Wide use of broad-spectrum antibiotics in very low birth weight infants with spontaneous focal intestinal perforation-is it really justified?

PURPOSE: Very low birth weight (VLBW) infants are at a risk of spontaneous focal intestinal perforation (FIP). Treatment includes supportive care, antibiotics, and drainage with/without surgery. Broad-spectrum antibiotic agents like carbapenems are applied frequently, although their use is not well-supported by the limited evidence of causal pathogens. We hypothesize that the use of carbapenems may not be necessary in VLBW infants with FIP. Our primary objective was to evaluate the antimicrobial use in VLBW infants with FIP in a cohort of the German Neonatal Network (GNN). The secondary objective was to characterize a subset in detail as a benchmark for future targets of stewardship. METHODS: Data on VLBW infants with FIP was collected prospectively within the GNN, a collaboration of 68 neonatal intensive care units (NICU). With regards to the primary objective, patient characteristics and antimicrobial treatment were extracted from the predefined GNN database. To address our secondary objective, an additional on-site assessment of laboratory and microbiological culture results were performed. RESULTS: In the GNN cohort, 613/21,646 enrolled infants (2.8%) developed FIP requiring surgery. They were frequently treated with carbapenems (500/613 (81.6%)) and vancomycin (497/613 (81.1%)). In a subset of 124 VLBW infants, 77 (72.6%) had proof of gram-positive bacteria in the abdominal cavity, coagulase-negative staphylococci (CoNS) predominantly. Despite the low prevalence of gram-negative bacteria (n = 6 (4.8%)), the combination of meropenem and vancomycin was prescribed most frequently (n = 96 (78.0%)). CONCLUSION: The use of carbapenems as broad-spectrum antimicrobials agents might not be justified in most VLBW infants with FIP. Knowledge on the development of the neonatal gut microbiota, local resistance patterns and individual microbiological findings should be taken into consideration when implementing antimicrobial stewardship programs (ASPs).

Extrauterine Placental Perfusion and Oxygenation in Infants With Very Low Birth Weight: A Randomized Clinical Trial.

Importance: An extrauterine placental perfusion (EPP) approach for physiological-based cord clamping (PBCC) may support infants with very low birth weight (VLBW) during transition without delaying measures of support. Objective: To test whether EPP in resuscitation of infants with VLBW results in higher hematocrit levels, better oxygenation, or improved infant outcomes compared with delayed cord clamping (DCC). Design, Setting, and Participants: This nonblinded, single-center randomized clinical trial was conducted at a tertiary care neonatal intensive care unit. Infants with a gestational age greater than 23 weeks and birth weight less than 1500 g born by cesarean delivery between May 2019 and June 2021 were included. Data were analyzed from October through December 2021. Intervention: Prior to cesarean delivery, participants were allocated to receive EPP or DCC. In the EPP group, infant and placenta, connected by an intact umbilical cord, were detached from the uterus and transferred to the resuscitation unit. Respiratory support was initiated while holding the placenta over the infant. The umbilical cord was clamped when infants showed regular spontaneous breathing, stable heart rates greater than 100 beats/min, and adequate oxygen saturations. In the DCC group, cords were clamped 30 to 60 seconds after birth before infants were transferred to the resuscitation unit, where respiratory support was started. Main Outcomes and Measure: The primary outcome was the mean hematocrit level in the first 24 hours after birth. Secondary prespecified outcome parameters comprised oxygenation during transition and short-term neonatal outcome. Results: Among 60 infants randomized and included, 1 infant was excluded after randomization; there were 29 infants in the EPP group (mean [SD] gestational age, 27 weeks 6 days [15.0 days]; 14 females [48.3%]) and 30 infants in the DCC group (mean [SD] gestational age, 28 weeks 1 day [17.1 days]; 17 females [56.7%]). The mean (SD) birth weight was 982.8 (276.6) g and 970.2 (323.0) g in the EPP and DCC group, respectively. Intention-to-treat analysis revealed no significant difference in mean hematocrit level (mean difference [MD], 2.1 percentage points; [95% CI, -2.2 to 6.4 percentage points]). During transition, infants in the EPP group had significantly higher peripheral oxygen saturation as measured by pulse oximetry (adjusted MD at 5 minutes, 15.3 percentage points [95% CI, 2.0 to 28.6 percentage points]) and regional cerebral oxygen saturation (adjusted MD at 5 minutes, 11.3 percentage points [95% CI, 2.0 to 20.6 percentage points]). Neonatal outcome parameters were similar in the 2 groups. Conclusions and Relevance: This study found that EPP resulted in similar hematocrit levels as DCC, with improved cerebral and peripheral oxygenation during transition. These findings suggest that EPP may be an alternative procedure for PBCC in infants with VLBW. Trial Registration: ClinicalTrials.gov Identifier: NCT03916159.

Morbidity of Respiratory Syncytial Virus (RSV) Infections: RSV Compared With Severe Acute Respiratory Syndrome Coronavirus 2 Infections in Children Aged 0-4 Years in Cologne, Germany.

The aim of this retrospective analysis was to provide information on how infections with respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ in symptoms, clinical course, outcome, and utilization of hospital care. We investigated 748 polymerase chain reaction results from symptomatic children aged 0-4 years in Cologne, Germany. One hundred sixty-nine patients tested positive for RSV (22.6%) and 24 children for SARS-CoV-2 (3.2%). Symptomatic patients with RSV infection were hospitalized significantly longer. RSV-positive patients needed oxygen supplementation significantly more often as well as high-flow therapy. With regard to care efforts, RSV-infected patients put higher pressure on the hospital and utilized more hospital resources.

Molds and More: Rare Fungal Infections in Preterm Infants <24 Weeks of Gestation.

BACKGROUND: Extreme immature infants are at an increased risk of fungal infection due to immaturity of the skin barrier and the immune system. Besides Candida infections, in particular, Aspergillus may cause life-threatening diseases in preterm infants. Frequently, Aspergillus primarily affects the skin and may cause extensive damage. METHODS: We searched our hospital database for fungal infections other than Candida in preterm infants treated between 2015 and 2020 at our level III neonatal intensive care unit of the University Hospital of Cologne. RESULTS: In total, 13 preterm infants were identified. Of these, 11 had cutaneous Aspergillosis, one infant had severe enterocolitis caused by Aspergillus and Rhizopus and one had invasive intraabdominal Trichosporon mucoides infection. All infants were born <24 weeks of gestation, were delivered due to premature labor or chorioamnionitis, and had received prenatal steroids and/or hydrocortisone. Voriconazole and liposomal Amphotericin B were first-line treatments and the length of treatment varied between 3 and 148 days. Two infants died associated with severe infection. Liver toxicity was observed in six infants treated with Voriconazole. Therapeutic drug management for Voriconazole was performed in four infants. Target levels were not achieved by the doses that are recommended. CONCLUSIONS: Rare fungal infections, predominantly cutaneous Aspergillosis affects the most immature preterm infants and may cause severe disease. Treatment with Voriconazole has a high rate of liver toxicity and target levels are difficult to achieve in extremely immature infants.

A multi-centre randomised controlled trial of respiratory function monitoring during stabilisation of very preterm infants at birth.

AIM: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range. METHODS: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes. RESULTS: Among 288 infants randomised (median (IQR) gestational age 26+2 (25+3-27+1) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no differences in other respiratory function measurements, oxygen saturation, heart rate or FiO2. There were no differences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028). CONCLUSION: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. TRIAL REGISTRATION: Dutch Trial Register NTR4104, clinicaltrials.gov NCT03256578.

Is it all MIS-C? Unusual findings in a series of nine German patients with multi-system inflammatory syndrome in children after SARS-CoV-2 infection.

OBJECTIVES: Multi-system inflammatory syndrome in children (MIS-C) is a post-viral inflammatory vasculopathy of children and adolescents following Covid-19 infection. Since the incidence of SARS-CoV-infections has been increasing in Germany since October 2020, we observe an increasing number of children presenting with MIS-C. DESIGN: We present detailed clinical characteristics of a cohort of nine children with MIS-C admitted to a tertiary PICU at the University Hospital of Cologne between March 2020 and February 2021. RESULTS: The clinical sings and symptoms are largely in line with recent reports. All but one patient had positive SARS-CoV-2 antibodies. Latency form infection to MIS-C was 4-6 weeks. Two children presented with unusual findings: A girl had encephalomyelitis and a boy developed MIS-C side to side with acute leukemia. CONCLUSION: MIS-C has been increasing in Germany paralell to SARS-CoV-2 infections. Rarely, unuasual findings may be associated with MIS-C.

Peritoneal dialysis in extremely and very low-birth-weight infants.

The outcome of extremely low-birth-weight (ELBW) and very low-birth-weight (VLBW) infants has substantially improved in recent years. As acute kidney injury is frequent in these infants due to various risk factors, there is an increasing demand for renal replacement therapy in these patients. Data on that topic, however, are scarce. We review the available literature on that topic and report our experience on temporary dialysis in three extremely immature infants (two ELBW and one VLBW) with acute kidney failure. Peritoneal dialysis (PD) was performed for 19, 23, and 44 days until recovery of native renal function. At recent follow-up of 18 and 24 months, two patients are in good clinical condition with chronic kidney disease stages 1 and 4, respectively. One patient deceased at the age of 12 months due to secondary liver failure. The dialysis regimen applied in our study differed significantly from older infants with extremely short dwell times and accordingly high numbers of daily cycles. The use of rigid acute PD catheters was associated with less catheter-related complications (leakage, dislocation, and obstruction) as compared to ascites drainage catheters. In summary, PD was technically feasible and effective also in extremely immature infants, but frequent adjustments of dialysis regimens and high numbers of daily cycles posed immense efforts on both, parents and medical staff.

Maternal Obesity Alters Neurotrophin-Associated MAPK Signaling in the Hypothalamus of Male Mouse Offspring.

PURPOSE: Maternal obesity has emerged as an important risk factor for the development of metabolic disorders in the offspring. The hypothalamus as the center of energy homeostasis regulation is known to function based on complex neuronal networks that evolve during fetal and early postnatal development and maintain their plasticity into adulthood. Development of hypothalamic feeding networks and their functional plasticity can be modulated by various metabolic cues, especially in early stages of development. Here, we aimed at determining the underlying molecular mechanisms that contribute to disturbed hypothalamic network formation in offspring of obese mouse dams. METHODS: Female mice were fed either a control diet (CO) or a high-fat diet (HFD) after weaning until mating and during pregnancy and gestation. Male offspring was sacrificed at postnatal day (P) 21. The hypothalamus was subjected to gene array analysis, quantitative PCR and western blot analysis. RESULTS: P21 HFD offspring displayed increased body weight, circulating insulin levels, and strongly increased activation of the hypothalamic insulin signaling cascade with a concomitant increase in ionized calcium binding adapter molecule 1 (IBA1) expression. At the same time, the global gene expression profile in CO and HFD offspring differed significantly. More specifically, manifest influences on several key pathways of hypothalamic neurogenesis, axogenesis, and regulation of synaptic transmission and plasticity were detectable. Target gene expression analysis revealed significantly decreased mRNA expression of several neurotrophic factors and co-factors and their receptors, accompanied by decreased activation of their respective intracellular signal transduction. CONCLUSION: Taken together, these results suggest a potential role for disturbed neurotrophin signaling and thus impaired neurogenesis, axogenesis, and synaptic plasticity in the pathogenesis of the offspring's hypothalamic feeding network dysfunction due to maternal obesity.

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface.

MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. SIGNIFICANCE: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Use of whole exome sequencing in the NICU: Case of an extremely low birth weight infant with syndromic features.

Single gene (Mendelian) disorders are one of the leading causes of neonatal morbidity and mortality. However, in the setting of preterm birth phenotypic features of genetic diseases are often undifferentiated and are clinically very difficult to interpret based on the wide range of differential diagnoses. We report an extremely low birth weight infant (ELBW) born prematurely at 23 + 0 gestational weeks after twin pregnancy with a novel clinical manifestation with persistent hyperglycaemia as well as the known manifestations of disease-associated hypokinesia, renal salt wasting, and multifocal atrial tachycardia. The patient died of heart failure on the 72nd day of life. Whole exome sequencing (WES) revealed a previously well established, disease-causing heterozygous likely pathogenic variant in the Harvey rat sarcoma viral oncogene homolog (HRAS)-gene (c.35G > C, p. G12A, rs104894230), which implied the clinical diagnosis of Costello syndrome (CS; OMIM#190020.0004). The twin brother merely had complications related to preterm birth and did not show any CS symptoms. In conclusion, our case illustrated that CS should be considered in ELBW infants showing a life-threatening combination of complex cardiac arrhythmia and hypokinesia. If a syndromic disorder is suspected in the neonatal intensive care unit (NICU) setting, rapid WES is a useful, non-invasive diagnostic tool in critically ill ELBW infants.

Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma.

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

Comparison of Two Respiratory Support Strategies for Stabilization of Very Preterm Infants at Birth: A Matched-Pairs Analysis.

Objective: Respiratory support for stabilizing very preterm infants at birth varies between centers. We retrospectively compared two strategies that involved either increasing continuous positive airway pressures (CPAP), or increasing oxygen supplementation. Methods: Matched-pairs of infants (<28 weeks of gestation) were born either at the Leiden University Medical Center [low-pressure: CPAP 5-8 cmH2O and/or positive pressure ventilation (PPV) and fraction of inspired oxygen (FiO2) 0.3-1.0; n = 27], or at the University Hospital of Cologne (high-pressure: CPAP 12-35 cmH2O, no PPV and FiO2 0.3-0.4; n = 27). Respiratory support was initiated non-invasively via facemask at both units. Infants (n = 54) were matched between centers for gestational age and birth weight, to compare physiological and short-term clinical outcomes. Results: In the low-pressure group, 20/27 (74%) infants received 1-2 sustained inflations (20, 25 cm H2O) and 22/27 (81%) received PPV (1:19-3:01 min) using pressures of 25-27 cm H2O. Within 3 min of birth [median (IQR)], mean airway pressures [12 (6-15) vs. 19 (16-23) cmH2O, p < 0.001] and FiO2 [0.30 (0.28-0.31) vs. 0.22 (0.21-0.30), p < 0.001] were different in low- vs. high-pressure groups, respectively. SpO2 and heart rates were similar. After 3 min, higher FiO2 levels [0.62 (0.35-0.98) vs. 0.28 (0.22-0.38), p = 0.005] produced higher SpO2 levels [77 (50-92) vs. 53 (42-69)%, p < 0.001] in the low-pressure group, but SpO2/FiO2 and heart rates were similar. While intubation rates during admission were significantly different (70 vs. 30%, p = 0.013), pneumothorax rates (4 vs. 19%, p = 0.125) and the occurrence of spontaneous intestinal perforations (0 vs. 15%, p = 0.125) were similar between groups. Conclusion: Infants (<28 weeks) can be supported non-invasively at birth with either higher or lower pressures and while higher-pressure support may require less oxygen, it does not eliminate the need for oxygen supplementation. Future studies need to examine the effect of high pressures and pressure titration in the delivery room.

Supporting breathing of preterm infants at birth: a narrative review.

Most very preterm infants have difficulty aerating their lungs and require respiratory support at birth. Currently in clinical practice, non-invasive ventilation in the form of continuous positive airway pressure (CPAP) and positive pressure ventilation (PPV) is applied via facemask. As most very preterm infants breathe weakly and unnoticed at birth, PPV is often administered. PPV is, however, frequently ineffective due to pressure settings, mask leak and airway obstruction. Meanwhile, high positive inspiratory pressures and spontaneous breathing coinciding with inflations can generate high tidal volumes. Evidence from preclinical studies demonstrates that high tidal volumes can be injurious to the lungs and brains of premature newborns. To reduce the need for PPV in the delivery room, it should be considered to optimise spontaneous breathing with CPAP. CPAP is recommended in guidelines and commonly used in the delivery room after a period of PPV, but little data is available on the ideal CPAP strategy and CPAP delivering devices and interfaces used in the delivery room. This narrative review summarises the currently available evidence for why PPV can be inadequate at birth and what is known about different CPAP strategies, devices and interfaces used the delivery room.

Intranasal breast milk for premature infants with severe intraventricular hemorrhage-an observation.

For nasal application of neurotrophins and mesenchymal stem cells, successful delivery to the brain and therapeutic effects are known from experimental data in animals. Human breast milk contains neurotrophins and stem cells, but gavage tube feeding in preterm infants bypasses the naso-oropharynx. This is a first exploration on additional nasal breast milk and neuromorphological outcome after severe neonatal brain injury. We present a retrospective summary of 31 very low birth weight preterm infants with intraventricular hemorrhage °3/4 from one third-level neonatal center. All were breast milk fed. Sixteen infants additionally received nasal drops of fresh breast milk daily with informed parental consent for at least 28 days. Cerebral ultrasound courses were reviewed by a pediatric radiologist blinded to the intervention. The main outcome measure was severity of porencephalic defects before discharge. Clinical covariates were comparable in both groups. With nasal breast milk, a trend to a lower incidence for severe porencephalic defects (21% vs. 58%) was detected. Incidences were lower for progressive ventricular dilatation (71% vs. 91%) and surgery for posthemorrhagic hydrocephalus (50% vs. 67%).Conclusion: The hypothesis is generated that early intranasal application of breast milk could have a beneficial effect on neurodevelopment in preterm infants. Controlled investigation is needed. What is Known: • Successful delivery to the brain and therapeutic effects are known for nasal application of neurotrophins and mesenchymal stem cells from experimental data in animal studies. • Human breast milk contains neurotrophins and stem cells, but gavage tube feeding in preterm infants bypasses the naso-oropharynx. What is New: • This is the first report on additional nasal breast milk application in very low birth weight preterm infants with severe brain injury observing a trend for less severe porencephalic defects. • The hypothesis is generated that nasal breast milk might exert neuroprotective effects in preterm infants.

Mask Continuous Positive Airway Pressure Therapy with Simultaneous Extrauterine Placental Transfusion for Resuscitation of Preterm Infants - A Preliminary Study.

BACKGROUND: Delayed cord clamping or cord milking improves cardiovascular stability and outcome of preterm infants. However, both techniques may delay initiation of respiratory support. To allow lung aeration during cord blood transfusion, we implemented an extrauterine placental transfusion (EPT) approach. This study aimed to provide a detailed description of the EPT procedure and to evaluate its impact on the outcome of infants. METHODS: A retrospective analysis was performed comprising 60 preterm infants (220/7 to 316/7 weeks of gestation). Of these, 40 were transferred to the resuscitation unit with the placenta still connected to the infant. In this EPT group, continuous positive airway pressure support was initiated while, simultaneously, placental blood was transfused by holding the placenta 40-50 cm above the infant's heart. The cords of another 20 infants were clamped before respiratory support was started (standard group). Data on the infants' outcome were compared retrospectively. In a subgroup of 22 infants (n = 14 EPT, n = 8 standard), respiratory function monitor recordings were performed and both heart rates and SpO2 levels in the first 10 min of life were compared between groups. RESULTS: Although infants in the EPT group were lighter (EPT: 875 ± 355 g, standard: 1,117 ± 389 g; p = 0.02) and younger (266/7 weeks ± 19 days vs. 282/7 weeks ± 18 days; p = 0.045), there was no difference in neonatal outcome, including the incidence of intraventricular hemorrhage, bronchopulmonary disease, and red blood cell transfusions (all p > 0.1). Moreover, no differences in SpO2 levels and heart rates were observed in the infants whose resuscitations were recorded using a respiratory function monitor. CONCLUSIONS: In this retrospective analysis, EPT had no negative effects on the outcome of the infants, which warrants further evaluation in prospective randomized studies.

An Echocardiographic Screening Program Helps to Identify Pulmonary Hypertension in Extremely Low Birthweight Infants with and without Bronchopulmonary Dysplasia: A Single-Center Experience.

BACKGROUND: Pulmonary hypertension (PH) affects 1 in 6 infants with a birthweight <1,000 g (extremely low birthweight; ELBW) and is frequently associated with bronchopulmonary dysplasia (BPD). If untreated, the mortality rates of the disease are high. OBJECTIVES: The aim of this study was to characterize risk factors for PH in ELBW infants and to describe the timing of onset of the disease by setting up a screening program. METHODS: ELBW infants treated at the Department of Neonatology (level III neonatal intensive care unit at the University of Cologne Medical Centre, Germany) between January 2010 and March 2015 were included. Echocardiography screening for PH was performed either before discharge or if BPD was diagnosed. Additionally, infants had at least 1 echocardiographic scan after discharge. Survival with PH, age at diagnosis of PH, and risk factors associated with PH were assessed. RESULTS: In total, 34/188 (18%) infants had PH. Of these, 14 (41%) were identified after discharge. Another 11 (32%) were diagnosed with PH without suffering from moderate or severe BPD. The risk factors for diagnosis of PH were moderate (odds ratio, OR 4 [2-8]) or severe BPD (OR 13 [2-71]), prolonged rupture of membranes >7 days (OR 5 [1-19]), and birthweight below the 3rd percentile (OR 3 [1-9]). All infants with PH before discharge and 50% diagnosed after discharge were treated with sildenafil (2.0 mg/kg/day). PH resolved and sildenafil was discontinued in all patients after a median duration of 13 months (IQR 8-20). CONCLUSIONS: An echocardiographic screening program may help to identify infants with PH. Examinations should include all ELBW infants irrespective of the presence of BPD and be continued after discharge.

Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment.

BACKGROUND: Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables. METHODS: A cohort of 695 neuroblastoma patients was divided into a discovery set (n=75) for multigene predictor generation, a training set (n=411) for risk score development, and a validation set (n=209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score. RESULTS: The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9±3.4 vs 63.6±14.5 vs 31.0±5.4; P<.001), and its prognostic value was validated by multivariable analysis. CONCLUSION: We here propose a translational strategy for developing risk assessment systems based on hazard ratios of relevant prognostic variables. Our final neuroblastoma risk score comprised two multigene predictors only, supporting the notion that molecular properties of the tumor cells strongly impact clinical courses of neuroblastoma patients.

A Myc Activity Signature Predicts Poor Clinical Outcomes in Myc-Associated Cancers.

Myc transcriptional activity is frequently deregulated in human cancers, but a Myc-driven gene signature with prognostic ability across multiple tumor types remains lacking. Here, we selected 18 Myc-regulated genes from published studies of Myc family targets in epithelial ovarian cancer (EOC) and neuroblastoma. A Myc family activity score derived from the 18 genes was correlated to MYC/MYCN/MYCL1 expression in a panel of 35 cancer cell lines. The prognostic ability of this signature was evaluated in neuroblastoma, medulloblastoma, diffuse large B-cell lymphoma (DLBCL), and EOC microarray gene expression datasets using Kaplan-Meier and multivariate Cox regression analyses and was further validated in 42 primary neuroblastomas using qPCR. Cell lines with high MYC, MYCN, and/or MYCL1 gene expression exhibited elevated expression of the signature genes. Survival analysis showed that the signature was associated with poor outcome independently of well-defined prognostic factors in neuroblastoma, breast cancer, DLBCL, and medulloblastoma. In EOC, the 18-gene Myc activity signature was capable of identifying a group of patients with poor prognosis in a "high-MYCN" molecular subtype but not in the overall cohort. The predictive ability of this signature was reproduced using qPCR analysis of an independent cohort of neuroblastomas, including a subset of tumors without MYCN amplification. These data reveal an 18-gene Myc activity signature that is highly predictive of poor prognosis in diverse Myc-associated malignancies and suggest its potential clinical application in the identification of Myc-driven tumors that might respond to Myc-targeted therapies. Cancer Res; 77(4); 971-81. ©2016 AACR.

Survival Among Infants Born at 22 or 23 Weeks' Gestation Following Active Prenatal and Postnatal Care.

IMPORTANCE: Rates of survival for infants born at the border of viability are still low and vary considerably among neonatal intensive care units. OBJECTIVE: To determine whether higher survival rates and better short-term outcomes for infants born at 22 or 23 weeks' gestation may be achieved by active prenatal and postnatal care. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 106 infants born at 22 or 23 weeks of gestation at a level III neonatal intensive care unit at the University of Cologne Medical Centre in Cologne, Germany, between January 1, 2010, and December 31, 2014. Data analysis was performed in June 2015. EXPOSURES: Active prenatal and postnatal care. MAIN OUTCOMES AND MEASURES: Survival until hospital discharge and survival without neonatal or short-term severe complications (defined as high-grade intraventricular hemorrhage, surgery for abdominal complications, bronchopulmonary dysplasia, or retinopathy of prematurity). RESULTS: Of 106 liveborn infants (45 born at 22 weeks and 61 born at 23 weeks and 6 days), 20 (19%) received palliative care (17 born at 22 weeks and 3 born at 23 weeks), and 86 (81%) received active care (28 born at 22 weeks and 58 born at 23 weeks). Of the 86 infants who received active care (mean [SD] maternal age, 32 [6] years), 58 (67%) survived until hospital discharge (17 born at 22 weeks and 41 born at 23 weeks). Eighty-five infants survived without severe complications, with 1 infant born at 22 weeks excluded because of missing data (6 of 27 [22%] born at 22 weeks, and 16 of 58 [28%] born at 23 weeks). Survival was predicted by the Apgar score after 5 minutes (odds ratio, 0.62 [95% CI, 0.46-0.84]) and birth weight (odds ratio, 0.001 [95% CI, 0.00-0.40]). CONCLUSIONS AND RELEVANCE: One in 4 infants born at the border of viability and offered active care survived without severe complications. This finding should be considered for individualized parental approaches and decision making. Active follow-up information is required to determine childhood outcomes.

An 18 gene expression-based score classifier predicts the clinical outcome in stage 4 neuroblastoma.

BACKGROUND: The prognosis of children with metastatic stage 4 neuroblastoma (NB) has remained poor in the past decade. PATIENTS AND METHODS: Using microarray analyses of 342 primary tumors, we here developed and validated an easy to use gene expression-based risk score including 18 genes, which can robustly predict the outcome of stage 4 patients. RESULTS: This classifier was a significant predictor of overall survival in two independent validation cohorts [cohort 1 (n = 214): P = 6.3 × 10(-5); cohort 2 (n = 27): P = 3.1 × 10(-2)]. The prognostic value of the risk score was validated by multivariate analysis including the established markers age and MYCN status (P = 0.027). In the pooled validation cohorts (n = 241), integration of the risk score with the age and/or MYCN status identified subgroups with significantly differing overall survival (ranging from 35 to 100 %). CONCLUSION: Together, the 18-gene risk score classifier can identify patients with stage 4 NB with favorable outcome and may therefore improve risk assessment and treatment stratification of NB patients with disseminated disease.