Previous Treatment Cycles Research Articles

Assisted oocyte activation significantly improves zygote formation, cleavage, and implantation rates in patients with a history of fertilization failures.

Fertilization check performed at the 18th hour following classic in vitro fertilization procedure (IVF) or intracytoplasmic sperm injection (ICSI) is a critical stage in assisted reproduction. The success of the treatment is significantly reliant on the quantity of zygotes exhibiting two pronuclei. Consequently, low fertilization rates or complete fertilization failure are highly undesirable outcomes for both patients and reproductive specialists. Applying additional calcium ionophore for oocyte activation subsequent to ICSI may offer benefits and potentially enhance treatment outcomes, particularly for patients who have experienced low or absent fertilization rates (FR) in previous treatment cycles. The aim of the study is to evaluate the efficacy of Ca2+ ionophore application for oocyte activation. A retrospective analysis of 924 oocytes obtained from 120 patients who underwent ICSI cycles with a history of low or no fertilization as a result of previous unsuccessful treatment rounds. The next ART cycle followed with additional oocyte Ca2+ ionophore activation applied in 57 of the cases in order to optimize the treatment process (Group 1), and 63 patients were included and their outcomes followed as a control group (Group 2).We conducted a comparative analysis of results in both groups. The study's primary outcomes encompassed fertilization, cleavage embryo quality, blastocyst rate, and established clinical pregnancies. At day 1fertilization check we had 274/386 zygotes (71%FR) in group 1 and 132/410 in group 2 (32.2%FR), (P<0.0001). Twenty-two (34.9%) cycles in group 2 resulted in total fertilization failure (TFF). At the cleavage stage top-quality embryos from group 1 were significantly higher (P = 0.0021) in comparison to group 2. Forty-eight embryo transfers (ET) were performed in group 1 resulting in 41.67% clinical pregnancies versus 33 ET and only 4 pregnancies (12.12%) for group 2 (P = 0.0044). The results confirm the appropriateness of assisted oocyte activation as an additional method in cases of previous fertilization failure cycles.

Insights into the Window of Opportunity and Outcome Measures in Patients with Moderate to Severe Hidradenitis Suppurativa Treated with Secukinumab: A Real-World Study.

The concept of a window of opportunity in hidradenitis suppurativa (HS) management suggests that early initiation of biological therapy leads to better outcomes, though its timing remains uncertain. We conducted a retrospective observational multicenter study, including consecutive patients with moderate to severe HS who initiated secukinumab treatment following prior failure with systemic antibiotics or adalimumab. Therapeutic burden was defined as the sum of previous systemic treatment cycles and previous major surgical interventions for HS. Patients were followed up for 24weeks. Main outcomes were safety and effectiveness, assessed through the proportion of patients achieving HS Clinical Response (HiSCR) and a 55% reduction in International HS Severity Score System (IHS4-55). Additionally, potential predictors of response to secukinumab were studied. Analysis was performed on an intention-to-treat basis. A total of 67 patients (33 men, 34 women) were included, with a mean age of 41.55 (11.94) years and a mean baseline IHS4 of 17.88 (11.13). The mean therapeutic burden was 6.06 (3.49). At week24, 10.45% (7/67) of patients experienced adverse events, with three leading to treatment discontinuation. At week24, 41.79% (28/67) of patients achieved HiSCR, and 44.78% (30/67) of patients achieved IHS4-55. HiSCR could not be calculated in 12 patients with a baseline AN count < 3. A lower therapeutic burden was significantly associated with a higher likelihood of achieving HiSCR and IHS4-55 at week24. Secukinumab showed safety and efficacy in real-world patients with HS, and the inverse correlation found between therapeutic burden and treatment response supports the concept of a window of opportunity, offering insights into its timing.

The Meteoritics Trial: efficacy of methotrexate after remission-induction with tocilizumab and glucocorticoids in giant cell arteritis—study protocol for a randomized, double-blind, placebo-controlled, parallel-group phase II study

BackgroundGlucocorticoids (GC) are the standard treatment for giant cell arteritis (GCA), even though they are associated with adverse side effects and high relapse rates. Tocilizumab (TCZ), an interleukin-6 receptor antagonist, has shown promise in sustaining remission and reducing the cumulative GC dosage, but it increases the risk of infections and is expensive. After discontinuation of TCZ, only about half of patients remain in remission. Additionally, only few studies have been conducted looking at remission maintenance, highlighting the need for alternative strategies to maintain remission in GCA. Methotrexate (MTX) has been shown to significantly decrease the risk of relapse in new-onset GCA and is already a proven safe drug in many rheumatologic diseases.MethodsThis study aims to evaluate the efficacy and safety of MTX in maintaining remission in patients with GCA who have previously been treated with GC and at least 6 months with TCZ. We hypothesize that MTX can maintain remission in GCA patients, who have achieved stable remission after treatment with GC and TCZ, and prevent the occurrence of relapses. The study design is a monocentric, randomized, double-blind, placebo-controlled, parallel-group phase II trial randomizing 40 GCA patients 1:1 into a MTX or placebo arm. Patients will receive 17.5 mg MTX/matching placebo weekly by subcutaneous injection for 12 months, with the possibility of dose reduction if clinically needed. A 6-month follow-up will take place. The primary endpoint is the time to first relapse in the MTX group versus placebo during the 12-month treatment period. Secondary outcomes include patient- and investigator-reported outcomes and laboratory findings, as well as the prevalence of aortitis, number of vasculitic vessels, and change in intima-media thickness during the study.DiscussionThis is the first clinical trial evaluating remission maintenance of GCA with MTX after a previous treatment cycle with TCZ. Following the discontinuation of TCZ in GCA, MTX could be a safe and inexpensive drug.Trial registrationClinicalTrials.gov, NCT05623592. Registered on 21 November 2022.EU Clinical Trials Register, 2022-501058-12-00.German Clinical Trials Register DRKS00030571.

Long-term clinical and histological safety and efficacy of the CO2 laser for treatment of genitourinary syndrome of menopause: an original study

Objective This study aimed to evaluate histological modifications of the vaginal mucosa after repeated microablative fractional CO2 laser treatments. As secondary objectives we evaluated the clinical effects associated with repeated microablative fractional CO2 laser treatments using validated questionnaires. Methods A prospective intervention study was performed in the Division of Gynecology and Obstetrics, Urogynecology Unit, IRCCS San Raffaele Scientific Institute with 15 postmenopausal women complaining of genitourinary syndrome of menopause symptoms. The cohort of patients was submitted to at least two previous laser treatment cycles in the past years. The Vaginal Health Index (VHI), visual analog scale (VAS), Female Sexual Function Index (FSFI), Urinary Distress Inventory-6 (UDI-6), International Consultation on Incontinence Questionnaire – Urinary Incontinence (ICIQ-UI) and 5-point Likert scale were used. Moreover, histological examinations were carried out on all samples. Results At 4 weeks after the last treatment, the VHI score and all FSFI items were significantly increased compared with baseline. We observed a statistically significant decrease in both frequency and severity for all urinary symptoms after the follow-up. We observed a statistically significant increase in the number of epithelial cell layers with a consequent increase in epithelial thickness, in the number of glycogen-filled cells and in the number of papillae after the laser treatment. No signs of fibrosis were observed as neovascularization was observed in each woman. Conclusions This is the first study demonstrating the histological persistency of efficacy in repeated annually laser treatment cycles, with tissue changes always leading to regenerative results without any sign of fibrosis. Clinical Trial Registration ClinicalTrials.gov ID: NCT04868812 (release date: 27 April 2021).

P-231 The effect of warming blastocysts in Vitrolife media previously vitrified in Cook media on reproductive potential and clinical outcome

Abstract Study question Does the use of a different manufacturer’s media for vitrification and warming of blastocysts affect pregnancy, miscarriage and live birth rates. Summary answer Warming blastocysts in Vitrolife media, previously vitrified in Cook media, does not significantly affect the pregnancy or live birth rate. What is known already Current good practice is to vitrify and warm blastocysts in media manufactured by the same company. This is due to the optimisation of the protocols and media composition intending to maintain high survival rates and associated pregnancy rates. However, circumstances can arise, such as supply and production issues, whereby it is not possible to source the same media for warming vitrified blastocysts as the media they were vitrified in. Study design, size, duration This retrospective cohort study was conducted at TFP-Oxford Fertility. Frozen embryo transfer (FET) cycles included in the study were performed between 2018 and 2022. Embryos that had undergone genetic testing were excluded from the study. The mean women's age was 35 in the control group (Cook warming media) and 36 in the study group (Vitrolife warming media). The average number of embryos transferred was 1.06 vs 1.17 in control vs study group. Participants/materials, setting, methods For the present study 817 patients underwent FET between 2016 and 2018 whereby blastocysts were vitrified in cook media (Sydney IVF Blastocyst Vitrification Kit, K-SIBV-5000) and warmed in cook media (Sydney IVF Blastocyst Warming Kit, K-SIBW-5000). In comparison 704 patients underwent a FET between 2018 and 2022 whereby blastocysts were vitrified in cook media and warmed in vitrolife warming media (Rapidwarm™ Blast, 10120). The pregnancy, clinical pregnancy and live birth rates were compared. Main results and the role of chance Fisher’s exact test was used to calculate the p value and a level of 0.05 was used for significance. The results showed that there was no significant difference in the pregnancy rate, clinical pregnancy rate or live birth rate for blastocysts warmed in Vitrolife media vs Cook media (59.0% vs 57.0% p = 0.56, 47.2% vs 43.9% p = 0.44, 39.3% vs 37.0% p = 0.72) Limitations, reasons for caution This is a retrospective study at a single centre. The number of previous treatment cycles per couple was not included in the study. The study only looked at a comparison of Cook and Vitrolife warming media, no other commercially available media was tested. Wider implications of the findings Although good practice to vitrify and warm blastocysts in the same manufacturer media, our results show that the reproductive potential and clinical outcome may not be adversely affected by using a different manufacturer’s media. However, composition of the media and protocol should be considered and further studies should be conducted. Trial registration number not applicable

Incremental Treatment Response by Cycle With Collagenase Clostridium Histolyticum for Peyronie's Disease: A Pooled Analysis of Two Phase 3 Trials

OBJECTIVETo evaluate cumulative and incremental changes in penile curvature after each treatment cycle of collagenase clostridium histolyticum (CCH) in men with Peyronie's disease (PD). METHODSData from 2 phase 3, randomized, placebo-controlled trials were analyzed post hoc. Treatment was administered in up to 4 treatment cycles (per cycle: 2 injections, 1-3 days apart, of CCH 0.58 mg or placebo; subsequent penile modeling) at 6-week intervals. Penile curvature was measured at baseline and after each treatment cycle (weeks 6, 12, 18, and 24). Successful response was defined as ≥20% reduction from baseline penile curvature. RESULTSOverall, 832 men (CCH, n = 551; placebo, n = 281) were included in the analysis. After each cycle, mean cumulative percent reduction from baseline penile curvature was significantly greater with CCH vs placebo (P <.001). Following one cycle, 29.9% of CCH recipients exhibited a successful response. Among nonresponders, additional cycles of injections led to further successful responses: 60.8% of first cycle failures achieved response after fourth cycle (8 injections), 42.7% of cycle 1-2 failures achieved response after fourth cycle, and 23.5% of cycle 1-3 failures achieved response after fourth cycle. CONCLUSIONData showed incremental benefits from each of the 4 CCH treatment cycles. Completion of a full series of 4 CCH treatment cycles may optimize improvements in penile curvature in men with PD, including among those who did not clinically respond to previous treatment cycles.

Gender and Drug-Resistant Tuberculosis in Nigeria.

We conducted a retrospective study of 2555 DR-TB patients admitted to treatment between 2010 and 2016 in six geopolitical zones in Nigeria. We characterized the gender distribution of DR-TB cases and the association between demographics and clinical data, such as age, treatment category, number of previous TB treatment cycles, and geopolitical zone, with gender. The independent effects of being a male or female DR-TB patient were determined using bivariate and multivariate analyzes with statistical significance of p < 0.05 and a 95% confidence interval. Records from a total of 2555 DR-TB patients were examined for the study. A majority were male (66.9%), largest age-group was 30-39 years old (35.8%), most had MDR-TB (61.4%), were HIV-negative (76.6%), and previously treated for TB (77.1%). The southwest treatment zone had the highest proportion of DR-TB patients (36.9%), and most DR-TB diagnoses occurred in 2016 (36.9%). On bivariate analysis, age, HIV status, treatment zone, and clinical patient group in DR-TB were significantly associated with male gender. On multivariate analysis, males aged 20-29 years (AOR: 0.19, 95% CI: 0.33-0.59, p = 0.001) and HIV-positive males (AOR: 0.44, 95% CI: 0.33-0.59, p = 0.001) had lower likelihood of MDR-TB as males in the south-south treatment zone (AOR: 1.88, 95% CI: 1.23-2.85, p = 0.03), and being male and aged ≥60 years (AOR: 2.19, 95% CI: 1.05-4.54, p = 0.036) increased the probability of DR-TB. The older male population from south-southern Nigeria and women of childbearing age had lower incidence of DR-TB than men of the same age. Tailored interventions to reduce HIV and DR-TB prevalence in the general population, particularly among women of childbearing potential, and treatment support for young and older men are relevant strategies to reduce DR-TB in Nigeria.

Inter-Cycle Variation in Endometrial Thickness in Fresh Embryo Transfer Cycles: Predictors and Association with Pregnancy Outcome

Background: The use of intracytoplasmic sperm injection (ICSI) has increased substantially worldwide, primarily in couples with non-male factor infertility. We recently published the results of a large randomised controlled trial (RCT) comparing ICSI and IVF showing no significant improvement of ICSI over IVF in couples with normal semen concentration and motility. Here, we assess the cost-effectiveness of ICSI in these couples, with additional attention for subgroups. Aim: To evaluate the inter-cycle variation in endometrial combined thickness (ECT) in fresh embryo transfer cycles Method: This was a retrospective cohort study in a single university affiliated fertility clinic in Chengu, China. We studied women undergoing IVF/ ICSI treatment in a fresh stimulated cycle, and measured endometrial combined thickness on the day of HCG trigger in consecutive stimulated IVF/ICSI cycles. Inter-cycle variation in ECT was the main outcome measure. Secondary outcomes were the relationship between ECT and treatment outcomes clinical pregnancy, live birth and miscarriage. Results: The mean ECT in consecutive fresh stimulated cycles was 10.28 ⊠ 2.15mm in cycle 1 (n=7038), 9.93 ⊠ 2.11mm in cycle 2 (n=1287), 9.49 ⊠ 2.22mm in cycle 3 (n=148) and 8.63 ⊠ 1.82mm in cycle 4 (n=17) (p [Formula: see text]0.01.). An incremental increase in the clinical pregnancy rate was demonstrated for each additional millimetre in ECT up to a threshold level of 12-15mm. There was no evidence of systematic bias on the visual assessment of the Bland Altman plot in women undergoing 2 consecutive cycles of treatment (mean bias 0.46, (95% limits of agreement -5.62 to 5.65)). Multivariate predictors of ECT were the number of previous treatment cycles, secondary infertility, infertility diagnoses of anovulation, endometriosis, male factor or unexplained infertility and the number of follicles greater than 14mm on the day of HCG trigger. There was a small, significant interaction between female age and ECT on the outcome clinical pregnancy. Conclusion: There is a slight decrease in mean ECT in women undergoing consecutive stimulated IVF/ICSI cycles which is potentially explained by the increased occurrence of pregnancy with thicker ECT. Each millimetre increase in late follicular ECT increases the odds ratio of clinical pregnancy to a threshold level of 12-15mm.

Collagenase Clostridium Histolyticum Treatment for Peyronie's Disease: Analysis of Outcomes and Cumulative Benefits After Each Injection Cycle

ABSTRACT Introduction The efficacy and safety of collagenase clostridium histolyticum (CCH) for the treatment of Peyronie's disease (PD) were demonstrated in two phase 3, randomized, double-blind, placebo-controlled studies. CCH injections were administered in up to 4 treatment cycles at 6-week intervals; each cycle included two injections 1-3 days apart. Objective To evaluate incremental changes in penile curvature over the course of CCH treatment in men with PD. Methods A post hoc analysis was conducted using pooled data from the 2 placebo-controlled trials. Change from baseline and from the previous penile curvature measurement were calculated after each of the 4 treatment cycles (Weeks 6, 12, 18, and 24). For all patients, treatment included penile plaque modeling. For CCH vs placebo, mean percentage change in penile curvature was compared using a two-sample t-test; percentage of patients classified as treatment responders (defined as curvature reduction ≥20%) was compared using Fisher's exact test. Results The population included 832 adult men (CCH [n=551]; placebo [n=281]) who received ≥1 injection of study medication. At baseline, mean ± standard deviation (SD) penile curvature was 50.6±14.7 degrees in the CCH group and 50.4±14.1 degrees in the placebo group. Compared with baseline, the mean ± SD percentage change in penile curvature was -12.8±20.3% for CCH vs -6.2±18.8% for placebo after the first treatment cycle, -22.6±23.5% vs -10.6±23.1% after the second, -29.9±25.0% vs -14.6±24.0% after the third, and -33.1±28.0% vs -16.6±25.5% after the fourth (all P&amp;lt;0.001 vs placebo; Figure 1A). Comparing change from the previous measurement (ie, incremental change from previous treatment cycle [eg, between first and second; second and third, etc]), mean ± SD percentage reduction in penile curvature was 11.1±21.8% vs 5.0±16.4% after the second treatment cycle (P&amp;lt;0.001 vs placebo), 9.6±21.8% vs 3.9±17.0% after the third (P&amp;lt;0.001) and 6.3±23.0% vs 2.0±17.2% after the fourth (P=0.009; Figure 1B). The percentage of patients with ≥20% reduction in penile curvature since the previous measurement (cycle) was 29.9% for CCH group vs 18.3% for the placebo group after the first treatment cycle (P=0.0003), 29.1% vs 16.9% after the second (P=0.0002), 25.2% vs 12.8% after the third (P&amp;lt;0.0001), and 20.2% vs 10.9% after the fourth (P=0.001). For patients with a response after 2 treatment cycles (CCH [n=219]; placebo [n=77]), 40.2% of the CCH-treated patients vs 19.5% of the placebo-treated patients had an additional reduction of ≥20% after completing 4 treatment cycles (P=0.001). In patients with &amp;lt;20% reduction after the initial 2 treatment cycles (CCH [n=205]; placebo [n=168]), 29.8% of patients in the CCH group were classified as treatment responders after completing the fourth injection cycle (versus 20.8% of placebo-treated patients; P=0.057). Conclusions Data support that incremental benefits were obtained from each of the 4 CCH treatment cycles administered to men with Peyronie's disease. Results would suggest benefits with performing a full series of 4 CCH injections, even among men who are initial non-responders. Disclosure Yes, this is sponsored by industry/sponsor: Endo Pharmaceuticals Inc. Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Endo Pharmaceuticals Inc.

30-Day Mortality Following Systemic Anti-Cancer Treatment (SACT) Review in Driving Quality of Care in Hematologic Malignancies in a Tertiary Care Hospital

IntroductionThere is growing evidence to support SACT 30-day mortality rate as a key metric for assessing quality of cancer care and a key indicator of avoidable harm to patients from SACT due therapy-related or poor patient selection factors. This has been established for solid organ malignancy. However, data in patients with hematologic malignancy is limited. At the Gloucestershire Hospitals NHS Foundation Trust, a large district general hospital providing specialist care to over 600,000 people, we collated data from our in-house SACT dataset to assess factors that impact the 30-day SACT mortality and establish a benchmark for multidisciplinary, educational mortality meeting discussions on mortality in patients receiving SACT. We aimed to review cases characterizing patients, causes of death and the role of SACT in deaths.MethodsThis retrospective study included all patients aged 18 years or older with a hematologic malignancy who received SACT between Jan 1, 2016, and Mar 31, 2021, irrespective of the number of previous treatment cycles or regimens and irrespective of their response within the disease trajectory. SACT was defined as any cytotoxic chemotherapy, immunotherapies such as monoclonal antibodies, and targeted biological treatments. We calculated 30-day mortality after the most recent cycle of SACT for these patients. We analyzed whether patient, tumor type, and therapy-related factors were associated with the risk of 30-day mortality.ResultsA total of 1903 patients with hematologic malignancy received SACT. The 30-day mortality rate for our center was 3.89% for patients receiving SACT and 4.9% of all-cause mortality. In the 30-day mortality cohort the median patient age at death was 71 years (interquartile range (IQR) 52-86); ratio of men to women, 1.18. 30-day mortality increased with age for patients treated with palliative intent or intent to remission (OR 4.9, 95% CI .985-26.255; p=0.0171). Median duration of 30-mortality post SACT was 17 days (IQR 8-22). The commonest malignancy was plasma cell dyscrasias (54%) and 68% receiving treatments with intent to remission. ECOG performance status was 0-2 at final SACT cycle in 65%, 3 in 27% and 4 in 8%. 47% of patients were receiving their first cycle (median number of cycles received 2; IQR 1-3) and 43% receiving first line therapy (median lines of therapy 2; IQR 1-3). Therapy naïve patients had significantly higher 30-day mortality than those who received previous SACT (OR 3.435, 95% CI 2.06-5.66; p<0·0001). 42% of deaths occurred in hospital and 54% were attributed to primary refractory and/or aggressive disease. Other causes of death included infection (19% neutropenic, 15% non-neutropenic) including COVID-19 (3%), major bleed (5%), thromboembolism (1%) and cardiac event (1%).ConclusionsSACT data provides “real world” assessment of treatment patterns and outcomes in routine malignant hematology practice. It highlights the importance of systematic data collection and analyses to better inform factors associated with higher risk of 30-day mortality in patients with hematologic malignancy, which ultimately promotes review of clinical decision making and offers an opportunity for service improvements. Our findings shed light into some of the factors that affect the risk of early mortality of patients with hematologic malignancy and provides a way to measure if the health service is improving. The insights into risk factors for 30-day mortality will aid in better understanding for treating clinicians and their patients on predictors of potential harms and benefits of SACT thereby carefully balancing patients' personalized expectations with representative outcomes and treatment risks and should be the focus of discussions about SACT, particularly in pretreated or older patient groups. Neutropenic sepsis remains a significant cause of SACT related mortality warranting further improvements in care. Prospective case discussions together with this retrospective review have generated service improvements at our center including standardizing chemotherapy helpline pathways, systematizing SACT mandatory data recording on e-prescribing system and mandatory response assessments as part of SACT protocols' review. Future research work to examine outcomes based on subtypes of hematologic malignancy and on larger datasets is critical for improving our understanding at delivering the right drugs to the right patients. DisclosuresNo relevant conflicts of interest to declare.

P-225: A first-in-human study of FOR46 in patients with triple refractory Multiple Myeloma

<h3>Background</h3> Cluster of differentiation 46 (CD46) is highly expressed in multiple myeloma, especially in patients (pts) with gain of chromosome 1q and in the refractory setting. In vitro studies show upregulation and enhanced cytotoxicity upon treatment with pomalidomide, dexamethasone or lenalidomide. FOR46, an anti-CD46 antibody-drug conjugate with vc-MMAE, recognizes a tumor selective epitope of CD46 and is taken up by malignant cells by macropinocytosis, which is a relatively tumor selective uptake mechanism. <h3>Methods</h3> Pts with MM were enrolled who had progressed on proteasome inhibitors, immunomodulatory drugs and CD38-targeted therapies. An accelerated titration followed by 3+3 dose escalation design was used. FOR46, at protocol specified doses, was infused intravenously over 30-60 minutes on Day 1 of 21-day cycles. Following excess toxicity (neutropenia and fatigue) in a patient (pt) with high body mass index (BMI), dosing was changed from actual weight (AW) to adjusted body weight (ABW). G-CSF secondary prophylaxis was required for pts experiencing grade (gr) ≥ 3 neutropenia during a previous treatment cycle. The initial protocol had 2.4 mg/kg AW as the highest dose. When the MTD was not defined using ABW dosing, escalation was held pending protocol amendment to allow a higher dose and expansion to 10 patients at 2.4 mg/kg ABW began. Safety was evaluated using CTCAE v5.0 and efficacy was evaluated per IMWG criteria. Dexamethasone was only allowed for infusion reaction prophylaxis. CD46 antigen density was determined on patient MM cells via flow cytometry. <h3>Results</h3> Fifteen pts were enrolled at 6 pre-defined dose levels from 0.1 to 2.4 mg/kg with 1 patient each at the 0.1, 0.3 and 0.6 mg/kg dose levels, 3 at 1.2 and 1.8 mg/kg and 6 at 2.4 mg/kg. Median age was 68 (range 33 – 79) with 4 females. Gain 1q was present in 9 pts, absent in 5 pts and unknown in 1. The median number of prior lines of therapy was 6 (range 3-17). The only dose-limiting toxicity (DLT) was gr 4 neutropenia in 1 high BMI patient dosed by AW. This was the only DLT among 6 pts at 2.4 mg/kg dosed by a mix of AW (n=3) and ABW (n=3). One of 3 at 2.4 mg/kg ABW had non-dose limiting gr 4 neutropenia. The most common related adverse event was gr 4 neutropenia in 3 pts (20%). One patient (6.7%) had gr 4 thrombocytopenia and 1 each (6.7%) had gr 3 AST elevation, neutropenia, anemia, nausea, and peripheral neuropathy (PN). Of the 6 response-evaluable pts in the 1.8 and 2.4 mg/kg cohorts, 3 had partial responses (PRs) lasting 21, 30, and 15 weeks, respectively. Of the PRs, 1 pt did not have gain of 1q21. In addition to the fifteen pts in dose escalation cohorts, 10 have been enrolled in an expansion cohort at 2.4 mg/kg by ABW. <h3>Conclusion</h3> FOR46 demonstrates an acceptable toxicity profile using ABW dosing. There is encouraging evidence of efficacy in triple refractory MM. A protocol amendment allowing additional dose escalation to 2.7 mg/kg by ABW has been approved. NCT03650491

P–651 Strict embryo-endometrial synchrony does not contribute to the successful pregnancy during vitrified-warmed embryo transfer with hormone replacement cycles

Abstract Study question Does strict embryo-endometrium synchronization relate to pregnancy during vitrified-warmed embryo transfer (ET) with hormone replacement (HRT) cycles? Summary answer A 12-hour delay in the embryo-endometrial synchrony was acceptable, and this delay was not an independent predictor of pregnancy during vitrified-warmed ET with HRT cycles. What is known already Embryo-endometrium synchrony is considered to be necessary for successful pregnancy in both fresh and frozen-thawed cycles. Until now, the date of ET has been determined by the synchronization of the embryo developmental stage and the endometrium on a daily basis. To date, with the advent of the time-lapse incubator, it is possible to observe the embryo development from fertilization over time and to calculate the exact time from fertilization of the transferred embryo. However, there are very few studies on the extent to which increases the accuracy of synchronization between embryo and endometrium contributes to a successful pregnancy. Study design, size, duration This retrospective cohort study included 319 consecutive cycles during vitrified-warmed ET with HRT between August 2016 and August 2018. This study was conducted in an academically affiliated private practice. Participants/materials, setting, methods We analyzed 319 vitrified-warmed single-blastocyst transfer cycles. All frozen expanded blastocysts were inseminated by intracytoplasmic sperm injection (ICSI) and cultured in a time-lapse incubator. We calculated time for the in vitro culture of the embryo after ICSI (t1) and time for progesterone-priming (t2) up to ET. The difference between t1 and t2 (delta-t) was used as an indicator of embryo-endometrium synchrony. We examined the relationship between delta-t and treatment outcomes using multivariate logistic analysis. Main results and the role of chance The mean patient’s age at oocyte retrieval was 35.7 (SD 4.3). The number of pregnant cycles was 157 in all treatment cycles (pregnancy rate, 49.2%). The mean value of delta-t was 9.9 h (SD 2.6) in all cycles. There was no significant difference of delta-t in pregnant (mean, SD: 10.0 h, 2.8 h) and non-pregnant cycles (mean, SD: 10.0 h, 2.3 h). Treatment cycles were classified according to the quartile of delta-t, and we examined the percentages of pregnant cycles in each group. There were no significant differences in pregnancy rates among the groups (p = 0.75). On multivariate logistic analysis, patient’s age (adjusted odds ratio [aOR]: 0.94, 95% confidence interval [CI]: 0.89–0.99), previous treatment cycles (aOR: 0.74, 95% CI: 0.56–0.99), endometrial thickness at ET (aOR: 1.19, 1.04–1.36), and good quality blastocysts (&amp;gt;3BB according to Gardner’s classification) at vitrification (aOR: 2.49, 95% CI: 1.23–5.05) were independent predictive factors for pregnancy. On the other hand, delta-t did not contribute to pregnancy (aOR: 1.00, 95% CI: 0.99–1.00). Limitations, reasons for caution We did not examine the effects of embryo-endometrium synchrony during vitrified-warmed ET in a natural cycle. Therefore, careful interpretation of the significance of embryo-endometrium synchrony during the vitrified-warmed ET should be taken. Wider implications of the findings: We showed the embryo-endometrium synchrony did not contribute to the pregnancy during vitrified-warmed ET with HRT cycles. These results cast doubt on the existence of an optimal implantation window by changing the timing of ET with the results of gene expression testing of the endometrium. Trial registration number Not applicable

Comparison of anxiety scores between unexplained primary and secondary infertile couples

Objective To investigate the anxiety levels among infertile women and their partners also factors that may affect the anxiety status Study design A total of 403 infertile couples who applied to Infertility Outpatient Clinics of a University-affiliated Teaching and Research Hospital were included in the study. The infertile group was divided into two groups as primary and secondary infertile. One hundred and thirty-two fertile couples who applied to Gynecology Outpatient Clinics composed the control group. Hamilton Anxiety Rating Scale (HAM-A) form was filled by the infertile couples to evaluate the anxiety status before they started their treatment. Results Three hundred and twenty infertile and 84 fertile couples completed the study. The mean total scores of HAM-A of women were similar between the groups. So were the scores of their husbands. In all groups, women had significantly higher mean total HAM-A scores than their husbands. There was no association between the mean HAM-A score of women and age, BMI, AFC, duration of marriage, duration of infertility, number of previous treatment cycles. Education status, working status and family structure of women did not correlate with the mean HAM-A score. Conclusion Unexplained primary and secondary infertile couples had similar anxiety scores before the commencement of fertility treatments. However, the scores were higher in women than their male partners. Since the burden of treatment and the likelihood of treatment failure might increase the level of anxiety the women could be offered proper cognitive coping and relaxation interventions.

Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes.

Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes.

Comparison of depression between primary and secondary infertile couples

Objective We aimed to compare the depression levels between primary and secondary infertile couples and to investigate the related factors that may affect depression. Study design Two hundred and fifty primary and secondary infertile couples, who admitted to Gynecology and Infertility Clinics of Pendik Teaching and Research Hospital affiliated with Marmara University were enrolled in this study. Sixty-four BMI-matched fertile female patients who applied to the General Gynecology Clinic and their husbands were taken as the control group. Beck Depression Inventory (BDI) form was filled by the infertile couples to evaluate the depression status before they started their cycles. Results The mean total BDI scores were alike between groups among women. Mild depression was found to be higher in the primary infertile women and moderate depression was higher in women of the control group. Women had statistically higher depression scores than male partners. Primary infertile, secondary infertile, and fertile women had higher depression scores than their male partners in the corresponding groups. There was no significant difference in mean total BDI scores among males between the groups. The percentage of distribution of male partners in each level of depression was similar between the groups. Conclusions Only a weak positive correlation between the mean total BDI score and the number of previous treatment cycles was found. Psychiatric support before and during the upcoming fertility treatment might reduce the perception of the probable treatment failure.

AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance

The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of AsiDNA to monitor the effects of treatment on tumor growth and transcriptional modifications. No resistant clones were selected after AsiDNA treatment (frequency < 3x10−8) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10−7 resistant clones per treated cell. Cyclic treatments promote cumulative sensitivity characterized by a higher mortality of cells having undergone previous treatment cycles. This sensitization was stable, and transcriptome analysis revealed a major gene downregulation with a specific overrepresentation of genes coding for targets of DNA-PK. Such changes were also detected in tumor models which showed impaired growth after cycles of AsiDNA treatment.

The impact of intentional endometrial injury on reproductive outcomes: a systematic review and meta-analysis.

Endometrial injury is an intentional damage made to the endometrium, usually produced by a Pipelle catheter. Over the last two decades, endometrial injury has been studied to improve implantation rates and decrease the incidence of implantation failure in invitro fertilization (IVF) cycles. Recently, additional studies of endometrial injury, performed not only in patients with implantation failure but also in intrauterine insemination cycles, have been conducted, and the endometrial injury made by hysteroscopy has been researched. The evidence describing the impact of endometrial injury is controversial; therefore, we conducted a systematic review and meta-analysis to examine the issue. Our objective is to review the research that has been done until now and perform a meta-analysis regarding endometrial injury and its influence on implantation success and pregnancy rates in patients with at least one failed IVF cycle. In particular, we aim to study the efficacy of the procedure and look for confounding factors, such as maternal age, in assessing the efficacy of endometrial injury. The systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Study protocol can be assessed at PROSPERO International prospective register of systematic reviews (registration number CRD42018092773). Searches were conducted by an experienced research librarian in the following databases: MEDLINE(R) using the OvidSP interface and PUBMED, Embase, Web of Science and Cochrane Library. This review considered for inclusion randomized-controlled trials examining the success of performing local endometrial injury on IVF outcomes in women with previous failed IVF cycles. Ten studies, comprising a total of 1260 patients, were selected. Overall, when studying the effect of endometrial injury on clinical pregnancy rates (CPRs) and live birth rates (LBRs), higher rates were shown in the endometrial injury group. However, endometrial injury did not significantly improve CPRs and LBRs, when considering sub-group analyses of studies including patients with two or more failed IVF cycles, studies examining older patients or studies which did not include hysteroscopy. There was no significant difference found regarding multiple pregnancy rates, while a handful of studies showed an improvement in miscarriage rates. Endometrial injury should be used restrictively and not routinely in clinics. Maternal age and number of previous failed treatment cycles may be contributing factors which can influence the results when studying the effect of endometrial local injury. It is possible that the relative contribution of endometrial receptivity to the chances of implantation decreases with any additional failed cycle. The optimal study to prove the efficacy of local endometrial injury on implantation and pregnancy rates, should be a random-controlled trial studying the effect of local endometrial injury in oocyte donation cycles, in recipients with repeated implantation failure. This kind of study will conclude whether local endometrial injury is an efficient procedure with minimum confounding factors, and may assist in defining the population, even outside of donation cycles, that will benefit from the procedure.

Cost Effectiveness of Long-Term Incobotulinumtoxin-A Treatment in the Management of Post-stroke Spasticity of the Upper Limb from the Australian Payer Perspective.

BackgroundIn Australia, the reimbursement of botulinum neurotoxin-A (BoNT-A) on the Pharmaceutical Benefits Scheme for the treatment of moderate to severe spasticity of the upper limb following a stroke (PSS-UL) is restricted to four treatment cycles per upper limb per lifetime. This analysis examined the cost effectiveness of extending the treatment beyond four treatments among patients with an adequate response to previous treatment cycles.MethodsA Markov state transition model was developed to perform a cost-utility analysis of extending the use of incobotulinumtoxin-A beyond the current restriction of four treatment cycles among patients who have shown a successful response in previous treatment cycles (’known responders’). The Markov model followed patients in 12-weekly cycles for 5 years, estimating the proportion of patients with or without response over this period in each of the modelled treatment arms. Post hoc analysis of an open-label extension phase study informed the Markov model. The perspective of the analysis was the Australian healthcare system, meaning only direct healthcare costs were included. Utility values by response status were derived from EQ-5D data from a published double-blind, placebo-controlled study. The primary outcome measure was the incremental cost per quality-adjusted life-year (QALY). Univariate and probabilistic sensitivity analyses were conducted.ResultsThe open-label extension study data demonstrated the probability of treatment response after four injections was greater among ‘known responders’ than those without prior response. The incremental cost per QALY gained of continued use of incobotulinumtoxin-A beyond the current restriction of four treatments was A$59,911.ConclusionLimiting BoNT-A treatment to four cycles per patient per lifetime is likely to be suboptimal in many patients with PSS-UL. Treatment response beyond four cycles is highest among known responders, and allowing such patients to continue treatment beyond four cycles appears cost effective.

INTEREST IN CD2, a global patient-centred study of long-term cervical dystonia treatment with botulinum toxin

BackgroundLongitudinal cohort studies provide important information about the clinical effectiveness of an intervention in the routine clinical setting, and are an opportunity to understand how a population presents for treatment and is managed.MethodsINTEREST IN CD2 (NCT01753349) is a prospective, international, 3-year, longitudinal, observational study following the course of adult idiopathic cervical dystonia (CD) treated with botulinum neurotoxin type A (BoNT-A). The primary objective is to document long-term patient satisfaction with BoNT-A treatment. Here we report baseline data.ResultsThis analysis includes 1036 subjects (67.4% of subjects were female; mean age was 54.7 years old; mean TWSTRS Total score was 31.7). BoNT-A injections were usually given in line with BoNT-A prescribing information. The most commonly injected muscles were splenius capitis (87.3%), sternocleidomastoid (82.6%), trapezius (64.3%), levator scapulae (40.9%) and semispinalis capitis (26.9%); 35.5% of subjects were injected using a guidance technique. Most subjects (87.8%) had been previously treated with BoNT-A (median interval between last pre-study injection and study baseline was 4 months); of these 84.8% reported satisfaction with BoNT-A treatment at peak effect during their previous treatment cycle and 51.5% remained satisfied at the end of the treatment. Analyses by geographical region revealed heterogeneity in the clinical characteristics and BoNT-A injection practice of CD subjects presenting for routine treatment.ConclusionsThese baseline analyses provide sizeable data regarding the epidemiology and clinical presentation of CD, and demonstrate an international heterogeneity of clinical practice. Future longitudinal analyses of the full 3-year study will explore how these factors impact treatment satisfaction.

Prognostic factors for patients undergoing vitrified-warmed human embryo transfer cycles: a retrospective cohort study

We examined the prognostic factors for pregnancy in 210 vitrified-warmed embryo transfer (ET) cycles in 121 patients. The univariate analysis showed that age, gravida, the number of cycles associated with infertility caused by endometriosis, the number of previous assisted reproductive technology (ART) treatment cycles, and the number of ICSI procedures were significantly lower in pregnant cycles compared with non-pregnant cycles. The percentages of ET using at least one intact embryo and of ET using at least one embryo that had developed further after warming were significantly higher in pregnant cycles compared with non-pregnant cycles. Multivariate logistic regression analysis showed that previous ART treatment cycles, ET with at least one intact embryo, and ET using at least one embryo that had developed further were independent prognostic factors for pregnancy in vitrified-warmed ET cycles. We conclude that fewer previous ART treatment cycles, ET using at least one intact embryo, and ET with embryos that have developed further after warming might be favourable prognostic factors for pregnancy in vitrified-warmed ET cycles.