Appraisal of cancer drugs: a comparison of the French health technology assessment with value frameworks of two oncology societies.

OBJECTIVES: Our primary objective was to compare the grading of the value of cancer drugs ('Amélioration du Service Médical Rendu' [ASMR] level) by the French health technology assessment authority ('Haute Autorité de santé' [HAS]) with that by the American Society of Clinical Oncology Value Framework (ASCO-VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Our secondary objective was to study the drivers of the French grading system. METHODS: We included new drugs for solid tumors assessed by the HAS between 2010 and 2016 and compared their ASMR level to scores calculated by the 2016-updated ASCO-VF and 2015 ESMO-MCBS. RESULTS: We investigated 27 new cancer drugs assessed by the French HAS between 2010 and 2016. Among the 17 drugs eligible for comparison, the correlation between ASMR levels and ASCO and ESMO scores was weak (r = 0.34 and r = 0.27, respectively). The agreement between the HAS and ESMO regarding the level of meaningful additional benefit was moderate (kappa = 0.43). We found no significant association between 12 potential variables and ASMR level of additional benefit of drugs. CONCLUSION: Our findings show inconsistencies in cancer drug appraisals among the three appraisers.

[Environment and lifestyle: Impacts on male fertility?] / Toxiques, mode de vie, environnement : quels impacts sur la fertilité masculine ?

In this last century, an increase of men infertility has been registered. It has been suggested that environmental factors could a negative impact over sperm quality. Among these factors, impact of environmental toxicant has been spread by media. In this review of scientific literature, we identify several environmental factors that could impact men fertility in a negative way. These factors are tobacco, marijuana, weight, body mass index, heat, nutritional state, electromagnetic waves and altitude. For each of these factors, the impact over men fertility, their mechanism, as well their influence over the use of Assisted Reproductive Technics are reported.

Disparities in reproductive outcomes according to the endometrial preparation protocol in frozen embryo transfer : The risk of early pregnancy loss in frozen embryo transfer cycles.

PURPOSE: The purpose of this study was to determine the effect of stimulated and artificial endometrial preparation protocols on reproductive outcomes in frozen embryo transfer (FET) cycles. METHODS: We performed a retrospective study of 1926 FET cycles over a 3.5-year period in the Fertility Unit at a University Hospital. Stimulated and artificial protocols were used for endometrial preparation. The embryos for FET were obtained from either in vitro fertilization or intracytoplasmic sperm injection cycles. Live birth rate and early pregnancy loss rates were retrospectively compared. In artificial protocols, oral or vaginal administration of oestradiol 2 mg two or three times a day was followed by vaginal supplementation with progesterone 200 mg two or three times a day. In stimulated protocols, recombinant follicle-stimulating hormone was administered from day 4 onward. Vaginal ultrasound was used for endometrial and ovarian monitoring. A pregnancy test was performed 14 days after FET. If it was positive, oestradiol and progesterone were administered up until the 12th week of gestation in artificial cycles. We defined early pregnancy losses as biochemical pregnancies (preclinical losses) and miscarriages. RESULTS: Data on 865 artificial cycles (45% of the total) and 1061 stimulated cycles (55%) were collected. Early pregnancy loss rate was significantly lower for stimulated cycles (34.2%) than for artificial cycles (56.9%), and the live birth rate was significantly higher for stimulated cycles (59.7%) than for artificial cycles (29.1%). CONCLUSION: In frozen embryo transfer, artificial cycles were associated with more early pregnancy loss and lower live birth rate than stimulated cycles.

To be or not to be [fertile], that is the question.

BACKGROUND: According to our literature analysis, there are no data focused on spermatozoa emotional representations in childless men and data on the emotional repercussions of a diagnosis of infertility on men are still scarce. Thus, in this work, we investigated what the presence or absence of spermatozoa in the semen symbolize for men. MATERIAL AND METHODS: To answer this question, 441 childless heterosexual men participated in an anonymous, prospective, Internet-based survey. RESULTS: In response to the question "What would having a high or normal sperm count symbolize for you?" the most frequent answer was "ability to father a child". Men living with a partner were significantly more likely than single men to answer "ability to father a child" (p < 0.05) and less likely to answer "virility" and/or "ability to have an erection/ejaculation" (p = 0.001). In response to the question "If you found out that you had a low sperm count or no spermatozoa at all, how would you feel?", most of the men stated that they would be disappointed. Men living with a partner were more likely to state that they would feel ashamed (p < 0.05) or guilty with regard to their partner (p < 0.0001). CONCLUSIONS: These preliminary results should help us to improve (i) the way that male infertility is announced (it is easier to find the right words if one understands the possible importance of having a high sperm count) and (ii) the psychological, marital and sexual counselling provided to men with a diagnosis of infertility.

CONTEXTE: Dans la littérature, peu d'articles traitent du ressenti des hommes vis à vis de leurs spermatozoïdes. Que signifie pour un homme "avoir ou non des spermatozoïdes"? Voilà la question que nous nous sommes posée. MATERIEL ET METHODES: Pour y répondre nous avons élaboré un questionnaire qui a été rempli en ligne par 441 hommes hétérosexuels âgés de 18 à 45 ans et sans enfants. RESULTATS: A la question, "que signifie pour vous avoir des spermatozoïdes?", la majorité d'entre eux a répondu "être père". Les hommes en couple ont statistiquement répondu plus fréquemment "être père" (p < 0.05) et significativement moins fréquemment "être un (vrai) homme", "être viril", "être capable d'avoir une érection/éjaculation" comparativement aux hommes célibataires (p = 0.001). A la question, "qu' éprouveriez vous si on vous annonçait que vous n'aviez pas de spermatozoïdes ou moins que la normale?" la majorité d'entre eux à répondu "je serais déçu". Les hommes en couples ont répondu significativement plus fréquemment qu'ils se sentiraient honteux (p < 0.05) ou coupables vis à vis de leur partenaire (p < 0.0001). CONCLUSIONS: Ces résultats préliminaires doivent nous aider à mieux comprendre le ressenti des hommes vis à vis de leurs spermatozoïdes et nous aider, nous spécialistes de l'infertilité, à mieux annoncer des infertilités par azoospermie ou oligospermie en adoptant une démarche de conseil psychologique, sexuel et conjugal dans l'annonce de cette infertilité masculine. En effet "ne pas avoir un nombre élevé de spermatozoïdes et a fortiori ne pas en avoir du tout" peut avoir un impact négatif sur l'homme en termes d'humeur, de culpabilité et d'estime de soi.

A human morphologically normal spermatozoon may have noncondensed chromatin.

According to numerous assisted reproductive medicine practitioners, semen with normal characteristics might not require further investigation. However, on the scale of the individual spermatozoon, it is well known that normal morphology does not guarantee optimal nuclear quality. Here, for 20 patients with normal sperm characteristics and a high proportion of spermatozoa with noncondensed chromatin, we subsequently assessed chromatin condensation status (aniline blue staining) and morphology (Papanicolaou staining) of the same 3749 spermatozoa. Although the overall proportion of morphologically normal spermatozoa was not correlated with the overall proportion of spermatozoa with noncondensed chromatin, an individual spermatozoon's morphology appeared to be closely related to its chromatin condensation status. Morphologically normal spermatozoa with noncondensed chromatin were seen in all patients; the proportion averaged 23.3% [min 10.9%-max 44.4%]. Morphologically abnormal spermatozoa were more likely to have noncondensed chromatin than morphologically normal ones (P < 0.0001). Small-, large- or multiple-headed spermatozoa presented the highest degree of noncondensation (>80% for each type), and more than half the vacuolated spermatozoa also presented noncondensed chromatin. However, a morphologically normal spermatozoon may also have a noncondensed chromatin.

[How can we nowadays select the best embryo to transfer?]. / Comment sélectionner aujourd'hui le meilleur embryon à transférer ?

Multiple pregnancies stand as the most common adverse outcome of assisted reproduction technologies (ART) and the dangers associated with those pregnancies have been reduced by doing elective single embryo transfers (e-SET). Many studies have shown that e-SET is compatible with a continuously high pregnancy rate per embryo transfer. Yet, it still becomes necessary to improve the selection process in order to define the quality of individual embryos - so that the ones we choose for transfer are more likely to implant. First, analysis of embryo morphology has greatly helped in this identification and remains the most relevant criterion for choosing the embryo. The introduction of time-lapse imaging provides new criteria predictive of implantation potential, but the real contribution of this system - including the benefit/cost ratio - seems to be not yet properly established. In this context, extended culture until blastocyst stage is an essential practice but it appears wise to keep it for a population showing a good prognosis. Then, the failure of aneuploid embryos to implant properly led to achieve preimplantation genetic screening (PGS) in order to increase pregnancy and delivery rates after ART. However, PGS by fluorescence in situ hybridization (FISH) at day 3 is a useless process - and may even be harmful. Another solution involves using comparative genomic hybridisation (CGH) and moving to blastocyst biopsy. Finally, it is envisaged that morphology will also be significantly aided by non-invasive analysis of biomarkers in the culture media that give a better reflection of whole-embryo physiology and function.

High-magnification selection of spermatozoa prior to oocyte injection: confirmed and potential indications.

Intracytoplasmic morphologically selected sperm injection (IMSI) involves the use of differential interference contrast microscopy at high magnification (at least ·6300) to improve the observation of live human spermatozoa (particularly by showing sperm head vacuoles that are not necessarily seen at lower magnifications) prior to intracytoplasmic sperm injection (ICSI) into the oocyte. However, a decade after IMSI's introduction, the technique's indications and ability to increase pregnancy and/or birth rates (relative to conventional ICSI) are subject to debate. In an attempt to clarify this debate, this work performed a systematic literature review according to the PRISMA guidelines. The PubMed database was searched from 2001 onwards with the terms 'IMSI', 'MSOME' and 'high-magnification, sperm'. Out of 168 search results, 22 relevant studies reporting IMSI outcomes in terms of blastocyst, pregnancy, delivery and/or birth rates were selected and reviewed. The studies' methodologies and results are described and discussed herein. In view of the scarcity of head-to-head IMSI versus ICSI studies, the only confirmed indication for IMSI is recurrent implantation failure following ICSI. All other potential indications of IMSI require further investigation.

Evidence for a self-associating equilibrium intermediate during folding of human growth hormone.

It has been previously shown, by equilibrium denaturation, that human growth hormone (hGH) folds by a cooperative two-state process. This is in contrast to the folding pathways of other nonhuman growth hormones that contain stable monomeric and multimeric equilibrium intermediates. We have reinvestigated the equilibrium denaturation of hGH at higher protein concentrations and found smooth transitions from the native to denatured state, but the calculated free energy for unfolding, delta G, decreases with increasing protein concentration. The effect of protein concentration on the delta G of unfolding is due to the presence of folding intermediates that have a tendency to self-associate. A correlation was found between the equilibrium denaturation data and the observation of precipitation that occurs upon refolding, suggesting that the presence of self-associated folding intermediates leads to precipitation. Direct evidence for the existence of a soluble, associated intermediate was obtained by dynamic light scattering (DLS) and equilibrium analytical ultracentrifugation. Peptide fragments from the third helix of either hGH or bovine growth hormone (bGH) were capable of inhibiting the formation of this aggregated species and prevent precipitation during refolding. The data show that the folding pathway of hGH is similar to that of nonhuman growth hormones except for differences in the tendency for intermediates to self-associate. These findings are relevant to the design and interpretation of equilibrium folding experiments, and may be important to understanding mechanistic details of protein folding and aggregation in vivo.

Altering the association properties of insulin by amino acid replacement.

The importance of ProB28 and LysB29 on the self-association of insulin was established by systematically truncating the C terminus of the B chain. The relationship between structure and association was further explored by making numerous amino acid replacements at B28 and B29. Association was studied by circular dichroism, size-exclusion chromatography and ultracentrifugation. Our results show that the location of a prolyl residue at B28 is critical for high-affinity self-association. Removal of ProB28 in a series of C-terminal truncated insulins, or amino acid replacement of ProB28, greatly reduced association. The largest disruption to association was achieved by replacing LysB29 with Pro and varying the amino acid at B28. Several of the analogs were predominantly monomers in solutions up to 3 mg/ml. These amino acid substitutions decreased association by primarily disrupting the formation of dimers. Such amino acid substitutions also substantially reduced the Zn-induced insulin hexamer formation. The formation of monomeric insulins through amino acid replacements was accompanied by conformational changes that may be the cause for decreased association. It is demonstrated that self-association of insulin can be drastically altered by substitution of one or two key amino acids.

Detection of an equilibrium intermediate in the folding of a monomeric insulin analog.

To determine the conformational properties of the C-terminal region of the insulin B-chain relative to the helical core of the molecule, we have investigated the fluorescence properties of an insulin analog in which amino acids B28 and B29 have been substituted with a tryptophan and proline residue respectively, ([WB28,PB29]insulin). The biological properties and far-UV circular dichroism (CD) spectrum of the molecule indicate that the conformation is similar to that of native human insulin. Guanidine hydrochloride (GdnHCl)-induced equilibrium denaturation of the analog as monitored by CD intensity at 224 nm indicates a single cooperative transition with a midpoint of 4.9 M GdnHCl. In contrast, when the equilibrium denaturation is observed by steady-state fluorescence emission intensity at 350 nm, two distinct transitions are observed. The first transition accounts for 60% of the observed signal and has a midpoint of 1.5 M GdnHCl. The second transition roughly parallels that observed by CD measurements with an approximate midpoint of 4.5 M GdnHCl. The near-UV CD spectrum, size-exclusion, and ultracentrifugation properties of [WB28,PB29]insulin indicate that this analog does not self-associate in a concentration-dependent manner as does human insulin. Thus, the observed fluorescence changes must be due to specific conformational transitions which occur upon unfolding of the insulin monomer with the product of the first transition representing a stable folding intermediate of this molecule.