PURPOSE OF REVIEW:To summarize recent evidence from randomized clinical trials (RCT) and meta-analysis of patent ductus arteriosus (PDA) closure therapies versus conservative/expectant management on key outcomes such as bronchopulmonary dysplasia (BPD) or death in very preterm (<32 weeks' gestation) infants. RECENT FINDINGS:Of 10 completed RCTs in the past decade of medical therapies before 2 weeks of age to close a PDA, none demonstrated benefit in reducing moderate-severe BPD/death by 36 weeks postmenstrual age as compared to placebo treatment. When combined, the meta-analysis of the 10 RCTs showed an elevated risk of BPD/death [relative risk (RR): 1.10, 95% confidence interval (CI), 1.01-1.19) and higher risk of death by 36 weeks postmenstrual age or discharge (RR: 1.25; 95% CI, 1.01-1.56). A 2025 Cochrane meta-analysis also found a similar concerning trend of increased mortality following early medical treatment for PDA. Despite their recent popularity, there are no published trials demonstrating safety or efficacy of transcatheter PDA closure. SUMMARY:We now have ample evidence for all clinicians to finally acknowledge that conservative PDA management is the correct path forward. Clinical experimentation is no longer acceptable, and expectant PDA management must be adopted as the current standard if we are to adhere to our foundational principle, 'first, do no harm'.
PURPOSE OF REVIEW:To summarize existing evidence about the long-term effects of bronchopulmonary dysplasia (BPD) and postnatal corticosteroid (PNC) treatment to enable evidence-based risk-stratification and individualized decision-making in very preterm (<32 weeks' gestation) infants. RECENT FINDINGS:BPD remains a top risk factor for neurodevelopmental impairments (NDI) or death and BPD rates are rising in Western nations. Conversely, clinical trials and meta-regression data suggest medium (2-4 mg/kg cumulative dose) or high dose (4-8 mg/kg) dexamethasone use after a week of age reduces BPD/death and may improve or at worst have no effect on survival without NDI, as compared to placebo. Data from a validated meta-regression of all dexamethasone RCTs suggest dexamethasone effects are modified by the baseline risk of BPD: in infants with >50-70% risk of BPD, dexamethasone improved survival free of cerebral palsy, but had an opposite effect when BPD risk was <30%. A recent network meta-analysis of all PNC RCTs identified: moderately early-initiated (days 8-14), medium dose dexamethasone provided the largest reduction in BPD/death; high dose courses between 8 and 27 days were also highly effective; low dose dexamethasone, hydrocortisone, and inhaled or intratracheal steroids are ineffective or exhibit low potency in reducing BPD/death. SUMMARY:Current evidence supports the use of medium dose systemic dexamethasone - preferably between days 8 and 14 in ventilator-dependent infants at >50-70% risk of developing BPD. While more NDI follow-up data are needed, this regimen is proven to reduce BPD risk and may also reduce NDI risk, considering PNC effects on BPD reduction appear stronger than any direct NDI toxicity. Practical suggestions are provided to enable transition from the current prevalent use of late initiated (>3-4 weeks of age), low dose dexamethasone to moderately early, medium dose dexamethasone to reduce the ongoing high rates of BPD in very preterm infants.
Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. Intensifying chemotherapy has failed to improve patient survival for metastatic or relapsed RMS and RMS survivors often suffer from significant long‑term toxicities. More efficient and less toxic new therapies are critically needed. RMS expresses high levels of anti‑apoptotic protein Bcl‑2 and an oncogenic transcription factor Forkhead box protein M1 (FOXM1), which is also known to inhibit tumor cell apoptosis. The present study used a combination therapy of a recently developed non‑toxic FOXM1 inhibitor, RCM‑1 and the FDA‑approved Bcl2 inhibitor, venetoclax, which is not effective as a monotherapy in solid tumors. Compared with venetoclax alone, the combination therapy efficiently inhibited RMS growth in the animal model by decreasing tumor cell proliferation and inducing tumor cell apoptosis. RNA‑sequencing analysis demonstrated that the combination therapy uniquely decreased expression of ATPase Plasma Membrane Ca2+ Transporting 4 (ATP2B4), a plasma membrane calcium channel that is highly expressed in RMS compared with normal muscle cells. RCM‑1, but not venetoclax treatment, inhibited ATP2B4 and enhanced the sensitivity of RMS cells to apoptosis. Knockdown of ATP2B4 decreased RMS tumor cell proliferation, migration and colony formation in vitro. Furthermore, knockdown of ATP2B4 increased tumor cell apoptosis, while overexpression of ATP2B4 decreased tumor cell apoptosis in vitro. In the animal model of RMS, depletion of ATP2B4 decreased tumor growth. In summary, combining RCM‑1 with venetoclax sensitized RMS cells to apoptosis by decreasing ATP2B4. This made ATP2B4 a promising therapeutic target for RMS and provides a rationale for exploring this combination in early‑stage clinical trials.
OBJECTIVE:To evaluate diffuse white matter abnormality (DWMA) volume at term-equivalent age as an independent predictor of neurodevelopmental outcomes in preterm infants. STUDY DESIGN:In this multicentre prospective cohort study, 392 preterm infants (≤32 weeks' gestation) underwent term-equivalent MRI with automated DWMA quantification. The primary outcome was cognitive function at 3 years corrected age using the Differential Ability Scales-II General Conceptual Ability (GCA) score. Secondary outcomes included motor function (Bayley-III) and cerebral palsy (CP) at 2 years. Multivariable regression analysed DWMA's prognostic value. RESULTS:Follow-up was available for 89% (GCA) and 87% (Bayley-III/CP) of participants (mean gestational age 29 (SD: 2.5 weeks). Mean GCA was 94 (20.2); Bayley motor composite was 93 (14.5). CP was diagnosed in 12% of children (28 Gross Motor Function Classification System level I, six level II and III and five level IV and V). Higher DWMA volume independently predicted lower cognitive (β=-1.9; 95% CI -3.7 to -0.1), though only marginally over existing predictors (p=0.04), and motor scores (β=-2.0; 95% CI -3.3 to -0.7; p=0.003) and increased CP risk (adjusted OR=1.7; 95% CI 1.2 to 2.4; p=0.003) after controlling for clinical and socioeconomic factors. Socioeconomic disadvantages have amplified DWMA's adverse effects. CONCLUSIONS:This first external validation study demonstrates that objective DWMA quantification independently predicts multiple developmental outcomes through age 3 in preterm infants. The findings validate DWMA's pathological significance and support its utility as an early biomarker for risk stratification and targeted intervention.
