Overview of trials on artificial intelligence algorithms in breast cancer screening - A roadmap for international evaluation and implementation.

Accumulating evidence from retrospective studies demonstrate at least non-inferior performance when using AI algorithms with different strategies versus double-reading in mammography screening. In addition, AI algorithms for mammography screening can reduce work load by moving to single human reading. Prospective trials are essential to avoid unintended adverse consequences before incorporation of AI algorithms into UK's National Health Service (NHS) Breast Screening Programme (BSP). A stakeholders' meeting was organized in Newnham College, Cambridge, UK to undertake a review of the current evidence to enable consensus discussion on next steps required before implementation into a screening programme. It was concluded that a multicentre multivendor testing platform study with opt-out consent is preferred. AI thresholds from different vendors should be determined while maintaining non-inferior screening performance results, particularly ensuring recall rates are not increased. Automatic recall of cases using an agreed high sensitivity AI score versus automatic rule out with a low AI score set at a high sensitivity could be used. A human reader should still be involved in decision making with AI-only recalls requiring human arbitration. Standalone AI algorithms used without prompting maintain unbiased screening reading performance, but reading with prompts should be tested prospectively and ideally provided for arbitration.

Enhanced Expression of a Novel Lamin A/C Splice Variant in Idiopathic Pulmonary Fibrosis Lung.

In idiopathic pulmonary fibrosis (IPF), the normal delicate lung architecture is replaced with rigid extracellular matrix (ECM) as a result of the accumulation of activated myofibroblasts and excessive deposition of ECM. Lamins have a role in fostering mechanosignaling from the ECM to the nucleus. Although there is a growing number of studies on lamins and associated diseases, there are no prior reports linking aberrations in lamins with pulmonary fibrosis. Here, we discovered, through analysis of RNA sequencing data, a novel isoform of lamin A/C that is more highly expressed in IPF compared with control lung. This novel LMNA (lamin A/C) splice variant includes retained introns 10 and 11 and exons 11 and 12 as documented by rapid amplification of cDNA ends. We found that this novel isoform is induced by stiff ECM. To better clarify the specific effects of this novel isoform of lamin A/C and how it may contribute to the pathogenesis of IPF, we transduced the lamin transcript into primary lung fibroblasts and alveolar epithelial cells and found that it impacts several biological effects, including cell proliferation, senescence, cell contraction, and the transition of fibroblasts to myofibroblasts. We also observed that type II epithelial cells and myofibroblasts in the IPF lung exhibited wrinkled nuclei, and this is notable because this has not been previously described and is consistent with laminopathy-mediated cellular effects.

High grade spindle cell carcinoma of the ovary arising in an endometrioid cystadenoma: A case report

@#Spindle Cell Carcinoma of the Ovary is arate form of cancer with controversial histogenesis. It shares the histologic, cytologic, and molecular properties of both epithelial and mesenchymal differentiation of ovarian neoplasms, which makes diagnosis very challenging among pathologists. Endometrioid cystadenoma is a benign ovarian neoplasms classified under epithelial ovarian tumors.Malignant transformation of benign ovarian neoplasms is known as a rare complication, occurring in approximately 0.9% of patients with ovarian endometriosis. Clear cell adenocarcinoma is the most common endometriosis-associated ovarian cancer followed by endometrioid cancer. This is the case of a 56-year old post-menopausal patient initially presenting with increasingabdominal girth. Whole abdominal ultrasound revealed a large pelvo-abdominal mass. Transvaginal and transabdominal ultrasound findings of bilateral ovarian new growth with benign sonologic features. The patient underwent bilateral salpingo-oophorectomy. Histopathologic findings of the specimen submitted revealed high-grade spindle cell carcinoma arising in an endometrioid cystadenoma of the right ovary, and endometrioid cystadenofibroma with focal epithelial proliferation.

An optoacoustic imaging feature set to characterise blood vessels surrounding benign and malignant breast lesions.

Combining optoacoustic (OA) imaging with ultrasound (US) enables visualisation of functional blood vasculature in breast lesions by OA to be overlaid with the morphological information of US. Here, we develop a simple OA feature set to differentiate benign and malignant breast lesions. 94 female patients with benign, indeterminate or suspicious lesions were recruited and underwent OA-US. An OA-US imaging feature set was developed using images from the first 38 patients, which contained 14 malignant and 8 benign solid lesions. Two independent radiologists blindly scored the OA-US images of a further 56 patients, which included 31 malignant and 13 benign solid lesions, with a sensitivity of 96.8% and specificity of 84.6%. Our findings indicate that OA-US can reveal vascular patterns of breast lesions that indicate malignancy using a simple feature set based on single wavelength OA data, which is therefore amenable to application in low resource settings for breast cancer management.

International Regulatory Standards for the Qualitative Measurement of Deep Brain Stimulation in Clinical Research.

Deep brain stimulation (DBS) has progressed to become a promising treatment modality for neurologic and psychiatric disorders like epilepsy and major depressive disorder due to its growing personalization. Despite evidence pointing to the benefits of DBS if tested on these personalized qualitative metrics, rather than randomized-control trial quantitative standards, the evaluation of these novel devices appears to be based on the latter. This study surveyed the presence of this trend in the national regulatory guidelines of the prominent DBS researching countries. It was found that two governing bodies, in the European Union and Australia, acknowledged the option for qualitative measures. These findings support further development of national regulatory guidelines, so the neuroscientific community developing these neurotechnologies can better understand the impact their treatments have on patients.

Opportunities in cancer imaging: risk-adapted breast imaging in screening.

In the UK, women between 50-70 years are invited for 3-yearly mammography screening irrespective of their likelihood of developing breast cancer. The only risk adaption is for women with >30% lifetime risk who are offered annual magnetic resonance imaging (MRI) and mammography, and annual mammography for some moderate-risk women. Using questionnaires, breast density, and polygenic risk scores, it is possible to stratify the population into the lowest 20% risk, who will develop <4% of cancers and the top 4%, who will develop 18% of cancers. Mammography is a good screening test but has low sensitivity of 60% in the 9% of women with the highest category of breast density (BIRADS D) who have a 2.5- to fourfold breast cancer risk. There is evidence that adding ultrasound to the screening mammogram can increase the cancer detection rate and reduce advanced stage interval and next round cancers. Similarly, alternative tests such as contrast-enhanced mammography (CESM) or abbreviated MRI (ABB-MRI) are much more effective in detecting cancer in women with dense breasts. Scintimammography has been shown to be a viable alternative for dense breasts or for follow-up in those with a personal history of breast cancer and scarring as result of treatment. For supplemental screening to be worthwhile in these women, new technologies need to reduce the number of stage II cancers and be cost effective when tested in large scale trials. This article reviews the evidence for supplemental imaging and examines whether a risk-stratified approach is feasible.

A meta-analysis comparing the diagnostic performance of abbreviated MRI and a full diagnostic protocol in breast cancer.

AIM: To undertake a meta-analysis of the diagnostic performance of abbreviated (ABB) magnetic resonance imaging (MRI) and full diagnostic protocol MRI (FDP-MRI) in breast cancer. MATERIALS AND METHODS: This meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy (PRISMA-DTA) guidelines. The PubMed and EMBASE databases were searched through August 2019 for studies comparing the diagnostic performance of ABB-MRI and FDP-MRI in the breast. Studies were reviewed by two authors independently according to eligibility and exclusion criteria and split into two subgroups (screening population studies and studies using cohorts enriched with known cancers) to avoid bias. Quality assessment and bias for diagnostic accuracy was determined with Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The diagnostic accuracy for each subgroup was pooled using a bivariate random effects model and summary receiver operating characteristic (sROC) curves produced. Sensitivities and specificities were compared using a paired t-test. RESULTS: Five screening (62/2,588 cancers/patients) and eight enriched cohort (540/1,432 cancers/patients) studies were included in the meta-analysis. QUADAS-2 assessment showed a low risk of bias in most studies. The pooled sensitivity/specificity/area under the receiver operating characteristic curve (AUC) for screening studies was 0.90/0.92/0.94 for ABB-MRI and 0.92/0.95/0.97 for FDP-MRI. The pooled sensitivity/specificity/AUC for enriched cohort studies was 0.93/0.83/0.94 for ABB-MRI and 0.93/0.84/0.95 for FDP-MRI. There was no significant difference in sensitivity or specificity using ABB-MRI or FDP-MRI (p=0.18 and 0.27, p=0.18 and 0.93, respectively). CONCLUSION: The diagnostic performances of the ABB-MRI and FDP-MRI protocols used in either screening or enriched cohorts were comparable. There was a large variation in patient population, study methodology, and abbreviated protocols reported.

Ubiquitin Modification of the Epstein-Barr Virus Immediate Early Transactivator Zta.

The Epstein-Barr virus (EBV) immediate early transactivator Zta plays a key role in regulating the transition from latency to the lytic replication stages of EBV infection. Regulation of Zta is known to be controlled through a number of transcriptional and posttranscriptional events. Here, we show that Zta is targeted for ubiquitin modification and that this can occur in EBV-negative and in EBV-infected cells. Genetic studies show critical roles for both an amino-terminal region of Zta and the basic DNA binding domain of Zta in regulating Zta ubiquitination. Pulse-chase experiments demonstrate that the bulk population of Zta is relatively stable but that at least a subset of ubiquitinated Zta molecules are targeted for degradation in the cell. Mutation of four out of a total of nine lysine residues in Zta largely abrogates its ubiquitination, indicating that these are primary ubiquitination target sites. A Zta mutant carrying mutations at these four lysine residues (lysine 12, lysine 188, lysine 207, and lysine 219) cannot induce latently infected cells to produce and/or release infectious virions. Nevertheless, this mutant can induce early gene expression, suggesting a possible defect at the level of viral replication or later in the lytic cascade. As far as we know, this is the first study that has investigated the targeting of Zta by ubiquitination or its role in Zta function.IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous human pathogen and associated with various human diseases. EBV undergoes latency and lytic replication stages in its life cycle. The transition into the lytic replication stage, at which virus is produced, is mainly regulated by the viral gene product, Zta. Therefore, the regulation of Zta function becomes a central issue regarding viral biology and pathogenesis. Known modifications of Zta include phosphorylation and sumoylation. Here, we report the role of ubiquitination in regulating Zta function. We found that Zta is subjected to ubiquitination in both EBV-infected and EBV-negative cells. The ubiquitin modification targets 4 lysine residues on Zta, leading to both mono- and polyubiquitination of Zta. Ubiquitination of Zta affects the protein's stability and likely contributes to the progression of viral lytic replication. The function and fate of Zta may be determined by the specific lysine residue being modified.

Ten lessons of leadership: reflections of a female academic.

The defining qualities and characteristics of a good leader - visionary, decisive, clear communicator, honesty and integrity, commitment and passion, being inspirational, accountable, well organised with the ability to delegate and empower-have been well documented. There are many articles with advice on how to lead, and there are excellent courses on leadership. In this article, I would like to explore how the general advice pertains to academia (and an academic radiologist), and whether this advice is relevant and whether the principles of leadership are the same. I have reflected on my own career and I have come up with my own 10 lessons of leadership that I have learnt over my working life. There are elements of leadership that are common across different sectors of business and healthcare, and examining how these are relevant to academia can be illuminating.

The Impact of the Deepwater Horizon Oil Spill upon Lung Health-Mouse Model-Based RNA-Seq Analyses.

We used a transcriptomic approach to interrogate the effects of a saline-accommodated fraction from the Macondo 252 well (MC252) oil and Corexit dispersants on lung tissue. Wild-type C57BL/6 male and female mice were exposed on days 0, 7 and 13 by oropharyngeal aspiration to saline accommodated fractions (SAF) of crude oil from the Macondo (MC252) well, Corexit 9500, Corexit 9527, 9500+oil and 9527+oil or a saline solution as the vehicle control. These treatments did not cause overt toxicity, with the exception of the Corexit exposures which caused brief weight loss after the first exposure. On day 14, total RNA was isolated from the left lung for RNA-seq analyses. KEGG-pathway-based differential expression revealed that Corexit 9527 elicited the strongest changes involving the upregulation of 19 KEGG pathways (FDR < 0.10), followed by Corexit 9500 with the upregulation of seven pathways (FDR < 0.10). As an important signature, pathways related to a response to DNA damage (e.g., p53 signaling and mismatch repair) dominate those upregulated by Corexit 9527 and Corexit 9500. In addition, pro-inflammatory pathways (e.g., cytokine-cytokine receptor interaction, IL-17 signaling pathway and TNF signaling pathways) were upregulated selectively in oil-treated male mice. Surprisingly, oil + dispersant combinations caused lesser effects than the individual treatments at the transcriptomic level. Overall, these findings support potential genotoxicity, inflammation and cell death due to dispersant or oil exposures. Similar exposures to lung tumor bearing K-RasLA1 mice provided evidence for tumor promotion by oil and Corexit dispersant treatments. Our mouse RNA-seq analyses may be relevant to the pulmonary health hazards of MC252 oil and dispersants experienced in exposed populations.

Reduced hypertrophy in vitro after chondrogenic differentiation of adult human mesenchymal stem cells following adenoviral SOX9 gene delivery.

BACKGROUND: Mesenchymal stem cell (MSC) based-treatments of cartilage injury are promising but impaired by high levels of hypertrophy after chondrogenic induction with several bone morphogenetic protein superfamily members (BMPs). As an alternative, this study investigates the chondrogenic induction of MSCs via adenoviral gene-delivery of the transcription factor SOX9 alone or in combination with other inducers, and comparatively explores the levels of hypertrophy and end stage differentiation in a pellet culture system in vitro. METHODS: First generation adenoviral vectors encoding SOX9, TGFB1 or IGF1 were used alone or in combination to transduce human bone marrow-derived MSCs at 5 × 102 infectious particles/cell. Thereafter cells were placed in aggregates and maintained for three weeks in chondrogenic medium. Transgene expression was determined at the protein level (ELISA/Western blot), and aggregates were analysed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy. RESULTS: SOX9 cDNA was superior to that encoding TGFB1, the typical gold standard, as an inducer of chondrogenesis in primary MSCs as evidenced by improved lacuna formation, proteoglycan and collagen type II staining, increased levels of GAG synthesis, and expression of mRNAs associated with chondrogenesis. Moreover, SOX9 modified aggregates showed a markedly lower tendency to progress towards hypertrophy, as judged by expression of the hypertrophy markers alkaline phosphatase, and collagen type X at the mRNA and protein levels. CONCLUSION: Adenoviral SOX9 gene transfer induces chondrogenic differentiation of human primary MSCs in pellet culture more effectively than TGFB1 gene transfer with lower levels of chondrocyte hypertrophy after 3 weeks of in vitro culture. Such technology might enable the formation of more stable hyaline cartilage repair tissues in vivo.

Artificial intelligence in clinical imaging: a health system approach.

The development and application of artificial intelligence (AI) to radiology requires an approach that encompasses a health system. The UK government and National Health Service (NHS) are creating an ecosystem to facilitate academic/industrial partnerships aimed at accelerating the creation of relevant and robust AI tools, which will improve the development and delivery of healthcare imaging. A series of recent initiatives are described, which will drive the development and adoption of AI in clinical imaging.

Detection of Epstein-Barr Virus Infection in Non-Small Cell Lung Cancer.

Previous investigations proposed a link between the Epstein-Barr virus (EBV) and lung cancer (LC), but the results are highly controversial largely due to the insufficient sample size and the inherent limitation of the traditional viral screening methods such as PCR. Unlike PCR, current next-generation sequencing (NGS) utilizes an unbiased method for the global assessment of all exogenous agents within a cancer sample with high sensitivity and specificity. In our current study, we aim to resolve this long-standing controversy by utilizing our unbiased NGS-based informatics approaches in conjunction with traditional molecular methods to investigate the role of EBV in a total of 1127 LC. In situ hybridization analysis of 110 LC and 10 normal lung samples detected EBV transcripts in 3 LC samples. Comprehensive virome analyses of RNA sequencing (RNA-seq) data sets from 1017 LC and 110 paired adjacent normal lung specimens revealed EBV transcripts in three lung squamous cell carcinoma and one lung adenocarcinoma samples. In the sample with the highest EBV coverage, transcripts from the BamHI A region accounted for the majority of EBV reads. Expression of EBNA-1, LMP-1 and LMP-2 was observed. A number of viral circular RNA candidates were also detected. Thus, we for the first time revealed a type II latency-like viral transcriptome in the setting of LC in vivo. The high-level expression of viral BamHI A transcripts in LC suggests a functional role of these transcripts, likely as long non-coding RNA. Analyses of cellular gene expression and stained tissue sections indicated an increased immune cell infiltration in the sample expressing high levels of EBV transcripts compared to samples expressing low EBV transcripts. Increased level of immune checkpoint blockade factors was also detected in the sample with higher levels of EBV transcripts, indicating an induced immune tolerance. Lastly, inhibition of immune pathways and activation of oncogenic pathways were detected in the sample with high EBV transcripts compared to the EBV-low LC indicating the direct regulation of cancer pathways by EBV. Taken together, our data support the notion that EBV likely plays a pathological role in a subset of LC.

Artificial intelligence in breast imaging.

This article reviews current limitations and future opportunities for the application of computer-aided detection (CAD) systems and artificial intelligence in breast imaging. Traditional CAD systems in mammography screening have followed a rules-based approach, incorporating domain knowledge into hand-crafted features before using classical machine learning techniques as a classifier. The first commercial CAD system, ImageChecker M1000, relies on computer vision techniques for pattern recognition. Unfortunately, CAD systems have been shown to adversely affect some radiologists' performance and increase recall rates. The Digital Mammography DREAM Challenge was a multidisciplinary collaboration that provided 640,000 mammography images for teams to help decrease false-positive rates in breast cancer screening. Winning solutions leveraged deep learning's (DL) automatic hierarchical feature learning capabilities and used convolutional neural networks. Start-ups Therapixel and Kheiron Medical Technologies are using DL for breast cancer screening. With increasing use of digital breast tomosynthesis, specific artificial intelligence (AI)-CAD systems are emerging to include iCAD's PowerLook Tomo Detection and ScreenPoint Medical's Transpara. Other AI-CAD systems are focusing on breast diagnostic techniques such as ultrasound and magnetic resonance imaging (MRI). There is a gap in the market for contrast-enhanced spectral mammography AI-CAD tools. Clinical implementation of AI-CAD tools requires testing in scenarios mimicking real life to prove its usefulness in the clinical environment. This requires a large and representative dataset for testing and assessment of the reader's interaction with the tools. A cost-effectiveness assessment should be undertaken, with a large feasibility study carried out to ensure there are no unintended consequences. AI-CAD systems should incorporate explainable AI in accordance with the European Union General Data Protection Regulation (GDPR).

The inflamed biceps tendon as a pain generator in the shoulder: A histological and biomolecular analysis.

INTRODUCTION: The long head of the biceps (LHB) is often resected in shoulder surgery. However, its contribution to inflammatory processes in the shoulder remains unclear. In the present study, inflamed and noninflamed human LHBs were comparatively characterized for features of inflammation. MATERIALS AND METHODS: Twenty-two resected LHB tendons were classified into inflamed ( n = 11) and noninflamed ( n = 11) samples. For histological examination, samples were stained with hematoxylin eosin, Azan, van Gieson, and Masson Goldner trichrome. Neuronal tissue was immunohistochemically visualized. In addition, specific inflammatory marker gene expression of primary LHB-derived cell cultures were analyzed. RESULTS: Features of tendinopathy, such as collagen disorganization, infiltration by inflammatory cells, neovascularization, and extensive neuronal innervation were found in the tendinitis group. Compared to noninflamed samples, inflamed LHBs showed a significantly increased inflammatory marker gene expression. CONCLUSION: Structural and biomolecular differences of both groups suggest that the LHB tendon acts as an important pain generator in the shoulder joint. These findings can, on the one hand, contribute to the understanding of the biomolecular genesis of LHB tendinitis and, on the other hand, provide possibilities for new therapeutic approaches.

Embodiment and Estrangement: Results from a First-in-Human "Intelligent BCI" Trial.

While new generations of implantable brain computer interface (BCI) devices are being developed, evidence in the literature about their impact on the patient experience is lagging. In this article, we address this knowledge gap by analysing data from the first-in-human clinical trial to study patients with implanted BCI advisory devices. We explored perceptions of self-change across six patients who volunteered to be implanted with artificially intelligent BCI devices. We used qualitative methodological tools grounded in phenomenology to conduct in-depth, semi-structured interviews. Results show that, on the one hand, BCIs can positively increase a sense of the self and control; on the other hand, they can induce radical distress, feelings of loss of control, and a rupture of patient identity. We conclude by offering suggestions for the proactive creation of preparedness protocols specific to intelligent-predictive and advisory-BCI technologies essential to prevent potential iatrogenic harms.

Proportions of resting memory T cells and monocytes in blood have prognostic significance in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive decline of lung function. Here, we tested the importance of differential proportions of blood immune cells to IPF clinical outcomes. We used Cibersort to deconvolute immune cell components based on PBMCs or whole blood IPF genomics datasets. We found that a higher proportion of resting memory (RM) T cells was associated with a better survival and a higher DLco (diffusing capacity for carbon monoxide) in IPF patients. The association was also found in opposite direction for monocytes. Additionally, in IPF patients as compared to healthy controls, proportions of monocytes were observed to be higher, yet RM T cells were observed to be lower. Taken together, our result suggests a beneficial effect of RM T cells and a detrimental effect of monocytes for IPF. Future genomics studies of IPF should be more focused on these two types of cells.