•Early-onset preeclampsia is associated with bronchopulmonary dysplasia in very preterm neonates.•Adjusting for intermediates in the primary analysis is over-adjusting.
Bronchopulmonary dysplasia ...(BPD) is a severe common complication of preterm birth with considerable short and long-term consequences. As more evidence is emerging that dysregulation of angiogenesis is implicated in the pathogenesis of preeclampsia as well as in fetal lung development, we assessed if preeclampsia is associated with development of BPD in very preterm neonates.
A retrospective cohort study of 308 infants born between 24+0 and 31+6 weeks of gestation in 2011 and 2012. We performed association analysis with univariable and multivariable logistic regression, adjusting for confounders. Models were additionally adjusted for intermediates, to show how an association can be disguised by over adjusting.
BPD was diagnosed at 36+0 weeks postmenstrual age and defined as the need for oxygen (FiO2 > 0.21) for at least 12 h per day, for more than 28 days before or at 36+0 weeks postmenstrual age, and classified as mild, moderate or severe.
After applying our exclusion criteria, we report our primary outcome on 247 mother-neonate pairs. Fifty-nine neonates developed BPD (23.9%) which was moderate to severe in 27 of them (10.9%). Preeclampsia was associated with BPD, adjusted odds ratio, 95% confidence interval: 4.22 (1.63, 10.91). However, after adjusting for additional intermediates no statistical significance remained, adjusted odds ratio, 95% confidence interval: 1.87 (0.49, 7.24).
This study shows that early-onset preeclampsia is associated with development of BPD in the very preterm neonate. Part of this association is mediated by fetal growth restriction and mode of delivery.
Congenital diaphragmatic hernia (CDH) is a rare congenital defect. Most cases are currently diagnosed either prenatally by ultrasound or shortly after birth. Late presentation of CDH is uncommon, and ...symptoms vary greatly. Here we describe two cases. The first concerns a 9-year-old boy with abdominal pain. The symptoms were interpreted as constipation and he was admitted for a high enema. After a few hours he developed severe respiratory distress; chest X-ray revealed a tension gastrothorax, and thoracostomy resulted in immediate respiratory improvement. In the second case, a 6-month-old girl presented with haematemesis and electrolyte imbalance. She was admitted for rehydration and correction of the electrolyte balance. A chest X-ray was performed because of persistent vomiting, and this showed an intrathoracal stomach. Late presentation of CDH is often misdiagnosed, with the risk of serious morbidity and mortality. Tension gastrothorax is a rare, life-threatening complication which should be treated by emergency gastric decompression..
Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug ...responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.
Perforation of the colon as a result of endoscopic manipulation is considered a severe adverse event. The goal of this review is to present the expected incidence of perforation in relation to ...varying levels of difficulty in endoscopic exploration and polypectomy together with the whole context of mechanisms, predisposing factors, diagnosis, and the strategic management plan.
An extensive search was undertaken in the Medline database for recent articles (published from 2000 onwards) in the English language using specific terms relating to the reported frequency of perforation during diagnostic and therapeutic colonoscopy in various medical settings and including morbidity, mortality, and appropriate management. Additional articles were retrieved irrespective of publication date to supplement where necessary data on important issues such as mechanisms of perforation, risk factors, diagnosis, and prevention.
The frequency of perforation was found to be 1 in 1400 for overall colonoscopies and 1 in 1000 for therapeutic colonoscopies. Varying perforation rates have been estimated for polypectomies, endoscopic mucosal resections, and endoscopic submucosal dissections. The mortality has dropped to 0 % in most studies, with the highest reported percentage being 0.02 %. Advanced age, female sex, the presence of multiple co-morbidities, diverticulosis, and bowel obstruction have been shown to increase the risk of perforation. The decision between surgery and nonoperative treatment will depend on the type of injury, the quality of bowel preparation, the underlying colonic pathology, and the clinical stability of the patient.
The perforation rate has declined in recent years in relation to more historical series, but there is now an increasing trend as a consequence of advanced interventional endoscopy. Awareness and experience are the only preventive measures that can limit the incidence of perforation.
Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo ...spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.
Background
Preterm care involves clinical measures almost exclusively aimed at keeping the preterm alive and ready for discharge from hospital. Children are then enrolled in clinical follow‐up care ...after this stressful period, but mental or specialised care for parents and child is often not embedded in the routine of a neonatal hospital ward and the family is then dependent on institutions for mental health or child health clinics, that is, regular care that is regionally scattered. This study aimed to investigate experiences of parents with regular care and compare them with parents visiting a fixed, specialised, multidisciplinary institute, outside the hospital walls, for preterm follow‐up care.
Methods
A survey was conducted among 56 parents (regular follow‐up care N = 26; multidisciplinary follow‐up care N = 30) of children born prematurely. The survey consisted out of items like parents' experiences with follow‐up care, like the organisation of care, supportive care, environmental support and experienced stress.
Results
Parents receiving multidisciplinary follow‐up care reported higher levels of satisfaction with organisation of care (F = 5.45; p = 0.023) and supportive care (F = 11.69; p = 0.001) than parents receiving regular follow‐up care. Also, it was found that the extent of support from the social environment alleviated stress but only in parents receiving regular follow‐up care (ß = −0.47; p = 0.016).
Conclusions
The current study findings indicate that experience with follow‐up care is valued higher when receiving multidisciplinary care than regular care, and the degree in environmental support alleviates stress in parents receiving regular care.
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) ...patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.
Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical ...efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.
We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the fi rst drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR.
Double balloon enteroscopy (DBE) is a new technique for the visualization of the small bowel. Although the technique is widely used, little is known about the complications. A few complications have ...been reported in the literature, mainly in case reports. The aim of this study was to establish the complication rate of both diagnostic and therapeutic DBE.
A total of 10 centers (nine academic centers and one teaching hospital) across four continents participated in the study. Complications were defined according to the literature. A therapeutic DBE was defined as a DBE with use of argon plasma coagulation, a polypectomy snare, injection of fluids (other than ink for marking), removal of foreign body, or balloon dilation.
A total 85 adverse events were reported in 2362 DBE procedures. In all, 40 events fulfilled the definition of a complication, 13 in 1728 diagnostic DBE (0.8 %) and 27 during 634 therapeutic procedures (4.3 %). The complications were rated minor in 21 (0.9 %), moderate in 6 (0.3 %) and severe in 13 procedures (0.6 %). No fatal complications were reported. Seven cases of pancreatitis were reported, six after diagnostic (0.3 %) and one after therapeutic (0.2 %) DBE.
Diagnostic DBE is safe with a low complication rate. The complication rate of therapeutic DBE is high compared with therapeutic colonoscopy. The reason for this is unclear. The incidence of pancreatitis after DBE is low (0.3 %), but has to be considered in patients with persistent abdominal complaints after a DBE procedure.
PDF
