Biomarkers in Lung Cancer Screening: a Narrative Review.

Although when used as a lung cancer screening tool low-dose computed tomography (LDCT) has demonstrated a significant reduction in lung cancer related mortality, it is not without pitfalls. The associated high false positive rate, inability to distinguish between benign and malignant nodules, cumulative radiation exposure, and resulting patient anxiety have all demonstrated the need for adjunctive testing in lung cancer screening. Current research focuses on developing liquid biomarkers to complement imaging as non-invasive lung cancer diagnostics. Biomarkers can be useful for both the early detection and diagnosis of disease, thereby decreasing the number of unnecessary radiologic tests performed. Biomarkers can stratify cancer risk to further enrich the screening population and augment existing risk prediction. Finally, biomarkers can be used to distinguish benign from malignant nodules in lung cancer screening. While many biomarkers require further validation studies, several, including autoantibodies and blood protein profiling, are available for clinical use. This paper describes the need for biomarkers as a lung cancer screening tool, both in terms of diagnosis and risk assessment. Additionally, this paper will discuss the goals of biomarker use, describe properties of a good biomarker, and review several of the most promising biomarkers currently being studied including autoantibodies, complement fragments, microRNA, blood proteins, circulating tumor DNA, and DNA methylation. Finally, we will describe future directions in the field of biomarker development.

In-plane quasi-single-domain BaTiO3 via interfacial symmetry engineering.

The control of the in-plane domain evolution in ferroelectric thin films is not only critical to understanding ferroelectric phenomena but also to enabling functional device fabrication. However, in-plane polarized ferroelectric thin films typically exhibit complicated multi-domain states, not desirable for optoelectronic device performance. Here we report a strategy combining interfacial symmetry engineering and anisotropic strain to design single-domain, in-plane polarized ferroelectric BaTiO3 thin films. Theoretical calculations predict the key role of the BaTiO3/PrScO3 [Formula: see text] substrate interfacial environment, where anisotropic strain, monoclinic distortions, and interfacial electrostatic potential stabilize a single-variant spontaneous polarization. A combination of scanning transmission electron microscopy, piezoresponse force microscopy, ferroelectric hysteresis loop measurements, and second harmonic generation measurements directly reveals the stabilization of the in-plane quasi-single-domain polarization state. This work offers design principles for engineering in-plane domains of ferroelectric oxide thin films, which is a prerequisite for high performance optoelectronic devices.

Ion thrusters for electric propulsion: Scientific issues developing a niche technology into a game changer.

The transition from old space to new space along with increasing commercialization has a major impact on space flight, in general, and on electric propulsion (EP) by ion thrusters, in particular. Ion thrusters are nowadays used as primary propulsion systems in space. This article describes how these changes related to new space affect various aspects that are important for the development of EP systems. Starting with a historical overview of the development of space flight and of the technology of EP systems, a number of important missions with EP and the underlying technologies are presented. The focus of our discussion is the technology of the radio frequency ion thruster as a prominent member of the gridded ion engine family. Based on this discussion, we give an overview of important research topics such as the search for alternative propellants, the development of reliable neutralizer concepts based on novel insert materials, as well as promising neutralizer-free propulsion concepts. In addition, aspects of thruster modeling and requirements for test facilities are discussed. Furthermore, we address aspects of space electronics with regard to the development of highly efficient electronic components as well as aspects of electromagnetic compatibility and radiation hardness. This article concludes with a presentation of the interaction of EP systems with the spacecraft.

Minor histocompatibility antigen UTY as target for graft-versus-leukemia and graft-versus-haematopoiesis in the canine model.

Male patients with female-stem-cell donors have better prognosis compared to female-to-male combinations due to Y-encoded minor histocompatibility antigens recognized by female-alloimmune-effector lymphocytes in the context of a graft-versus-leukemia (GvL) effect. We provide data in a dog-model that the minor histocompatibility antigen UTY might be a promising target to further improve GvL-immune reactions after allogeneic-stem-cell transplantations. Female-canine-UTY-specific T cells (CTLs) were stimulated in vitro using autologous-DCs loaded with three HLA-A2-restricted-UTY-derived peptides (3-fold-expansion), and specific T cell responses were determined in 3/6 female dogs. CTLs specifically recognized/lysed autologous-female-peptide-loaded DCs, but not naïve-autologous-female DCs and monocytes. They mainly recognized bone-marrow (BM) and to a lower extent DCs, monocytes, PBMCs and B-cells from DLA-identical-male littermates and peptide-loaded T2-cells in an MHC-I-restricted manner. A UTY-/male-specific reactivity was also obtained in vivo after stimulation of a female dog with DLA-identical-male PBMCs. In summary, we demonstrated natural UTY processing and presentation in dogs. We showed that female-dog CTLs were specifically stimulated by HLA-A2-restricted-UTY peptides, thereby enabling recognition of DLA-identical-male cells, mainly BM cells. These observations suggest UTY as a promising candidate-antigen to improve GvL-reactions in the course of immunotherapy.

[Current place of the Hühner test in the work-up of couple infertility]. / Place actuelle du test de Hühner dans l'exploration de la stérilité conjugale.

The interest of the postcoital test (PCT) has been subject to debate in the last ten years. In France, it is considered as part of the basic fertility work-up, since it is no longer recommended as routine investigation in English literature. However, there is no evidence-based demonstration to support the test being ostracized. PCT is still useful as a diagnostic tool to control intercourse, quantify sperm concentration and evaluate sperm mobility in the cervical mucus.

Significance of ovarian histology in the management of patients presenting a premature ovarian failure.

BACKGROUND: Premature ovarian failure (POF) is a heterogeneous syndrome, possibly due to mutations of genes involved in the normal development of the ovary and/or follicles. Based essentially on animal models, these mutations are associated with various ovarian phenotypes, from a complete absence of follicles to a partial follicular maturation. The aim of the present study was to determine whether ovarian histology, compared to pelvic ultrasonography, would be helpful in identifying which patients display an impaired follicular reserve and/or growth, and in orientating the search for POF aetiology. METHODS AND RESULTS: We studied a cohort of 61 patients suffering from POF with a normal karyotype. Their median age (range) at diagnosis was 26 years (15-39). The FSH plasma level was high, 67.0 IU/l (13-155). Estradiol and inhibin B plasma levels were low: 18.5 pmol/l (18.5-555) and 5 pg/ml (5-105) respectively. Both pelvic ultrasonography and ovarian biopsies were performed in each patient. The presence of follicles suggested at ultrasonography was confirmed at histology in 56% of the patients. Ovarian histology led to the distinction of two phenotypes: (i) small-sized ovaries, deprived of follicles; and (ii) normal-sized ovaries with partial follicular maturation. To confirm the value of ovarian biopsies, samples from 20 normal women were studied. These demonstrated that ovarian biopsy at random enables reliable assessment of follicular presence, especially when their size is <2 mm. CONCLUSION: Ovarian histology appears to be a reliable tool in evaluating the follicular reserve, and helpful and complementary to clinical and hormonal phenotyping in orienting the search for the various genetic causes of POF syndrome.

Kinetics of SRY gene appearance in maternal serum: detection by real time PCR in early pregnancy after assisted reproductive technique.

BACKGROUND: Fetal DNA circulating in maternal serum offers a possibility for non-invasive prenatal diagnosis but its kinetics during very early pregnancy is still unclear. In order to clarify this point, the studies on the kinetics of fetal DNA appearance in maternal serum were conducted on patients undergoing assisted reproduction. METHODS: Using a quantitative real time PCR assay, the presence of SRY gene sequences was evaluated in the serum of patients at the onset of pregnancy. RESULTS: Twenty-seven patients were originally studied but first trimester abortion occurred in five cases. Among the 22 ongoing pregnancies, ten were found to bear at least one male fetus and all sera from these women gave positive results for SRY gene detection. The SRY gene was found to be detectable as soon as day 18 after embryo transfer in one case and it had been found in the other nine patients by day 37. CONCLUSIONS: Fetal DNA is found in maternal serum even before the fetal circulation is established, which is highly suggestive that it is released, at least in part, from the trophoblast. Detection of fetal DNA in maternal serum very early in pregnancy may have clinical implications such as with the management of pregnant women carrying a fetus at risk for congenital adrenal hyperplasia.

[Dating biometry with crown-rump length, precision of a routine practice]. / Précision de la biométrie de datation à l'échographie du premier trimestre dans la pratique courante.

OBJECTIVE: The goal of this study was to determine the accuracy of an everyday practice for assessing gestational age by ultrasound and redefine the correction of gestational age policy. MATERIALS AND METHODS: This study used first trimester measurements taken during a three-year period. We considered all births from pregnancies that began by an in vitro fertilization procedure. We examined 143 consecutive files containing 257 measurements made by 72 different operators. We applied two reference curves to calculate the date the pregnancy began and the centiles of the prediction interval for +/- 7, +/- 5 and +/- 3 days. RESULTS: The prediction intervals for +/-7, +/-5, +/-3 days excluded 2%, 6%, and 25% respectively of the embryos from one of the two reference curves. These intervals were 1%, 5% and 20%, were better for the other curve. CONCLUSION: Correction of gestational age has to take into consideration variations in the embryo length. We correct the gestational age only if the difference with ultrasound assessment is more than one week.

Semen alterations in HIV-1 infected men.

BACKGROUND: Couples in whom the man is infected by human immunodeficiency virus (HIV) increasingly request assisted reproductive technology (ART) to allow safe procreation. Semen quality is critical in such situations. METHODS: Semen characteristics were evaluated in 189 HIV-infected men requesting ART. At the time of semen analysis all men were healthy and 177 were receiving anti-retroviral therapy. Comparisons were made with HIV-seronegative men, partners of women requiring IVF because of tubal infertility, after matching for age and sexual abstinence delay. RESULTS: The most significant semen alterations found in the HIV-infected men were reduced percentages of rapidly progressive sperm [median (range), 10% (0-30%) compared with 15% (5-30%) in the controls, P < 0.001], and increased concentrations of non-spermatic cells [3 x 10(6)/ml (0.2-16 x 10(6)/ml) compared with 1.1 x 10(6)/ml (0.1-14 x 10(6)/ml) in the controls, P < 0.001]. HIV-infected men also showed lower ejaculate volumes [2.8 ml (0.6-9.3 ml) compared with 3.6 ml (1.1-11 ml), P < 0.05] and total sperm counts [262.5 x 10(6) (0-1003 x 10(6)) compared with 310.5 x 10(6) (48.3-1679 x 10(6)), P < 0.05]. CONCLUSIONS: Semen evaluation in a large population of HIV-infected men requesting ART evidenced several alterations. Some of these anomalies might be related to anti-retroviral treatments.

[Acceptability and value of autoinjection of gonadotropins for ovarian stimulation in intrauterine insemination]. / Acceptabilité et intérêt de l'auto-injection de gonadotrophines pour la stimulation en vue d'une insémination intra-utérine.

OBJECTIVES: To evaluate the acceptability, the personal and economic benefit of subcutaneous self-injections of recombinant FSH within mono-ovulating stimulation for Intra Uterine Insemination (IUI). PATIENTS AND METHODS: Women aged < 42 years' old, enrolled for a series of three IIU associated with ovarian stimulation with FSH. All had an infertility > 2 years, at least one patent fallopian tube, and normal FSH and estradiol levels at day three of the cycle. In the male partner, the migration test yielded > 10(6) mobile spermatozoa with survivals > 10% after 24 h. Once entered in the study, the patients (with or without their partners) were informed and shown how to administer the injection. After each cycle, they filled up a questionnaire evaluating the training and the possible difficulties they had with their infertility treatment. RESULTS: Forty women were treated. 103 cycles were achieved (including 40 first cycles, 35 second cycles and 28 third cycles) 99 IUI were performed and ten pregnancies were obtained. Four cycles were cancelled: Premature fall of estradiol levels (n = 2), multiple pregnancy risk (n = 1) and spontaneous ovulation (n = 1). Three pregnancies occurred spontaneously between treatment cycles. All the patients appreciate to perform subcutaneous self-injections (themselves or by the partner) without any deleterious effect on stimulation cycles results and they expressed their will to continue for the next treatment cycles. CONCLUSION: After a quick initiation to subcutaneous injections, and its use, women appreciated their active involvement in the treatment and the self-sufficiency so achieved. By planning an educational program, medical staff could participate to improve the stress experienced by the women and their partners through the infertility treatment.

[Fertility preservation by ovarian tissue cryopreservation]. / Préservation de la fertilité par congélation de tissu ovarien.

Female fertility may be compromised after radio or chemotherapy for malignant as well as non-malignant diseases. It could be saved by cryopreservation of ovarian tissue, since it is now well established that primordial follicles can survive freezing. Many births have been obtained in rodents with thawed ovarian fragments, after grafting or in vitro folliculogenesis. Both techniques are more difficult in large animal species, and need further development to enter clinical practice. However, storing ovarian samples is already indicated, especially in younger patients who will require restoration of their fertility in a far future.

Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin).

OBJECTIVE: To confirm the value of a single dose of 3 mg of cetrorelix in preventing the occurrence of premature LH surges. DESIGN: Multicenter randomized, prospective study. SETTING: Reproductive medicine units. PATIENT(S): Infertile patients undergoing ovarian stimulation for IVF-ET. INTERVENTION(S): A single dose of 3 mg of cetrorelix (Cetrotide; ASTA Medica, Frankfurt, Germany) (115 patients) was administered in the late follicular phase. A depot preparation of triptorelin (Decapeptyl; Ipsen-Biotech, Paris, France) was chosen as a control agent (39 patients). Ovarian stimulation was conducted with hMG (Menogon; Ferring, Kiel, Germany). MAIN OUTCOME MEASURE(S): Premature LH surges (LH level >10 IU/L), progesterone level greater than 1 ng/L, and IVF results. RESULT(S): No LH surge occurred after cetrorelix administration. The patients in the cetrorelix group had a lower number of oocytes and embryos. The percentage of mature oocytes and fertilization rates were similar in both groups, and the pregnancy rates were not statistically different. The length of stimulation, number of hMG ampules administered, and occurrence of the ovarian hyperstimulation syndrome were lower in the cetrorelix group. Tolerance of cetrorelix was excellent. CONCLUSION(S): A cetrorelix single-dose protocol prevented LH surges in all patients studied. It compares favorably to the "long protocol" and could be a protocol of choice in IVF-ET.

Dating biometry during the first trimester: accuracy of an every-day practice.

OBJECTIVE: The goal of this study was to determine the accuracy of an every-day practice for assessing gestational age by ultrasound measurement of the greatest embryonic length (GEL). DESIGN: This retrospective study used measurements taken during the first trimester. SUBJECTS: We considered all births in this hospital between 1 January 1992 and 31 December 1994 from pregnancies that began by an in-vitro fertilization procedure (IVF). We examined 143 consecutive files, containing 257 measurements made by 72 different operators. METHODS: The precision of seven embryo growth curves was compared. We calculated for each curve its ability to predict (95% prediction interval) the date the pregnancy began, using these dated pregnancies. RESULT: For GEL measurements between 3 and 80 mm, which includes most of our population, Robinson and Wisser (2) were the most appropriate curves. The 95% prediction interval was 9.5 and 10.2 days respectively. CONCLUSION: Dating pregnancies in every-day practice with GEL is nearly as accurate as prospective studies with only one or two scanners.

New natural inactivating mutations of the follicle-stimulating hormone receptor: correlations between receptor function and phenotype.

Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12+/-3% residual activity, whereas in patient 1 a 24+/-4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient.

Predictive value of early human chorionic gonadotrophin serum profiles for fetal growth retardation.

The possibility of using first trimester maternal serum human chorionic gonadotrophin (HCG) profiles to predict fetal growth retardation (FGR) was tested in 236 women with singleton pregnancies obtained after in-vitro fertilization (IVF). Pregnancies were monitored by serial analysis (two or more) of serum HCG at at least 48 h intervals. Serum was obtained between the 13th and the 35th day after conception (i.e. on the day of IVF). Early miscarriage occurred in 23.7% and FGR in 10.9% of pregnancies. Serum HCG profiles were higher than the 90th and lower than the 10th percentile in 12.3% and 19.5% of the cases respectively. FGR was significantly more frequent in women with serum HCG profiles lower than the 10th percentile than in women with normal profiles (45.5% versus 7.2%; P < 0.001), with a relative risk of 6.5 (95% confidence interval 2.7-15.6). FGR rates were similar in women with normal and high profiles of serum HCG. Pre-eclampsia and premature delivery rates were similar in women with normal and abnormal profiles of serum HCG. First trimester serum HCG should be further investigated as a potential marker of FGR.

Pregnancies, growth and development of children conceived by subzonal injection of spermatozoa.

Subzonal injection of spermatozoa (SUZI) was one of the first micromanipulation techniques efficient in treating male factor infertility and unexplained in-vitro fertilization failures. The aim of this retrospective study was to evaluate the in-vitro development of embryos conceived by SUZI, the obstetric outcome, the rate of congenital malformations and subsequent follow-up in children. Fifty-five pregnancies were obtained between 1991 and 1994 (54 after fresh embryos were transferred and one after cryopreserved embryos were transferred). Among the 50 clinical pregnancies, there were seven miscarriages (14%) and two ectopic pregnancies (4%). Among the 41 resulting evolutive pregnancies, the discovery of one anencephaly led to a medical abortion. Forty deliveries including six twin pregnancies occurred, leading to the births of 45 live neonates and one stillbirth. The gender distribution of the offspring included 17 males and 29 females (ratio 0.59:1). Birth weight, length and head circumference were within the expected ranges. Two children presented a malformation: the first one had one thumb with congenital shelf and the second a polymalformative neurological syndrome. Growth curves were normal for all these children except one (weight above the 2 SD curve). Medical follow-up detected no pathological features in these children apart from a physical disability in one girl. In this small series a 4.2% rate of malformation was observed, particularly affecting the neural tube, in SUZI offspring. However, no firm conclusions can be drawn since the study was carried out on a small cohort. SUZI is no longer performed but these observations suggest that it is necessary to collect extensive data about children conceived by microfertilization.

[Intracytoplasmic sperm injection (ICSI) in the management of azoospermia]. / L'injection intra cytoplasmique de spermatozoïdes (ICSI) dans la prise en charge des azoospermies.

OBJECTIVES: The objective of this study was to analyse all attempts of ICSI performed in our centre between 1995 and 1997 with surgically harvested sperm for the treatment of secretory and excretory azoospermia. MATERIAL AND METHODS: 71 infertile couples, in which the man suffered from secretory (n = 8) or excretory azoospermia (n = 63), were managed with 94 attempts of ICSI. RESULTS: ICSI was able to be performed 85 times with 82 embryo transfers resulting in 29 clinical pregnancies. The clinical pregnancy rate per ICSI attempt was comparable with sperm obtained on the day of ICSI or previously harvested and frozen (30.5% and 31.4% respectively). The clinical pregnancy rate per ICSI attempt was 33.3% for testicular sperm (n = 18), and 30.3% for epididymal sperm (n = 76). Twenty-seven clinical pregnancies (32.1%) were obtained for men with excretory azoospermia (47.2% for vas deferens agenesis and 20.8% for acquired urinary tract obstruction, p = 0.01), and 2 (20%) for men with secretory azoospermia. CONCLUSION: ICSI can achieve pregnancy in infertile couples in whom no other solution can be considered. Cryopreservation allows surgical harvesting to be dissociated from ICSI without decreasing the pregnancy rate, justifying freezing of sperm during any surgical procedure on the seminal tract. The better results obtained in congenital excretory azoospermia compared to acquired obstructions, usually post-infectious, suggest a harmful effect of infection on the quality of sperm.

[Intra-cytoplasmic sperm injection with testicular sperm: what strategy?]. / ICSI avec sperme testiculaire: quelle stratégie?

The pregnancy rate after ICSI with surgically retrieved spermatozoa varies according to the etiology and to the level of sperm retrieval in the genital tract. The use of testicular sperm in all cases is discussed.

Psychological reactions after multifetal pregnancy reduction: a 2-year follow-up study.

This study had two objectives. Firstly we assessed the effects of multifetal pregnancy reduction on the mothers' emotional well-being and the relationship with the children during the 2 years following intervention. Secondly at 2 years we compared mothers who had a reduction with mothers who had not and had delivered triplets. The comparisons focused on the mothers' health and their relationship with the children. Women having had a reduction in two hospitals in Paris, between May 1992 and June 1993, were contacted just after intervention for a prospective study. In all, 18 women were included. At 1 and 2 years, 10 women participated. At 2 years, 10 additional women were included. The answers of these 20 mothers were compared to those of 11 consecutive mothers of 2 year old triplets, assessed by the same psychologist in a previous prospective study. Semi-structured interviews were conducted at home. The mothers' social characteristics, their parity, the children's condition at birth and 4 months were very similar between the reduction and triplet groups. One year after birth one-third of the women in the reduction group reported persistent depressive symptoms related to the reduction, mainly sadness and guilt. The others made medical and rational comments expressing no emotion. At 2 years all but two women seemed to have overcome the emotional pain associated with the reduction. The comparison with mothers of triplets indicated that the mothers' anxiety and depression, and difficult relationship with the children were less acute in the reduction group. These results presented some limitations, since a high number of women who miscarried or refused to participate in the follow-up were not assessed at 1 and 2 years. However, a majority of women who participated in the study 2 years after intervention seemed able to accept a multifetal pregnancy reduction to achieve parental goals.