for travel/accommodations/meeting expenses from the European Society of Breast Imaging (MRI educational course, annual scientific meeting) and Siemens Healthcare (lectures). K.J. No relevant relationships. A.E.E. No relevant relationships. P.E. No relevant relationships. E.A.M. No relevant relationships. H.A.M. Grant from NIBIB and NIMH through the NIH BRAIN Initiative (R01 EB028157). L.C.P. Grant from NIH (R01CA247910). E.J.S. Grant from National Institutes of Health/National Cancer Institute (P30 CA008748)., (2022 by the Radiological Society of North America, Inc.)

Purpose: Multiple efforts are underway to increase the inclusion of racial minority participants in genomic research and new forms of individualized medicine. These efforts should include studies that characterize how individuals from minority communities experience genomic medicine in diverse health-care settings and how they integrate genetic knowledge into their understandings of health-care needs., Methods: As part of a large, multisite genomic sequencing study, we surveyed individuals to assess their decision to pursue genomic risk evaluation. Participants included Latino patients recruited at Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, and non-Latino patients recruited at a large academic medical center (Mayo Clinic in Rochester, MN). Both groups agreed to receive individualized genomic risk assessments., Results: Comparisons between cohorts showed that Latino respondents had lower levels of decisional conflict about pursuing genomic screening but generally scored lower on genetic knowledge. Latino respondents were also more likely to have concerns about the misuse of genomic information, despite both groups having similar views about the value of genomic risk evaluation., Conclusion: Our results highlight the importance of evaluating sociocultural factors that influence minority patient engagement with genomic medicine in diverse health-care settings.

As genomic sequencing expands to screen larger numbers of individuals, offering genetic counseling to everyone may not be possible. One approach to managing this limitation is for a genetic counselor to communicate clinically actionable results in person or by telephone, but report other results by mail. We employed this approach in a large genomic implementation study. In this paper, we describe participants' experiences receiving genomic screening results by mail. We conducted 50 semi-structured telephone interviews with individuals who received neutral genomic screening results by mail. Most participants were satisfied receiving neutral results by mail. Participants generally had a good understanding of results; however, a few participants had misunderstandings about their genomic screening results, including mistaken beliefs about their disease risk and the comprehensiveness of the test. No one reported plans to alter health behaviors, defer medical evaluations, or take other actions that might be considered medically problematic. Reporting neutral results by mail is unlikely to cause recipients distress or generate misunderstandings that may result in reduced vigilance in following recommended preventive health strategies. Nonetheless, some individuals may benefit from additional genetic counseling support to help situate their results in the context of personal concerns and illness experiences.

Purpose: To assess the feasibility and diagnostic accuracy of multispectral MRI (MSI) in the detection and localization of biopsy markers during MRI-guided breast biopsy., Methods: This prospective study included 20 patients undergoing MR-guided breast biopsy. In 10 patients (Group 1), MSI was acquired following tissue sampling and biopsy marker deployment. In the other 10 patients (Group 2), MSI was acquired following tissue sampling but before biopsy marker deployment (to simulate deployment failure). All patients received post-procedure mammograms. Group 1 and Group 2 designations, in combination with the post-procedure mammogram, served as the reference standard. The diagnostic performance of MSI for biopsy marker identification was independently evaluated by two readers using two-spectral-bin MR and one-spectral-bin MR. The κ statistic was used to assess inter-rater agreement for biopsy marker identification., Results: The sensitivity, specificity, and accuracy of biopsy marker detection for readers 1 and 2 using 2-bin MSI were 90.0% (9/10) and 90.0% (9/10), 100.0% (10/10) and 100.0% (10/10), 95.0% (19/20) and 95.0% (19/20); and using 1-bin MSI were 70.0% (7/10) and 80.0% (8/10), 100.0% (8/8) and 100.0% (10/10), 85.0% (17/20) and 90.0% (18/20). Positive predictive value was 100% for both readers for all numbers of bins. Inter-rater agreement was excellent: κ was 1.0 for 2-bin MSI and 0.81 for 1-bin MSI., Conclusion: MSI is a feasible, diagnostically accurate technique for identifying metallic biopsy markers during MRI-guided breast biopsy and may eliminate the need for a post-procedure mammogram., Competing Interests: YW and PS are inventors on QSM-related patents issued to Cornell University and hold equity in Medimagemetric LLC. KP received payment for activities not related to the present article including lectures including service on speakers bureaus and for travel/accommodations/meeting expenses unrelated to activities listed from the European Society of Breast Imaging (MRI educational course, annual scientific meeting), and the IDKD 2019 (educational course). EM has received a grant from GRAIL, Inc. for research not related to the present article. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eskreis-Winkler, Simon, Reichman, Spincemaille, Nguyen, Christos, Drotman, Prince, Pinker, Sutton, Morris and Wang.)

Purpose: The aim of the study was to characterize experiences of Latino participants receiving genomic screening results., Methods: Participants were recruited at a federally qualified health center in the USA. In-person, semi-structured interviews were conducted in either Spanish or English by a bilingual, bicultural interviewer. Questions focused on motivations for pursuing genomic sequencing, concerns about receiving genomic screening results, and perceived benefits of receiving genomic information. Interviews were audio-recorded, transcribed, and translated., Results: Fifty individuals completed an interview; 39 were conducted in Spanish. Participants described mixed motivations for pursuing genomic screening. Participants viewed the benefits of genomic screening in relation to not only their personal health but to the health of their families and their communities. Participants tended to have few concerns about genomic screening. Those concerns related to potential loss of privacy, misuses of genomic information, and the possibility of receiving distressing results. Some participants had misunderstandings about the scope of the test and the potential implications of their results. Most felt it was better to know about a genetic predisposition to disease than to remain uninformed. Participants felt that genomic screening was worthwhile., Discussion: This is one of the first studies to examine the experiences of Latino individuals receiving genomic screening results. Our results suggest that many Latino patients in the US see value in genomic screening and have limited concerns about its potential to cause harm. These results inform ongoing efforts to increase the availability of genomic medicine to underrepresented populations and add to our understanding of sociocultural drivers in the adoption of precision medicine., (© 2021 S. Karger AG, Basel.)

Purpose: Breast MRI background parenchymal enhancement (BPE) can potentially serve as a prognostic marker, by possible correlation with molecular subtype. Oncotype Dx, a gene assay, is a prognostic and predictive surrogate for tumor aggressiveness and treatment response. The purpose of this study was to investigate the association between contralateral non-tumor breast magnetic resonance imaging (MRI) background parenchymal enhancement and tumor oncotype score., Methods: In this retrospective study, patients with ER+ and HER2- early stage invasive ductal carcinoma who underwent preoperative breast MRI, oncotype risk scoring, and breast conservation surgery from 2008-2010 were identified. After registration, BPE from the pre and three post-contrast phases was automatically extracted using a k-means clustering algorithm. Four metrics were calculated: initial enhancement (IE) relative to the pre-contrast signal, late enhancement, overall enhancement (OE), and area under the enhancement curve (AUC). Histogram analysis was performed to determine first order metrics which were compared to oncotype risk score groups using Mann-Whitney tests and Spearman rank correlation analysis., Results: This study included 80 women (mean age = 51.1 ± 10.3 years); 46 women were categorized as low risk (≤17) and 34 women were categorized as intermediate/high risk (≥18) according to Oncotype Dx. For the mean of the top 10% pixels, significant differences were noted for IE (p = 0.032), OE (p = 0.049), and AUC (p = 0.044). Using the risk score as a continuous variable, correlation analysis revealed a weak but significant correlation with the mean of the top 10% pixels for IE (r = 0.26, p = 0.02), OE (r = 0.25, p = 0.02), and AUC (r = 0.27, p = 0.02)., Conclusion: BPE metrics of enhancement in the non-tumor breast are associated with tumor Oncotype Dx recurrence score, suggesting that the breast microenvironment may relate to likelihood of recurrence and magnitude of chemotherapy benefit., Competing Interests: EM received a grant from GRAIL Inc. for research not related to the present article. MS is currently employed by Promaxo in San Francisco, CA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Sadinski, Haddad, Bae, Martinez, Morris, Gibbs and Sutton.)

Importance: After neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) is an optimal outcome and a surrogate end point for improved disease-free and overall survival. To date, surgical resection remains the only reliable method for diagnosing pCR., Objective: To evaluate the accuracy of magnetic resonance imaging (MRI)-guided biopsy for diagnosing a pCR after NAC compared with reference-standard surgical resection., Design, Setting, and Participants: Single-arm, phase 1, nonrandomized controlled trial in a single tertiary care cancer center from September 26, 2017, to July 29, 2019. The median follow-up was 1.26 years (interquartile range, 0.85-1.59 years). Data analysis was performed in November 2019. Eligible patients had (1) stage IA to IIIC biopsy-proven operable invasive breast cancer; (2) standard-of-care NAC; (3) MRI before and after NAC, with imaging complete response defined as no residual enhancement on post-NAC MRI; and (4) definitive surgery. Patients were excluded if they were younger than 18 years, had a medical reason precluding study participation, or had a prior history of breast cancer., Interventions: Post-NAC MRI-guided biopsy without the use of intravenous contrast of the tumor bed before definitive surgery., Main Outcomes and Measures: The primary end point was the negative predictive value of MRI-guided biopsy, with true-negative defined as negative results of the biopsy (ie, no residual cancer) corresponding to a surgical pCR. Accuracy, sensitivity, positive predictive value, and specificity were also calculated. Two clinical definitions of pCR were independently evaluated: definition 1 was no residual invasive cancer; definition 2, no residual invasive or in situ cancer., Results: Twenty of 23 patients (87%) had evaluable data (median [interquartile range] age, 51.5 [39.0-57.5] years; 20 women [100%]; 13 White patients [65%]). Of the 20 patients, pre-NAC median tumor size on MRI was 3.0 cm (interquartile range, 2.0-5.0 cm). Nineteen of 20 patients (95%) had invasive ductal carcinoma; 15 of 20 (75%) had stage II cancer; 11 of 20 (55%) had ERBB2 (formerly HER2 or HER2/neu)-positive cancer; and 6 of 20 (30%) had triple-negative cancer. Surgical pathology demonstrated a pCR in 13 of 20 (65%) patients and no pCR in 7 of 20 patients (35%) when pCR definition 1 was used. Results of MRI-guided biopsy had a negative predictive value of 92.8% (95% CI, 66.2%-99.8%), with accuracy of 95% (95% CI, 75.1%-99.9%), sensitivity of 85.8% (95% CI, 42.0%-99.6%), positive predictive value of 100%, and specificity of 100% for pCR definition 1. Only 1 patient had a false-negative MRI-guided biopsy result (surgical pathology showed <0.02 cm of residual invasive cancer)., Conclusions and Relevance: This study's results suggest that the accuracy of MRI-guided biopsy to diagnose a post-NAC pCR approaches that of reference-standard surgical resection. MRI-guided biopsy may be a viable alternative to surgical resection for this population after NAC, which supports the need for further investigation., Trial Registration: ClinicalTrials.gov Identifier: NCT03289195.

Social scientists have advocated for the use of participatory research methods for Global Health project design and planning. However, community-engaged approaches can be time and resource-intensive. This article proposes a feasible framework for conducting a participatory needs assessment in time-limited settings using multiple, triangulated qualitative methods. This framework is outlined through a case study: a participatory needs assessment to inform the design of an ultrasound-guided biopsy training program in Nigeria. Breast cancer is the leading cause of death for Nigerian women and most cases in Nigeria are diagnosed at an advanced stage; timely diagnosis is impeded by fractious referral pathways, costly imaging equipment, and limited access outside urban centers. The project involved participant observation, surveys, and focus groups at the African Research Group for Oncology (ARGO) in Ile-Ife, Nigeria. Through this timely research and engagement, participants spoke about diagnostic challenges, institutional power dynamics, and infrastructure considerations for program implementation.

Introduction: Minority communities have had limited access to advances in genomic medicine. Mayo Clinic and Mountain Park Health Center, a Federally Qualified Health Center in Phoenix, Arizona, partnered to assess the feasibility of offering genomic screening to Latino patients receiving care at a community-based health center. We examined primary care provider (PCP) experiences reporting genomic screening results and integrating those results into patient care., Methods: We conducted open-ended, semi-structured interviews with PCPs and other members of the health care team charged with supporting patients who received positive genomic screening results. Interviews were recorded, transcribed, and analyzed thematically., Results: Of the 500 patients who pursued genomic screening, 10 received results indicating a genetic variant that warranted clinical management. PCPs felt genomic screening was valuable to patients and their families, and that genomic research should strive to include underrepresented minorities. Providers identified multiple challenges integrating genomic sequencing into patient care, including difficulties maintaining patient contact over time; arranging follow-up medical care; and managing results in an environment with limited genetics expertise. Providers also reflected on the ethics of offering genomic sequencing to patients who may not be able to pursue diagnostic testing or follow-up care due to financial constraints., Conclusions: Our results highlight the potential benefits and challenges of bringing advances in precision medicine to community-based health centers serving under-resourced populations. By proactively considering patient support needs, and identifying financial assistance programs and patient-referral mechanisms to support patients who may need specialized medical care, PCPs and other health care providers can help to ensure that precision medicine lives up to its full potential as a tool for improving patient care.

Purpose: The incidence of breast cancer is rising in Nigeria, and one major barrier to care is the lack of affordable and appropriate breast cancer diagnosis by ultrasound (US)-guided biopsy. The prohibitive cost of US devices limits their availability in low- and middle-income countries. The emergence of mobile health (mHealth) imaging devices may offer an acceptable low-cost alternative. The purpose of this research was to perform a comprehensive needs assessment to understand knowledge, use, training needs, and attitudes as regards image-guided biopsy in Nigeria to inform the development of an mHealth-based US-guided biopsy training program., Methods: A multistakeholder needs assessment was conducted at the Sixth Annual African Research Group for Oncology Symposium. Voluntary anonymous surveys were administered to all attendees. A subset of attendees (ie, surgeons, radiologists, pathologists, and nurses) participated in six focus groups. Survey items and interview guides were developed collaboratively with local and international input., Results: Surveys focusing on use, training needs, and attitudes regarding US-guided biopsies were completed with a 55% response rate (n = 54 of 98) among participants from 22 hospitals across Nigeria. Respondents expressed dissatisfaction with the way breast biopsies were currently performed at their hospitals and high interest in having their institution participate in a US-guided biopsy training program. Focus group participants (n = 37) identified challenges to performing US-guided procedures, including equipment functionality and cost, staff training, and access to consumables. Groups brainstormed the design of an mHealth US-guided biopsy training program, preferring a train-the-trainer format combining in-person teaching with independent modules., Conclusion: A multidisciplinary needs assessment of local stakeholders identified a need for and acceptability of an mHealth-based US-guided biopsy training program in Nigeria.

Importance: Regional nodal irradiation (RNI) for node-positive breast cancer reduces distant metastases and improves survival, albeit with limited reduction in regional nodal recurrences. The mechanism by which RNI robustly reduces distant metastases while modestly influencing nodal recurrences (ie, the presumed target of RNI) remains unclear., Objective: To determine whether some distant metastases putatively arise from occult regional nodal disease and whether regional recurrences otherwise remain largely undetected until an advanced cancer presentation., Design, Setting, and Participants: This cohort study examined patients presenting with de novo stage IV breast cancer to the Memorial Sloan Kettering Cancer Center in New York, New York, from 2006 to 2018. Medical records were reviewed to ascertain clinicopathological parameters, including estrogen receptor status and survival. Pretreatment positron emission tomography-computed tomography (PET-CT) imaging was reviewed to ascertain the extent of regional nodal involvement at metastatic diagnosis using standard nodal assessment criteria. A subset underwent regional lymph node biopsy for diagnostic confirmation and served to validate the radiographic nodal assessment. Data analysis was performed from October 2019 to February 2020., Exposures: Untreated metastatic breast cancer., Main Outcome and Measures: The primary outcome was the likelihood of regional nodal involvement at the time of metastatic breast cancer presentation and was determined by reviewing pretreatment PET-CT imaging and lymph node biopsy findings., Results: Among 597 women (median [interquartile range] age, 53 [44-65] years) with untreated metastatic breast cancer, 512 (85.8%) exhibited regional lymph node involvement by PET-CT or nodal biopsy, 509 (85%) had involvement of axillary level I, 328 (55%) had involvement in axillary level II, 136 (23%) had involvement in axillary level III, 101 (17%) had involvement in the supraclavicular fossa, and 96 (16%) had involvement in the internal mammary chain. Lymph node involvement was more prevalent among estrogen receptor-negative tumors (92.4%) than estrogen receptor-positive tumors (83.6%). Nodal involvement at the time of metastatic diagnosis was not associated with overall survival., Conclusions and Relevance: These findings suggest that a majority of patients with de novo metastatic breast cancer harbor regional lymph node disease at presentation, consistent with the hypothesis that regional involvement may precede metastatic dissemination. This is in alignment with the findings of landmark trials suggesting that RNI reduces distant recurrences. It is possible that this distant effect of RNI may act via eradication of occult regional disease prior to systemic seeding. The challenges inherent in detecting isolated nodal disease (which is typically asymptomatic) may account for the more modest observed benefit of RNI on regional recurrences. Alternative explanations of nodal involvement that arises concurrently or after metastatic dissemination remain possible, but do not otherwise explain the association of RNI with distant recurrence.

As applications of genomic sequencing have expanded, offering genetic counseling support to all patients is arguably no longer practical. Additionally, whether individuals desire and value genetic counseling services for genomic screening is unclear. We offered elective genetic counseling to 5110 individuals prior to undergoing sequencing and 2310 participants who received neutral results to assess demand. A total of 0.2% of the study participants accessed genetic counseling services prior to sequencing, and 0.3% reached out after receiving neutral results. We later conducted 50 interviews with participants to understand why they did not access these services. Many interviewees did not recall the availability of genetic counseling and were unfamiliar with the profession. Interviewees described not needing counseling before sequencing because they understood the study and felt that they could cope with any result. Counseling was considered equally unnecessary after learning neutral results. Although the participants had questions about their results, they did not feel that speaking with a genetic counselor would be helpful. Genomic screening efforts that employ opt-in models of genetic counseling may need to clarify the potential value of genetic counseling support from the outset and feature genetic counseling services more prominently in program materials.

Background: Ultrafast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived kinetic parameters have demonstrated at least equivalent accuracy to standard DCE-MRI in differentiating malignant from benign breast lesions. However, it is unclear if they have any efficacy as prognostic imaging markers. The aim of this study was to investigate the relationship between ultrafast DCE-MRI-derived kinetic parameters and breast cancer characteristics., Methods: Consecutive breast MRI examinations between February 2017 and January 2018 were retrospectively reviewed to determine those examinations that meet the following inclusion criteria: (1) BI-RADS 4-6 MRI performed on a 3T scanner with a 16-channel breast coil and (2) a hybrid clinical protocol with 15 phases of ultrafast DCE-MRI (temporal resolution of 2.7-4.6 s) followed by early and delayed phases of standard DCE-MRI. The study included 125 examinations with 142 biopsy-proven breast cancer lesions. Ultrafast DCE-MRI-derived kinetic parameters (maximum slope [MS] and bolus arrival time [BAT]) were calculated for the entire volume of each lesion. Comparisons of these parameters between different cancer characteristics were made using generalized estimating equations, accounting for the presence of multiple lesions per patient. All comparisons were exploratory and adjustment for multiple comparisons was not performed; P values < 0.05 were considered statistically significant., Results: Significantly larger MS and shorter BAT were observed for invasive carcinoma than ductal carcinoma in situ (DCIS) (P < 0.001 and P = 0.008, respectively). Significantly shorter BAT was observed for invasive carcinomas with more aggressive characteristics than those with less aggressive characteristics: grade 3 vs. grades 1-2 (P = 0.025), invasive ductal carcinoma vs. invasive lobular carcinoma (P = 0.002), and triple negative or HER2 type vs. luminal type (P < 0.001)., Conclusions: Ultrafast DCE-MRI-derived parameters showed a strong relationship with some breast cancer characteristics, especially histopathology and molecular subtype.

Background: For breast cancer patients undergoing neoadjuvant chemotherapy (NAC), pathologic complete response (pCR; no invasive or in situ) cannot be assessed non-invasively so all patients undergo surgery. The aim of our study was to develop and validate a radiomics classifier that classifies breast cancer pCR post-NAC on MRI prior to surgery., Methods: This retrospective study included women treated with NAC for breast cancer from 2014 to 2016 with (1) pre- and post-NAC breast MRI and (2) post-NAC surgical pathology report assessing response. Automated radiomics analysis of pre- and post-NAC breast MRI involved image segmentation, radiomics feature extraction, feature pre-filtering, and classifier building through recursive feature elimination random forest (RFE-RF) machine learning. The RFE-RF classifier was trained with nested five-fold cross-validation using (a) radiomics only (model 1) and (b) radiomics and molecular subtype (model 2). Class imbalance was addressed using the synthetic minority oversampling technique., Results: Two hundred seventy-three women with 278 invasive breast cancers were included; the training set consisted of 222 cancers (61 pCR, 161 no-pCR; mean age 51.8 years, SD 11.8), and the independent test set consisted of 56 cancers (13 pCR, 43 no-pCR; mean age 51.3 years, SD 11.8). There was no significant difference in pCR or molecular subtype between the training and test sets. Model 1 achieved a cross-validation AUROC of 0.72 (95% CI 0.64, 0.79) and a similarly accurate (P = 0.1) AUROC of 0.83 (95% CI 0.71, 0.94) in both the training and test sets. Model 2 achieved a cross-validation AUROC of 0.80 (95% CI 0.72, 0.87) and a similar (P = 0.9) AUROC of 0.78 (95% CI 0.62, 0.94) in both the training and test sets., Conclusions: This study validated a radiomics classifier combining radiomics with molecular subtypes that accurately classifies pCR on MRI post-NAC.

Background: To assess the incidence of benign and malignant peri-implant fluid collections and/or masses on magnetic resonance imaging (MRI) in women with silicone implants who are being screened for silent implant rupture., Methods: The institutional review board approved this HIPAA-compliant retrospective study and waived informed consent. Women who underwent silicone implant oncoplastic and/or cosmetic surgery and postoperative implant-protocol MRI from 2000 to 2014 were included. Peri-implant fluid collections and/or masses were measured volumetrically. A benign peri-implant fluid collection and/or mass was pathologically proven or defined as showing 2 years of imaging and/or clinical stability. A malignant peri-implant fluid collection was pathologically proven. Incidence of peri-implant fluid collections and/or masses and positive predictive value (PPV) were calculated on a per-patient level using proportions and exact 95% confidence intervals (CIs). Fisher's exact test was used in the analysis to test statistical significance pre-defined as P-value < 0.05., Results: A total of 1070 women with silicone implants were included (mean age, 50.7 years; range, 40.4-53.8). Median time between reconstructive surgery and first MRI was 88.9 months (range, 0.8-1363.3). Eighteen women (1.7%) had a peri-implant fluid collection and/or mass: 15/18 (83.3%) had adequate follow-up; and only 1/15 was malignant implant associated anaplastic large cell lymphoma, with a PPV of 6.7% (95% CI: 0.003-0.0005). The median peri-implant fluid collection size was 89 mL (range, 18-450 mL)., Conclusion: Peri-implant fluid collections and/or masses identified at silicone implant protocol breast MR imaging are rarely seen 24 months after reconstructive surgery. Image-guided fine-needle aspiration with flow cytometry may be warranted to evaluate for implant-associated lymphoma., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: DNA biobanks frequently obtain broad permissions from sample donors, who agree to allow their biospecimens to be used for a variety of future purposes. A limitation of this approach is that it may not be possible to discuss or anticipate all potential uses of biospecimens at the time patient consent is obtained. We surveyed biobank participants to clarify their views regarding the need to be informed about research involving whole genome sequencing (WGS). Methods: We invited 1200 participants in the Mayo Clinic Biobank to complete a survey inquiring about their support for WGS; their interest in being recontacted before WGS of their biospecimens; whether they would consent to WGS if asked; and the acceptability of proceeding with WGS if sample donors could not be reached. Results: Six hundred eighty-seven biobank participants returned completed surveys (57% response). More than 96% of biobank participants were supportive of WGS and would give permission for WGS of their sample, if asked. Nonetheless, 61% of biobank participants felt they should be recontacted before WGS was done. Participants were divided regarding the permissibility of conducting WGS if efforts to recontact sample donors were unsuccessful. Discussion: Our findings highlight a potential discrepancy between the broad permissions granted by biobank participants at the time they donated biospecimens and their views about the application of WGS to their samples. Biobank participants appear to value the ability to confirm their commitment to genetic research when the studies in question involve WGS, a technological capacity they may not have anticipated at the time they donated their biospecimens. Efforts to reevaluate biobank participants' views about the acceptability of new technologies may help to ensure alignment of participants' current beliefs and research applications that would have been difficult to anticipate at the time biospecimens were collected.

Efforts to characterize stakeholder attitudes about the implementation of genomic medicine would benefit from a validated instrument for measuring public views of the potential benefits and harms of genomic technologies, which would facilitate comparison across populations and clinical settings. We sought to develop a scale to evaluate attitudes about the future of genomic medicine. We developed a 21-item scale that examined the likelihood of various outcomes of genomic medicine. The scale was administered to participants in a genomic sequencing study. Exploratory factor analysis was conducted and bivariate correlations were calculated. The genomic orientation (GO) scale was completed by 2895 participants. A two-factor structure was identified, corresponding to an optimism subscale (16 items, α = 0.89) and a pessimism subscale (5 items, α = 0.63). Genomic optimism was positively associated with a perceived value of genetic test results, higher health literacy, and decreased decisional conflict about participation in a genomic research study. Genomic pessimism was associated with concerns about genetic testing, lower health literacy, and increased decisional conflict about the decision to participate in the study. The GO scale is a promising tool for measuring both positive and negative views regarding the future of genomic medicine and deserves further validation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: We assessed the decision-making of individuals pursuing genomic sequencing without a requirement for pretest genetic counselling. We sought to describe the extent to which individuals who decline genetic counselling reported decisional conflict or struggled to make a decision to pursue genomic testing., Methods: We administered a 100-item survey to 3037 individuals who consented to the Return of Actionable Variants Empirical study, a genomic medicine implementation study supported by the National Institutes of Health (USA) eMERGE consortium. The primary outcomes of interest were self-reported decisional conflict about the decision to participate in the study and time required to reach a decision., Results: We received 2895 completed surveys (response rate=95.3%), and of these respondents 97.8% completed the decisional conflict scale in its entirety. A majority of individuals (63%) had minimal or no decisional conflict about the pursuit of genomic sequencing and were able to reach a decision quickly (78%). Multivariable logistic regression analyses identified several characteristics associated with decisional conflict, including lower education, lower health literacy, lower self-efficacy in coping, lack of prior experience with genetic testing, not discussing study participation with a family member or friend, and being male., Conclusion: As genomic sequencing is used more widely, genetic counselling resources may not be sufficient to meet demand. Our results challenge the notion that all individuals need genetic counselling in order to make an informed decision about genomic sequencing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: People with advanced ovarian or gastrointestinal cancer may develop malignant bowel obstruction (MBO). They are able to tolerate limited, if any, oral or enteral (via a tube directly into the gut) nutrition. Parenteral nutrition (PN) is the provision of macronutrients, micronutrients, electrolytes and fluid infused as an intravenous solution and provides a method for these people to receive nutrients. There are clinical and ethical arguments for and against the administration of PN to people receiving palliative care., Objectives: To assess the effectiveness of home parenteral nutrition (HPN) in improving survival and quality of life in people with inoperable MBO., Search Methods: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1), MEDLINE (Ovid), Embase (Ovid), BNI, CINAHL, Web of Science and NHS Economic Evaluation and Health Technology Assessment up to January 2018, ClinicalTrials.gov (http://clinicaltrials.gov/) and in the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/). In addition, we handsearched included studies and used the 'Similar articles' feature on PubMed for included articles., Selection Criteria: We included any studies with more than five participants investigating HPN in people over 16 years of age with inoperable MBO., Data Collection and Analysis: We extracted the data and assessed risk of bias for each study. We entered data into Review Manager 5 and used GRADEpro to assess the quality of the evidence., Main Results: We included 13 studies with a total of 721 participants in the review. The studies were observational, 12 studies had only one relevant treatment arm and no control and for the one study with a control arm, very few details were given. The risk of bias was high and the certainty of evidence was graded as very low for all outcomes. Due to heterogeneity of data, meta-analysis was not performed and therefore the data were synthesised via a narrative summary.The evidence for benefit derived from PN was very low for survival and quality of life. All the studies measured overall survival and 636 (88%) of participants were deceased at the end of the study. However there were varying definitions of overall survival that yielded median survival intervals between 15 to 155 days (range three to 1278 days). Three studies used validated measures of quality of life. The results from assessment of quality of life were equivocal; one study reported improvements up until three months and two studies reported approximately similar numbers of participants with improvements and deterioration. Different quality of life scales were used in each of the studies and quality of life was measured at different time points. Due to the very low certainty of the evidence, we are very uncertain about the adverse events related to PN use. Adverse events were measured by nine studies and data for individual participants could be extracted from eight studies. This revealed that 32 of 260 (12%) patients developed a central venous catheter infection or were hospitalised because of complications related to PN., Authors' Conclusions: We are very uncertain whether HPN improves survival or quality of life in people with MBO as the certainty of evidence was very low for both outcomes. As the evidence base is limited and at high risk of bias, further higher-quality prospective studies are required.

Complementary strategies of small-angle x-ray scattering (SAXS) and crystallographic analysis are often used to determine atomistic three-dimensional models of macromolecules and their variability in solution. This combination of techniques is particularly valuable when applied to macromolecular complexes to detect changes within the individual binding partners. Here, we determine the x-ray crystallographic structure of a F(ab) fragment in complex with CD32b, the only inhibitory Fc-γ receptor in humans, and compare the structure of the F(ab) from the crystal complex to SAXS data for the F(ab) alone in solution. We investigate changes in F(ab) structure by predicting theoretical scattering profiles for atomistic structures extracted from molecular dynamics (MD) simulations of the F(ab) and assessing the agreement of these structures to our experimental SAXS data. Through principal component analysis, we are able to extract principal motions observed during the MD trajectory and evaluate the influence of these motions on the agreement of structures to the F(ab) SAXS data. Changes in the F(ab) elbow angle were found to be important to reach agreement with the experimental data; however, further discrepancies were apparent between our F(ab) structure from the crystal complex and SAXS data. By analyzing multiple MD structures observed in similar regions of the principal component analysis, we were able to pinpoint these discrepancies to a specific loop region in the F(ab) heavy chain. This method, therefore, not only allows determination of global changes but also allows identification of localized motions important for determining the agreement between atomistic structures and SAXS data. In this particular case, the findings allowed us to discount the hypothesis that structural changes were induced upon complex formation, a significant find informing the drug development process. The methodology described here is generally applicable to deconvolute global and local changes of macromolecular structures and is well suited to other systems., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

We present a segmentation approach that combines GrowCut (GC) with cancer-specific multi-parametric Gaussian Mixture Model (GCGMM) to produce accurate and reproducible segmentations. We evaluated GCGMM using a retrospectively collected 75 invasive ductal carcinoma with ERPR+ HER2- (n = 15), triple negative (TN) (n = 9), and ER-HER2+ (n = 57) cancers with variable presentation (mass and non-mass enhancement) and background parenchymal enhancement (mild and marked). Expert delineated manual contours were used to assess the segmentation performance using Dice coefficient (DSC), mean surface distance (mSD), Hausdorff distance, and volume ratio (VR). GCGMM segmentations were significantly more accurate than GrowCut (GC) and fuzzy c-means clustering (FCM). GCGMM's segmentations and the texture features computed from those segmentations were the most reproducible compared with manual delineations and other analyzed segmentation methods. Finally, random forest (RF) classifier trained with leave-one-out cross-validation using features extracted from GCGMM segmentation resulted in the best accuracy for ER-HER2+ vs. ERPR+/TN (GCGMM 0.95, expert 0.95, GC 0.90, FCM 0.92) and for ERPR + HER2- vs. TN (GCGMM 0.92, expert 0.91, GC 0.77, FCM 0.83).

Here we develop a tool to predict resectability of HER2+ breast cancer at breast conservation surgery (BCS) utilizing features identified on preoperative breast MRI. We identified patients with HER2+ breast cancer who obtained pre-operative breast MRI and underwent BCS between 2002-2013. From the contoured tumor on pre-operative MRI, shape, histogram, and co-occurrence and size zone matrix texture features were extracted. In univariate analysis, Spearman's correlation coefficient (Rs) was used to assess the correlation between each image feature and an endpoint (surgical re-excision). For multivariate modeling, we employed a support vector machine (SVM) method in a manner of leave-one-out cross-validation (LOOCV). Of 109 patients with HER2+breast cancer who underwent BCS, 39% underwent surgical re-excision. 62% had residual cancer at re-excision. In univariate analysis, solidity (Rs = -0.32, p = 0.009) and extent (Rs = -0.29, p = 0.019) were significantly associated with re-excision. Skewness in post-contrast 1, 2, and 3 (Rs = 0.25, p = 0.045; Rs = 0.30, p = 0.015; Rs = 0.28, p = 0.026) and kurtosis in post-contrast 1 (Rs = 0.26, p = 0.035) were also statistically significant. LOOCV-based SVM test achieved 74.4% specificity and 71.4% sensitivity when 21 features were used. Thus, tumor texture, histogram and morphological MRI features may assist surgical planning, encouraging wide margins or mastectomy in patients who may otherwise go on to re-excision.

Objective: To examine the prognostic capabilities of intravoxel incoherent motion (IVIM) metrics and their ability to predict response to neoadjuvant treatment (NAT). Additionally, to observe changes in IVIM metrics between pre- and post-treatment MRI., Methods: This IRB-approved, HIPAA-compliant retrospective study observed 31 breast cancer patients (32 lesions). Patients underwent standard bilateral breast MRI along with diffusion-weighted imaging before and after NAT. Six patients underwent an additional IVIM-MRI scan 12-14 weeks after initial scan and 2 cycles of treatment. In addition to apparent diffusion coefficients (ADC) from monoexponential decay, IVIM mean values (tissue diffusivity D t , perfusion fraction f p , and pseudodiffusivity D p ) and histogram metrics were derived using a biexponential model. An additional filter identified voxels of highly vascular tumor tissue (VTT), excluding necrotic or normal tissue. Clinical data include histology of biopsy and clinical response to treatment through RECIST assessment. Comparisons of treatment response were made using Wilcoxon rank-sum tests., Results: Average, kurtosis, and skewness of pseudodiffusion D p significantly differentiated RECIST responders from nonresponders. ADC and D t values generally increased (∼70%) and VTT% values generally decreased (∼20%) post-treatment., Conclusion: D p metrics showed prognostic capabilities; slow and heterogeneous pseudodiffusion offer poor prognosis. Baseline ADC/D t parameters were not significant predictors of response. This work suggests that IVIM mean values and heterogeneity metrics may have prognostic value in the setting of breast cancer NAT.

Background: In this study, we sought to investigate if computer-extracted magnetic resonance imaging (MRI) phenotypes of breast cancer could replicate human-extracted size and Breast Imaging-Reporting and Data System (BI-RADS) imaging phenotypes using MRI data from The Cancer Genome Atlas (TCGA) project of the National Cancer Institute., Methods: Our retrospective interpretation study involved analysis of Health Insurance Portability and Accountability Act-compliant breast MRI data from The Cancer Imaging Archive, an open-source database from the TCGA project. This study was exempt from institutional review board approval at Memorial Sloan Kettering Cancer Center and the need for informed consent was waived. Ninety-one pre-operative breast MRIs with verified invasive breast cancers were analysed. Three fellowship-trained breast radiologists evaluated the index cancer in each case according to size and the BI-RADS lexicon for shape, margin, and enhancement (human-extracted image phenotypes [HEIP]). Human inter-observer agreement was analysed by the intra-class correlation coefficient (ICC) for size and Krippendorff's α for other measurements. Quantitative MRI radiomics of computerised three-dimensional segmentations of each cancer generated computer-extracted image phenotypes (CEIP). Spearman's rank correlation coefficients were used to compare HEIP and CEIP., Results: Inter-observer agreement for HEIP varied, with the highest agreement seen for size (ICC 0.679) and shape (ICC 0.527). The computer-extracted maximum linear size replicated the human measurement with p  < 10 -12 . CEIP of shape, specifically sphericity and irregularity, replicated HEIP with both p values < 0.001. CEIP did not demonstrate agreement with HEIP of tumour margin or internal enhancement., Conclusions: Quantitative radiomics of breast cancer may replicate human-extracted tumour size and BI-RADS imaging phenotypes, thus enabling precision medicine., Competing Interests: In this retrospective study, all patient data were Health Insurance Portability and Accountability Act-compliant and acquired under institutional review board approval that waived the need for informed consent.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Asthma is a very common disease that can occur at any age. In the UK and in many other countries it is mainly managed in primary care. The published evidence suggests that the key to improving diagnosis and management lies in better training and education rather than in the discovery of new medications. An asthma improvement project managed through the British Lung Foundation is attempting to do this. The project has three pilot sites: two in England supported by the Department of Health and one in Scotland supported by the Scottish Government. If the project is successful it will be rolled out to other health areas within the UK. The results of this project are not yet available. This article highlights the challenges encountered in setting up the project and may well be applicable to other areas in the UK and to other countries where similar healthcare systems exist. The encountered challenges reflect the complex nature of healthcare systems and electronic data capture in primary care. We discuss the differences between general practices in their ability and willingness to support the project, the training and education of their staff on asthma management, governance issues in relation to information technology systems, and the quality of data capture. Virtually all the challenges have now been overcome, but discussing them should ensure that others become aware of them at an early stage should they wish to undertake similar projects in the future.

Pathologic evaluation of breast specimens requires a fixation and staining procedure of at least 12 hours duration, delaying diagnosis and post-operative planning. Here we introduce an MRI technique with a custom-designed radiofrequency resonator for imaging breast and lymph tissue with sufficient spatial resolution and speed to guide pathologic interpretation and offer value in clinical decision making. In this study, we demonstrate the ability to image breast and lymphatic tissue using 7.0 Tesla MRI, achieving a spatial resolution of 59 × 59 × 94 μm(3) with a signal-to-noise ratio of 15-20, in an imaging time of 56 to 70 minutes. These are the first MR images to reveal characteristic pathologic features of both benign and malignant breast and lymph tissue, some of which were discernible by blinded pathologists who had no prior training in high resolution MRI interpretation.

Although substantial progress has been made in the screening and management of breast cancer, globally it remains the most common cause of cancer and cancer death in women. While breast cancer is potentially curable when detected at an early stage, it remains incurable in the metastatic setting. Thus, given its high prevalence, improved prevention and treatment of metastases remains a clinically meaningful unmet need. We review here the advances made in the last several years in the screening and treatment of breast cancer and explore how our increased insight into the underlying biology of breast cancer has influenced our efforts to individualize patient care.

Objectives: The purpose of our study was to assess the chondrogenic potential and the MR signal effects of GadofluorineM-Cy labeled matrix associated stem cell implants (MASI) in pig knee specimen., Materials and Methods: Human mesenchymal stem cells (hMSCs) were labeled with the micelle-based contrast agent GadofluorineM-Cy. Ferucarbotran-labeled hMSCs, non-labeled hMSCs and scaffold only served as controls. Chondrogenic differentiation was induced and gene expression and histologic evaluation were performed. The proportions of spindle-shaped vs. round cells of chondrogenic pellets were compared between experimental groups using the Fisher's exact test. Labeled and unlabeled hMSCs and chondrocytes in scaffolds were implanted into cartilage defects of porcine femoral condyles and underwent MR imaging with T1- and T2-weighted SE and GE sequences. Contrast-to-noise ratios (CNR) between implants and adjacent cartilage were determined and analyzed for significant differences between different experimental groups using the Kruskal-Wallis test. Significance was assigned for p<0.017, considering a Bonferroni correction for multiple comparisons., Results: Collagen type II gene expression levels were not significantly different between different groups (p>0.017). However, hMSC differentiation into chondrocytes was superior for unlabeled and GadofluorineM-Cy-labeled cells compared with Ferucarbotran-labeled cells, as evidenced by a significantly higher proportion of spindle cells in chondrogenic pellets (p<0.05). GadofluorineM-Cy-labeled hMSCs and chondrocytes showed a positive signal effect on T1-weighted images and a negative signal effect on T2-weighted images while Ferucarbotran-labeled cells provided a negative signal effect on all sequences. CNR data for both GadofluorineM-Cy-labeled and Ferucarbotran-labeled hMSCs were significantly different compared to unlabeled control cells on T1-weighted SE and T2*-weighted MR images (p<0.017)., Conclusion: hMSCs can be labeled by simple incubation with GadofluorineM-Cy. The labeled cells provide significant MR signal effects and less impaired chondrogenesis compared to Ferucarbotran-labeled hMSCs. Thus, GadoflurineM-Cy might represent an alternative MR cell marker to Ferucarbotran, which is not distributed any more in Europe or North America.

Objective: To combine insights from multiple disciplines into a set of questions that can be used to investigate contextual factors affecting health decision making., Background: Decision-making processes and outcomes may be shaped by a range of non-medical or 'contextual' factors particular to an individual including social, economic, political, geographical and institutional conditions. Research concerning contextual factors occurs across many disciplines and theoretical domains, but few conceptual tools have attempted to integrate and translate this wide-ranging research for health decision-making purposes., Methods: To formulate this tool we employed an iterative, collaborative process of scenario development and question generation. Five hypothetical health decision-making scenarios (preventative, screening, curative, supportive and palliative) were developed and used to generate a set of exploratory questions that aim to highlight potential contextual factors across a range of health decisions., Findings: We present an exploratory tool consisting of questions organized into four thematic domains - Bodies, Technologies, Place and Work (BTPW) - articulating wide-ranging contextual factors relevant to health decision making. The BTPW tool encompasses health-related scholarship and research from a range of disciplines pertinent to health decision making, and identifies concrete points of intersection between its four thematic domains. Examples of the practical application of the questions are also provided., Conclusions: These exploratory questions provide an interdisciplinary toolkit for identifying the complex contextual factors affecting decision making. The set of questions comprised by the BTPW tool may be applied wholly or partially in the context of clinical practice, policy development and health-related research., (© 2010 Blackwell Publishing Ltd.)

The purpose of this study was to compare viable and nonviable bilabeled mesenchymal stem cells (MSCs) in arthritic joints with magnetic resonance imaging (MRI) and optical imaging (OI). MSCs were labeled with ferucarbotran and DiD. MRI and OI of bilabeled cells were compared with controls. Six rats with arthritis received intra-articular injections of bilabeled viable MSCs into the right knee and nonviable MSCs into the left knee. Animals underwent MRI and OI preinjection and at 4, 24, 48, and 72 hours postinjection. The results were analyzed with a mixed random effects model and Fisher probability. Bilabeled MSCs showed increased MRI and OI signals compared to unlabeled controls (p < .0001). After intra-articular injection, bilabeled MSCs caused significant T2 and T2* effect on MRI and fluorescence on OI up to 72 hours postinjection (p < .05). There was no significant difference between viable and nonviable MSC signal in the knee joints; however, some of the viable cells migrated to an adjacent inflamed ankle joint (p < .05). Immunohistochemistry confirmed viable MSCs in right knee and ankle joints and nonviable MSCs in the left knee. Viable and nonviable cells could not be differentiated with MRI or OI signal intensity but were differentiated based on their ability to migrate in vivo.

Objective: To evaluate a combined indocyanine green-enhanced optical imaging/radiography system for the detection of arthritic joints in a rat model of antigen-induced arthritis., Methods: Arthritis of the knee and ankle joints was induced in 6 Harlan rats, using peptidoglycan-polysaccharide polymers. Three rats served as untreated controls. Optical imaging of the knee and ankle joints was done with an integrated optical imaging/radiography system before and up to 24 hours following intravenous injection of 10 mg/kg indocyanine green. The fluorescence signal intensities of arthritic and normal joints were compared for significant differences, using generalized estimating equation models. Specimens of knee and ankle joints were further processed and evaluated by histology., Results: Immediately after administration, indocyanine green provided a significant increase in the fluorescence signal of arthritic joints compared with baseline values (P < 0.05). The fluorescence signal of arthritic joints was significantly higher compared with that of nonarthritic control joints at 1-720 minutes after intravenous injection (P < 0.05). Fusion of indocyanine green-enhanced optical imaging and radiography allowed for anatomic coregistration of the inflamed tissue with the associated joint. Hematoxylin and eosin staining confirmed marked synovial inflammation of arthritic joints and the absence of inflammation in control joints., Conclusion: Indocyanine green-enhanced optical imaging is a clinically applicable tool for detection of arthritic tissue. Using relatively high doses of indocyanine green, long-term enhanced fluorescence of arthritic joints can be achieved. This may facilitate simultaneous evaluations of multiple joints in a clinical setting. Fusion of indocyanine green-enhanced optical imaging scans with radiography increases anatomic resolution.

The objective of this work is to establish an optical imaging technique that would enable monitoring of the integration of mesenchymal stem cells (MSC) in arthritic joints. Our approach is based on first developing a labeling technique of MSC with the fluorescent dye DiD followed by tracking the cell migration kinetics from the spatial distribution of the DiD fluorescence in optical images (OI). The experimental approach involves first the in vitro OI of MSC labeled with DiD accompanied by fluorescence microscopy measurements to establish localization of the signal within the cells. Thereafter, DiD-labeled MSC were injected into polyarthritic, athymic rats and the signal localization within the experimental animals was monitored over several days. The experimental results indicate that DiD integrated into the cell membrane. DiD-labeled MSC localization in the arthritic ankle joints was observed with OI indicating that this method can be applied to monitor MSC in arthritic joints.

Background: The development of postoperative granulation tissue is one of the main postoperative risks after lumbar spine surgery. This granulation tissue may lead to persistent or new clinical symptoms or complicate a follow up surgery. A sensitive non-invasive imaging technique, that could diagnose this granulation tissue at the bedside, would help to develop appropriate treatments. Thus, the purpose of this study was to establish a fast and economic imaging tool for the diagnosis of granulation tissue after lumbar spine surgery, using a new integrated Optical Imaging (OI)/X-ray imaging system and the FDA-approved fluorescent contrast agent Indocyanine Green (ICG)., Methods: 12 male Sprague Dawley rats underwent intervertebral disk surgery. Imaging of the operated lumbar spine was done with the integrated OI/X-ray system at 7 and 14 days after surgery. 6 rats served as non-operated controls. OI/X-ray scans of all rats were acquired before and after intravenous injection of the FDA-approved fluorescent dye Indocyanine Green (ICG) at a dose of 1 mg/kg or 10 mg/kg. The fluorescence signal of the paravertebral soft tissues was compared between different groups of rats using Wilcoxon-tests. Lumbar spines and paravertebral soft tissues were further processed with histopathology., Results: In both dose groups, ICG provided a significant enhancement of soft tissue in the area of surgery, which corresponded with granulation tissue on histopathology. The peak and time interval of fluorescence enhancement was significantly higher using 10 mg/kg dose of ICG compared to the 1 mg/kg ICG dose. The levels of significance were p < 0.05. Fusion of OI data with X-rays allowed an accurate anatomical localization of the enhancing granulation tissue., Conclusion: ICG-enhanced OI is a suitable technique to diagnose granulation tissue after lumbar spine surgery. This new imaging technique may be clinically applicable for postoperative treatment monitoring. It could be also used to evaluate the effect of anti-inflammatory drugs and may even allow evaluations at the bedside with new hand-held OI scanners.

Rationale and Objectives: This study was performed to assess the imaging characteristics and pharmacokinetics of 1,3-Bis-[7-(3-amino-2,4,6-triiodophenyl)-heptanoyl]-2-oleoyl glycerol (DHOG, Fenestra LC), a hepatobiliary contrast agent for microCT., Materials and Methods: We investigated the abdomen of 18 female C3H mice in a MicroCAT II microCT scanner before contrast agent injection and at multiple time points up to 48 hours after intravenous injection of DHOG (1 g I/kg body weight). The contrast agent effect was determined quantitatively and dynamically by measuring pre- and postcontrast Hounsfield units (HU) of the liver, aorta, spleen, and kidneys. Based on additional phantom measurements, the reproducibility of lesion detection was estimated for different lesion sizes., Results: DHOG caused a marked early postcontrast enhancement of blood in the aorta and a very high enhancement of the spleen, both slowly declined after 90 minutes. The liver parenchyma showed a slow contrast agent accumulation and clearly increased HU data between 3 and 7 hours after injection. No significant renal parenchymal enhancement or excretion was noticed. At early time points after administration, DHOG exhibits characteristics of a macromolecular contrast agent by demonstrating a blood pool effect. At later time points, DHOG provides a prolonged, marked liver enhancement on microCT images due to its specific liver uptake. For a lesion size of 1 mm diameter, the variability in between two scans was 27.7 HU (P < .05) and the variability for different planes of one scan was 19.8 HU (P < .05)., Conclusions: DHOG yields a very good visualization of the liver and delineation of the surrounding structures with a long plateau. It is a very suitable contrast agent for liver imaging in mice for microCT imaging. The presented protocol provides a high reproducibility for lesion detection with a relatively low radiation dose.