Association of hysterectomy and invasive epithelial ovarian and tubal cancer: a cohort study within UKCTOCS.

OBJECTIVE: To investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer. DESIGN: Prospective cohort study. SETTING: Thirteen NHS Trusts in England, Wales and Northern Ireland. POPULATION: A total of 202 506 postmenopausal women recruited between 2001 and 2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014. METHODS: Multiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow up or 31 December 2014. Cox proportional hazards regression models were used to assess the association. MAIN OUTCOME MEASURES: Invasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review. RESULTS: Hysterectomy with conservation of one or both adnexa was reported in 41 912 (20.7%; 41 912/202 506) women. Median follow up was 11.1 years (interquartile range 9.96-12.04), totalling >2.17 million woman-years. Among women who had undergone hysterectomy, 0.55% (231/41 912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160 594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (hazard ratio 0.98, 95% CI 0.85-1.13, P = 0.765). CONCLUSIONS: This large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. These data are important both for clinical counselling and for refining risk prediction models. TWEETABLE ABSTRACT: Hysterectomy does not alter risk of invasive epithelial ovarian and tubal cancer.

Serial endometrial thickness and risk of non-endometrial hormone-dependent cancers in postmenopausal women in UK Collaborative Trial of Ovarian Cancer Screening.

OBJECTIVE: Estrogen is a well-established risk factor for various cancers. It causes endometrial proliferation, which is assessed routinely as endometrial thickness (ET) using transvaginal ultrasound (TVS). Only one previous study, restricted to endometrial and breast cancer, has considered ET and the risk of non-endometrial cancer. The aim of this study was to explore the association between baseline and serial ET measurements and nine non-endometrial hormone-sensitive cancers, in postmenopausal women, using contemporary statistical methodology that attempts to minimize the biases typical of endogenous serial data. METHODS: This was a cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). In the ultrasound arm of UKCTOCS, 50639 postmenopausal women, aged 50-74, underwent annual TVS examination, of whom 38 105 had a valid ET measurement, no prior hysterectomy and complete covariate data, and were included in this study. All women were followed up through linkage to national cancer registries. The effect of ET on the risk of six estrogen-dependent cancers (breast, ovarian, colorectal, bladder, lung and pancreatic) was assessed using joint models for longitudinal biomarker and time-to-event data, and Cox models were used to assess the association between baseline ET measurement and these six cancers in addition to liver cancer, gastric cancer and non-Hodgkin's lymphoma (NHL). All models were adjusted for current hormone-replacement therapy (HRT) use, body mass index, age at last menstrual period, parity and oral contraceptive pill use. RESULTS: The 38 105 included women had a combined total of 267 567 (median, 8; interquartile range, 5-9) valid ET measurements. During a combined total of 407 838 (median, 10.9) years of follow-up, 1398 breast, 351 endometrial, 381 lung, 495 colorectal, 222 ovarian, 94 pancreatic, 79 bladder, 62 gastric, 38 liver cancers and 52 NHLs were registered. Using joint models, a doubling of ET increased significantly the risk of breast (hazard ratio (HR), 1.21; 95% CI, 1.09-1.36; P = 0.001), ovarian (HR, 1.39; 95% CI, 1.06-1.82; P = 0.018) and lung (HR, 1.25; 95% CI, 1.02-1.54; P = 0.036) cancers. There were no statistically significant associations between ET and the remaining six cancers. CONCLUSION: Postmenopausal women with high/increasing ET on TVS are at increased risk of breast, ovarian and lung cancer. It is important that clinicians are aware of these risks, as TVS is a common investigation. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Sonographers' self-reported visualization of normal postmenopausal ovaries on transvaginal ultrasound is not reliable: results of expert review of archived images from UKCTOCS.

OBJECTIVE: In the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), self-reported visualization rate (VR) of the ovaries by the sonographer on annual transvaginal sonographic (TVS) examinations was a key quality control (QC) metric. The objective of this study was to assess self-reported VR using expert review of a random sample of archived images of TVS examinations from UKCTOCS, and then to develop software for measuring VR automatically. METHODS: A single expert reviewed images archived from 1000 TVS examinations selected randomly from 68 931 TVS scans performed in UKCTOCS between 2008 and 2011 with ovaries reported as 'seen and normal'. Software was developed to identify the exact images used by the sonographer to measure the ovaries. This was achieved by measuring caliper dimensions in the image and matching them to those recorded by the sonographer. A logistic regression classifier to determine visualization was trained and validated using ovarian dimensions and visualization data reported by the expert. RESULTS: The expert reviewer confirmed visualization of both ovaries (VR-Both) in 50.2% (502/1000) of the examinations. The software identified the measurement image in 534 exams, which were split 2:1:1 providing training, validation and test data. Classifier mean accuracy on validation data was 70.9% (95% CI, 70.0-71.8%). Analysis of test data (133 exams) provided a sensitivity of 90.5% (95% CI, 80.9-95.8%) and specificity of 47.5% (95% CI, 34.5-60.8%) in detecting expert confirmed visualization of both ovaries. CONCLUSIONS: Our results suggest that, in a significant proportion of TVS annual screens, the sonographers may have mistaken other structures for normal ovaries. It is uncertain whether or not this affected the sensitivity and stage at detection of ovarian cancer in the ultrasound arm of UKCTOCS, but we conclude that QC metrics based on self-reported visualization of normal ovaries are unreliable. The classifier shows some potential for addressing this problem, though further research is needed. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Novel Blood-Based Biomarkers and Disease Modifying Therapies for Alzheimer's Disease. Are We Ready for the New Era?

Recent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer's disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer's disease, of increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer's disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements.

Expression of the Fabs of human auto-antibodies in Escherichia coli: optimization and determination of their fine binding characteristics and cross-reactivity.

The Fabs of three human auto-antibodies (B3/33H11, anti-DNA; UK4, anti-phospholipid) and six related hybrids have been cloned and expressed in Escherichia coli, and their relative binding to single-stranded or double-stranded DNA or to cardiolipin has been assessed in the presence of modulators (salts and serum). We describe optimized conditions that have led to significant improvement in the quality and quantity of the purified auto-antibodies. Protein expression of the assembled and functionally active Fabs was achievable with a yield of up to 5 to 9 mg/l of culture. The comparative DNA/cardiolipin-binding analyses of the nine Fabs in the presence of modulators demonstrated that B3 and 33H11 L chains possess both anti-DNA and anti-cardiolipin activities. This is the first report of the demonstration that both anti-DNA and anti-cardiolipin activities may lie on the same light chain of a human auto-antibody. We provide evidence that the auto-antibodies that appeared to be similar, in that they bound DNA or cardiolipin in conventional ELISA immunoassays, exhibited significant difference in their cross-reactivity and binding to the antigen in the presence of modulators. Such auto- antigen specificity and/or cross-reactivity may dictate the potential of an auto-antibody to cause pathogenicity and may provide an explanation as to why apparently similar auto-antibodies behave differently in vivo.

Functional and modelling studies of the binding of human monoclonal anti-DNA antibodies to DNA.

The relationships between the antigen-binding specificities of four human monoclonal anti-DNA antibodies and the structural aspects of the combining sites of two of these were examined. Competition ELISAs were used to examine the reactivities of two IgM MAbs (WRI-176 and RT-79) and two IgG mAbs (D5 and B3) to a wide range of polynucleotides. The mAbs WRI-176 and RT-79 were found to bind predominantly ssDNA, with a preference for poly (dT), whilst D5 and B3 bound components of both ss- and dsDNA, and Z-DNA. The mAb B3 also exhibited a preference for A(T) rich nucleotides. Computer models were generated for the Fv regions of WRI-176 and B3. Models for RT-79 and D5 were not generated as the structure of the long CDR-H3 loops in these mAbs could not be predicted. The B3 combining site contains a groove flanked by three arginines at positions CDR-L1-27A, CDR-L2-54 and CDR-H2-53. Using interactive molecular graphics, B-DNA was docked into the B3 antigen combining site along the plane of the VH/VL interface, whilst Z-DNA was best-fitted at approximately 90 degrees to this direction. The models provide a hypothesis to explain the ability of a single autoantibody to bind two different antigens. In addition, aspects of the base specificity of B3 may be explained. The model of the WRI-176 Fv region revealed a relatively flat surface, on which a large number of hydrophobic and aromatic residues were present. Trp-H52, in particular, is prominent on the surface. This may participate in ssDNA binding through base stacking interactions. The models allow identification of potential targets for site-directed mutagenesis.

Anti-cardiolipin/beta-2 glycoprotein activities co-exist on human anti-DNA antibody light chains.

We have recently shown that the human anti-DNA antibodies B3 and 33H11 also bind cardiolipin and that the anti-autoantigen activity resides predominantly on their lambda light chains. We now show that the two auto-antibodies possess strong reactivity to the plasma-protein 2-Glycoprotein I (beta2-GPI) also. Utilizing chain shuffling experiments involving an unrelated anti-p185 antibody 4D5 with insignificant reactivity to cardiolipin or to beta2-GPI, we now demonstrate that hybrid Fabs with constituent light chain, but not the heavy chain, of B3 or 33H11, exhibit anti-cardiolipin activity. Furthermore, the constructs possessing the auto-antibody-derived light chain also exhibited significant reactivity to beta2-GPI. The results suggest that anti-DNA, anti-cardiolipin and anti-beta2-GPI activities co-exist on the light chains of the antibodies studied and, importantly, these activities could be transferred to antibody constructs by their light chains alone. Computer-generated models of the three-dimensional structures of the auto-antibodies and their hybrids, suggest predominant interaction of their light chains with domain IV of beta2-GPI.

Structure-function analysis and the molecular origins of anti-DNA antibodies in systemic lupus erythematosus.

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE or 'lupus') develop a wide variety of clinical and serological manifestations including the presence of antibodies to double-stranded DNA (dsDNA), which are often diagnostic and potentially pathogenic. In this review, we have examined the links between the structure and function of anti-dsDNA antibodies, emphasising their clinical associations. We have also reviewed studies involving animal models, the analysis of human antibody sequences and studies of, and using, computer modelling and crystal structure.

A comparison of two techniques for the detection of an antibody in human serum to Chang liver cell surface antigens.

The antibody-dependent cell-mediated cytotoxicity technique (ADCC) and an isotopic antiglobulin technique have been compared for their abilities to detect human serum antibodies to Chang liver cell membrane antigens. The optimal conditions were established for the latter technique, which was found to be superior with respect to reproducibility and sensitivity. Also, unlike ADCC, the isotopic antiglobulin technique was unaffected by other factors, such as immune complexes present in pathological sera.

Analysis of antibody reactivity in the sera of 42 patients with paraproteinaemia.

The clinical expression of disease in patients with conditions in which autoimmunity is thought to contribute to the pathogenesis of disease is the result of an unfortunate combination of predisposing and environmental factors. The presence of autoantibodies showing a variety of antigen specificities in sera from many of these patients has been closely correlated with particular spectra of organ involvement or tissue destruction. Their precise role in the disease process is as yet unclear. Sera from patients with paraproteinaemia also often contain autoantibodies to a variety of cell components, although symptoms of autoimmune disease are rarely found in this group of individuals. In this study of 42 sera from patients with paraproteinaemia we have confirmed the presence of autoantibodies in 33% (13/42) of samples. Amongst the autoantibodies detected were those to human neutrophils (3), U1RNP (8) and cardiolipin (4). In five sera, the immunoglobulin class of autoantibody did not correlate with that of the monoclonal band. This study extends previous reports of the repertoire of autoantibodies present in sera from patients with paraproteinaemia.

NCX-911, a novel nitric oxide-releasing PDE5 inhibitor relaxes rabbit corpus cavernosum in the absence of endogenous nitric oxide.

Phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in treating erectile dysfunction (ED) in conditions where there is a lack of endogenous nitric oxide (NO). Therefore, NO-releasing PDE5 inhibitors have been developed. Here we report the effect of such a compound, NCX-911, on the tone and nitrergic relaxations of rabbit corpus cavernosum in the absence or presence of a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 500 microM). NCX-911 was found to be as potent as sildenafil at inducing relaxation of rabbit cavernosum (EC(50) values 997.8+/-195.7 and 1000.5+/-140.8 nM, respectively). The potency of NCX-911 was not altered, but that of sildenafil decreased five-fold in the presence of L-NAME (EC(50) values 1281.2+/-268.3 and 4959.1+/-882.1, nM respectively, P<0.001 for sildenafil). Both compounds potentiated nitrergic relaxations with similar potencies. These results suggest that NO-releasing PDE5 inhibitors could potentially be more useful than PDE5 inhibitors in the treatment of ED in conditions where there is a lack of endogenous NO.

Current oral treatments for erectile dysfunction.

Erectile dysfunction (ED) is defined as the inability to achieve and maintain a penile erection adequate for satisfactory sexual intercourse. It is a significant male health problem of global dimensions affecting approximately 150 million men worldwide. A broad range of options are currently available for the management of ED. They include oral agents (phosphodiesterase 5 inhibitors, dopamine agonists and alpha-receptor blocking drugs), intracavernosal injection (papaverine, phentolamine, prostaglandin E1, vasoactive intestinal peptide), transurethral vasoactive agents (prostaglandin E1), vacuum erection devices, vascular surgery and penile prostheses. Here we review the physiology of penile erection and the currently available oral preparations. In addition, novel therapeutic strategies to improve erectile function are discussed.

Cialis (tadalafil): a new treatment for erectile dysfunction.

Oral phosphodiesterase inhibitors have become the mainstay of treatment for erectile dysfunction. A novel and potent phosphodiesterase inhibitor, tadalafil, known as Cialis, has been introduced in the UK as an alternative to the other currently available phosphodiesterase inhibitors for the treatment of erectile dysfunction.

Priapism: a medical emergency.

Priapism is defined as a prolonged penile erection that fails to subside despite orgasm. It is a medical emergency which should be diagnosed and treated early to preserve erectile function and avoid corporal fibrosis resulting from anoxia of the corporal tissue. Decompression is usually successful with no permanent damage if treatment is provided within 12 hours of onset.

Oral agents for erectile dysfunction.

Erectile dysfunction is a common disease affecting the lives of millions of men worldwide. Sildenafil was the first oral treatment licensed for male erectile dysfunction. However, there are now a number of other options available. In this article the currently available oral treatments are reviewed.

An explanation of workplace-based assessments in postgraduate dental training and a review of the current literature.

Workplace-based assessments (WBAs) are trainee-led formative assessments that measure the highest level of competence of the ability to do a task. So far WBAs are the only available assessment tools to measure performance integrated into practice. Over the years, WBAs have become an integral part of dental foundation and specialty training. The numerous WBAs available can be broadly categorised into three types. The first type involves observation of clinical encounters, for example mini-clinical evaluation exercises; direct observation of procedural skills; and dental evaluation of performance and procedure-based assessments. The second type involves discussion of clinical cases, such as case-based discussions. Finally, the third type includes the mini-peer assessment tool, team assessment of behaviour, 360° assessments and multi-source feedback, and all involve receiving feedback from a combination of colleagues, staff and patients. This article describes the WBAs currently used in postgraduate dental training and explores their strengths, weaknesses, perceived value by trainees and trainers and how these tools can be used in a reliable and valid way.