Artificial Intelligence for Breast Cancer Risk Assessment.

Breast cancer risk prediction models based on common clinical risk factors are used to identify women eligible for high-risk screening and prevention. Unfortunately, these models have only modest discriminatory accuracy with disparities in performance in underrepresented race and ethnicity groups. The field of artificial intelligence (AI) and deep learning are rapidly advancing the field of breast cancer risk prediction with the development of mammography-based AI breast cancer risk models. Early studies suggest mammography-based AI risk models may perform better than traditional risk factor-based models with more equitable performance.

DNA damage signalling from the placenta to foetal blood as a potential mechanism for childhood leukaemia initiation.

For many diseases with a foetal origin, the cause for the disease initiation remains unknown. Common childhood acute leukaemia is thought to be caused by two hits, the first in utero and the second in childhood in response to infection. The mechanism for the initial DNA damaging event are unknown. Here we have used in vitro, ex vivo and in vivo models to show that a placental barrier will respond to agents that are suspected of initiating childhood leukaemia by releasing factors that cause DNA damage in cord blood and bone marrow cells, including stem cells. We show that DNA damage caused by in utero exposure can reappear postnatally after an immune challenge. Furthermore, both foetal and postnatal DNA damage are prevented by prenatal exposure of the placenta to a mitochondrially-targeted antioxidant. We conclude that the placenta might contribute to the first hit towards leukaemia initiation by bystander-like signalling to foetal haematopoietic cells.

Evidence for bystander signalling between human trophoblast cells and human embryonic stem cells.

Maternal exposure during pregnancy to toxins can occasionally lead to miscarriage and malformation. It is currently thought that toxins pass through the placental barrier, albeit bi-layered in the first trimester, and damage the fetus directly, albeit at low concentration. Here we examined the responses of human embryonic stem (hES) cells in tissue culture to two metals at low concentration. We compared direct exposures with indirect exposures across a bi-layered model of the placenta cell barrier. Direct exposure caused increased DNA damage without apoptosis or a loss of cell number but with some evidence of altered differentiation. Indirect exposure caused increased DNA damage and apoptosis but without loss of pluripotency. This was not caused by metal ions passing through the barrier. Instead the hES cells responded to signalling molecules (including TNF-α) secreted by the barrier cells. This mechanism was dependent on connexin 43 mediated intercellular 'bystander signalling' both within and between the trophoblast barrier and the hES colonies. These results highlight key differences between direct and indirect exposure of hES cells across a trophoblast barrier to metal toxins. It offers a theoretical possibility that an indirectly mediated toxicity of hES cells might have biological relevance to fetal development.

Histology of failed metal-on-metal hip arthroplasty; three distinct sub-types.

The histological specimens from 29 failed metal-on-metal (MoM) hip arthroplasties treated at our institution were reviewed. Five patients had a failed MoM total hip arthroplasty (THA), and 24 patients a failed hip resurfacing. Clinical and radiographic features of each hip were correlated with the histological findings. We report three major histological subtypes. Patients either have a macrophage response to metal debris, a lymphocytic response (ALVAL) or a mixed picture of both. In addition we observe that the ALVAL response is located deep within tissue specimens, and can occur in environments of low wear debris. The macrophage response is limited to the surface of tissue specimens, with normal underlying tissue. Patients with subsequently confirmed ALVAL underwent revision surgery sooner than patients whose histology confirms a macrophage response (3.8 vs. 6.9 years p<0.05). Both histological subtypes (ALVAL and macrophage dominant) are responsible for abnormal soft tissue swellings.

Consequences of exposure to peri-articular injections of micro- and nano-particulate cobalt-chromium alloy.

Metal hip replacements generate both metal particles and ions. The biological effects of peri-articular exposure to nanometre and micron sized cobalt chrome (CoCr) wear particles were investigated in a mouse model. Mice received injections of two clinically relevant doses of nanoparticles (32 nm), one of micron sized (2.9 µm) CoCr particles or vehicle alone into the right knee joint at 0, 6, 12 and 18 weeks. Mice were analysed for genotoxic and immunological effects 1, 4 and 40 weeks post exposure. Nanoparticles but not micron particles progressively corroded at the injection site. Micron sized particles were physically removed. No increase of Co or Cr was seen in peripheral blood between 1 and 40 weeks post exposure to particles. No significant inflammatory changes were observed in the knee tissues including ALVAL or necrosis. DNA damage was increased in bone marrow at one and forty weeks and in cells isolated from frontal cortex at 40 weeks after injection with nanoparticles. Mice exposed to the micron sized, but not nanoparticles became immunologically sensitized to Cr(III), Cr (VI) and Ni(II) over the 40 week period as determined by lymphocyte transformation and ELISpot (IFN-γ and IL-2) assays. The data indicated that the response to the micron sized particles was Th1 driven, indicative of type IV hypersensitivity. This study adds to understanding of the potential adverse biological reactions to metal wear products.

'23 h Model' for breast surgery: an early experience.

The principles of fast track surgery are well established in colorectal surgery. It is an evidence based model aimed at reducing length of stay, convalescence and morbidity by optimising both clinical and organisational factors. Despite this, the implementation of fast track surgery in breast cancer patients has been slow. The 23 h discharge model for breast cancer surgery patients has been outlined by the NHS Improvement Programme and is a breakthrough from traditional inpatient care. This paper outlines the early experience of implementation of this model in a single institution during a 3-month audit period. Over 80% of patients undergoing non-reconstructive breast surgery were discharged safely within '23 h'. This suggests that good communication links, reorganisation of existing resources, active user involvement (both patients and clinical team) and strong project management ensures fast-tracking to be safe for the patient with significant economic benefits for the hospital.

Metal-on-metal bearings: the evidence so far.

Lately, concerns have arisen following the use of large metal-on-metal bearings in hip replacements owing to reports of catastrophic soft-tissue reactions resulting in implant failure and associated complications. This review examines the literature and contemporary presentations on current clinical dilemmas in metal-on-metal hip replacement.

Early failure of the Ultima metal-on-metal total hip replacement in the presence of normal plain radiographs.

Metal-on-metal total hip replacement has been targeted at younger patients with anticipated long-term survival, but the effect of the production of metal ions is a concern because of their possible toxicity to cells. We have reviewed the results of the use of the Ultima hybrid metal-on-metal total hip replacement, with a cemented polished tapered femoral component with a 28 mm diameter and a cobalt-chrome (CoCr) modular head, articulating with a 28 mm CoCr acetabular bearing surface secured in a titanium alloy uncemented shell. Between 1997 and 2004, 545 patients with 652 affected hips underwent replacement using this system. Up to 31 January 2008, 90 (13.8%) hips in 82 patients had been revised. Pain was the sole reason for revision in 44 hips (48.9%) of which 35 had normal plain radiographs. Peri-prosthetic fractures occurred in 17 hips (18.9%) with early dislocation in three (3.3%) and late dislocation in 16 (17.8%). Infection was found in nine hips (10.0%). At operation, a range of changes was noted including cavities containing cloudy fluid under pressure, necrotic soft tissues with avulsed tendons and denuded osteonecrotic upper femora. Corrosion was frequently observed on the retrieved cemented part of the femoral component. Typically, the peri-operative findings confirmed those found on pre-operative metal artefact reduction sequence MRI and histological examination showed severe necrosis. Metal artefact reduction sequence MRI proved to be useful when investigating these patients with pain in the absence of adverse plain radiological features.

DNA damaging bystander signalling from stem cells, cancer cells and fibroblasts after Cr(VI) exposure and its dependence on telomerase.

The bystander effect is a feature of low dose radiation exposure and is characterized by a signaling process from irradiated cells to non irradiated cells, which causes DNA and chromosome damage in these 'nearest neighbour' cells. Here we show that a low and short dose of Cr(VI) can induce stem cells, cancer cells and fibroblasts to chronically secrete bystander signals, which cause DNA damage in neighboring cells. The Cr(VI) induced bystander signaling depended on the telomerase status of either cell. Telomerase negative fibroblasts were able to receive DNA damaging signals from telomerase positive or negative fibroblasts or telomerase positive cancer cells. However telomerase positive fibroblasts were resistant to signals from Cr(VI) exposed telomerase positive fibroblasts or cancer cells. Human embryonic stem cells, with positive Oct4 staining as a marker of pluripotency, showed no significant increase of DNA damage from adjacent Cr and mitomycin C exposed fibroblasts whilst those cells that were negatively stained did. This selectivity of DNA damaging bystander signaling could be an important consideration in developing therapies against cancer and in the safety and effectiveness of tissue engineering and transplantation using stem cells.

Effects of hTERT on genomic instability caused by either metal or radiation or combined exposure.

Genomic instability is considered to be an important component in carcinogenesis. It can be caused by low-dose exposure to agents, which appear to act through induction of stress-response pathways related to oxidative stress. These agents have been studied mostly in the radiation field but evidence is accumulating that chemicals, especially heavy metals such as Cr (VI), can also act in the same manner. Previous work showed that metal ions could initiate long-term genomic instability in human primary fibroblasts and this phenomenon was regulated by telomerase. The aim of this study was to examine the difference in clonogenic survival and cytogenetic damage after exposure to Cr (VI) and radiation both singly and in combination in normal human fibroblasts (hTERT- cells) and engineered human fibroblasts, infected with a retrovirus carrying a cDNA encoding hTERT, which rendered these cells telomerase positive and replicatively immortal (hTERT+ cells). Cr (VI) induced genomic instability in hTERT- cells but not in hTERT+ cells, whereas radiation induced genomic instability in hTERT+ cells and to a lesser extent in hTERT- cells. Combined exposure caused genomic instability in both types of cells. However, this genomic instability was more pronounced in hTERT- cells after radiation followed by Cr (VI) and more pronounced in hTERT+ cells after Cr (VI) followed by radiation. Moreover, the biological effects provoked by combined exposure of Cr (VI) and radiation also led to a synergistic action in both types of cells, compared to either Cr (VI) treatment only or radiation exposure only. This study suggests that telomerase can prevent genomic instability caused by Cr (VI), but not by radiation. Furthermore, genomic instability may be prevented by telomerase when cells are exposed to radiation and then Cr (VI) but not after exposure to Cr (VI) and then radiation.

A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium exposures from industry and surgical implants.

Humans are exposed to cobalt (Co) and chromium (Cr) from industry and surgical devices, most notably orthopedic joint replacements. This review compares the potential health effects of exposure to Co and Cr contaminants from these two different sources, both in the locally exposed tissues and at sites distant to the primary exposure. Surgical implantation results largely in exposures to ions, corrosion products, and particles of Co and Cr. Industrial exposures are predominantly to metal compounds and particles. Although there are large literatures on industrial and surgical exposures to these metals, there has yet to be a systematic comparison of the two to test whether more general lessons might be learned about the human toxicology of Co and Cr. Both industrial and surgical exposures cause inflammatory and other immune reactions in the directly exposed tissues. In the lung there is a well-established risk of cancer following long-term exposures to hexavalent Cr; however, the development of sarcoma in the connective tissues adjacent to implants in response to metal particles is rare. Both types of exposure are associated with changes in the peripheral blood, including evidence of oxidative stress, and altered numbers of circulating immune cells. There is dissemination of Co and Cr to sites distant to the orthopedic implant, but less is known about systemic dissemination of these metals away from the lung. The effects of industrial exposures in the reproductive, renal, and cardiac systems have been investigated, but this has yet to be explored after surgical exposures. The form of the metal (and associated elements) in both instances is key to the toxicological effects arising in the body and further characterization of debris released from devices is certainly recommended, as is the impact of nanotoxicology on the health and safety of workers and patients. Biomonitoring schemes currently used in industry could be translated, if required, into suitable programs for orthopedic out-patients. Cross-communication between experts in industrial and occupational medicine and regulatory agencies may be useful.

Macrophages detoxify the genotoxic and cytotoxic effects of surgical cobalt chrome alloy particles but not quartz particles on human cells in vitro.

Particles of surgical cobalt chrome alloy are cytotoxic and genotoxic to human fibroblasts in vitro. In vivo orthopaedic patients are exposed to cobalt chrome particles as a result of wear of a joint replacement. Many of the wear debris particles that are produced are phagocytosed by macrophages that accumulate at the site of the worn implant and are disseminated to local and distant lymph nodes the liver and the spleen. In this study we have tested whether this process of phagocytosis could have altered the cytotoxic and genotoxic properties of the cobalt chrome particles. Quartz particles have been investigated as a control. Micron-sized particles of cobalt chrome alloy were internalised by either white cells of peripheral blood or by THP-1 monocytes for 1 week and 1 day, respectively. The particles were then extracted and presented at different doses to fibroblasts for 1 day. There was a reduction of the cytotoxicity and genotoxicity of the cobalt chrome particles after phagocytosis by white cells or THP-1 cells. Cobalt chrome particles that were internalised by fibroblasts also showed a reduction of their cytotoxicity but not their genotoxicity. In contrast the cytotoxicity and genotoxicity of quartz particles was increased after internalisation by THP-1 cells. The surface morphology of the cobalt chrome particles but not the quartz particles was changed after phagocytosis by THP-1 cells. This study suggests that the genotoxic and cytotoxic properties of particles that fall within the size range for phagocytosis may be highly complex in vivo and depend on the combination of material type and previous phagocytosis. These results may have relevance for particle exposure from orthopaedic implants and from environmental or industrial pollution.

Regulation of endogenous gene expression using small molecule-controlled engineered zinc-finger protein transcription factors.

Small-molecule-regulated gene expression offers the promise of titrating the dose and duration of action of DNA-based therapies. To this end, we show that engineered zinc-finger protein transcription factors (ZFP TFs) can be coupled with a drug-inducible regulatory domain to permit small-molecule control of endogenous gene transcription. We constructed a drug-responsive ZFP TF via the fusion of a ZFP DNA-binding domain (DBD) targeting the human VEGF-A gene and an effector domain containing a truncated progesterone receptor ligand-binding domain linked to the NFkappaB p65 activation domain. Introduction of this engineered ZFP TF into human or murine cells allowed expression of the chromosomal VEGF-A gene to be induced upon addition of mifepristone, a synthetic steroid analog. Mifepristone-dependent VEGF-A induction was rapid, dose-dependent and reversible. Moreover, stable lines expressing the drug-responsive ZFP TF could be maintained in a state of continuous induction for at least 30 days without loss of viability. Potent VEGF-A induction was demonstrated using different engineered ZFP DBDs, thus this approach may represent a general solution to small-molecule regulation of targeted endogenous genes.

Orthopaedic metals and their potential toxicity in the arthroplasty patient: A review of current knowledge and future strategies.

The long-term effects of metal-on-metal arthroplasty are currently under scrutiny because of the potential biological effects of metal wear debris. This review summarises data describing the release, dissemination, uptake, biological activity, and potential toxicity of metal wear debris released from alloys currently used in modern orthopaedics. The introduction of risk assessment for the evaluation of metal alloys and their use in arthroplasty patients is discussed and this should include potential harmful effects on immunity, reproduction, the kidney, developmental toxicity, the nervous system and carcinogenesis.

Biological effects of metal-on-metal hip replacements.

The advantages seen by patients receiving total hip arthroplasties and the implications of the release of both metal particles and soluble metal ions are discussed. This paper describes some of the early changes that have been observed in metal-on-metal hip arthroplasties, in terms of both changes in metal levels in blood and chromosome changes.

Effects of hTERT on metal ion-induced genomic instability.

There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longer-term genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERT- cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased beta-galactosidase staining and apoptosis. This instability was not present in telomerase-positive hTERT+ cells. In contrast, in hTERT+ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERT- cells. The growth and survival of both metal-exposed hTERT+ and hTERT- cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

Functional and prognostic implications of left ventricular contractile reserve in patients with asymptomatic severe mitral regurgitation.

OBJECTIVE: To evaluate contractile reserve (CR) determined by exercise echocardiography in predicting clinical outcome and left ventricular (LV) function in asymptomatic severe mitral regurgitation (MR). DESIGN: Cohort study. SETTING: Regional cardiac centre. PATIENTS AND OUTCOME MEASURES: LV volumes and ejection fraction (EF) were measured at rest and after stress in 71 patients with isolated MR. During follow up (mean (SD) 3 (1) years), EF and functional capacity were serially assessed and cardiac events (cardiac death, heart failure, and new atrial fibrillation) were documented. RESULTS: CR was present in 45 patients (CR+) and absent in 26 patients (CR-). Age, resting LV dimensions, EF, and MR severity were similar in both groups. Mitral surgery was performed in 19 of 45 (42%) CR+ patients and 22 of 26 (85%) CR- patients. In patients undergoing surgery, CR was an independent predictor of follow up EF (p = 0.006) and postoperative LV dysfunction (EF < 50%) persisted in five patients, all in the CR- group. Event-free survival was lower in surgically treated patients without CR (p = 0.03). In medically treated patients, follow up EF was preserved in those with intact CR but progressively deteriorated in patients without CR, in whom functional capacity also deteriorated. CONCLUSIONS: Evaluation of CR by exercise echocardiography may be useful for risk stratification and may help to optimise the timing of surgery in asymptomatic severe MR.

Metal-specific differences in levels of DNA damage caused by synovial fluid recovered at revision arthroplasty.

Previous research has shown an increase in chromosomal aberrations in patients with worn implants. The type of aberration depended on the type of metal alloy in the prosthesis. We have investigated the metal-specific difference in the level of DNA damage (DNA stand breaks and alkali labile sites) induced by culturing human fibroblasts in synovial fluid retrieved at revision arthroplasty. All six samples from revision cobalt-chromium metal-on-metal and four of six samples from cobalt-chromium metal-on-polyethylene prostheses caused DNA damage. By contrast, none of six samples from revision stainless-steel metal-on-polyethylene prostheses caused significant damage. Samples of cobalt-chromium alloy left to corrode in phosphate-buffered saline also caused DNA damage and this depended on a synergistic effect between the cobalt and chromium ions. Our results further emphasise that epidemiological studies of orthopaedic implants should take account of the type of metal alloy used.

An unusual lymphocytic perivascular infiltration in tissues around contemporary metal-on-metal joint replacements.

BACKGROUND: Metal-on-metal bearing surfaces have been reintroduced for use during total hip replacement. To assess tissue reactions to various types of articulations, we studied the histological appearance of periprosthetic tissues retrieved from around metal-on-metal and metal-on-polyethylene total hip replacements and compared these findings with the appearance of control tissues retrieved at the time of primary arthroplasty. METHODS: Periprosthetic tissues were obtained at the time of revision of twenty-five cobalt chromium-on-cobalt chromium, nine cobalt chromium-on-polyethylene, and ten titanium-on-polyethylene total hip arthroplasties. Control tissues were obtained from nine osteoarthritic hips at the time of primary total hip arthroplasty. Each tissue sample was processed for routine histological analysis, and sections were stained with hematoxylin and eosin. Quantitative stereological analysis was performed with use of light microscopy. RESULTS: Tissue samples obtained from hips with metal-on-metal implants displayed a pattern of well-demarcated tissue layers. A prominent feature, seen in seventeen of twenty-five tissue samples, was a pattern of perivascular infiltration of lymphocytes. In ten of the tissue samples obtained from hips with metal-on-metal prostheses, there was also an accumulation of plasma cells in association with macrophages that contained metallic wear-debris particles. The surfaces of tissues obtained from hips with metal-on-metal prostheses were more ulcerated than those obtained from hips with other types of implants, particularly in the region immediately superficial to areas of perivascular lymphocytic infiltration. The lymphocytic infiltration was more pronounced in samples obtained at the time of revision because of aseptic failure than in samples retrieved at the time of autopsy or during arthrotomy for reasons other than aseptic failure. Total-joint-replacement and surface-replacement designs of metal-on-metal prostheses were associated with similar results. Tissue samples obtained from hips with metal-on-polyethylene implants showed far less surface ulceration, much less distinction between tissue layers, no pattern of lymphocytic infiltration, and no plasma cells. The inflammation was predominantly histiocytic. Tissues retrieved from hips undergoing primary joint replacement showed dense scar tissue and minimal inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: The pattern and type of inflammation seen in periprosthetic tissues obtained from hips with metal-on-metal and metal-on-polyethylene implants are very different. At the present time, we do not know the prevalence or clinical implications of these histologic findings, but we suggest that they may represent a novel mode of failure for some metal-on-metal joint replacements.