Hospital Universitario Dexeus

Resistance to KRAS G12C inhibitors is a major cause of poor prognosis in non-small cell lung cancer (NSCLC). Sotorasib and fulzerasib target the KRAS protein in the guanosine diphosphate (GDP)-bound inactive state. Used in monotherapy in non-small cell lung cancer (NSCLC) patients, these drugs yielded response rates of 41% and 49% and median progression-free survival of 6.3 and 9.7 months, respectively. Mounting evidence points out that feedback activation of epidermal growth factor receptor (EGFR) inhibits the hydrolysis of KRAS guanosine triphosphate (GTP)-bound active state and reactivates RAS-mitogen-activated protein kinase (MAPK) signaling, leading to drug resistance. Here, we demonstrated that cetuximab enhanced the antitumor growth effect of fulzerasib in vitro in H358 cells and prolonged the survival of mice bearing subcutaneous H358 xenografts. Moreover, we demonstrated that cotreatment suppressed the expression of ERK, AKT, as well as MRAS and YAP1. Additionally, the combination of fulzerasib with cetuximab also abolished the viability of H358 cells, being less effective for H23 and H2030 cells. This effect was accompanied by YAP1 and MRAS overexpression, especially in H2030 cells. Ultimately, we demonstrated that MIG6, a feedback negative regulator of EGFR, is suppressed in the three cell lines starting at the 24-h time point with fulzerasib or sotorasib. Concurrently, ASS1, initially low in all three cell lines, was upregulated following therapy with fulzerasib or sotorasib, with or without cetuximab. These alterations were associated with increased fumarate levels in all three cell lines examined. Notably, the cotreatment response of H358 cells mirrors clinical trials with KRAS G12C colorectal cancer and NSCLC patients, where the combination of cetuximab with KRAS G12C inhibitors resulted in increased response and progression-free survival. Our findings provide insight into further tailoring EGFR inhibitor cotreatment in KRAS G12C NSCLC patients.

Diminished ovarian reserve (DOR) is common in women with infertility and is associated with poorer in vitro fertilization (IVF) outcomes. Testosterone is widely used off-label in this patient group, although evidence for its efficacy and safety is limited. To address this, we conducted a triple-blind, placebo-controlled, randomized clinical trial evaluating whether transdermal testosterone gel prior to IVF improves clinical pregnancy rates in women with DOR. Females aged 18-43 with infertility and DOR according to the Bologna criteria were recruited at 10 fertility clinics in Europe between April 2015 and November 2022. Of 316 assessed for eligibility, 290 were enrolled and randomized. Two were excluded from the primary analysis as their treatment coincided with the onset of the COVID-19 pandemic, and they did not start ovarian stimulation, leaving 288 participants. Participants were randomized to 5.5 mg of transdermal testosterone or matching placebo once daily for ~9 weeks prior to ovarian stimulation. All participants received ovarian stimulation in a long GnRH-agonist cycle with 300IU/day of highly purified human menopausal gonadotropin; fresh embryo transfer was performed if an embryo was available. The primary outcome was clinical pregnancy rate following fresh embryo transfer, defined as an intrauterine gestational sac with an embryo demonstrating cardiac activity at ≥7 weeks' gestation. Of the 288 participants, 134 were randomized to testosterone and 154 to placebo. Clinical pregnancy rates did not differ significantly, occurring in 21 women (15.7%) in the testosterone group and 23 (14.9%) in the placebo group (risk ratio (RR), 1.05; 95% confidence interval (CI) 0.61 to 1.81, p = 0.86). The study was terminated for futility at the prespecified interim analysis based on a conditional power calculation once 70% of the target sample size were randomized. In this study, transdermal testosterone did not improve clinical pregnancy rates compared with placebo in patients with infertility and DOR. Trial Registration: ClinicalTrials.gov: NCT02418572, EudraCT: 2014-001835-35.

Extremely preterm (EP) infants, defined as those born before 28 weeks of gestation or weighing less than 1000 g, face high rates of long-term complications despite improved neonatal survival. This narrative review summarizes current evidence and international consensus on the post-discharge follow-up of EP infants, with emphasis on neurodevelopment, somatic growth, pulmonary and sensory outcomes, and family-centered care. Key domains include early identification of cerebral palsy using neurological assessments such as the General Movements and Hammersmith scales, cognitive monitoring with standardized tools (e.g., Bayley Scales), nutritional and growth surveillance beyond anthropometrics, structured respiratory evaluations including immunoprophylaxis, and timely screening for vision and hearing deficits. In addition, the integration of caregiver-reported outcomes and mental health screening is essential to tailor follow-up strategies and support parental wellbeing. Models of care vary globally, from tertiary-based programs to hybrid and community-integrated approaches, highlighting the need for adaptable, interdisciplinary frameworks. Coordinated long-term follow-up that extends into early childhood is vital to reduce disparities and optimize functional outcomes in this vulnerable population. What is Known: • Extremely preterm infants are at high risk for long-term neurodevelopmental, respiratory, nutritional, and sensory complications, even when neonatal survival improves. • Neurodevelopmental tools such as the Bayley, General Movements, and Hammersmith Scales are widely used for early screening of cognitive and motor outcomes. What is New: • It highlights the importance of Patient-Reported Outcome Measures in complementing clinical surveillance with caregiver perspectives. • It underscores the limitations of early assessments alone and supports extending developmental monitoring into the preschool and school-age years.

IntroductionTriple-negative breast cancer (TNBC) is a challenging subtype of breast cancer to treat because it lacks the expression of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2). A significant majority of deaths related to cancer are caused by tumor metastasis and angiogenesis. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a significant role in angiogenesis. Instead of developing new molecules, drug repurposing, also known as repositioning, seeks innovative uses for outdated drugs or those that fail due to ineffectiveness.MethodsIn this study, we performed high-throughput virtual screening of FDA approved drug library taken from Enamine bioactive collection targeting VEGFR proteins, and the top hit compounds analyzed by molecular dynamics simulations and MM-GBSA were considered for further in vitro analyses against human breast cancer cells, MDA-MB-231 and MDA-MB-468 cells followed by in ovo assay using the Chorioallantoic Membrane (CAM) model.ResultsThe results revealed that risperidone was effective against triple-negative breast cancer, with IC50 values ranging from 46.53 to 49.76 µM. The findings of our study demonstrated that risperidone, an antipsychotic drug, could successfully inhibit human breast cancer cells in silico, in vitro and in ovo.DiscussionWe could prove that a structure-based drug repurposing approach is an effective strategy to produce a promising antiangiogenic repurposed drug that could also inhibit VEGFR2 in breast cancer. Although risperidone showed modest potency, its clinical availability and repurposing potential support further evaluation in preclinical and clinical settings.