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BACKGROUND: The prevalence of mild cognitive impairment (MCI) and its subsequent progression to dementia has increased progression to dementia has increased worldwide, making it a topic of interest. of interest, and it has been observed that approximately 23% of cases are avoidable through preventable through vigorous exercise. METHODS: A systematic review with meta-analysis was conducted by searching in the PubMed, Scopus, CINAHL, and Web of Science databases. For inclusion, studies had to incorporate High Intensity Training (HIT) as a primary or significant component of the overall intervention for older adults with MCI. Out of the 611 articles identified, 14 randomized clinical trials met the criteria for inclusion in the review. RESULTS: Fourteen trials were included in the systematic review, and seven were included in the meta-analysis. A total of 1839 participants were included in the studies, with 1014 receiving a high-intensity training-based intervention, and 998 were considered in the meta-analysis. Compared to usual care or sedentary activities, the high-intensity training interventions had a positive effect on cognition, either improving it or delaying the decline (g = 0.710 (95% CI: 0.191 - 1.229; p = 0.007). Additionally, the meta-analysis determined that a frequency of 3 sessions per week (g = 0.964, CI = 0.091 - 1.837, p = 0.030) of approximately 60 minutes (g = 0.756, CI = 0.052 - 1.460, p = 0.035) each was the best dose to obtain better effects on global cognition. CONCLUSION: Low-frequency and short-duration high-intensity training interventions are sufficient to improve or at least delay the decline in global cognition.

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(1) Background: Cardiac donation after circulatory death (DCD) is an emerging paradigm in organ transplantation. However, this technique is recent and has only been implemented by highly experienced centers. This study compares the characteristics and outcomes of thoraco-abdominal normothermic regional perfusion (TANRP) and static cold-storage DCD and traditional donation after brain death (DBD) cardiac transplants (CT) in a newly stablished transplant program with restricted donor availability. (2) Method: We performed a retrospective, single-center study of all adult patients who underwent a CT between November 2019 and December 2023, with a follow-up conducted until August 2024. Data were retrieved from medical records. A review of the current literature on DCD CT was conducted to provide a broader context for our findings. The primary outcome was survival at 6 months after transplantation. (3) Results: During the study period, 76 adults (median age 56 years [IQR: 50-63 years]) underwent CT, and 12 (16%) were DCD donors. DCD donors had a similar age (46 vs. 47 years, p = 0.727), were mostly male (92%), and one patient had left ventricular dysfunction during the intraoperative DCD process. There were no significant differences in recipients' characteristics. Survival was similar in the DCD group compared to DBD at 6 months (100 vs. 94%) and 12 months post-CT survival (92% vs. 94%), p = 0.82. There was no primary graft dysfunction in the DCD group (9% in DBD, p = 0.581). The median total hospital stay was longer in the DCD group (46 vs. 21 days, p = 0.021). An increase of 150% in transplantation activity due to DCD was estimated. (4) Conclusions: In a new CT program that utilized older donors and included recipients with similar illnesses and comorbidities, comparable outcomes between DCD and DBD hearts were observed. DCD was rapidly incorporated into the transplant activity, demonstrating an expedited learning curve and significantly increasing the availability of donor hearts.

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BACKGROUND: The phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer (aOC) that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical (overall population first, then the homologous recombination-deficient [HRd] population). Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cutoff date, 08Apr2024). RESULTS: Median follow-up was 73.9 months. In the overall population, the OS hazard ratio (HR) was 1.01 (95% CI, 0.84-1.23; P= 0.8834) for niraparib (n= 487) versus placebo (n;= 246). In the HRd (n= 373) and homologous recombination-proficient (n= 249) populations, the OS HRs were 0.95 (95% CI, 0.71-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. CONCLUSIONS: In patients with newly diagnosed aOC at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were twice as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

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INTRODUCTION: DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n = 202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results used for study enrollment. METHODS: This phase 2, open-label study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥ 1 systemic treatment or without alternative treatments. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival. RESULTS: In total, 111 (41.6%) and 151 (56.6%) patients were enrolled with IHC 3+ and IHC 2+ tumors, respectively. In patients with IHC 3+ tumors, investigator-assessed confirmed ORR was 51.4% [95% confidence interval (CI) 41.7, 61.0], and median DOR was 14.2 months (95% CI 10.3, 23.6). In patients with IHC 2+ tumors, investigator-assessed ORR was 26.5% (95% CI 19.6, 34.3), and median DOR was 9.8 months (95% CI 4.5, 12.6). Safety was consistent with the known profile of T-DXd. CONCLUSION: In line with previously reported results, T-DXd demonstrated clinically meaningful benefit in patients with HER2-expressing tumors, with the greatest benefit in patients with IHC 3+ tumors. These data support the antitumor activity of T-DXd in HER2-expressing solid tumors, irrespective of whether patients are identified by local or central HER2 IHC testing.

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OBJECTIVE: Research has not often delved into the experiences of the Moroccan-heritage community in Western societies. We followed a mixed-methods approach, combining qualitative with quantitative methods, applying an intersectionality perspective to analyze the feelings and perceptions of Moroccan-heritage people about their situation in Spain, interaction with Spaniards, perceived discrimination, and metaperceptions to understand their affective reactions to injustice (Studies 1 and 2), and willingness to mobilize (Study 2). METHOD: In Study 1, we conducted four discussion groups with Moroccan-heritage women (n = 12) and men (n = 13) separately. In Study 2, we analyzed with a quantitative survey (n = 147) participants' identity fusion with Morocco and Spain, perceived metaprejudice and discrimination, metadehumanization, the evaluation of the ingroup situation, affective reactions to their situation, and support of collective actions for their rights. RESULTS: The analysis of Study 1 revealed experiences of discrimination and spontaneous positive but also negative metaperceptions, especially among women, including an alarming metadehumanization. Quantitative analyses in Study 2 confirmed gender differences, with women reporting worse feelings and perceptions, and confirmed that metadehumanization was crucial to predict indignation and anger of Moroccan-heritage people, while perceived discrimination was significant for mobilization. CONCLUSIONS: Although gender differences need additional clarification, these findings advance our theoretical knowledge about the sources of shared grievances among disadvantaged group members and the role of metadehumanization in their affective reactions to injustice. Interventions are urgent to address metadehumanization and canalize its affective consequences to promote social change. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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BACKGROUND: Magnetic ionic liquids (MILs) have been explored in dispersive liquid-liquid microextraction (DLLME). Their usage allows to substitute centrifugation and/or filtration steps by a quick magnetic separation. Besides, effervescence-assisted DLLME is one of the most known options to improve the dispersion of the extractant in the sample, while allowing to avoid the consumption of external energy during dispersion. Despite these interesting features, only one study incorporates MILs containing the tetrachloroferrate anion in effervescence tablets. These MILs are highly viscous and liquid at room temperature, thus compromising the stability of the tablets when used as extraction microdevices in effervescence-assisted DLLME, and only allowing their use in the conventional MIL-DLLME mode. RESULTS: A new class of effervescence tablets containing a Ni(II)-based MIL, that is solid at room temperature, is here proposed. This type of tablets permits their use, for first time, in the in situ DLLME mode, occurring through the transformation of a water-soluble MIL into a water-insoluble MIL microdroplet. This way, the tablet formulation included: the MIL, the metathesis reagent lithium bis[(trifluoromethyl)sulfonyl]imide, NaH2PO4 and K2CO3 as effervescence precursors salts, and Na2SO4 as salting-out and desiccating agent. The method is combined with high-performance liquid-chromatography and both fluorescence and ultraviolet detection, for the determination of monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and benzophenones (BPs), as biomarkers in urine. The method simply involved the addition of the effervescence tablet to the sample, thus taken place simultaneously the effervescence process and the metathesis reaction, without requiring any external energy consumption. The method presented limits of detection down to 10 ng L-1 for OH-PAHs and to 0.60 µg L-1 for BPs, inter-day relative standard deviations lower than 17 %, and average relative recoveries of 94 % in urine. The determined OH-PAHs contents in urine were between 0.40 and 16 µg L-1, and between 17.8 and 334 µg L-1 for BPs. SIGNIFICANCE: We have developed the first MIL-based effervescence tablets that are completely solid, thus improving the stability and robustness of these microdevices with respect to previously reported tablets involving MILs, while permitting to perform into the in situ DLLME mode (thus gaining in extraction efficiency). This approach including the MIL-based effervescence tablets constitutes an alternative on-site platform for the analysis of urine, as satisfactory precision, accuracy, and sensitivity are achieved despite not involving any external energy input within the analytical sample preparation setup. This method also constitutes the first application of MIL-based effervescence tablets for bioanalysis.

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Objective: In 2022, several cases of ocular hypertension (OHT) related to EyeCee One preloaded IOLs were reported. The aim of this study was to determine the presurgical and surgical variables associated with this response. Methods and analysis: An analysis was conducted on patients who underwent isolated cataract surgery between September 2022 and December 2022 at the Hospital Universitario del Henares. The influence of potential factors was studied using the Kruskal-Wallis test and multiple regression analysis. Results: A total of 353 cataract surgeries were included in the study. No significant differences between the different IOLs were found related to a change in the IOP on the first postoperative day (p = 0.395), but the change in the IOP after 1 month was higher in the EyeCee One group (p = 0.016). Approximately 6.1% of the patients who received EyeCee One had an IOP increase greater than 10 mmHg, compared to only 0.8% of the patients who received other IOLs. The odds ratio (OR) of experiencing an IOP increase greater than 10 mmHg in the EyeCee One group at the 1-month visit was 7.99 (1.52-41.99). The multiple regression analysis showed that receiving the EyeCee One lens was associated with a 2-mmHg increase in IOP. A previous history of glaucoma or OHT was not associated with greater IOP. Two patients in the EyeCee One group developed severe visual loss. Conclusion: Patients who received the EyeCee One IOL experienced significant increases in IOP at the 1-month visit. A small number of patients might suffer visual loss secondary to the rise in IOP.

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Several treatment-oriented classifications for the management of peri-implant marginal mucosal defects (PMMDs) have been published to date. While each classification provides valuable insights into key diagnostic and therapeutic aspects, there is a marked heterogeneity regarding the recommended clinical guidelines to achieve success in specific scenarios. The purpose of this review was to critically analyze and organize the similarities and differences enclosed in the available classifications linked with treatment recommendations on the management of PMMDs at single implant non-molar sites with the purpose of providing an overview of recommended interdisciplinary treatment options to facilitate clinical decision-making processes.

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Previous studies have found inconsistent associations between heavy metals and metalloids (cadmium, lead, mercury, and arsenic), and reproductive outcomes. The biofluid concentrations of ten non-essential trace elements (Hg, Pb, As, Ba, Sr, Rb, Cs, Sn, Ni, and Co) were evaluated in 51 Spanish women undergoing ICSI, PGT-A, and SET/FET. Nine out of ten non-essential elements were detectable in follicular fluid, whole blood, and urine collected the day of vaginal oocyte retrieval (VOR) and the day of embryo transfer and then analyzed by ICP-MS or Tricell DMA-80 for mercury. Elevated mercury and strontium concentrations in follicular fluid were associated with poor ovarian response and preimplantation outcomes. Worst preimplantation outcomes were also identified in women with elevated whole-blood strontium or mercury, urinary arsenic, barium, and tin the day of VOR. High concentrations of urinary rubidium on VOR day were linked with enhanced fertilization and blastocyst development. Excessive titanium in whole blood was associated with lower odds of implantation, clinical pregnancy, and achieving a live birth in a given IVF cycle. Excessive urinary arsenic on the day of embryo transfer was associated with lower odds of live birth. Although these preliminary results need to be confirmed in larger populations, distinguishing organic and inorganic element forms, our findings show that some non-essential elements have a detrimental impact on human IVF outcomes.

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A vast body of evidence has shown that concrete concepts are processed faster and more accurately than abstract concepts in a variety of cognitive tasks. This phenomenon is widely known as the concreteness effect, and explanations for its occurrence seem to reflect differences in processing and organization for both types of representations. While there is considerable evidence to support this concreteness effect, the nature of these differences is still controversial. In developing an explanation, we have proposed a relatively different approach from a false memory perspective using the Deese-Roediger-McDermott paradigm. To explore the implications of the association in creating false memories, we explore behavioral and electrophysiologically the false memory effect, where targets were manipulated according to their association strength and their concreteness. Results showed that false recognition rates differed significantly between concrete and abstract critical words when they were associated strongly with their respective lists, which led to a higher proportion of abstract false alarms both in behavioral and electrophysiological experiments. The principal outcome, which was called the DIM-HA effect, was discussed in terms of theories of associative activation and qualitatively different representation.

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OBJECTIVES: Real-world data evaluating how approvals of novel treatment regimens for ovarian cancer have impacted the treatment paradigm, including first-line maintenance, are lacking. This analysis aimed to describe treatment patterns for advanced epithelial ovarian cancer in Europe and the USA in the first-line maintenance setting. Patient characteristics, biomarker testing rates, and drivers of treatment choice were also evaluated. METHODS: A retrospective chart review study of electronic medical records in Europe and the USA was conducted for patients diagnosed with epithelial ovarian cancer (June 1, 2017-May 31, 2020), in line with Healthcare Market Research guidelines. Eligible physicians extracted data from electronic medical records by completing standardized patient record forms, including questions on patient involvement in treatment decisions. Patients with advanced (stage III/IV) disease were stratified by country and diagnosis date to provide information on treatment patterns. RESULTS: Patient record forms for 7072 patients with epithelial ovarian cancer were completed by 416 physicians; 5386 patients had stage III/IV ovarian cancer. Over time, the percentage of patients who were tested for BRCA mutations or homologous recombination deficiency increased. Patient preference was documented as a reason for treatment selection in approximately one-sixth of cases in the first-line adjuvant and first-line maintenance settings. The use of first-line maintenance poly(ADP-ribose) polymerase inhibitor monotherapy increased over time, while the use of vascular endothelial growth factor inhibitor monotherapy decreased. CONCLUSIONS: This real-world study showed that treatment patterns for advanced epithelial ovarian cancer varied by country. Rates of physician-reported patient involvement in treatment decisions in the first-line adjuvant and maintenance treatment settings for ovarian cancer were low, highlighting an unmet need for initiatives to improve patient involvement in shared decision-making regarding maintenance therapy selection.

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Cells sense and respond to mechanical forces through mechanotransduction, which regulates processes in health and disease. In single adhesive cells, mechanotransduction involves the transmission of force from the extracellular matrix to the cell nucleus, where it affects nucleocytoplasmic transport (NCT) and the subsequent nuclear localization of transcriptional regulators, such as YAP (also known as YAP1). However, if and how NCT is mechanosensitive in multicellular systems is unclear. Here, we characterize and use a fluorescent sensor of nucleocytoplasmic transport (Sencyt) and demonstrate that NCT responds to mechanical forces but not cell density in cell monolayers. Using monolayers of both epithelial and mesenchymal phenotype, we show that NCT is altered in response both to osmotic shocks and to the inhibition of cell contractility. Furthermore, NCT correlates with the degree of nuclear deformation measured through nuclear solidity, a shape parameter related to nuclear envelope tension. In contrast, YAP is sensitive to cell density, showing that the YAP response to cell-cell contacts is not via a mere mechanical effect of NCT. Our results demonstrate the generality of the mechanical regulation of NCT.

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INTRODUCTION: We aimed to determine the effect of years of schooling (YoS) and age on the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-MX) scores in preclinical carriers group (PCG) and non-carriers group (NCG) of the APP V717I mutation. METHODS: We included 39 first-degree Mexican relatives of APP V717I carriers (PCG = 15; NCG = 24). We report eight CERAD-MX tasks: Mini-Mental State Examination (MMSE), Word List Learning (WLL), Delayed Recall (WLD) and Recognition (WLR), Constructional Praxis Copy (CPC) and Recall (CPR), Semantic Verbal Fluency (SVF), and Verbal Boston Naming (VBN), comparing both groups' performance and simulating new samples' random vectors by inverse transform sampling. RESULTS: PCG and NCG performed similarly on CERAD-MX. In both groups, YoS and age influence all z scores. A positive age effect resulted for PCG on CPC and SVF; for the NCG on MMSE, SVF, and VBN. DISCUSSION: All tasks are influenced by YoS. Higher YoS/younger age or YoS/older age interactions affected different tasks, suggesting that YoS confounds outcomes. Highlights: Years of schooling (YoS) and age affect the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer's Disease scores of APP V717I preclinical carriers.Preclinical carriers underperformed non-carriers on Constructional Praxis Recall.Fewer YoS emerges as a confounding variable when detecting cognitive failures.Younger participants in both groups overperformed the older ones in the Memory tasks.Randomized data simulation increases statistical power when analyzing rare diseases.

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(1) Background: Mild cognitive impairment in older adults is a condition characterized by a decrease in mental abilities that affects their quality of life. The aim of this study is to evaluate the effects of an aerobic training program based on dance on depression, sleep quality, and quality of life in older adults with mild cognitive impairment. (2) Methods: This study employed a randomized controlled trial design with a total of 92 older adults with cognitive impairment, randomly assigned to an experimental group (n = 47) undergoing dance-based aerobic training and a control group (n = 45) who did not receive any intervention. Depression was assessed using the Yesavage Geriatric Depression Scale, sleep quality through the Pittsburgh Sleep Quality Index (PSQI), and quality of life through the SF-36 questionnaire. (3) Results: Statistically significant improvements were observed in depression (t(46) = 4.783, p = 0.000) and in the PSQI domains: subjective sleep quality (t(46) = 3.333, p = 0.002, and Cohen's d = 0.35), sleep duration (t(46) = 5.511, p = 0.000, and Cohen's d = 0.73) and PSQI total score (t(46) = 2.116, p = 0.040, and Cohen's d = 0.20). Regarding quality of life, improvements were observed in all domains of the questionnaire: the general health (t(46) = -9.374, p = 0.000, and Cohen's d = 0.03), physical function (t(46) = -9.374, p = 0.000, and Cohen's d = 0.03), the physical role (t(46) = -5.954, p = 0.000, and Cohen's d = 1.06), the emotional role (t(46) = -6.200, p = 0.000, and Cohen's d = 0.80), social function (t(46) = -5.585, p = 0.000, and Cohen's d = 0.53), physical pain, (t(46) = -9.224, p = 0.000, and Cohen's d = 1.04), vitality (t(46) = 2.289, p = 0.027, and Cohen's d = 1.27), mental health, (t(46) = -7.985, p = 0.000, and Cohen's d = 1.33), the physical summary component, (t(46) = -13.532, p = 0.000, and Cohen's d = 1.81), and in the mental summary component (t(46) = -10.6 81, p = 0.000, and Cohen's d = 0.06); (4) Conclusions: The results of the present study showed that they suggest that a dance-based aerobic training program improves mental health and quality of life in older people with mild cognitive impairment, providing a non-pharmacological approach to improve general well-being in this population.

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OBJECTIVE: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification. METHODS: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens. RESULTS: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001). CONCLUSIONS: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions.

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Spain is one of the eight EU-27 countries that failed to reduce early school leaving (ESL) below 10% in 2020, and now faces the challenge of achieving a rate below 9% by 2030. The determinants of this phenomenon are usually studied using cross-sectional data at the micro level and without differentiation by gender. In this study, we analyse it for the first time for Spain using panel data (between 2002 and 2020), taking into account the high regional inequalities at the macroeconomic level and the masculinisation of the phenomenon. The results show a positive relationship between ESL and socio-economic variables such as the adolescent fertility rate, immigration, unemployment or the weight of the industrial and construction sectors in the regional economy, with significant gender differences that invite us to discuss educational policies. Surprisingly, youth unemployment has only small but significant impact on female ESL.

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BACKGROUND: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. METHODS: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival. RESULTS: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P = 0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. CONCLUSIONS: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.).

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OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.

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PURPOSE: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016). METHODS: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years). RESULTS: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia). CONCLUSION: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety.

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