PREDICT-GTN 2: Two-factor streamlined models match FIGO performance in gestational trophoblastic neoplasia.

OBJECTIVE: The International Federation of Gynecology and Obstetrics (FIGO) scoring system uses the sum of eight risk-factors to predict single-agent chemotherapy resistance in Gestational Trophoblastic Neoplasia (GTN). To improve ease of use, this study aimed to generate: (i) streamlined models that match FIGO performance and; (ii) visual-decision aids (nomograms) for guiding management. METHODS: Using training (n = 4191) and validation datasets (n = 144) of GTN patients from two UK specialist centres, logistic regression analysis generated two-factor models for cross-validation and exploration. Performance was assessed using true and false positive rate, positive and negative predictive values, Bland-Altman calibration plots, receiver operating characteristic (ROC) curves, decision-curve analysis (DCA) and contingency tables. Nomograms were developed from estimated model parameters and performance cross-checked upon the training and validation dataset. RESULTS: Three streamlined, two-factor models were selected for analysis: (i) M1, pre-treatment hCG + history of failed chemotherapy; (ii) M2, pre-treatment hCG + site of metastases and; (iii) M3, pre-treatment hCG + number of metastases. Using both training and validation datasets, these models showed no evidence of significant discordance from FIGO (McNemar's test p > 0.78) or across a range of performance parameters. This behaviour was maintained when applying algorithms simulating the logic of the nomograms. CONCLUSIONS: Our streamlined models could be used to assess GTN patients and replace FIGO, statistically matching performance. Given the importance of imaging parameters in guiding treatment, M2 and M3 are favoured for ongoing validation. In resource-poor countries, where access to specialist centres is problematic, M1 could be pragmatically implemented. Further prospective validation on a larger cohort is recommended.

PREDICT-GTN 1: Can we improve the FIGO scoring system in gestational trophoblastic neoplasia?

Gestational trophoblastic neoplasia (GTN) patients are treated according to the eight-variable International Federation of Gynaecology and Obstetrics (FIGO) scoring system, that aims to predict first-line single-agent chemotherapy resistance. FIGO is imperfect with one-third of low-risk patients developing disease resistance to first-line single-agent chemotherapy. We aimed to generate simplified models that improve upon FIGO. Logistic regression (LR) and multilayer perceptron (MLP) modelling (n = 4191) generated six models (M1-6). M1, all eight FIGO variables (scored data); M2, all eight FIGO variables (scored and raw data); M3, nonimaging variables (scored data); M4, nonimaging variables (scored and raw data); M5, imaging variables (scored data); and M6, pretreatment hCG (raw data) + imaging variables (scored data). Performance was compared to FIGO using true and false positive rates, positive and negative predictive values, diagnostic odds ratio, receiver operating characteristic (ROC) curves, Bland-Altman calibration plots, decision curve analysis and contingency tables. M1-6 were calibrated and outperformed FIGO on true positive rate and positive predictive value. Using LR and MLP, M1, M2 and M4 generated small improvements to the ROC curve and decision curve analysis. M3, M5 and M6 matched FIGO or performed less well. Compared to FIGO, most (excluding LR M4 and MLP M5) had significant discordance in patient classification (McNemar's test P < .05); 55-112 undertreated, 46-206 overtreated. Statistical modelling yielded only small gains over FIGO performance, arising through recategorisation of treatment-resistant patients, with a significant proportion of under/overtreatment as the available data have been used a priori to allocate primary chemotherapy. Streamlining FIGO should now be the focus.

A global approach to addressing the policy, research and social challenges of male reproductive health.

Male infertility is a global health issue; yet to a large extent, our knowledge of its causes, impact and consequence is largely unknown. Recent data indicate that infertile men have an increased risk of somatic disorders such as cancer and die younger compared to fertile men. Moreover, several studies point to a significant adverse effect on the health of the offspring. From the startling lack of progress in male contraception combined with the paucity of improvements in the diagnosis of male infertility, we conclude there is a crisis in male reproductive health. The Male Reproductive Health Initiative has been organized to directly address these issues (www.eshre.eu/Specialty-groups/Special-Interest-Groups/Andrology/MRHI). The Working Group will formulate an evidence-based strategic road map outlining the ways forward. This is an open consortium desiring to engage with all stakeholders and governments.

Computed tomography chest imaging offers no advantage over chest X-ray in the initial assessment of gestational trophoblastic neoplasia.

BACKGROUND: The International Federation of Gynaecology and Obstetrics (FIGO) score identifies gestational trophoblastic neoplasia (GTN) patients as low- or high-risk of single-agent chemotherapy resistance (SACR). Computed tomography (CT) has greater sensitivity than chest X-ray (CXR) in detecting pulmonary metastases, but effects upon outcomes remain unclear. METHODS: Five hundred and eighty-nine patients underwent both CXR and CT during GTN assessment. Treatment decisions were CXR based. The number of metastases, risk scores, and risk category using CXR versus CT were compared. CT-derived chest assessment was evaluated as impact upon treatment decision compared to patient outcome, incidence of SACR, time-to-normal human chorionic gonadotrophin hormone (TNhCG), and primary chemotherapy resistance (PCR). RESULTS: Metastasis detection (p < 0.0001) and FIGO score (p = 0.001) were higher using CT versus CXR. CT would have increased FIGO score in 188 (31.9%), with 43 re-classified from low- to high-risk, of whom 23 (53.5%) received curative single-agent chemotherapy. SACR was higher when score (p = 0.044) or risk group (p < 0.0001) changed. Metastases on CXR (p = 0.019) but not CT (p = 0.088) lengthened TNhCG. Logistic regression analysis found no difference between CXR (area under the curve (AUC) = 0.63) versus CT (AUC = 0.64) in predicting PCR. CONCLUSIONS: CT chest would improve the prediction of SACR, but does not influence overall treatment outcome, TNhCG, or prediction of PCR. Lower radiation doses and cost mean ongoing CXR-based assessment is recommended.

Evidence for Rapid Oxidative Phosphorylation and Lactate Fermentation in Motile Human Sperm by Hyperpolarized 13C Magnetic Resonance Spectroscopy.

Poor sperm motility is a common cause of male infertility for which there are no empirical therapies. Sperm motility is powered by adenosine triphosphate but the relative importance of lactate fermentation and Oxidative Phosphorylation (OxPhos) is debated. To study the relationship between energy metabolism and sperm motility we used dissolution Dynamic Nuclear Polarization (dDNP) for the first time to show the rapid conversion of 13C1-pyruvate to lactate and bicarbonate, indicating active glycolytic and OxPhos metabolism in sperm. The magnitude of both lactate and bicarbonate signals were positively correlated with the concentration of progressively motile sperm. After controlling for sperm concentration, increased progressive sperm motility generated more pyruvate conversion to lactate and bicarbonate. The technique of dDNP allows 'snapshots' of sperm metabolism to be tracked over the different stages of their life. This may provide help to uncover the causes of poor sperm motility and suggest new approaches for novel treatments or therapies.

Why don't some men with banked sperm respond to letters about their stored samples?

Abstract Long-term storage of banked sperm, especially when it is not needed, for reproductive purposes, is costly and poses practical problems for sperm banks. For sperm banks to function efficiently, men must understand the implications of unnecessary storage, and make timely decisions about disposal of their own samples. Men who bank sperm prior to cancer treatment are routinely offered follow-up consultations to test their fertility, update consent and, where necessary, expedite referral for Assisted Conception. Yet sperm banks report that men do not respond to letters, suggesting samples are stored needlessly. We conducted semi-structured interviews with six men with a history of not responding to letters, to document reasons for non-response. Interviews were transcribed and analysed using Interpretive Phenomenological Analysis. Men's reasons for not responding are a complex interplay between past, present and future perspectives. In terms of their past, information is important on diagnosis, because men must understand that fertility can change after treatment. Present and future concerns focus on fears of being told fertility has not recovered and being pressured to dispose of banked sperm. The challenge is to devise invitation letters that address men's concerns while offering them tangible benefits and peace of mind.

Banking sperm is only the first of many decisions for men: what healthcare professionals and men need to know.

Sperm banking is recommended for all males prior to cancer treatment where there are risks of infertility. Subsequent decisions about monitoring fertility, use of banked sperm or disposal are less well understood, with adverse consequences for men and cost implications. We review the literature around key decision points: Diagnosis of cancer, monitoring fertility, use of banked sperm and sperm disposal. The results suggest that decisions about banking are compromised by concerns to initiate treatment quickly; subsequent decisions about monitoring fertility, use of banked sperm or disposal are coloured by the views of family members, men's failure to understand the longer-term implications and their reluctance to avail themselves of health care generally. Methodological limitations of current research include low response rates, increased focus on germ cell cancers and a lack of research outside North America. There is evidence that men and oncologists could use sperm banks more "wisely". Lack of longitudinal work means it is not possible to determine the long-term consequences of banking for men's general health and well-being, or identify barriers to fertility monitoring or disposal. We argue that sperm banking should be considered as a series of decisions, all involving implications for fertility, contraception and social and psychological adjustment to cancer.

Raised inflammatory markers in semen from men with asymptomatic chlamydial infection.

The aim of this study was to determine whether interleukin (IL)-6 and IL-8 concentrations, as well as numbers of seminal leukocytes in a population of infertile men, some of whom were Chlamydia trachomatis positive, were related to chlamydial infection. Our patient group included 255 men attending for diagnostic semen analysis as part of infertility investigations. Significantly raised levels of IL-8, but not IL-6, were found in C trachomatis-infected patients but not in uninfected patients. Raised IL-8 levels in semen were also associated with an increase in semen volume. There was a relationship between C trachomatis infection and lower progressive motile sperm, as well as an increase in seminal leukocytes. The overall prevalence rate for C trachomatis was 6.2%, and more infections were detected in semen than in first void urine. This study supports the suggestion that IL-8 might be used as a marker for male genital tract infection, especially when due to C trachomatis. In this study, there was a relationship between the presence of C trachomatis in semen and alterations of some semen parameters. Further investigations should be performed to understand the disparities of first void urine and semen testing for detection of C trachomatis in males.

The use of pornographic materials by adolescent male cancer patients when banking sperm in the UK: legal and ethical dilemmas.

Increased awareness of the importance of fertility concerns to teenage cancer survivors is leading to growing numbers of male teenagers being offered sperm banking at the time of diagnosis. This is now extending to males diagnosed with other conditions where gonadotoxic agents are used in treatment. The storage of sperm in these circumstances is a challenging aspect of health care, given the complex issues and timescale involved. UK law has been enacted to protect legal minors from the potentially harmful effects of exposure to pornographic materials, yet there is reason to suppose that their use in this context could have therapeutic benefit in aiding successful masturbation. This paper uses material gained through consultation with the eleven largest UK sperm banks and 94 male teenage cancer survivors, to discuss the associated legal and ethical dilemmas, including those around the role of parents/carers. Findings suggest that there is variable practice in sperm banks, that almost a quarter of teenage males wanted access to soft porn when banking sperm, and half wanted to bring in their own materials. It concludes that there is an urgent need for any legal barriers to the therapeutic use of pornographic materials to be understood and examined.

Practical aspects of sperm banking for cancer patients.

Semen storage is now routinely offered to men of reproductive age who are diagnosed with malignant disease and who require surgical or chemotherapeutic treatments that have a significant risk of leaving them sterile or subfertile. There is a perception by the public at large and professionals in the field that this is a routine and simple process. Yet, semen storage for such men requires a number of unique skills from a multidisciplinary team of oncologists, nurses, counsellors and scientists (andrologists or embryologists) in order to provide a quality service to the patient. All too often it is seen as 'just another branch' of assisted conception treatment but there are sufficient unique issues for it to be considered a specialty in its own right. In the absence of professional guidelines to outline 'best practice', the British Andrology Society invited interested parties to attend a one-day workshop. This was designed as an interactive workshop for all those involved in the process of semen storage, be they clinicians, nurses, counsellors and scientific staff from either the disciplines of reproductive medicine or oncology. It was intended to examine the process of semen storage for such patients from the point of initial diagnosis, through the process of banking semen samples, to the point at which they are either used in treatment or are discarded. The programme was designed to promote maximum interaction between the speakers and the audience and between those from different specialties and disciplines so that they may learn from each other, developing and improving the service that is provided to these men.