Treatment Cycles Research Articles

O-184 Piezo-ICSI reduces oocyte degeneration, improves ICSI success rates and has shown less dependence on the experience level of embryologists: cumulative data with 65,033 MII oocytes

Abstract Study question Dose piezo-ICSI improve the overall success rates of in ICSI operations compared with the conventional ICSI by the operators with different level of experience? Summary answer Piezo-ICSI showed lower oocyte degeneration rate during or after ICSI operations compared to the conventional ICSI for embryologists with different level of experience. What is known already Intracytoplasmic sperm injection (ICSI) with a glass micropipette can sometimes result in degeneration of the injected oocyte. Piezo-assisted ICSI has been developed as an alternative method to prevent such degeneration occurring during the procedure. It employs gentler and controlled impacts generated from the piezo electric elements attached to the injection micropipette holder to penetrate oolemma, and it does not require reciprocal aspiration of ooplasm required in the conventional ICSI. While there have been numerous study reports demonstrating the improvements in fertilization rates with piezo-ICSI, most of these studies have the limitation in the size study of population. Study design, size, duration We conducted a retrospective analysis of the ICSI results with 65,033 MII oocytes in 15,687 treatment cycles carried out between January 2018 and February 2023. ICSI were performed using the piezo-assisted equipment with flat-tip micropipettes (PIEZO PMM4G, Prime Tech Ltd., [n = 51,484, Piezo-group]) or in the conventional ICSI method with spiked-tip micropipettes (n = 13,549, C-group). Participants/materials, setting, methods Following the insemination with ICSI, the oocyte degeneration rate, fertilization rate per MII oocytes and blastocyst formation rate per 2PN embryos were evaluated in both the Piezo- and C-groups (n = 51,484 and n = 13,549, respectively). We also evaluated the degeneration rates and fertilization rates of ICSI by the operators: i.e., well-experienced embryologists (at least 10 years of experience) and less experienced embryologists (5 years or less of experience). Main results and the role of chance The fertilization and blastocyst formation rates in the Piezo-group were 83.8% (43,140/51,484) and 54.0% (23,300/43,140), respectively, which were significantly higher than the C-group (74.8% [10,132/13,549] and 36.6% [3,674/10,132], respectively, p < 0.01). The oocyte degeneration rate in the Piezo-group was 2.9% (1,493/51,484), which was significantly lower than the C-group (6.9% [933/13,549], p < 0.05). For the patients over 40 years old, the degeneration rate was also significantly lower in the Piezo-group (3.0% [632/20,770]) than the C-group (7.1% [351/4927], p < 0.01), while the fertilization and blastocyst formation rates were higher in the Piezo-group (82.6% [17,164/20,770] and 46.6% [7,997/17,164], respectively) than the C-group (72.8% [3,588/4,927] and 25.8% [926/3,588], respectively, p < 0.01). We found a marked drop in the oocytes degeneration rates in the Piezo group recorded from both well-experienced and less experienced embryologists. The degeneration rates recorded by less experienced embryologists were 2.8% (119/4,242) in Piezo-group and 8.6% (8/93) in the C group (p < 0.01), while the records by well-experienced embryologists were 2.7% (815/29,681) in the Piezo-group and 6.9% (555/8,037) in the C-group, respectively (p < 0.01). The fertilization rates of the Piezo-group by less experienced and well-experienced embryologists were 84.1%(3,569/4,242) and 83.4% (24,757/29,681), respectively, which were significantly higher the C-group (71.0％ [66/93] and 76.7％ [6,167/8,037], respectively, p < 0.01). Limitations, reasons for caution It is a retrospective study, in which the ICSI operations with piezo and the conventional methods were not equally assigned to the embryologists, especially, for those less experienced, thereby the number of conventional ICSI operations was more skewed to well-experienced embryologists than the less experienced colleagues. Wider implications of the findings Our results with piezo-ICSI showed a marked drop in the oocyte degeneration while achieving comparable fertilization rates amongst operators with different levels of experience. We found these as major advantages over the conventional method in standardizing the ICSI operation by filling the gap between embryologists with different length of carrier. Trial registration number Not applicable

P-750 Is maximalization of the ovum pick-up (OPU) procedure beneficial for the outcome of assisted reproductive technology (ART) cycles?

Abstract Study question Is aspiration of more oocytes than the antral follicle count (AFC) beneficial for the current (pregnancy/live birth rates) and future products of an ART cycle? Summary answer Aspirating more oocytes than the AFC does not influence the outcome of the fresh cycle but is beneficial for fertility preservation and cumulative pregnancy rates. What is known already AFC is a reliable and immediate indicator for ovarian reserve assessment and is in correlation with the ovarian response to gonadotropin stimulation. Additionally, correlation between AFC and embryo quality, clinical pregnancy and live birth rates was reported. There is no data concerning the impact of the ratio between the AFC and actual number of oocytes retrieved on cycle outcome. Study design, size, duration Data of the first oocyte aspiration for ICSI performed between 2018-2022 in attempt to conceive (ICSI, n = 399) or for planned oocyte vitrification (fertility preservation FP, n = 283) was retrieved. Each group was divided into two subgroups according to their ‘oocyte/AFC index’ (OAFCI): <1 and ≥1. The stimulation parameters, number of aspirated oocytes, their maturity rate, number of cryopreserved oocytes/embryos, clinical pregnancy (CPR) and live birth rates (LBR) were compared between the subgroups. Participants/materials, setting, methods The AFC was determined by professional sonographers using a 9 MHz transvaginal ultrasound probe. The most adjacent measurement to the stimulation initiation was used. Stimulation protocol and FSH dose were determined according to the AFC and individual clinical consideration. Patients not in their first cycle, natural cycle aspirations, and cases in which no oocytes were retrieved, were excluded. Main results and the role of chance OAFC≥1 was associated with higher pre-trigger estradiol (6159 pmol/L vs. 4304, p < 0.001 for ICSI, 4949 vs. 3488, p < 0.001 for FP), and longer duration of simulation (9.8 days vs. 9, p < 0.001 for both FP and ICSI). More oocytes were aspirated in OAFC≥1 groups in both FP (16.9±11.2 vs. 7.9±5.9, p < 0.001) and ICSI (17.4±9.8 vs. 10.7±6.7, p < 0.001). Oocyte maturity was unaffected by the OAFCI in the ICSI group, but was lower in FP group at OAFC≥1 (0.79 vs.0.84 p = 0.005). OAFCI≥1 was associated with a higher number of cryopreserved embryos (3.9 vs. 2.3, p < 0.001 for ICSI) and a higher number of vitrified oocytes (13.4 vs. 6.4 p < 0.001 for FP). The OAFCI had no impact on CPR (39% vs. 60%, p = 0.27) and LBR (19.9% vs. 24.8%, p = 0.33). On multivariate analysis controlling for age, gonadotropin dosage and duration of stimulation, OAFC≥1 was associated with a higher number of cryopreserved embryos (ICSI group aOR 1.2, 95% CI 1.1-1.3, p < 0.001), and vitrified oocytes (aOR 1.2, 95% CI 1.1-1.2, p < 0.001) and lower maturity index (aOR 0.1, 95% CI 0.03-0.51, p < 0.001) in the FP group. Limitations, reasons for caution Retrospective study analyzing results of treatment cycles without an intention to aspirate differently. Wider implications of the findings Aspiration of a more oocytes than the current AFC was not associated with higher CPR or LBR in the fresh cycle, but harbors the possibility to cryopreserve more oocytes and embryos. This might translate into higher cumulative pregnancy rates later on. Trial registration number Not applicable

Awareness of Food, Supplement, and Drug Interactions among Oncology Patients on Oral Chemotherapy

Abstract Background Food-drug interactions (FDIs) are very common, but under-reported due to a lack of proper history or lack of knowledge and limited research. Our study highlights the knowledge gap among oncology patients treated with capecitabine regarding food-oral chemotherapy interactions. Method A cross-sectional study was conducted among 110 breast and colon cancer patients, purposively sampled from the chemotherapy outpatient clinic from June 2021 to December 2021. A structured questionnaire and interviews were used to collect data, we asked them about the information they had received from the doctor and the way they were taking the medicine. Data were analyzed using SPSS, and the p-value of p < 0.05 was considered significant. Results Regarding the sociodemographic and clinical data of participants, their ages widely ranged from 20-83 years old, and their mean age was 54.78±13.18. The majority of participants were females 81(73.6%), non-employed 86(78.2%), colon cancer 72(65.5%) and received ≤4 cycles 66 (60%). Still, there is poor awareness concerning FDI among oncology patients and most participants were unaware of the possible interactions of capecitabine with grapefruits, vitamins, herbs, and antioxidants, but the majority 92 (83.6%) were taking their medication correctly concerning meal recommendations and only 18(16.4% )were not taking capecitabine within 30 minutes of meals. The current study showed that patients’ knowledge was not associated with age, sex, education, marital status, or occupation. The main factors that affected knowledge in the current study were the cancer site and the number of treatment cycles, as colon cancer patients and those who have received four or fewer cycles had better doctor-patient communication. Conclusion There is a lack of awareness about interactions between oral chemotherapy and various nutrients and supplements among patients in the current study. Patient education and better doctor-patient communication are recommended to ensure optimal oral chemotherapy intake and patient safety.

P-745 effectiveness and safety of consecutive single embryo transfer compared to double embryo transfer: results from UK HFEA registry

Abstract Study question How does two-consecutive single embryo transfer (2xSET) affect reproductive outcomes of in-vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) compared to double embryo transfer (DET)? Summary answer 2xSET may provide greater or comparable live birth rates with lower multiple birth, preterm birth, and pregnancy loss or neonatal death rates compared to DET. What is known already Elective single embryo transfer (SET) in IVF/ICSI is widely encouraged over DET to minimise the risk of multiple birth and associated morbidities. Despite this, UK multiple birth rates following IVF remain higher than spontaneous conception, with 5% of IVF pregnancies resulting in multiple birth compared to 0.4%-1.2% multiple gestation rates following spontaneous conception. Owing to advancements in cryopreservation techniques, live birth and ongoing pregnancy rates are now comparable between fresh and frozen embryo transfer. Consequently, 2xSET has been suggested as an alternate technique to achieve comparable live birth rates with fewer multiple gestation pregnancies compared to DET. Study design, size, duration This retrospective cohort study was conducted using Human Fertilisation and Embryology Authority (HFEA) register data, which encompasses national data from all IVF clinics in the UK. Within this analysis, all women who underwent their first oocyte collection and IVF or ICSI treatment cycle with subsequent SET, DET or 2xSET between 2010 and 2019 using either blastocyst or cleavage stage embryos were included (N = 125,149). Participants/materials, setting, methods This national retrospective cohort study utilised UK HFEA register data from 2010-2019, including all women who underwent their first oocyte collection and subsequent embryo transfer (N = 125,149). The rate of live birth, multiple birth, preterm birth, and pregnancy loss or neonatal death was compared between SET, DET, and 2xSET IVF/ICSI pregnancies using either blastocyst or cleavage stage embryos, and was stratified by maternal age. Data analysis was conducted in RStudio v4.2, alpha equals 0.05. Main results and the role of chance 2xSET pregnancies following blastocyst-stage transfer achieved a greater live birth occurrence rate of 0.47 (0.13) (median (interquartile range)) than SET, 0.41 (0.13), and DET, 0.38 (0.13) (P < 0.05). When using SET as a reference standard, 2xSET achieved a lower multiple birth rate, odds ratio (OR) of 6.87 (95%CI 6.14-7.68), than DET, OR 28.20 (95%CI 25.20-31.57), and lower preterm birth rate; OR 1.11 (95%CI 1.06-1.15) in 2xSET, and OR 2.80 (95%CI 2.67-2.94) in DET. Pregnancy loss or neonatal death rate was also lower in 2xSET, OR 1.14 (95%CI 1.08-1.21), compared to DET, OR 2.11 (95%CI 1.98-2.24). Conversely, in cleavage-stage embryo transfer pregnancies, no significant difference in live birth occurrence rate was observed, achieving rates of 0.27 (0.21) for SET, 0.26 (0.13) for DET, and 0.29 (0.18) for 2xSET. 2xSET was less likely to result in multiple birth than DET, OR 0.14 (95%CI 0.11-0.19). Moreover, when using SET as a reference standard, 2xSET was less likely to result in preterm birth than DET, OR 1.02 (95%CI 0.87-1.23) and 2.48 (95%CI 2.17-2.82) respectively, as well as pregnancy loss or neonatal death, OR 1.07 (95%CI 0.85-1.35) and 2.03 (95%CI 1.70-2.42) respectively. Limitations, reasons for caution Certain confounders are not recorded within HFEA registry data, including patient body mass index (BMI), evaluation of embryo quality, and endometrial thickness at embryo transfer. Consequently, while our analysis identifies broad trends in embryo transfer success and morbidity, results may differ within certain patient populations. Wider implications of the findings 2xSET may provide greater or comparable live birth rates with lower multiple birth and morbidity than DET. Promotion of 2xSET where appropriate for maternal age and embryo quality should be implemented to enhance reproductive outcomes and reduce the risk of morbidity in IVF/ICSI pregnancies. Trial registration number Not Applicable

O-276 Implantation failure is not associated with seven different vaginal bacterial community-state types; however, a distinct signature, including Ureaplasma parvum, is strongly linked to treatment failure

Abstract Study question Is microbial diversity or vaginal bacterial composition associated with embryonic implantation in women undergoing frozen-thawed embryo transfer? Summary answer While global diversity measures of microbial composition do not correlate with positive implantation, specific taxa may serve as predictors of treatment outcomes. What is known already Clinical studies have indicated a reduced likelihood of embryo implantation in women diagnosed with microbial dysbiosis. The application of Next-Generation Sequencing for microbiota analysis has significantly advanced our understanding of vaginal microbiome composition. Recent studies have proposed distinct vaginal microbiome patterns as potential predictors of IVF treatment success or failure. However, the evidence regarding the biological basis of test algorithms (such as the independent association of distinct community state types with outcomes) and the reliability of diagnostic test performance (including replicability and external validity) in predicting implantation success or failure in women undergoing embryo transfer remains less robust. Study design, size, duration In a prospective, single-centre observational cohort study (05/2017-03/2019, NCT03507673, local ethical approval reference no.18-005), conducted at a university-affiliated centre for reproductive medicine in Germany, vaginal swab samples were collected from infertile, asymptomatic female patients (n = 260), aged 18-45, undergoing frozen-thawed embryo transfer. Patients, each contributing a single treatment cycle, received sequential oral estradiol and oral estradiol/dydrogesterone in an HRT regimen for FET. Vaginal swabs were taken from baseline visit before transfer day and stored at –80 °C. Participants/materials, setting, methods 16S rRNA gene amplicon sequencing was performed targeting V3/V4 hypervariable region using Illumina MiSeq platform. Raw data assembly, filtering and taxonomic assignment were performed using mothur against EzBioCloud database. Statistical analyses, and visualization were conducted using R. Community structure via hierarchical clustering, alpha and beta diversity, and indicator species via LefSe analysis were assessed. Main results and the role of chance Based on a hierarchical clustering using the 25 most abundant bacterial taxa, seven separate community state types (CSTs) being either dominated by species of the genus Lactobacillus (CST-A, CST-B, CST-C, CST-E, CST-G) or Gardnerella (CST-F) or presenting a variable community composition (CST-D) were identified. A community state type dominated by Lactobacillus fornicalis was found in a small fraction of women and enhanced resolution among the Gardnerella genus impacts CST definitions in this sample. Embryonic implantation had no significant association to either alpha diversity measures or CST distribution; likewise, the previously suggested ratio of relative abundances of Lactobacillus iners vs. Lactobacillus crispatus was not associated with implantation. Lactobacillus fornicalis is positively linked to implantation, while Lactobacillus iners and Ureaplasma parvum were linked to implantation failure: above 50% relative abundance of Lactobacillus fornicalis, was associated with 75% positive implantation. Conversely, just 0.5% relative abundance of Ureaplasma parvum was associated with a decrease in implantation rate to approximately 20%. LefSe and binary regression analysis identified a relatively rare (6% in our sample) microbiome signature, mostly from CST-C (Lactobacillus iners dominated) with a very low likelihood of implantation, with Ureaplasma parvum as the common denominator. Limitations, reasons for caution Studies on the vaginal microbiome in IVF face issues such as study design variability, small sample-sizes, limited control for temporal dynamics, and patient heterogeneity. Attempts at establishing causal relationships through interventional studies in IVF have been limited and inconclusive. Understanding the microbiome’s functional aspects is crucial for reproductive outcome elucidation. Wider implications of the findings Current study findings don’t confirm previously reported associations between common vaginal bacterial CSTs and outcome. Therefore, screening for vaginal microbiome composition in asymptomatic women with subfertility is not recommended outside research. Signatures/taxae with an independent and strong negative association with implantation are likely to be rare yet deserve further attention. Trial registration number NCT03507673

O-079 Reflecting on the fertility journey: Insights from couples who discontinued fertility treatment without giving birth

Abstract Study question How can we enhance the experience of individuals pursuing fertility treatment, from the standpoint of those who have faced unsuccessful outcomes in their treatments? Summary answer The current study identified ways to improve couples’ experience by addressing their unmet needs within the context of fertility care. What is known already Couples seeking fertility treatment face many challenges. Previous studies reported that 20% to 30% of couples decide to discontinue treatment before achieving pregnancy. Exploring ways to improve the experience of individuals seeking fertility treatment is therefore important to reduce treatment dropout. Previous studies have addressed the needs of individuals seeking fertility care, particularly in terms of information and psychosocial support. These studies were predominantely quantitative, limiting the exploration of couples’ subjective perspective. The present study addressed this limitation by using a qualitative research design, allowing for the emergence of other unmet needs and a more nuanced description of couples’ experiences. Study design, size, duration Eleven Canadian couples (n = 22 participants) who stopped fertility treatment without giving birth took part in a qualitative study in Quebec, which was approved by the researchers’ institutional review board. Data were collected between December 2022 and August 2023 as part of a larger qualitative study examining the individual and relational experiences of couples who stopped fertility treatment as well as the clinical context that may have contributed to their decision of discontinuing treatment. Participants/materials, setting, methods Couples who experienced at least one unsuccessful fertility treatment cycle and decided to stop without giving birth were eligible to participate. Ten mixed-gender/sex and one same-gender/sex couples participated in a dyadic online semi-structured interview. Participants were aged between 28 and 47 years old. Four couples were childless. Each interview lasted between 40 and 65 minutes. Interviews were transcribed and verbatims were analyzed by two independent coders using the NVivo software through thematic analysis. Main results and the role of chance During the interviews, partners discussed unmet needs and suggested ways in which these needs could be addressed. Eight themes regarding ways to improve the experience of individuals seeking fertility treatment emerged as as result of the thematic analysis. Namely, (1) providing more information to set realistic expectations (e.g., discussing the demands of fertility treatment and the possibility of treatment not working), (2) improving the physical environment within fertility clinics (e.g., providing a room for couples to gather their thoughts after a difficult announcement), (3) enhancing the sensitivity and availability of healthcare professionals (e.g., showing empathy towards the challenges that couples may face), (4) supplying reliable and accessible information that are expressed in simple non-medical terms (e.g., taking the time to explain medical terms and procedures), (5) promoting patient autonomy regarding fertility care (e.g., suggesting treatment options that take their context into account), (6) providing psychological support (e.g., increasing access to mental health professionals), (7) making patient-centered fertility care more accessible (e.g., offering low-cost psychosocial support), and (8) normalizing the experience of infertility and fertility treatment (e.g., encouraging couples to talk about their experience, offering support groups). Limitations, reasons for caution Participants discontinued fertility treatment without giving birth, making them more likely to have had negative experiences in fertility clinics. Individuals undergoing treatment or who have had successful treatment outcomes might have different perspectives. Additionally, couples came from only four fertility clinics in Quebec, Canada, limiting the heterogeneity of the sample. Wider implications of the findings The present study highlighted areas where services for couples undergoing fertility treatment could be enhanced. Findings may help healthcare providers gain a deeper understanding of the needs of their patients, and inform the development of sensible and reliable resources, which might ultimately help reduce treatment discontinuation. Trial registration number not applicable

P-225 Implementing a more physiological method to trigger oocyte activation in cases of extremely poor fertilization with ICSI

Abstract Study question Can we utilize a more physiological compound to induce oocyte activation in couples with history of complete/partial fertilization failure with ICSI? Summary answer Recombinant human phospholipase-C-zeta (rhPLCζ) successfully activated oocytes with same efficiency as ionomycin, consistently normalized fertilization and enhanced clinical outcomes. What is known already While ICSI overcomes most aspects of male gamete dysfunction, partial or complete fertilization failure may seldomly occur mostly due absence of sperm-specific protein, known as PLCζ, which is required to trigger oocyte activation. Assisted oocyte activation (AOA), most often performed with an antibiotic (ionomycin), activates oocytes by triggering calcium release from intracellular storage. This agent induces indiscriminate permeabilization of ooplasmic membrane-bound organelles. This action has been considered nonspecific and may have possible deleterious effects on subsequent embryo development. Therefore, we propose a physiological alternative that employs a recombinant form of PLCζ, the native protein residing in the sperm perinuclear theca. Study design, size, duration In the past 12 months, couples with poor ICSI fertilization were included. PLCζ were assessed to confirm sperm-related oocyte activation deficiency with a normal threshold of ≥ 30%. In a preliminary comparison, sibling oocytes were equally allocated to AOA by ionomycin or to rhPLCζ at time of ICSI. Fertilization, embryo development, and clinical outcomes between the two cohorts. Subsequently, we describe the clinical outcomes of couples treated solely by rhPLCζ. Participants/materials, setting, methods Thirty couples, confirmed with low level of PLCζ in the ejaculates, were offered AOA with their subsequent ICSI cycles (IRB#0712009553). Conventional AOA was performed by exposing post-ICSI oocytes to 50 µM ionomycin. The rhPLCζ-AOA method was performed by co-injecting spermatozoa with 0.4pL of a rhPLCζ (5 µg/µL) during ICSI. Chi-square tests were utilized to compare rhPLCζ-AOA versus ionomycin-AOA and rhPLCζ-AOA versus history cycles. Main results and the role of chance In the preliminary study, 9 patients were included (maternal age: 35.7 ± 6, paternal age: 36.7 ± 6). PLCζ positivity was 11.7±3.6% confirming a sperm-related oocyte activation deficiency. A total of 123 oocytes were retrieved in 9 cycles, with maturity of 78.0% (96/123). The 96 MII oocytes were allocated to be treated with ionomycin-AOA (n = 58) or rhPLCζ-AOA (n = 38). While conventional ionomycin-AOA yielded a fertilization rate at 55.2% (32/58), rhPLCζ-AOA resulted in 63.1% (24/38). Both compounds generated embryos at similar rates and one pregnancy was achieve in each cohort. On the bases of such comparable outcomes, 21 couples had 40 previous cycles that generated a fertilization rate of 18.3% (60/327), cleavage rate of 51.7% (31/60), Following the replacement of 23 embryos in 14 transfer cycles, these cycles yielded 2 clinical pregnancies, but all resulted in pregnancy loss. In the subsequent cycles with rhPLCζ-AOA (n = 32), an enhanced fertilization rate was achieved at 41.1% (116/280, P<0.00001). The treatment cycle yielded a higher cleavage rate at 80.2% (93/116, P<0.0001), and after replacing 25 embryos in 17 embryo transfer cycles, yielded 6 pregnancies and 5 of them resulted in delivered or are ongoing. Limitations, reasons for caution We demonstrated that physiological rhPLCζ-AOA achieved an excelled fertilization and clinical outcomes comparing to the traditional ionomycin method. Although further observation is needed to confirm its safety, this approach represents a more physiological method capable of achieving fertilization, higher embryo cleavage and ultimately better pregnancy outcomes. Wider implications of the findings While ICSI has gained large popularity, poor fertilization may occasionally occur. The availability of an assisted oocyte activation that utilize a native compound capable of restoring fertilization capability of the male gamete is appealing and holds great promises. Trial registration number N/A

P-402 Comparison of uterine contractions in artificial hormone treatment versus aromatase inhibitor stimulated frozen embryo transfer cycles

Abstract Study question does uterine contractions differ between aromatase inhibitor stimulated (AIS) or artificial hormone treatment (AHT) Frozen Embryo transfer (FET) cycles Summary answer uterine contraction activity did not show any difference between artificial hormone treatment and aromatase inhibitor stimulated FET cycles What is known already FET cycles are prepared by different protocols. aromatase inhibitor stimulated (AIS) or artificial hormone treatment (AHT) protocols are two common protocols among others. These protocols have different cycle dynamics and might differ in pregnancy rates and different effects on perinatal outcomes. Although embryo related factors are most important for implantation endometrial receptivity and therefore uterine contractions might have a role in implantation. English literature provides scarce data on uterine contractions and pregnancy outcomes. Presence of prominent contractions were related to poor pregnancy outcomes in some studies whereas other few studies failed to show any effect in this sense Study design, size, duration this study is an observational cohort study of successive frozen embryo transfer (FET) cycles of eligible patients between 1st of july 2023 to 31th of October 2023 in a tertiary university hospital in vitro fertilization clinic with ultrasonographic video recordings at transfer day. During study period of four months, 147 out of 265 consecutive FET cycles were included in this study and study is approved by local ethical committee of the affiliated university (KA23/388). Participants/materials, setting, methods Total study group was composed of 99 artificial hormone treatment cycles and 48 aromatase inhibitor stimulated FET cycles after exclusion of patients with uterine congenital malformations, uterine fibroids,adenomyosis patients and patient with previous uterine surgery. Implantation rates, pregnancy rates and clinical pregnancy rates were recorded. Transvaginal ultrasonographic sagittal uterine video image recordings were obtained at transfer day one hour before embryo transfer. Recordings were reviewed by two researchers and uterine contractions were documented by agreement. Main results and the role of chance This is the first study comparing different FET cycles and uterine contraction activities. Patient characteristics were similar between two groups. Artificial hormone treatment and aromatase inhibitor stimulated cycle groups showed similar endometrial thicknesses (11.47±1.92 and 11.24±1.02, respectively p = 0.42) and top quality embryo transfer rates (22.6 % and 26.8% p = 0.82). Although AIH group showed a statistically insignificant advantage, clinical and ongoing pregnancy rates were similar between protocols (supplementary data). Uterine peristaltic activity was not statistically different between aromataze inhibitor stimulated and artificial hormone treatment FET cycle (1.54±1.75 versus 1.63±2.15 p = 0.81 recpectively). Furthermore uterine persistalsizm were similar in pregnant and non-pregnant patients /1.52±2.07 vs 1.72±1.93 p = 0.57). However as far as Aromatase inhibitor stimulated FET cycles were considered; pregnant patients had less uterine peristaltic activity when compared ton non-pregnant patient (45.7% and 15.4%, respectively p = 0.054 ) although this difference was at the border of statistical significance. Limitations, reasons for caution This is an observational study of relatively short duration with limited number of patients. Our study in AIS cycles have a tendency to fewer contractions in cycles ended up in pregnancy. Larger series of FET cycles might prove differences in uterine contraction frequencies and pregnancy outcomes in AIS FET cycles. Wider implications of the findings Our study supported new information on uterine contractility in different FET cycles protocols. Further large scale studies might provide new insights to uterine factor and its role in implantation as far as uterine contraactions are concerned. Trial registration number (KA23/388) local ethic committee approval

P-481 The decisional needs for women dealing with multiple IVF cycles: A qualitative study

Abstract Study question What are the decisional needs of women experiencing multiple unsuccessful IVF treatments? Summary answer The decisional needs of women experiencing multiple IVF cycles included the provision of tailored information, psychosocial support and available social resources, and collaborative decision-making. What is known already Treatment failures can be devastating for couples trying to conceive. Several studies have demonstrated that the information provisions promote decision-making. Nevertheless, there exists a deficiency in research regarding the manner in which patients perceive their clinical decision-making requirements. The determination of patients’ decisional requirements can uncover obstacles and facilitators to infertility treatment. Asia is experiencing the most rapid expansion in ART cycles, yet existing research on treatment decision-making primarily concentrates on Western populations. This study aimed to investigate the decisional needs related to clinical practices in the context of repeated unsuccessful treatment cycles, with a particular emphasis on Chinese women. Study design, size, duration This study utilized the qualitative methodology to investigate the decisional needs of participants who had undergone multiple failed IVF cycles. Between October 2022 to January 2023, a total of 25 participants were recruited. Participants/materials, setting, methods A purposive sampling method was employed to recruit Chinese females who had undergone a minimum of three embryo transfers and failed to achieve clinical pregnancy. Healthcare professionals from Chinese reproductive clinics referred participants. Data was collected via a 60-minute semi-structured interview. Thematic analysis was employed to identify the underlying themes. Main results and the role of chance Three prominent themes were identified: (1) “provision of customized information”, encompassing specific preferences for content, channels, and format. Participants expressed a need for content that specifically addresses the potential medical ramifications of multi-cycle therapy. They showed a preference for mutual support networks and online platforms, specifically self-media platforms like TikTok; (2) “the quest for psychosocial supports and available social resources”, with a particular focus on decision support and financial resources; and (3) “involvement of stakeholders’ preferences in decision-making”. Participants favored collaborative decision-making over shared decision-making and desired their partner’s involvement while still giving the doctor the lead. These themes were important foundations that provided information and empowerment to patients as they dealt with the complicated process of fertility treatment decision-making after experiencing repeated setbacks. Limitations, reasons for caution First, the recruitment method favored clinical patients and may have overlooked the needs of patients who disengaged from the hospital and decided to end treatment. Second, this study exclusively recruited women. Because women face greater decisional challenges than their partners, their needs deserve attention in a clinical setting. Wider implications of the findings To prepare patients for multiple IVF cycles, healthcare professionals should provide customized care, including specific information about the procedures and consequences of multiple cycles, the utilization of mutual support networks and online platforms, psychosocial resources, and stakeholder involvement. This can enable women to handle challenges following repeated treatment failures. Trial registration number not applicable

P-367 Letrozole or Tamoxifen co-administration during fertility preservation of breast cancer patients: a retrospective cohort study

Abstract Study question How do fertility preservation (FP) outcomes differ between breast cancer patients stimulated with FSH and Tamoxifen versus FSH and Letrozole? Summary answer Letrozole and Tamoxifen co-administration yielded similar number of retrieved and cryopreserved oocytes/embryos, as well as similar oocyte maturation and fertilization and rates. What is known already Oocyte/embryo cryopreservation is recommended before initiation of chemotherapy in cancer patients. The co-administration of Tamoxifen, a selective estrogen receptor modulator, or Letrozole, an aromatase inhibitor, during ovarian stimulation with gonadotropins, are used to limit the potentially harmful effects of a supra-physiological rise in estrogen levels on hormone-sensitive cancers. However, the optimal choice between the two is still unclear and with no sound evidence. Study design, size, duration Retrospective cohort study of all FP treatments of newly diagnosed breast cancer patients in two tertiary centers between 2000-2022. Collected data included 354 FP cycles of 290 patients and compared treatment parameters and outcomes of Tamoxifen or Letrozole co-administration. Participants/materials, setting, methods Breast cancer patients who underwent FP before chemotherapy were included. Patients with a history of radiation or gonadotoxic treatment, as well as those undergoing other fertility preservation treatments, such as ovarian tissue cryopreservation were excluded. Main results and the role of chance Overall, 215 Letrozole and 139 Tamoxifen treatment cycles were compared, with no significant demographic differences. Treatments with Letrozole had higher FSH dosages (3970IU vs. 2839IU, p < 0.001) but shorter duration (9.7 vs. 10.5 days, p < 0.001). The Letrozole group achieved lower peak E2 levels and endometrial thickness (1508pmol/L, 8.1mm vs. 8760pmol/L, 9.5mm, p < 0.001). The mean number of retrieved oocytes was comparable between the groups (13.6 with Letrozole vs 14.7 with Tamoxifen, p = 0.06). In 122 Letrozole and 46 Tamoxifen patients that underwent strictly oocytes cryopreservation the mean number of cryopreserved oocytes was comparable (11 vs. 12.1, p = 0.21). Moreover, in embryo cryopreservation cycles of 71 patients treated with Letrozole compared to 76 patients with Tamoxifen, no difference was observed in the number of cryopreserved embryos (6.2 vs. 7.0, p = 0.12). Oocyte maturation rate among strictly oocyte preservation cycles was comparable (86% with Letrozole vs. 83% with Tamoxifen, p = 0.80), as were fertilization rates in embryo cryopreservation cycles (62% vs. 63%, p = 0.8 and 71% vs. 76%, p = 0.3 in IVF and ICSI with Letrozole and Tamoxifen, respectively). Multivariate analysis, controlling for potential confounders showed no significant correlations between Tamoxifen or Letrozole co-administration and the number of retrieved oocytes or oocyte maturation rate. Limitations, reasons for caution The primary limitation of our study is its retrospective design and the variation in treatment duration and gonadotrophin dosages among groups. Wider implications of the findings This study provides reassurance that both Tamoxifen and Letrozole are equally effective options when co-administered in FP treatments of breast cancer patients. Trial registration number not applicable

P-016 Prevalence of high oxidative stress and poor sperm DNA fragmentation levels in different groups of patients

Abstract Study question What is the prevalence of patients with high oxidation-reduction potential (ORP) and high sperm DNA fragmentation (SDF) in different patient groups with and without varicocele? Summary answer A large percentage of normozoospermic patients and patients who are normally considered of manageable in assisted reproduction show high SDF and/or high ORP. What is known already Standard semen analysis, even according to WHO criteria, is very limited in predicting male fertility potential. Oxidative stress is widely recognized as a major contributor to male infertility. Therefore, sperm DNA fragmentation (SDF) is increasingly recommended as additional test in diagnostics. High levels of oxidative stress and SDF have also been reported in patients with varicocele. Yet, SDF and oxidative stress tests are not routinely tested in ART laboratories. Apart from the cost and/or complexity of these tests, a reason for the lack of usage is the lack of knowledge of the prevalence. Study design, size, duration This is a retrospective analysis of data obtained from 2,946 patients attending the Department of Urology, Hamad Medical Corporation, Doha, Qatar, for fertility diagnosis from January to December 2018. For this analysis only patients (n = 773) who had a full data set for sperm DNA fragmentation (SDF) and seminal oxidative stress as measured by means of the oxidation-reduction potential (ORP) were included. Participants/materials, setting, methods Apart from SDF and ORP, standard semen parameters (ejaculate volume, sperm concentration, total and progressive motility, and normal sperm morphology), and the presence of varicocele were determined. Semen parameters were determined according to WHO 2010 criteria. SDF was tested using the Halosperm G2 test (Halotech DNA SL, Madrid, Spain), while ORP was determined using the MiOXSYS® (Aytu BioScience, Englewood, CO). Patients were categorized as normo-, oligo-, astheno-, and teratozoospermic. Main results and the role of chance The mean sperm concentration of the patients was 33.5 × 106 sperm/mL with a mean total motility of 50.3%. The overall percentage of patients with high (>20% SDF) SDF was 57.4% and those with high (≥1.34 mV/106 sperm/mL) ORP 63.4%. Varicocele was diagnosed in 14.0% of the patients. In normozoospermic patients, 26.8% had high SDF, whereas in the non-normozoospermic group this was 59.8% (P = 0.0108). In non-oligozoospermic (53.7%), non-asthenozoospermic (34.7%) and non-teratozoospermic (43.4%) groups, SDF was significantly higher. High ORP values were recorded in 35.7% of normozoospermic, 53.4% non-oligozoospermic, 47.2% of non-asthenozoospermic, and 49.7% of teratozoospermic patients. The difference between the prevalence of high ORP in the normozoospermic (35.7%) and the non-normozoospermic group is significant (P = 0.0063). When both tests (high SDF or high ORP) were considered, 50.0% of normozoospermic, 76.9% of non-oligozoospermic, 59.7% of non-asthenozoospermic, and 71.2% of non-teratozoospermic patients showed seminal pathology. High SDF was detected in 59.3% of varicocele patients, while 50.0% of varicocele patients had high ORP values. In patients without varicocele, 57.1%, 65.6%, and 82.7% had high SDF, high ORP, and high SDF or high ORP, respectively. These percentages were significantly (P < 0.0003) higher than for the corresponding normal groups. Limitations, reasons for caution Although the overall sample size of 773 is reasonably high, after sub-grouping the sample size is much smaller. Since this study only analyzed the SDF and ORP in patients attending and andrological outpatient clinic, the results could be different if patients in IVF and/or ICSI treatment cycles were analyzed. Wider implications of the findings This study highlights that complementation of semen analysis with SDF and oxidative stress testing will identify a large percentage of patients who would benefit from andrological treatment before assisted reproductive techniques (ART). This approach would result in better chances of these patients for successful ART. Trial registration number not applicable

P-720 Ethnic diversity in fertility treatment in 2017-2021 using national register data, United Kingdom

Abstract Study question Are there any differences in fertility treatment use and outcomes across ethnic groups in the UK? Summary answer There are clear ethnic disparities – Black patients had lower IVF birth rates and started treatment later than White patients. What is known already Previous studies in US and UK have shown disparities in IVF outcomes, differences in perceptions around fertility treatment usage and prevalence of infertility across ethnicities. The mechanism in differences recorded in IVF outcomes by ethnicity is not fully understood due to the complexity influenced by existing social and economic inequalities, pre-existing diseases and other societal factors. Study design, size, duration The study used data from the UK national register held by the Human Fertilisation and Embryology Authority (HFEA), where all licensed clinics in the UK are required to submit treatment data. Participants/materials, setting, methods All treatment cycles recorded on the HFEA Register with a focus on cycles undertaken in 2017-2021 were analysed. This includes over 232,000 patients who had treatment between 2017 and 2021 and their partners. Five aggregated ethnic categories were used in most of the analyses (Asian, Black, Mixed, White and Other). Main results and the role of chance IVF pregnancy and birth rates have increased in all major ethnic groups since ethnicity data started being collected in 2008. However, Black and Asian patients consistently had lower pregnancy and birth rates compared with White patients. For Black patients aged 18-37, the average IVF birth rate per embryo transferred using fresh embryo transfers was on average 23%, compared to 32% for White patients in 2020-21. Among heterosexual couples, IVF cycles funded by the National Health Service (NHS) declined most among Black patients, decreasing from 60% in 2019 to 41% in 2021, compared to a decrease from 66% to 53% among White patients. Average age at starting treatment was higher among Black patients in heterosexual couples at 36.0 years of age, compared to the national average of 35.0 in 2021. Partner type varied by ethnicity and Black patients were more commonly single compared to other ethnic groups, with 6% of Black IVF patients and 62% of Black DI patients being single in 2017-21. Multiple birth rates have decreased across all ethnic groups, with disparities narrowing in recent years. Limitations, reasons for caution Due to the COVID-19 pandemic and large-scale work to upgrade the HFEA data submission system and migrate data to a new database, data on treatments and pregnancies from 2020-21 and outcomes from 2019-21 have not yet been validated. Around 13% of patients excluded due to unreported ethnicity data. Wider implications of the findings The HFEA and key stakeholders in UK have agreed a call to action to reduce the ethnic disparities through improving in development of clinical policy, information and awareness, NHS commissioning, and research to tackle the ethnic disparities in fertility treatment. Trial registration number NA

P-161 Mechanical phenotyping of mammalian oocytes using Atomic Force Microscopy (AFM) to evaluate their developmental potential

Abstract Study question Can we measure the mechanical properties of mammalian oocytes with AFM and use them as a biomarker to identify oocytes with the best development potential? Summary answer We characterized mammalian oocytes’ mechanical properties using AFM, correlated them with oocyte cortex organization, and explored these parameters in contexts critical for oocyte quality. What is known already Oocyte production is crucial for reproduction but prone to errors, yielding a significant number of poor-quality oocytes detrimental to fertility and offspring development. Indeed, oocyte quality determines embryo health post-fertilization. Current selection methods for oocytes rely on subjective morphological analyses. Remarkably, human and mouse oocyte quality correlates with mechanical properties, particularly cortical tension (CT). CT defects in oocytes are rather frequent and impair early embryonic development after fertilization. However, they do not induce any visible oocyte morphological alteration. Mechanical properties could, therefore, be used as a biomarker of oocyte quality. Study design, size, duration We designed an AFM protocol for the measurement and analysis of mammalian oocytes’ mechanical properties, including a new elasto-capillary model describing oocyte mechanics. Concomitantly, we analyzed oocyte cortex organization using spinning disk microscopy in live. We measured mouse oocytes at various stages of meiotic maturation (prophaseI, meiosisI, meiosisII), mutant mouse oocytes with known cortical tension defects, oocytes coming from young and aged mice, and human oocytes at various stages of meiotic maturation (prophaseI, meiosisI, meiosisII). Participants/materials, setting, methods Mouse oocytes were collected from 11-week-old and 44-56-week-old OF1 female mice. Human oocytes were collected from patients who underwent ovarian stimulation for Assisted Reproduction Technologies (ART) as part of their protocol. Only oocytes that were in prophaseI or meiosisI after ovarian punction and thus not suitable for the ART procedure were used in this study. All patients gave informed consent (agreement CNIL number 22_5725). Main results and the role of chance Our AFM approach allows measuring various mechanical parameters, including oocyte cortical tension, elasticity, and capillary indentation rate, quantifying whether the oocyte behaves predominantly as a droplet with surface tension or as an elastic material. We find that these parameters correlate to specific oocyte cortex organization, showing that a thin actin cortex enriched in myosin II is associated with high tension, high elastic modulus, and low capillary indentation rate. In contrast, a thick actin cortex with few myosin II is associated with low cortical tension, low elasticity, and high capillary indentation rate. We go further and show that these parameters can predict cortex organization. Indeed, oocytes from aged mice display altered mechanical parameters, reflecting specific changes in their cortex organization. Finally, we transferred our approach to human oocytes. We show that the mechanical parameters of mouse and human oocytes are in the same range. Still, in humans, they evolve differently from those of mice during meiotic maturation, again reflecting specific changes in the organization of their cortex. Thus, mechanical parameters correlate with oocytes quality, and can predict cortex organization in mouse and human. Limitations, reasons for caution AFM is hardly usable for clinical application, we are thus working in parallel on developing non-invasive devices to perform high-throughput measurements of oocyte mechanical properties in a non-invasive manner, to serve as a mechanical biomarker to identify oocytes with the best developmental potential for ART. Wider implications of the findings Ultimately, this project could improve ART procedures by increasing their success rate while decreasing treatment cycles and risks for the patient and newborn, and optimize protocols for oocyte freezing for fertility preservation. Trial registration number not applicable

P-597 Pain intensity of oocyte retrieval of low and moderate number of oocytes is only mild, questioning the need of anesthesia and analgesia

Abstract Study question What is the pain intensity of oocyte retrieval (oocyte pick-up, OPU) without anesthesia and analgesia in women with low or medium number of follicles? Summary answer Pain intensity is only mild and is only slightly different in cycles with up to 5 aspirated oocytes and in repeated In-Vitro-Fertilisation (IVF) cycles. What is known already OPU is usually performed with anesthesia. However, OPU with anesthesia requires more treatment time and is more expensive. Previous studies have assessed the pain of OPUs without anesthesia in conventionally stimulated IVF using 15 to 19 gauge (G) aspiration needles and found high pain scores. Therefore, anesthesia is usually used in such IVF treatments. In contrast, in Natural cycle IVF (NC-IVF) OPU is commonly performed without anesthesia. The pain intensity of such OPUs and of OPUs of medium number of follicles has never been systematically analysed. Study design, size, duration A prospective, cross-sectional, multi-center observational study analyzing IVF cycles without anesthesia and analgesia was performed in seven IVF centers in Germany and Switzerland between January 2022 and March 2023. Women who performed one to ten NC-IVF or minimal stimulation IVF treatment cycles were enrolled. 518 aspirations were performed with 17G needles and 1772 with 19G or 20G needles. In total, 2290 cycles from 1039 patients were recorded. Participants/materials, setting, methods Pain score was assessed using a Visual Analogue Scale (VAS), graded 0 to 10 (0 = no pain; 10 = worst pain possible). Information about ovarian stimulation, number of collected oocytes, needle size, aspiration pressure and complications were recorded. A descriptive analysis was performed first, followed by a statistical evaluation using a linear mixed model to analyze the effect of the number of oocytes retrieved and of the number of cycles on the pain score. Main results and the role of chance The number of oocytes retrieved varied from 0 to 16 (interquartile range 1-2). The pain score varied from 0 to 10 with a median pain score of 3.0 (interquartile range 2-4), defined as “mild” pain. Compared to a reference value of aspirations with 1 oocyte, the pain score increased slightly by 0.5 points if no oocyte was retrieved, by 0.42 points if 2-5 oocytes were retrieved and by 1.14 points if ≥ 6 oocytes were retrieved (p < 0.001). Pain decreased slightly with repeated aspirations (-0.05 points per cycle) (p = 0.028). Needle size did not affect the pain scores. Seventeen vaginal and abdominal bleedings were recorded, two requiring hospitalization (<0.1%). Limitations, reasons for caution As only NC-IVF and minimal stimulation IVF cycles were analysed using mainly 19G and 20G needles, the results cannot be extrapolated to cycles with a high ovarian response and to aspirations using larger volume needles. Wider implications of the findings In case of one or few follicles OPU can be offered without anesthesia and analgesia to reduce aspiration time and cost. Trial registration number NCT05125497

Prolonged water-only fasting in the management of low-grade follicular lymphoma: a case series

BackgroundFollicular lymphoma typically follows an indolent and relapsing course often requiring several treatment cycles to achieve remission. Some patients opt to use complementary and alternative therapies particularly when observation is a treatment option.Case presentationHere we present a case series of three patients, a 50-year-old, White, Hispanic female, 56-year-old, White, non-Hispanic male, and 49-year-old, White, non-Hispanic male, who elected to undergo one or more prolonged water-only fasting and refeeding interventions to manage low to intermediate grade follicular lymphoma. Fasting was well tolerated in each patient. Each patient also experienced a reduction in the size and avidity of hypermetabolic lymph nodes as independently determined by their respective oncologists.ConclusionThe reported cases demonstrate positive outcomes in low-grade follicular lymphoma coinciding with prolonged water-only fasting and exclusively whole-plant-food dietary interventions. These findings highlight the potential of such interventions and warrant further exploration through preliminary observational research.

P-749 Maternal and obstetric outcomes following the transfer of embryos warmed with fatty acid supplemented solutions

Abstract Study question Does fatty acid (FA) supplementation into warming solutions influence maternal and obstetric outcomes after single vitrified-warmed cleavage stage embryo transfer (SVCT)? Summary answer FA-supplemented warming solutions improve the live birth rate after SVCTs without exerting any adverse effects on maternal and obstetric outcomes. What is known already Vitrification procedures decrease the intracellular lipid content and impair developmental competence. Adding fatty acids (FAs) to the warming solution has been shown to recover the lipid content of the cytoplasm and improve developmental competence and clinical pregnancy by stimulating the beta-oxidation pathway in warmed embryos. Recently, the FA-supplemented warming solutions have been commercially released. However, influence of the FA-supplemented supplementation on live birth rate after embryo transfers and perinatal outcomes remains unknown. Study design, size, duration The clinical records of 701 treatment cycles in 701 women who underwent SVCTs were retrospectively analysed. Vitrified embryos were warmed using solutions (from April 2022 to June 2022, control group, n = 340) or FA-supplemented solutions (from July 2022 to September 2022, FA group, n = 361). All pregnant women were invited to respond to the questionnaire at 9 weeks of gestation and after delivery. Maternal and obstetric outcomes were obtained from a self-reported questionnaire completed by the patients. Participants/materials, setting, methods The embryos in the FA group were warmed with the FA-supplemented solutions (VT526, Kitazato Corporation) while the embryos in the control group were warmed with the non-supplemented solutions (VT506, Kitazato Corporation). SVCTs were performed on day 2 after ovulation in natural cycles. The live birth rate, incidence of pregnancy complications, and neonatal outcomes were compared between the control and FA groups. Main results and the role of chance The live birth rate was higher in the FA group than in the control group (P = 0.0399). The miscarriage rates were comparable between the groups. Multivariate logistic regression analysis also demonstrated a higher probability of live births in the FA group than in the control group (adjusted odds ratio, 1.46; P = 0.0404). Patients were stratified by median maternal age for further analysis (37 years). This subgroup analysis showed that the live birth rate was significantly higher in the FA group than in the control group in women younger than 37 years of age. However, the live birth rate was comparable between the two groups for women aged 37 years or older. The incidence and types of pregnancy complications were comparable between the control and FA groups. Furthermore, caesarean section rates were similar between the groups. The average gestational age and incidence of preterm delivery were comparable between the groups. Birth length and weight, incidence of low birth weight, incidence of small for gestational age and large for gestational age, and infant sex were comparable between the groups. The incidence of birth defects was similar between the groups. Multivariate logistic regression analysis revealed a similar trend. Limitations, reasons for caution The single-centre retrospective study limits the strength of the study, necessitating further multicentre studies to ascertain the generalizability of these findings to other clinics with different protocols and/or patient demographics. Furthermore, the number of perinatal cycles was low. Wider implications of the findings The FA-supplemented warming solutions improved the live birth rates after SVCTs, particularly in young patients. Furthermore, the incidence of pregnancy complications and infant health was not affected by the FA-supplemented solutions. Therefore, FA-supplemented solutions can be considered safe and effective at improving clinical outcomes and reducing the patient burden. Trial registration number not applicable

Мутации в генах KRAS/NRAS и эффективность индукционной терапии по трехкомпонентным схемам на основе бортезомиба у пациентов с впервые диагностированной множественной миеломой

AIM. To identify the KRAS and NRAS gene mutations in patients with newly diagnosed multiple myeloma (ММ) and to classify them according to the depth of antitumor response to bortezomib-based triplet induction therapy. MATERIALS & METHODS. The trial enrolled 89 patients with newly diagnosed MM prior to chemotherapy. Among them, there were 45 women and 44 men aged 30–82 years (median 58.5 years). ММ was diagnosed according to IMWG criteria (2014). Bone marrow (BM) plasma cells were isolated from the aspirate using gradient method with subsequent immunomagnetic CD138 marker selection. The KRAS and NRAS gene mutations in BM CD138+ cells were identified with Sanger sequencing method. The proteomic programs MutationTaster, Polyphen2, and FATHMM-XF were used for mutation analysis in the KRAS and NRAS genes. All patients received bortezomib-based triplet chemotherapy as first-line treatment. The response depth was assessed after completing 6 cycles of PAD and VCD regimens. Antitumor response was evaluated according to IMWG (2016) criteria. RESULTS. The mutation rate in the gene family RAS was 42 % (37/89). The analysis focused on the data from 33 patients with mutations detected and response identified after 6 cycles of treatment. In 22 out of 33 patients, deep response was not achieved, whereas 11 patients showed complete remission (CR) + very good partial remission (VGPR). In the group of patients without mutations in the gene family RAS, the response to therapy meeting the CR + VGPR criteria was 64 % (27/42). The differences appeared to be significant (p = 0.008). The clinical data and the evaluation of primary treatment outcomes provided the basis for distinguishing a group of 9 prognostically unfavorable mutations: NRAS Gly13Asp, Gln61His; KRAS Gly12Ala, Gly12Asp, Gly12Val, Gly13Asp, Gln61Arg, Gln61His, and Ala146Val. CONCLUSION. The mutations in KRAS and NRAS belonging to the gene family RAS had a negative effect on the efficacy of the bortezomib-based triplet induction therapy. Mutation variants in the RAS family genes differed in prognostic significance. The analysis results helped to identify the mutation variants associated with the worse response to therapy: NRAS Gly13Asp, Gln61His; KRAS Gly12Ala, Gly12Asp, Gly12Val, Gly13Asp, Gln61Arg, Gln61His, and Ala146Val.

Effects of Sintilimab Plus Radiotherapy on Levels of Spondin-2 and Glucose Transporter-1 in Patients with Cervical Cancer.

We aimed to evaluate the effects of sintilimab plus radiotherapy on levels of Spondin-2 and glucose transporter-1 (Glut-1) in patients with cervical cancer. A total of 112 patients with cervical cancer treated from January 2019 to January 2021 were selected in this randomized control trial and divided into a control group (n = 56) and a study group (n = 56) using the random number table method. Chemotherapy using docetaxel + cisplatin was performed for both groups, based on which the control group was given radiotherapy (external conformal radiotherapy + intracavitary irradiation), and the study group received sintilimab plus radiotherapy. The treatment lasted for six cycles, with 21 days as one cycle. The total response rate of the study group was higher than that of the control group (55.36% vs 33.93%) (P < 0.05). There were no significant differences in adverse effects between the two groups (P > 0.05). After six cycles of treatment, the levels of carcinoembryonic antigen, squamous cell carcinoma antigen, vascular endothelial growth factor-A, vascular endothelial growth factor receptor 2, Spondin-2 and Glut-1 decreased in both groups compared with those before treatment, and they were lower in the study group (P < 0.05). The survival rate of the study group was higher than that of the control group (87.50% vs 71.43%) (P < 0.05). Sintilimab plus radiotherapy can effectively reduce the levels of serum tumor markers, such as Spondin-2 and Glut-1, and enhance the clinical efficacy on patients with cervical cancer, without increasing adverse effects.

A randomized, double-blind, phase III study in India for comparing efficacy, safety, and PK of ZRC-3277 (pertuzumab biosimilar) with Perjeta® in patients with HER2-positive metastatic breast cancer

IntroductionTo evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of ZRC-3277 (pertuzumab biosimilar) with Perjeta® (pertuzumab) in previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and MethodsThis phase III, multicenter, double-blind study across 38 sites in India randomized (1:1) patients with HER2-positive MBC in either the ZRC-3277 or Perjeta® group. Both groups also received trastuzumab and docetaxel. Of 268 enrolled patients, mITT population had 243 patients (119 and 124 in the ZRC-3277 and Perjeta® groups, respectively). The primary objective was to compare the between-group objective response rate (ORR) after six cycles of treatment. ORR was determined by evaluating scans of computed tomography or magnetic resonance imaging following Response Evaluation Criteria in Solid Tumor (RECIST 1.1). Two-sided 95% confidence interval (95% CI) for the difference in ORR was determined to evaluate the non-inferiority of ZRC-3277 to Perjeta®. The secondary outcomes included the assessment of PK, immunogenicity, and safety between the two groups. ResultsIn the mITT population, 104 (87.39%) and 114 (91.94%) participants achieved the ORR in the ZRC-3277 and Perjeta® groups, respectively. For predefined -15% non-inferiority margin, obtained two-sided 95% CIs (-12.19%, 3.11%) for the difference in ORR (-4.55%) between the two groups demonstrated the non-inferiority of ZRC-3277 to Perjeta®. PK, immunogenicity, and safety were not significantly different between the two groups. ConclusionEfficacy, PK, immunogenicity, and safety profiles of ZRC-3277 was found to be similar to those of Perjeta®. MicroAbstractPerjeta® (pertuzumab) plus trastuzumab is a standard-of-care for HER2-positive MBC. A phase III, double-blind study, conducted by randomizing 268 patients who received either Perjeta® or ZRC-3277 (a pertuzumab biosimilar), demonstrated similar efficacy, safety, PK, and immunogenicity of ZRC-3277 compared with Perjeta®. ZRC-3277 provides a cost-effective option for patients of high disease-burden countries, such as India.

Efficacy and safety of LAU-7b in a Phase 2 trial in adults with cystic fibrosis

BackgroundLung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF. MethodsA double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at 24 weeks. ResultsA total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV1 points with LAU-7b and 1.95 ppFEV1 with placebo, a 0.77 ppFEV1 (40 s) difference, p=0.345, and a 0.95 ppFEV1 (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV1 through 24 weeks showed differences of 1.01 and 1.23 ppFEV1, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile. ConclusionAlthough the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.