The awareness of radiologists for the presence of lateral lymph nodes in patients with locally advanced rectal cancer: a single-centre, retrospective cohort study.

OBJECTIVES: Enlarged lateral lymph nodes (LLNs) are associated with increased (lateral) local recurrence rates. Size and anatomical location should therefore always be reported by radiologists and discussed during multidisciplinary meetings. The objective was to investigate how often LLNs are mentioned in MRI reports in a tertiary referral centre. METHODS: A single - centre, retrospective study of 202 patients treated for primary rectal cancer between 2012 and 2020, with at least a T2 tumour located within 12cm of the anorectal junction. The radiology reports were written by 30-40 consultant radiologists. MRI scans were independently re-assessed by an expert radiologist. The primary outcome was how often the presence or absence of LLNs was mentioned in the initial report. RESULTS: Primary MRI reports explicitly mentioned the presence or absence of LLNs in 89 (44%) cases. Of the 43 reports with present LLNs, only one (1%) reported on all features such as size, location or malignant features. Expert review revealed 17 LLNs which were ≥ 7 mm (short-axis); two of these were not mentioned in the original reports. In 14/43 (33%) cases, LLNs were discussed during the primary multidisciplinary meeting, while 17/43 (40%) restaging MRI reports failed to report on the previously visible LLN. Reporting LLNs increased significantly with higher N-stage (p = .010) and over time (p = .042). CONCLUSIONS: Though improving with time, there is still limited consistency in reporting LLNs. Only 44% of primary MRI reports mentioned LLNs and relevant features of those LLNs were seldomly reported. Given the importance of this information for subsequent treatment; increased awareness, proper training and the use of templates are needed. KEY POINTS: • Comprehensive reporting of lateral lymph nodes in primary MRI reports was limited to less than 50%. • Lateral lymph nodes are not always discussed during primary multidisciplinary meetings or mentioned in restaging reports. • Improvements in the awareness and knowledge of lateral lymph nodes are needed to ensure adequate multidisciplinary treatment decisions.

Reduced FSH and LH action: implications for medically assisted reproduction.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play complementary roles in follicle development and ovulation via a complex interaction in the hypothalamus, anterior pituitary gland, reproductive organs, and oocytes. Impairment of the production or action of gonadotropins causes relative or absolute LH and FSH deficiency that compromises gametogenesis and gonadal steroid production, thereby reducing fertility. In women, LH and FSH deficiency is a spectrum of conditions with different functional or organic causes that are characterized by low or normal gonadotropin levels and low oestradiol levels. While the causes and effects of reduced LH and FSH production are very well known, the notion of reduced action has received less attention by researchers. Recent evidence shows that molecular characteristics, signalling as well as ageing, and some polymorphisms negatively affect gonadotropin action. These findings have important clinical implications, in particular for medically assisted reproduction in which diminished action determined by the afore-mentioned factors, combined with reduced endogenous gonadotropin production caused by GnRH analogue protocols, may lead to resistance to gonadotropins and, thus, to an unexpected hypo-response to ovarian stimulation. Indeed, the importance of LH and FSH action has been highlighted by the International Committee for Monitoring Assisted Reproduction Technologies (ICMART) in their definition of hypogonadotropic hypogonadism as gonadal failure associated with reduced gametogenesis and gonadal steroid production due to reduced gonadotropin production or action. The aim of this review is to provide an overview of determinants of reduced FSH and LH action that are associated with a reduced response to ovarian stimulation.

Ultra-Orthodox Jews and infertility diagnosis and treatment.

BACKGROUND: 'Be fruitful and multiply' is the first God's command in the Bible. Every aspect in life of the Orthodox Jewish population, including the strive for fertility, is tightly covered by a wide set of commands and rules ('Halacha') that span more than 3,000 years. This is a unique example of a population that continues to adhere to such time-honored rules. OBJECTIVE: To describe rules that encourage fertility on one hand, but may hinder fertility and influence infertility diagnosis and treatment on the other. MATERIALS AND METHODS: Halacha rules that may affect fecundity. RESULTS: Orthodox Jews obey a complex set of rules that influence fertility. DISCUSSION AND CONCLUSION: This study provides fertility practitioners with background information that may help them when delivering professional care to Ultra-Orthodox Jewish infertile couples.

Should Cochrane reviews be performed during the development of new concepts?

Cochrane reviews are internationally recognized as the highest standard in evidence-based health care. A Cochrane analysis conducts systematic reviews of primary research in human health care, and the analysis includes a comprehensive search of all potentially relevant studies and the use of explicit, reproducible criteria in the selection of studies for review. Thus, Cochrane reviews, undoubtedly provide many useful clinical guidelines. In this opinion paper, however, it is questioned at what level of clinical development of a new strategy a Cochrane review should be conducted in order not to draw premature conclusions that may not be sustained later on. Previous examples of this are debated together with the most recent Cochrane review regarding GnRH agonist triggering of final oocyte maturation, in which debatable conclusions are drawn from early studies, when the concept was still under development. We question the current policy of meta-analysis and recommend that in the future, the meta-analysts should await the results of a sufficient number of well-performed studies with an established new regime before an analysis is performed in order to avoid too early and possibly biased conclusions.

GnRH agonist for triggering of final oocyte maturation: time for a change of practice?

BACKGROUND: GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase deficiency. Therefore, the challenge has been to rescue the luteal phase. Studies now report a luteal phase rescue, with a reproductive outcome comparable to that seen after hCG triggering. METHODS: This narrative review is based on expert presentations and subsequent group discussions supplemented with publications from literature searches and the authors' knowledge. Moreover, randomized controlled trials (RCTs) were identified and analysed either in fresh IVF cycles with embryo transfer (ET), oocyte donation cycles or cycles without ET; risk differences were calculated regarding pregnancy rate and OHSS rate. RESULTS: In fresh IVF cycles with ET (9 RCTs) no OHSS was reported after GnRHa triggering [0% incidence in the GnRHa group: risk difference 5% (with 95% CI: -0.07 to 0.02)]. Importantly, the delivery rate improved significantly after modified luteal support [6% risk difference in favour of the HCG group (95% CI: -0.14 to 0.2)] when compared with initial studies with conventional luteal support [18% risk difference (95% CI: -0.36 to 0.01)]. In oocyte donation cycles (4 RCTs) the OHSS incidence is 0% [10% risk difference (95% CI: 0.02-0.40)]. CONCLUSIONS: GnRHa triggering is a valid alternative to hCG triggering, resulting in an elimination of OHSS. After modified luteal support there is now a non-significant difference of 6% in delivery rate in favour of hCG triggering.

GnRH agonist for triggering final oocyte maturation in patients at risk of ovarian hyperstimulation syndrome: still a controversy?

PURPOSE: An update on the subject of ovarian hyperstimulation syndrome (OHSS) prevention with GnRH agonist ovulation trigger. METHODS: Review of pertinent English language studies published during the past 4 years. RESULTS: Randomized prospective studies support the notion that agonist trigger completely eliminates OHSS. Conflicting results regarding on going pregnancy rate probably reflect different approaches to luteal phase support. Embryos obtained and frozen after agonist trigger yield good clinical outcome in subsequent thaw cycles. CONCLUSIONS: The notion that agonist trigger can eliminate OHSS is strongly supported by randomized controlled trials. Further research is needed to assess optimal luteal support post agonist trigger.

Ovarian interleukin-1-induced gene expression: privileged genes threshold theory.

Interleukin (IL)-1, an established mediator of inflammation, is also a mediator of ovulation (a cyclic inflammatory-like process). We have shown that IL-1 beta induces the in vitro expression of genes believed to play important role in ovulation (IL-1 beta itself, its receptors, IL-1 beta receptor antagonist, glucose transporters 1 and 3, secretory and cytosolic phospholipase A(2), prostaglandin endoperoxide synthase 1 and 2). These experiments suggest that the target genes are turned on over a relatively narrow IL-1 beta dose range. Moreover, IL-1 induces gene expression in what appears to be a hierarchical manner. We hypothesize that IL-1 induces a host of ovulation-associated genes, in a manner that is not only dose-dependent, but also obeys a certain hierarchical order, serving as 'check gates' in securing successful ovulation.

Severe OHSS: yes, there is a strategy to prevent it!

Effective measures to prevent ovarian hyperstimulation syndrome (OHSS) remain controversial. It became almost 'common knowledge' that there is no strategy that may completely prevent OHSS. Extensive clinical experience (albeit not derived from prospective randomized studies) clearly documents the ability of a single administration of gonadotrophin-releasing hormone (GnRH) agonist to effectively trigger ovulation, while completely eliminating any threat of clinically significant OHSS. This strategy cannot be used if the pituitary is down-regulated (as is the case in most assisted reproductive cycles today), however, the newly-introduced GnRH antagonists open new opportunities for implementing this strategy, since the pituitary preserves its responsiveness to GnRH agonists. Combining GnRH antagonist-based ovarian stimulation (particularly in 'high responders'), with GnRH agonist-driven ovulation triggering will make severe OHSS a disease of the past in assisted reproduction.

Embryo implantation and GnRH antagonists: GnRH antagonists in ART: lower embryo implantation?

Recently, concerns have been raised regarding possible adverse effects of gonadotrophin-releasing hormone (GnRH) antagonists on extra-pituitary reproductive cells and organs, i.e. ovarian cells, oocyte, embryo, endometrium. These concerns are based on numerous in-vitro studies suggesting decreased biosynthesis of growth factors caused by local action of GnRH antagonists. Clinically, it has been shown that the use of high doses (< or =1 mg daily) of GnRH antagonists is associated with low implantation rates in IVF. Although such direct adverse effect of GnRH antagonists cannot be ruled out at this time, so far clinical experience points to profound LH suppression as the major caveat associated with the use of high doses of GnRH antagonists. Very low LH concentrations are associated with aberrant concentrations of oestradiol during ovarian stimulation, which may in turn adversely effect implantation potential. The clinical data available thus far on the use of GnRH antagonists originate from protocols designed for clinical studies. It is predicted that as more clinical experience is gained, and with protocol modifications to suit individual patient response, GnRH antagonists will be comparable with the agonists in terms of cycle outcome.

Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication.

A new treatment option for patients undergoing ovarian stimulation is the gonadotrophin-releasing hormone (GnRH) antagonist protocol, with the possibility to trigger a mid-cycle LH surge using a single bolus of GnRH agonist, reducing the risk of developing ovarian hyperstimulation syndrome (OHSS) in high responders and the chance of cycle cancellation. This report describes the use of 0.2 mg triptorelin (Decapeptyl) to trigger ovulation in eight patients who underwent controlled ovarian hyperstimulation with recombinant FSH (rFSH, Puregon) and concomitant treatment with the GnRH antagonist ganirelix (Orgalutran) for the prevention of premature LH surges. All patients were considered to have an increased risk for developing OHSS (at least 20 follicles > or =11 mm and/or serum oestradiol at least 3000 pg/ml). On the day of triggering the LH surge, the mean number of follicles > or =11 mm was 25.1 +/- 4.5 and the median serum oestradiol concentration was 3675 (range 2980-7670) pg/ml. After GnRH agonist injection, endogenous serum LH and FSH surges were observed with median peak values of 219 and 19 IU/l respectively, measured 4 h after injection. The mean number of oocytes obtained was 23.4 +/- 15.4, of which 83% were mature (metaphase II). None of the patients developed any signs or symptoms of OHSS. So far, four clinical pregnancies have been achieved from the embryos obtained during these cycles, including the first birth following this approach. It is concluded that GnRH agonist effectively triggers an endogenous LH surge for final oocyte maturation after ganirelix treatment in stimulated cycles. Our preliminary results suggest that this regimen may prove effective in triggering ovulation and could be said to prevent OHSS in high responders. The efficacy and safety of such new treatment regimen needs to be established in comparative randomized studies.

Ovarian stimulation in in vitro fertilization with or without the "long" gonadotropin-releasing hormone agonist protocol: effect on cycle duration and outcome.

OBJECTIVE: To study the correlation between stimulation duration of IVF cycles, with and without GnRH agonist (GnRH-a), and cycle outcome. DESIGN: Retrospective analysis of data. SETTING: University-affiliated IVF clinic. PATIENT(S): 998 IVF cycles in which long GnRH-a protocol was used, and 155 cycles with hMG only. INTERVENTION(S): IVF cycles. MAIN OUTCOME MEASURE(S): Cycle outcome in number of oocytes and embryos, and pregnancy rate. RESULT(S): The mean stimulation duration (+/-SD) was 9.6+/-1.7 and 6.7+/-1.0 for the GnRH-a and the hMG-only cycles, respectively (P<0.01). In the GnRH-a group, no statistically significant correlation between cycle duration and pregnancy rate was found. Interestingly, the patients treated for 9 days had the highest number of oocytes retrieved and the highest pregnancy rate. Stimulation duration was not affected by age in either protocol. GnRH-a cycles yielded a significantly higher number of oocytes and embryos compared to cycles without GnRH-a. The pregnancy rate was similar in both groups. CONCLUSION(S): Stimulation duration in the long GnRH-a protocol group was significantly longer than in the hMG-only group. Stimulation duration was not affected by age. No statistically significant correlation was found between stimulation duration and cycle outcome in the long protocol group.

A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles.

A simple programmed thaw cycle is described, during which the endometrium is prepared with oral oestradiol, followed by a natural progesterone source. This method involves minimal blood tests and uses inexpensive medications. Originally, an i.m. progesterone-in-oil preparation was used. Although highly successful in achieving high serum progesterone concentrations, the daily injections of the oily compound were found to be problematic from the patients' perspective. To examine the possibility of replacing the injectable progesterone with a vaginal preparation we conducted a prospective randomized study of 1 year's duration, during which time 170 and 184 thawing cycles were done with injectable and vaginal progesterone respectively. Although the progesterone blood concentrations obtained with the injectable preparation were more than twice those obtained with the vaginal progesterone, the clinical pregnancy rates (defined as percentage thawing cycles with gestational sac(s)/embryo transfer as demonstrated on ultrasound, 4 weeks after embryo transfer) were similar for both groups (15.9 and 16.8% respectively). Implantation and abortion rates were also comparable. These results agree with previous reports of higher uterine progesterone concentrations after the vaginal application. We conclude that the combination of oral oestradiol and vaginal progesterone is an effective, simple and inexpensive approach for programmed thaw cycles.

High doses of gonadotrophin-releasing hormone antagonist in in-vitro fertilization cycles do not adversely affect the outcome of subsequent freeze-thaw cycles.

The clinical application of gonadotrophin-releasing hormone (GnRH) antagonists instead of GnRH agonists, to prevent spontaneous premature luteinizing hormone surge during ovarian stimulation for assisted reproduction treatment has been advocated. A recent, double-blind, dose-finding study, including six dosages of the GnRH antagonist ganirelix, in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (FSH), has indicated that high doses of GnRH antagonist (1 or 2 mg once daily) are associated with a low implantation rate. This follow-up study reports on the pregnancy rate after replacement of cryopreserved embryos obtained in stimulation cycles of the above-mentioned trial. Ovarian stimulation was initiated on day 2 of the cycle, with daily injections of 150 IU recombinant FSH. Ganirelix (0.0625, 0.125, 0.25, 0.5, 1.0 or 2.0 mg) was administered once daily from stimulation day 6 onwards, up to and including the day of human chorionic gonadotrophin. Retrieved oocytes were fertilized by in-vitro fertilization (IVF) or intracytoplasmic sperm injection and a maximum of three fresh embryos was transferred. Excess embryos were frozen, and subsequently used in either natural or programmed cycles. Until June 1998, 11 ongoing pregnancies (12-16 weeks after embryo transfer) were achieved from 46 cycles in which embryos had been first frozen (23.9% per transfer). Six of these 11 patients had been treated with a high dose of ganirelix (1.0 or 2.0 mg) during the IVF cycles in which the embryos were obtained. In conclusion, our data suggest that high dosages of ganirelix do not adversely affect the potential of embryos to establish clinical pregnancy in freeze-thaw cycles.

Early transvaginal embryo aspiration: a safer method for selective reduction in high order multiple gestations.

Assisted reproduction technologies and ovulation induction for treatment of infertility continue to cause high order multiple gestations. Increased perinatal morbidity and mortality, as well as maternal morbidity, may complicate these pregnancies. Selective fetal reduction, an acceptable therapeutic approach in these cases, is usually performed at or after the ninth week of gestation, with KCl injected in the vicinity of the fetal heart, and is associated with a total pregnancy loss rate of 11.7%. We report our experience with 90 women who underwent early (mean 7.5 weeks gestation, range 7. 0-8.0 weeks) transvaginal selective embryo aspiration. The mean number of viable embryos before and after reduction was 3.5 and 2.1 respectively. Six (6.7%) pregnancies were lost before 24 gestational weeks. One miscarriage occurred at the tenth gestational week. The other five pregnancies were aborted at 17.3-21.6 weeks gestation. Additional interventions were performed in three of these pregnancies: genetic amniocentesis in two cases and cervical suture in one case. In the subset of 39 patients with>/=4 embryos, only one (2.6%) pregnancy loss was recorded. This loss rate is significantly lower (P < 0.05) than the 15.3% loss rate in patients with >/=4 fetuses calculated from other work. Four (4.4%) other pregnancies were complicated by premature delivery (25-28 weeks gestation). Mean gestational age of delivered pregnancies in our series was 35.7 weeks. In conclusion, early transvaginal embryo aspiration is a simple and relatively safe method for multiple pregnancy reduction. The overall pregnancy loss rate associated with early embryo aspiration is similar to that of procedures performed at later gestational age, but is significantly lower when the initial number of embryos is four or greater.

The rat intraovarian interleukin (IL)-1 system: cellular localization, cyclic variation and hormonal regulation of IL-1beta and of the type I and type II IL-1 receptors.

An increasing body of evidence supports the possibility that intraovarian interleukin (IL)-1 plays an intermediary role in the periovulatory cascade. To gain further insight into the intraovarian IL-1 hypothesis, we studied the cellular localization cyclic variation and hormonal regulation of IL-1beta, as well as of the type I and type II IL-1 receptors (IL-1R) in immature rats. In situ hybridization localized IL-1beta and type I IL-1R transcripts to the granulosa cell compartment, the innermost layers of the theca interna and to the oocyte of the untreated immature ovary. Molecular probing of whole ovarian material in the course of a simulated estrous cycle revealed a progressive preovulatory increase in IL-1beta and type I IL-1R transcripts to an in vivo peak at the time of ovulation (3.0- and 2.5-fold increases over untreated controls; P < 0.05). Comparable efforts to localize and probe for type II IL-IR transcripts failed to elicit a detectable signal. The basal in vitro expression pattern of IL-1beta and type II IL-1R transcripts by whole ovarian dispersates revealed an early (4 h) spontaneous increase to a peak (2.1- and 5.8-fold increases over time 0: P < 0.05) followed by a gradual decline to a 48 h nadir. Treatment of whole ovarian dispersates with the IL-1 receptor antagonist (IL-1RA) or with IL-1beta failed to alter the initial (4 h) burst of IL-1beta or of type II IL-1R expression thereby suggesting IL-1-independence. Treatment with hCG proved equally ineffective. However, longer-term treatment of whole ovarian dispersates with IL-1beta produced a significant secondary increase (5.9-fold over time 0; P < 0.05) in IL-1beta (but not type II IL-1R) transcripts by 48 h. This IL-1 effect was completely blocked by co-treatment with IL-1RA thereby suggesting mediation via a specific IL-1 receptor. Qualitatively comparable but quantitatively reduced results obtained for isolated granulosa cells. The basal in vitro expression pattern of type I IL-1R transcripts by whole ovarian dispersates revealed a progressive spontaneous increase (3.1-fold increase overall) over the 48 h culture. Treatment with IL-1beta produced a significant (P < 0.05) increase (5-fold) in type I IL-1R transcripts by 48 h, an effect which was completely blocked by co-treatment with IL-1RA. Taken together, these observations: (1) localize IL-1beta and its type I receptor to granulosa cells, the innermost layers of the theca interna and to the oocyte; (2) confirm their periovulatory in vivo expression pattern; (3) document their expression by untreated cultured whole ovarian dispersates; and (4) demonstrate their in vitro responsiveness to receptor-mediated/IL-1-driven autocrine amplification. The type II IL-1R was undetectable in vivo, its in vitro expression pattern proving IL-1- and hCG-independent. The periovulatory expression pattern of IL-1beta and its receptor (type I) is compatible with the notion that the intraovarian IL-1 system may play an intermediary role in the ovulatory process.