Ten-year experience of whole lung lavage in pediatric Pulmonary Alveolar Proteinosis.

BACKGROUND: Pulmonary Alveolar Proteinosis (PAP) is extremely rare and can be caused by hereditary dysfunction of the granulocyte macrophage colony-stimulating factor receptor (GM-CSF) receptor, autoantibodies against GM-CSF, or other diseases leading to alveolar macrophage (AM) dysfunction. This leads to protein accumulation in the lung and severe dyspnea and hypoxemia. Whole lung lavage (WLL) is the first line treatment strategy. METHODS: Here, we present data from more than ten years of WLL practice in pediatric PAP. WLL performed by the use of a single lumen or double lumen tube (SLT vs. DLT) were compared for technical features, procedure time, and adverse events. RESULTS: A total of n=57 procedures in six PAP patients between 3.5 and 14.3 years of age were performed. SLT based WLL in smaller children was associated with comparable rates of adverse events but with longer intervention times and postprocedural intensive care treatment when compared to DLT based procedures. DISCUSSION: Our data shows that WLL is feasible even in small children. DLT based WLL seems to be more effective, and our data supports the notion that it should be considered as early as possible in pediatric PAP. CONCLUSION: WLL lavage is possible in small PAP patients but should performed in close interdisciplinary cooperation and with age appropriate protocols.

Cationic LNP-formulated mRNA expressing Tie2-agonist in the lung endothelium prevents pulmonary vascular leakage.

Dysfunction of endothelial cells (ECs) lining the inner surface of blood vessels are causative for a number of diseases. Hence, the ability to therapeutically modulate gene expression within ECs is of high therapeutic value in treating diseases such as those associated with lung edema. mRNAs formulated with lipid nanoparticles (LNPs) have emerged as a new drug modality to induce transient protein expression for modulating disease-relevant signal transduction pathways. In the study presented here, we tested the effect of a novel synthetic, nucleoside-modified mRNA encoding COMP-Ang1 (mRNA-76) formulated into a cationic LNP on attenuating inflammation-induced vascular leakage. After intravenous injection, the respective mRNA was found to be delivered almost exclusively to the ECs of the lung, while sparing other vascular beds and bypassing the liver. The mode of action of mRNA-76, such as its activation of the Tie2 signal transduction pathway, was tested by pharmacological studies in vitro and in vivo in respective mouse models. mRNA-76 was found to prevent lung vascular leakage/lung edema as well as neutrophil infiltration in a lipopolysaccharide-challenging model.

Foreign body aspiration in children - being safe and flexible.

PURPOSE OF REVIEW: Anesthesia for foreign body removal in children can be quite challenging. Even though rigid bronchoscopy is considered the gold standard for foreign body removal, there is increasing evidence for successful foreign body removal using flexible bronchoscopy. This review discusses the recent implications for flexible bronchoscopy for the purpose of foreign body removal and will compare these findings to rigid bronchoscopy. RECENT FINDINGS: During the last few years, several observational studies on foreign body removal by flexible bronchoscopy have been published, with promising results. SUMMARY: Flexible bronchoscopy is a feasible and safe method for removing aspirated foreign bodies in children. In order to improve patient safety during the procedure, it is necessary for a pediatric anesthetist and a pediatric pulmonologist to work closely together. The anesthetist can take care of the administration of the anesthetic and maintenance of the vital functions, and the pulmonologist can carry out a safe and fast bronchoscopy. In the case of foreign body removal by flexible bronchoscopy, the anesthesiological procedure of choice should be general anesthesia with controlled ventilation via a laryngeal mask.

Surgical management of large tracheoesophageal fistula in infants after button battery ingestion.

OBJECTIVES: In recent years, an increase in severe and even fatal outcomes related to oesophageal or airway button battery (BB) ingestion by infants and small children has been reported. Extensive tissue necrosis caused by lodged BB can lead to major complications, including tracheoesophageal fistula (TEF). In these instances, best treatment remains controversial. While small defects may warrant a conservative approach, surgery often remains inevitable in highly complex cases with large TEF. We present a series of small children that underwent successful surgical management by a multidisciplinary team in our institution. METHODS: This is a retrospective analysis of n = 4 patients <18 months undergoing TEF repair from 2018 to 2021. RESULTS: Surgical repair under extracorporeal membrane oxygenation (ECMO) support was feasible in n = 4 patients by reconstructing the trachea with decellularized aortic homografts that were buttressed with pedicled latissimus dorsi muscle flaps. While direct oesophageal repair was feasible in 1 patient, 3 required esophagogastrostomy and secondary repair. The procedure was completed successfully in all 4 children with no mortality and acceptable morbidity. CONCLUSIONS: Tracheo-oesophageal repair after BB ingestion remains challenging and is associated with major morbidity. Bioprosthetic materials in conjunction with the interposition of vascularized tissue flaps between trachea and oesophagus appear to be a valid approach to manage severe cases.

Laparoscopic versus Open Inguinal Hernia Repair Is Feasible in Infants with Caudal Anesthesia and Spontaneous Respiration.

INTRODUCTION: Minimally invasive surgery (i.e., laparoscopy) and minimally invasive anesthesia (i.e., caudal anesthesia with spontaneous respiration) have separately shown benefits for inguinal hernia repair in infants, yet to what degree these techniques can be combined remains unknown. This study investigated whether laparoscopy impacts the feasibility of performing caudal anesthesia with spontaneous respiration in infants. METHODS: Prospectively collected data of all infants less than 12 months old and over 3 kg weight who underwent laparoscopic indirect hernia repair (LAP) at our department from 2019 to 2021 were compared with a historical control-matched group of infants who underwent open repair (OPEN) from 2017 to 2021. We assessed the patients' characteristics, anesthesia, and surgical data as well as intra- and postoperative complications. RESULTS: A total of 87 infants were included (LAP n = 29, OPEN n = 58). Caudal anesthesia with spontaneous respiration was feasible in 62.1% of cases (LAP n = 55.2%, OPEN n = 65.5%; nonsignificant). Neither group registered anesthetic intra- or postoperative complications. Sedatives were utilized in 97% of LAP patients versus 56.9% of OPEN patients (p < 0.00001). The airway was secured with a laryngeal mask in 89.7% of patients during LAP versus 41.4% during OPEN (p < 0.00001). No significant differences were found regarding the use frequency of opioids (48.3% LAP vs. 34.5% OPEN; nonsignificant) or neuromuscular blockers (6.9% LAP vs. 5.2% OPEN; nonsignificant). CONCLUSION: This is the first comparative study on caudal anesthesia and spontaneous respiration in infants undergoing laparoscopic versus open inguinal hernia surgery. Laparoscopy increased the need for ventilatory support and sedatives but did not significantly impair the feasibility of caudal anesthesia and spontaneous respiration.

Correlation between safety attitudes and early adoption of cognitive aids in the German culture sphere: a multicenter survey study.

BACKGROUND: Cognitive Aids (checklists) are a common tool to improve patient safety. But the factors for their successful implementation and continuous use are not yet fully understood. Recent publications suggest safety culture to play a key role in this context. However, the effects on the outcome of implementation measures remain unclear. Hospitals and clinics that are involved in cognitive aid development and research might have significantly different safety cultures than their counterparts, resulting in skewed assessments of proper implementation. Therefore, the objective of this study was to assess the correlation between cognitive aid implementation and safety attitudes of staff members in early adopting and later adopting clinics. METHODS: An online survey of the Safety Attitudes Questionnaire (SAQ) was carried out in German anaesthesiology departments during the initial implementation of a new checklist for emergencies during anesthesia ("eGENA" app). Subsequently an analysis between subgroups ("eGENA" app usage and occupation), with Kruskal-Wallis- and Mann-Whitney-U-Tests was carried out for the general SAQ, as well as it six subscales. RESULTS: Departments that introduced "eGENA" app (Median 3,74, IQR 0,90) reported a significantly higher median SAQ (U (NeGENA = 6, Nnon eGENA = 14) = 70,0, z = 2,31, p = 0,02, r = 0,516) than their counterparts (Median 2,82, IQR 0,77) with significant differences in the dimensions teamwork climate, work satisfaction, perception of management and working conditions. CONCLUSION: Early adopters of cognitive aids are likely to show a significantly higher perception of safety culture in the SAQ. Consequently, successful implementation steps from these settings might not be sufficient in different clinics. Therefore, further investigation of the effects of safety culture on cognitive aid implementation should be conducted.

Incidence and characteristics of errors detected by a short team briefing in pediatric anesthesia.

BACKGROUND: In our institution, a modified WHO surgical safety checklist was implemented more than ten years ago. In retrospect, we noticed that pediatric anesthesia was underrepresented in our surgical safety checklist modification. Therefore, we added a standardized team briefing (pedSOAP-M) immediately before induction of anesthesia and hypothesized that the use of this checklist was effective to detect relevant errors with potentially harmful consequences. AIMS: The primary aim was to assess the incidence and characteristics of the detected errors, and the secondary aim was to identify factors influencing error detection. METHODS: This prospective observational study was performed between November 2020 and October 2021 in five operation rooms at the Children's Hospital of Hannover Medical School, Germany. The subcategories of the pedSOAP-M checklist were suction, oxygen, airway, pharmaceuticals, and monitoring. Demographic and procedure-related data and the briefing results were documented anonymously and undated, using a standardized case report form. RESULTS: We enrolled 1030 and analyzed 1025 patients (aged 0-18 years). Relevant errors were detected in 111 (10.8%) cases (suction 2.5%, oxygen 3.0%, airway 0.2%, pharmaceuticals 2.4%, monitoring 3.0%). In the pharmaceuticals subcategory, the most common error was entering a wrong patient weight into the perfusor syringe pumps. Experienced anesthetists detected significantly more errors than less experienced ones. CONCLUSION: The briefing tool pedSOAP-M was effective in detecting relevant errors with potentially harmful consequences. The presence of an experienced anesthetist was associated with a higher efficacy of the briefing. Particular attention should be given to entering patient weight into the anesthesia workstation and the perfusor syringe pumps.

[Case Series Report: Management of Anesthesia in Children Undergoing Complex Surgery of Tracheoesophageal Fistula after Ingestion of Button Batteries]. / Fallberichte: Kinder mit tracheoösophagealer Fistel nach Knopfbatterieningestion.

Button battery ingestions in children increased in recent years and may lead to life-threatening complications, especially if the battery is impacted in the esophagus. The pH close to the negative pole of the battery can rise in a very alkalotic range (pH > 10) leading to severe tissue damage. Therefore, in this case series report, the clinical courses of four children with button battery ingestion leading to tracheoesophageal fistulas are presented. The diagnosis and removal of the button battery was delayed in all cases. The surgical reconstruction of the trachea was performed in intravenous anesthesia and with extended monitoring. The intraoperative oxygenation was maintained using a combination of extracorporeal membrane oxygenation (ECMO) and mechanical ventilation via an endobronchial tube. To prevent these life-threatening complications, the awareness of the parents and child care providers should be raised, and the manufacturers should redesign their products to secure the battery compartment. In children with suspected battery ingestions, the immediate localization and removal of the battery (< 2 h) is of highest importance. Local administration of honey or sucralfate can be considered in ingestions < 12 h but should not delay an endoscopic removal.

Interventional Bronchus Occlusion Using Amplatzer Devices - A Promising Treatment Option for Children with Persistent Air Leak.

BACKGROUND: Persistent air leak (PAL) is a severe complication of secondary spontaneous pneumothorax (SSP). Surgical interventions are usually successful when medical treatment fails, but can be associated with significant complications and loss of potentially recoverable lung parenchyma. METHODS: Retrospective analysis of efficacy and safety of interventional bronchus occlusions (IBO) using Amplatzer devices (ADs) in children with PAL secondary to SSP. RESULTS: Six patients (four males, 4-15 years of age) underwent IBO using ADs as treatment for PAL. Necrotizing pneumonia (NP) was the most common cause (n=4) of PAL. Three patients were previously healthy and three suffered from chronic lung disease. All patients required at least two chest tubes prior to the intervention for a duration of 15-43 days and all required oxygen or higher level of ventilatory support. In three cases, previous surgical interventions had been performed without success. All children improved after endobronchial intervention and we observed no associated complications. All chest tubes were removed within 5-25 days post IBO. In patients with PAL related to NP (n=4), occluders were removed bronchoscopically without re-occurrence of pneumothorax after a mean of 70 days (IQR: 46.5-94). CONCLUSION: IBO using ADs is a safe and valuable treatment option in children with PAL independent of disease severity and underlying cause. A major advantage of this procedure is its less invasiveness compared to surgery and the parenchyma- preserving approach.

Correlation of exhaled propofol with Narcotrend index and calculated propofol plasma levels in children undergoing surgery under total intravenous anesthesia - an observational study.

BACKGROUND: Exhaled propofol concentrations correlate with propofol concentrations in adult human blood and the brain tissue of rats, as well as with electroencephalography (EEG) based indices of anesthetic depth. The pharmacokinetics of propofol are however different in children compared to adults. The value of exhaled propofol measurements in pediatric anesthesia has not yet been investigated. Breathing system filters and breathing circuits can also interfere with the measurements. In this study, we investigated correlations between exhaled propofol (exP) concentrations and the Narkotrend Index (NI) as well as calculated propofol plasma concentrations. METHODS: A multi-capillary-column (MCC) combined with ion mobility spectrometry (IMS) was used to determine exP. Optimal positioning of breathing system filters (near-patient or patient-distant) and sample line (proximal or distal to filter) were investigated. Measurements were taken during induction (I), maintenance (M) and emergence (E) of children under total intravenous anesthesia (TIVA). Correlations between ExP concentrations and NI and predicted plasma propofol concentrations (using pediatric pharmacokinetic models Kataria and Paedfusor) were assessed using Pearson correlation and regression analysis. RESULTS: Near-patient positioning of breathing system filters led to continuously rising exP values when exP was measured proximal to the filters, and lower concentrations when exP was measured distal to the filters. The breathing system filters were therefore subsequently attached between the breathing system tubes and the inspiratory and expiratory limbs of the anesthetic machine. ExP concentrations significantly correlated with NI and propofol concentrations predicted by pharmacokinetic models during induction and maintenance of anesthesia. During emergence, exP significantly correlated with predicted propofol concentrations, but not with NI. CONCLUSION: In this study, we demonstrated that exP correlates with calculated propofol concentrations and NI during induction and maintenance in pediatric patients. However, the correlations are highly variable and there are substantial obstacles: Without patient proximal placement of filters, the breathing circuit tubing must be changed after each patient, and furthermore, during ventilation, a considerable additional loss of heat and moisture can occur. Adhesion of propofol to plastic parts (endotracheal tube, breathing circle) may especially be problematic during emergence. TRIAL REGISTRATION: The study was registered in the German registry of clinical studies (DRKS-ID:  DRKS00015795 ).

Prevention of postoperative bleeding after complex pediatric cardiac surgery by early administration of fibrinogen, prothrombin complex and platelets: a prospective observational study.

BACKGROUND: Postoperative bleeding is a major problem in children undergoing complex pediatric cardiac surgery. The primary aim of this prospective observational study was to evaluate the effect of an institutional approach consisting of early preventive fibrinogen, prothrombin complex and platelets administration on coagulation parameters and postoperative bleeding in children. The secondary aim was to study the rate of re-intervention and postoperative transfusion, the occurrence of thrombosis, length of mechanical ventilation, ICU stay and mortality. METHODS: In fifty children (age 0-6 years) with one or more predefined risk factors for bleeding after cardiopulmonary bypass (CPB), thrombelastography (TEG) and standard coagulation parameters were measured at baseline (T1), after CPB and reversal of heparin (T2), at sternal closure (T3) and after 12 h in the ICU (T4). Clinical bleeding was evaluated by the surgeon at T2 and T3 using a numeric rating scale (NRS, 0-10). RESULTS: After CPB and early administration of fibrinogen, prothrombin complex and platelets, the clinical bleeding evaluation score decreased from a mean value of 6.2 ± 1.9 (NRS) at T2 to a mean value of 2.1 ± 0.8 at T3 (NRS; P <  0.001). Reaction time (R), kinetic time (K), maximum amplitude (MA) and maximum amplitude of fibrinogen (MA-fib) improved significantly (P <  0.001 for all), and MA-fib correlated significantly with the clinical bleeding evaluation (r = 0.70, P <  0.001). The administered total amount of fibrinogen (mg kg- 1) correlated significantly with weight (r = - 0.42, P = 0.002), priming volume as percentage of estimated blood volume (r = 0.30, P = 0.034), minimum CPB temperature (r = - 0.30, P = 0.033) and the change in clinical bleeding evaluation from T2 to T3 (r = 0.71, P <  0.001). The incidence of postoperative bleeding (> 10% of estimated blood volume) was 8%. No child required a surgical re-intervention, and no cases of thrombosis were observed. Hospital mortality was 0%. CONCLUSION: In this observational study of children with an increased risk of bleeding after CPB, an early preventive therapy with fibrinogen, prothrombin complex and platelets guided by clinical bleeding evaluation and TEG reduced bleeding and improved TEG and standard coagulation parameters significantly, with no occurrence of thrombosis or need for re-operation. TRIAL REGISTRATION: German Clinical Trials Register DRKS00018109 (retrospectively registered 27th August 2019).

Ultrasound assessment of gastric emptying time after intake of clear fluids in children scheduled for general anesthesia-A prospective observational study.

BACKGROUND: While many clinics have changed their local regimen toward a more liberal policy regarding clear fluid fasting for general anesthesia, there is a lack of studies evaluating gastric emptying time in a clinical setting. AIMS: Based on this and before implementation of a more liberal preoperative clear fluid fasting policy for children, we studied gastric emptying time of clear fluids in children and hypothesized that the mean gastric emptying time would be 1 hour. METHODS: Between March and December 2019, children scheduled for general anesthesia at our University Children's Hospital were enrolled in this prospective observational study. After overnight fasting, gastric emptying was examined by sonographic measurements of the gastric antral area before and 5, 15, 30, 45, and 60 minutes after intake of water or fruit juice. RESULTS: Twenty-six children were enrolled in this study, and 24 aged 11 (range 4-17) years were included for statistical analysis. The median ingested fluid volume was 4.7 (range 1.8-11.8) mL kg-1 . The gastric antral area of the children initially increased and subsequently decreased after intake of clear fluids and correlated significantly with fasting time (r = -0.55, P < .0001). After 1 hour, the gastric antral area had returned to the baseline level in 20 children but not in four children with a fluid intake >5 mL kg-1 . There was no difference in the gastric antral area between water and fruit juice. Using a linear regression model, the calculated mean gastric emptying time of clear fluids was 52 minutes. CONCLUSION: This study showed that the gastric emptying time of children after intake up to 5 mL kg-1 clear fluids was <1 hour in a clinical setting. These results support the more liberal fasting regimen favoring a 1-hour fasting time and suggest 5 mL kg-1 as an upper limit for clear fluids (eg, water, sugared water or tea or diluted fruit juice) from 2 hours to 1 hour before induction of anesthesia in children.

Effect of etomidate on systemic and regional cerebral perfusion in neonates and infants with congenital heart disease: A prospective observational study.

BACKGROUND: Neonates and infants with congenital heart disease undergoing general anesthesia have an increased risk for critical cardiovascular events. Etomidate produces very minimal changes in hemodynamic parameters in older children with congenital heart disease. There is a lack of studies evaluating the effect of etomidate on systemic and regional cerebral perfusion in neonates and infants with congenital heart disease. AIM: The aim of this prospective observational study was to evaluate the effect of etomidate on systemic and regional cerebral perfusion in neonates and infants with congenital heart disease. METHODS: In fifty infants aged 0-11 months (24% neonates n = 12) with congenital heart disease, mean arterial blood pressure, cardiac index using electrical cardiometry, and regional cerebral oxygen saturation using near-infrared spectroscopy were measured at baseline and 1, 3, 5, and 10 minutes after induction by 0.4 mg kg-1 etomidate. Hypotension was defined as a mean arterial blood pressure under 35 mm Hg and cerebral desaturation as a regional cerebral oxygen saturation of less than 80% of baseline. RESULTS: Mean arterial blood pressure, cardiac index, and regional cerebral oxygen saturation remained stable above the predefined limits. Mean arterial blood pressure decreased slightly within a physiological range after 3 minutes (P = .005, 95% CI:-5.9 to -1.0). No significant change in cardiac index could be observed. CONCLUSION: Etomidate 0.4mg kg-1 does not impair systemic or regional cerebral perfusion in neonates or infants with congenital heart disease.

Systemic and regional cerebral perfusion in small infants undergoing minor lower abdominal surgery under awake caudal anaesthesia: An observational study.

BACKGROUND: Infants undergoing general anaesthesia have an increased risk of severe respiratory and cardiovascular critical events. Awake caudal anaesthesia is an alternative for small infants undergoing minor lower abdominal surgery. While clinical experience has shown stable intra-operative haemodynamic conditions, there are no studies evaluating systemic and regional cerebral perfusion during such a procedure. OBJECTIVES: The purpose of this study was to evaluate the effects of awake caudal anaesthesia on systemic and regional cerebral perfusion in small infants. DESIGN: A prospective observational cohort study. SETTING: Clinic of Anaesthesiology, University Children's Hospital, between November 2017 and June 2018. PATIENTS: Twenty small infants (postmenstrual age 36 to 54 weeks, weight 1800 to 5700 g) scheduled for lower abdominal surgery under awake caudal anaesthesia were enrolled in this study. INTERVENTION: Standard monitoring was expanded to include cardiac index using electrical velocimetry and regional cerebral oxygen saturation using near infrared spectroscopy. The caudal block was performed with 0.3% ropivacaine 1 ml kg Hypotension was defined as mean arterial blood pressure (BP) less than 35 mmHg and regional cerebral desaturation as regional cerebral oxygen saturation less than 80% of baseline. MAIN OUTCOMES: Mean arterial BP, cardiac index and regional cerebral oxygen saturation parameters under awake caudal anaesthesia. RESULTS: Mean arterial BP, cardiac index and regional cerebral oxygen saturation remained above the predefined lower limits. No episodes of hypotension or regional cerebral desaturation were observed. Operation time was 35 ±â€Š13 (range 20 to 71) min. The infants were discharged to the neonatal ward after the end of surgery, and milk was fed 22 ±â€Š15 (range 6 to 55) min thereafter. Five preterm infants experienced self-limiting episodes of apnoea intra-operatively. CONCLUSION: The current study shows that awake caudal anaesthesia does not impair systemic and regional cerebral perfusion in small infants. TRIAL REGISTRATION: German registry of clinical studies (DRKS-ID: 800015742).

Impact of Capnoperitoneum on Renal Perfusion and Urine Production in Infant and Adolescent Pigs: Crystalloid versus Colloid Fluid Resuscitation.

BACKGROUND: Infants are likely to develop anuria during laparoscopy which is uncommon in older patients. The reason for this susceptibility remains unknown. We compared the impact of CO2 pneumoperitoneum on renal perfusion and urine production in piglets compared with adolescent pigs. We furthermore investigated the effects of different resuscitation strategies. MATERIALS AND METHODS: Male piglets (n = 21) were divided into four groups: (a) infant controls (n = 5), (b) infants with crystalloid restitution (n = 6), (c) infants with colloidal restitution (n = 5), and (d) adolescents with crystalloid restitution (n = 5). Animals were ventilated, the central vessels and ureters were cannulated, and the animals were subjected to a 3-hour, 10 mm Hg CO2 pneumoperitoneum followed by 2-hour resuscitation. Renal perfusion was assessed by fluorescent microspheres and the rate of urine flow was measured. RESULTS: Urine production significantly decreased after insufflation only in the infant crystalloid and adolescent group, but not in controls or infants treated with colloids. In the infant crystalloid group, urine production remained at levels below 20% of baseline throughout the experiment. In this group, the renal perfusion dropped significantly after the beginning of the capnoperitoneum and remained significantly reduced throughout the experiment. CONCLUSION: Our data indicates that capnoperitoneum impairs renal perfusion and urine production in infants. In moderate-pressure capnoperitoneum, this effect cannot be compensated by application of crystalloids but with colloids.

First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors.

PURPOSE: Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions. PATIENTS AND METHODS: Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST. RESULTS: Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10. CONCLUSION: Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker.

Atu027 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models.

PURPOSE: Atu027, a novel RNA interference therapeutic, has been shown to inhibit lymph node metastasis in orthotopic prostate cancer mouse models. The aim of this study is to elucidate the pharmacologic activity of Atu027 in inhibiting hematogenous metastasis to the target organ lung in four different preclinical mouse models. EXPERIMENTAL DESIGN: Atu027 compared with vehicle or control small interfering RNA lipoplexes was tested in two experimental lung metastasis models (Lewis lung carcinoma, B16V) and spontaneous metastasis mouse models (MDA-MB-435, MDA-MB-231, mammary fat pad). Different dosing schedules (repeated low volume tail vein injections) were applied to obtain insight into effective Atu027 treatment. Primary tumor growth and lung metastasis were measured, and tissues were analyzed by immunohistochemistry and histology. In vitro studies in human umbilical vein endothelial cells were carried out to provide an insight into molecular changes on depletion of PKN3, in support of efficacy results. RESULTS: Intravenous administration of Atu027 prevents pulmonary metastasis. In particular, formation of spontaneous lung metastasis was significantly inhibited in animals with large tumor grafts as well as in mice with resected primary mammary fat pad tumors. In addition, we provide evidence that an increase in VE-cadherin protein levels as a downstream result of PKN3 target gene inhibition may change endothelial function, resulting in reduced colonization and micrometastasis formation. CONCLUSION: Atu027 can be considered as a potent drug for preventing lung metastasis formation, which might be suitable for preventing hematogenous metastasis in addition to standard cancer therapy.

Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression.

We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density.