Oxford Fertility

TPS7088 Background: Treatment options for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) can be limited if patients do not respond to both Bruton tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is). Nemtabrutinib is a once-daily, potent, noncovalent, reversible BTKi with a distinct kinase profile that inhibits BTK and other B-cell receptor relevant kinases. The multicenter, open-label, single-arm, phase 2 BELLWAVE-003 study (NCT04728893) is designed to evaluate nemtabrutinib at the recommended phase 2 dose (RP2D) in participants with R/R CLL/SLL, Richter transformation, mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, and Waldenström macroglobulinemia. Cohort J will evaluate nemtabrutinib in participants with R/R CLL/SLL who are relapsed/refractory to both a BTKi and BCL2i. Methods: Key eligibility criteria for cohort J include participants aged ≥18 years with CLL/SLL whose disease is R/R to prior therapy with both a BTKi (covalent or irreversible) and a BCL2i, and an ECOG PS of 0 to 2. Additional use of noncovalent or reversible BTKis is permitted if disease is R/R to such therapy. Participants must have received and not responded to, been intolerant to, or determined by their treating physician to be a poor PI3Ki candidate or ineligible for PI3Ki per local (institution) guidelines. Exclusion criteria include prior exposure to nemtabrutinib, active CNS disease, and prior systemic therapy with a monoclonal antibody within 5 half-lives or 4 weeks before allocation. Overall, the BELLWAVE-003 study comprises a dose escalation and confirmation phase (part 1) to establish the RP2D, and a cohort expansion phase (part 2). Part 1 evaluated nemtabrutinib in ≥6 to ≤20 participants with R/R CLL/SLL after ≥2 prior lines of therapy. The RP2D has been established as nemtabrutinib 65 mg QD. In part 2, ~460 participants will be enrolled across 9 expansion cohorts. Approximately 40 participants will be enrolled in cohort J. Treatment will continue until unacceptable toxicity, disease progression, or withdrawal. Adverse events will be monitored throughout and graded using NCI CTCAE version 5.0. Hematologic toxicities in participants with CLL will be assessed using iwCLL 2018 criteria. CT/MRI and/or PET will be performed every 12 weeks unless needed more frequently. The primary end point for cohort J is ORR per iwCLL 2018 criteria by independent central review (ICR). Additional end points include DOR and PFS per iwCLL 2018 criteria by ICR, OS, and safety and tolerability. Recruitment is ongoing. This is the first clinical trial with a dedicated cohort to assess noncovalent BTKis in patients whose disease has failed to respond to both BTKi and BCL2i. Clinical trial information: NCT04728893 .

Many first-time mothers (primiparous) within UK National Health Service (NHS) settings require an obstetric intervention to deliver their babies safely. While the antepartum period allows time for conversations about consent for planned interventions, such as elective caesarean section, current practice is that, in emergencies, consent is addressed in the moments before the intervention takes place. This paper explores whether there are limitations on the validity of consent offered in time-pressured and emotionally charged circumstances, specifically concerning emergency obstetric interventions. Using the legal framework of the Mental Capacity Act, Montgomery v. Lanarkshire Health Board (2015) and McCulloch v Forth Valley Health Board (2023), we argue that while women have the capacity to consent during labour, their autonomy is best supported by providing more information about instrumental delivery (ID) during the antepartum period. This conclusion is supported by some national guidelines, including those developed by the Royal College of Obstetricians and Gynaecologists, but not all. Further, we examine the extent to which these principles are upheld in modern-day practice. Data suggest there is relatively little antepartum information provision regarding ID within NHS settings, and that primiparous women do not report a thorough understanding of ID before labour. Based on these results, and bearing in mind the pressures under which NHS obstetric services currently operate, we recommend further research into patient and clinician perceptions of the consent process for ID. Pending these results, we discuss possible modes of information delivery in future practice.

The mouse and human embryo gradually loses totipotency before diversifying into the inner cell mass (ICM, future organism) and trophectoderm (TE, future placenta). The transcription factors TFAP2C and TEAD4 with activated RHOA accelerate embryo polarization. Here we show that these factors also accelerate the loss of totipotency. TFAP2C and TEAD4 paradoxically promote and inhibit Hippo signaling before lineage diversification: they drive expression of multiple Hippo regulators while also promoting apical domain formation, which inactivates Hippo. Each factor activates TE specifiers in bipotent cells, while TFAP2C also activates specifiers of the ICM fate. Asymmetric segregation of the apical domain reconciles the opposing regulation of Hippo signaling into Hippo OFF and the TE fate, or Hippo ON and the ICM fate. We propose that the bistable switch established by TFAP2C and TEAD4 is exploited to trigger robust lineage diversification in the developing embryo.

ImportanceFor women undertaking assisted conception, the dose of gonadotropin has historically been driven by clinical experience. A different and individualised strategy was developed for follitropin delta, a human cell line derived recombinant follicle stimulating hormone, with dose based on anti-Müllerian hormone (AMH) stratification; for women with a high ovarian reserve (AMH ≥15pmol/l; approx. 2.1ng/ml) the dose is based on the combination of AMH and body weight in a continuous manner. The clinical effectiveness of this approach to dosing for ovarian stimulation on live birth and safety is unknown. ObjectiveUndertake a one-stage meta-analysis of individual patient data from randomised trials comparing individualised dosing of follitropin delta versus other forms of follitropin (alpha, beta) for live birth rates and safety parameters in women undergoing ovarian stimulation for IVF. Evidence ReviewWe searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify eligible phase 3 trials between Jan 1 2000 and Feb 1 2023. All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drug interacting with log(AMH), age, and random effects for country and trial to compare the primary efficacy and safety outcomes of live birth and early ovarian hyperstimulation syndrome (OHSS) and/or the need for OHSS preventative measures, with ovarian stimulation parameters and neonatal outcomes also assessed. PROSPERO registration CRD42023399711. FindingsThree trials met inclusion criteria and included 2685 women undertaking 2,682 cycles between October 2013, and May 2020, with live birth follow-up through to February 1, 2023. For women with an elevated AMH (≥15 pmol/L), there was high quality evidence that the use of individualised dosing of follitropin delta was associated with an increased live birth rate (adjusted OR 1.64, 95%CI 1.14, 2.36). Safety outcomes were also improved with a reduced risk of both early OHSS and/or the need for preventative interventions (adj OR 0.27, 95% CI 0.15, 0.49) and early moderate or severe OHSS (adj OR 0.30, 95% CI 0.16, 0.58). These improvements in outcomes were obtained with a lower total dose of gonadotropin (-48.7μg, 95%CI -53.7, -43.8) and no adjustments in the daily dose. In contrast, similar live birth rates (adj OR 0.86, 95%CI 0.63, 1.17) and safety outcomes (adj OR 1.92 95%CI 0.76, 4.87) were observed for women with an AMH <15pmol/l. There were no clinical meaningful differences in neonatal outcomes. Conclusion and relevanceUsing follitropin delta in an AMH and weight-based algorithm rather than conventional licenced dosing of follitropin alpha or beta for ovarian stimulation women is associated with improved live birth rates and safety outcomes for women with elevated AMH levels.

The purpose of this study was to evaluate the differences in sperm function and embryo morphokinetics following sperm cryopreservation by ultra‐rapid freezing or rapid freezing methods compared to fresh spermatozoa. Thirty samples of normozoospermia were divided equally into fresh, ultra‐rapid freezing, and rapid freezing groups. In the rapid freezing, sperm suspension was placed horizontally on nitrogen vapor. In the ultra‐rapid freezing, sperm suspension with a straw‐in‐straw system was directly immersed in liquid nitrogen. Sperm function was assessed in terms of motility, morphology, viability, mitochondrial membrane potential, sperm DNA fragmentation, and acrosome reaction status. Also, the effects of two cryopreservation methods were assessed on global DNA methylation and DNA methyltransferase activity. Moreover, 730 embryos in three groups were cultured using time‐lapse imaging until day 6 for embryo morphokinetics. Progressive motility (38.80 ± 4.21 vs. 34.86 ± 4.19; p &lt; 0.001) and viability (64.30 ± 6.24 vs. 58.10 ± 8.69; p &lt; 0.01) in ultra‐rapid freezing were significantly higher than rapid group. DNA fragmentation and acrosome reaction were significantly increased in both cryopreserved groups (p &lt; 0.001). However, DNA fragmentation (16.30 ± 1.14 vs. 14.33 ± 2.94; p &lt; 0.01) was significantly higher in the rapid than the ultra‐rapid freezing group. No significant differences were noted in global DNA methylation (p &gt; 0.05) and DNA methyltransferases activity (p &gt; 0.05) in fresh compared to cryopreservation groups. The kinetic times, including tPB2, tPNa, tPNf, t2, t3, t4, t5, t6, t7, t8, and tM, showed a significant delay in cell divisions in both cryopreservation groups. Furthermore, tPNa, tPNf, and t8 occurred with a significantly higher delay in embryos fertilized by sperm from the rapid freezing compared to the ultra‐rapid freezing group. In addition, blastocysts formation was similar in both cryopreservation groups. Ultra‐rapid freezing preserved the sperm biological integrity and lead to better embryo morphokinetics compared to the rapid freezing method. However, both methods of sperm cryopreservation were epigenetically safe.

BackgroundUltra-hypofractionated regimens for definitive prostate cancer (PCa) radiotherapy are increasingly utilized due in part to promising safety and efficacy data complemented by greater patient convenience from a treatment course requiring fewer sessions. As such, stereotactic body radiation therapy (SBRT) is rapidly emerging as a standard definitive treatment option for patients with localized PCa. The commercially available magnetic resonance linear accelerator (MR-LINAC) integrates MR imaging with radiation delivery, providing several theoretical advantages compared to computed tomography (CT)-guided radiotherapy. MR-LINAC technology facilitates improved visualization of the prostate, real-time intrafraction tracking of prostate and organs-at-risk (OAR), and online adaptive planning to account for target movement and anatomical changes. These features enable reduced treatment volume margins and improved sparing of surrounding OAR. The theoretical advantages of MR-guided radiotherapy (MRgRT) have recently been shown to significantly reduce rates of acute grade ≥ 2 GU toxicities as reported in the prospective randomized phase III MIRAGE trial, which compared MR-LINAC vs CT-based 5 fraction SBRT in patients with localized PCa (Kishan et al. JAMA Oncol 9:365-373, 2023). Thus, MR-LINAC SBRT–utilizing potentially fewer treatments–is warranted and clinically relevant for men with low or intermediate risk PCa electing for radiotherapy as definitive treatment.Methods/DesignA total of 136 men with treatment naïve low or intermediate risk PCa will be randomized in a 1:1 ratio to 5 or 2 fractions of MR-guided SBRT using permuted block randomization. Randomization is stratified by baseline Expanded PCa Index Composite (EPIC) bowel and urinary domain scores. Patients undergoing 5 fractions will receive 37.5 Gy to the prostate over 10–14 days and patients undergoing 2 fractions will receive 25 Gy to the prostate over 7–10 days. The co-primary endpoints are GI and GU toxicities as measured by change scores in the bowel and urinary EPIC domains, respectively. The change scores will be calculated as pre-treatment (baseline) score subtracted from the 2-year score.DiscussionFORT is an international, multi-institutional prospective randomized phase II trial evaluating whether MR-guided SBRT delivered in 2 fractions versus 5 fractions is non-inferior from a gastrointestinal (GI) and genitourinary (GU) toxicity standpoint at 2 years post-treatment in men with low or intermediate risk PCa.Trial registrationClinicaltrials.gov identifier: NCT04984343. Date of registration: July 30, 2021.Protocol version: 4.0, Nov 8, 2022.

Acidic environments reduce the intracellular pH (pHi) of most cells to levels that are sub-optimal for growth and cellular functions. Yet, cancers maintain an alkaline cytoplasm despite low extracellular pH (pHe). Raised pHi is thought to be beneficial for tumor progression and invasiveness. However, the transport mechanisms underpinning this adaptation have not been studied systematically. Here, we characterize the pHe-pHi relationship in 66 colorectal cancer cell lines and identify the acid-loading anion exchanger 2 (AE2, SLC4A2) as a regulator of resting pHi. Cells adapt to chronic extracellular acidosis by degrading AE2 protein, which raises pHi and reduces acid sensitivity of growth. Acidity inhibits mTOR signaling, which stimulates lysosomal function and AE2 degradation, a process reversed by bafilomycin A1. We identify AE2 degradation as a mechanism for maintaining a conducive pHi in tumors. As an adaptive mechanism, inhibiting lysosomal degradation of AE2 is a potential therapeutic target.