Background: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. Methods: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. Results: Infants (n¼5609) born at mean (standard deviation [SD]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO 2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]¼1.16; 95% confidence interval [CI], 1.04e1.28

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Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences. Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes. Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1e6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO 2 <90% for 60 s) was reported in 40%. No associated risk factors could be identified among comorbidities, surgical, or anaesthesia management. Using propensity scoring to adjust for confounders, difficult anaesthesia tracheal intubation did not lead to an increase in 30 and 90 day morbidity or mortality. Conclusions:The results of the present study demonstrate a high incidence of difficult tracheal intubation in children less than 60 weeks post-conceptual age commonly resulting in severe hypoxaemia. Reassuringly, the morbidity and mortality at 30 and 90 days was not increased by the occurrence of a difficult intubation event. Clinical trial registration: NCT02350348.

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Background: Esophageal atresia (EA) with tracheoesophageal fistula is usually repaired in the neonatal period. Preferential ventilation through the fistula can lead to gastric distension. Bronchoscopy has a role in defining the site and size of the fistula, and may be carried out by the surgeon or the anesthetist. The use of bronchoscopy varies across different institutions.Methods: This is a multicenter case note review of infants with EA with tracheoesophageal fistula who underwent surgery between January 2010 and December 2015. This retrospective audit aims primarily to document the use of bronchoscopy during open and thoracoscopic repair at a selection of United Kingdom centers.Respiratory complications, that is relating to airway management, the respiratory system, and difficulty with ventilation, at induction and during surgery, are recorded.The range of techniques for anesthesia and analgesia in these centers is noted.Results: Bronchoscopy was carried out in 52% of cases. The incidence of respiratory complications was 7% at induction and 21% during surgery. Thoracoscopic repair usually took longer. One center used high-frequency oscillatory ventilation, on an elective basis during thoracoscopic repair, to facilitate surgical access and address concerns about hypoxemia and hypercarbia. Conclusion: The use of bronchoscopy varies considerably between institutions.Infants undergoing tracheoesophageal fistula repair are at risk of perioperative respiratory morbidity. The advent of thoracoscopic repair has introduced further variation. K E Y W O R D S anesthesia, bronchoscopy, esophageal atresia, newborn, thoracoscopy, thoracotomy, tracheoesophageal fistula | 641 AHMAD et Al. How to cite this article: Ahmad NS, Dobby N, Walker E, et al. A multicenter audit of the use of bronchoscopy during open and thoracoscopic repair of esophageal atresia with tracheoesophageal fistula. Pediatr Anesth. 2019;29:640-647.

The upgraded knowledge of tumor biology and microenviroment provides information on differences in neoplastic and normal cells. Thus, the need to target these differences led to the development of novel molecules (targeted therapy) active against the neoplastic cells’ inner workings. There are several types of targeted agents, including Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA (iRNA) molecules and microRNA. In the clinical practice, these new medicines generate a multilayered step in pharmacokinetics (PK), which encompasses a broad individual PK variability, and unpredictable outcomes according to the pharmacogenetics (PG) profile of the patient (e.g., cytochrome P450 enzyme), and to patient characteristics such as adherence to treatment and environmental factors. This review focuses on the use of targeted agents in-human phase I/II/III clinical trials in cancer-hematology. Thus, it outlines the up-to-date anticancer drugs suitable for targeted therapies and the most recent finding in pharmacogenomics related to drug response. Besides, a summary assessment of the genotyping costs has been discussed. Targeted therapy seems to be an effective and less toxic therapeutic approach in onco-hematology. The identification of individual PG profile should be a new resource for oncologists to make treatment decisions for the patients to minimize the toxicity and or inefficacy of therapy. This could allow the clinicians to evaluate benefits and restrictions, regarding costs and applicability, of the most suitable pharmacological approach for performing a tailor-made therapy.

The improved knowledge of pathogenetic mechanisms underlying lymphomagenesis and the discovery of the critical role of tumor microenvironments have enabled the design of new drugs against cell targets and pathways. The Food and Drug Administration (FDA) has approved several monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) for targeted therapy in hematology. This review focuses on the efficacy results of the currently available targeted agents and recaps the main ongoing trials in the setting of mature B-Cell non-Hodgkin lymphomas. The objective is to summarize the different classes of novel agents approved for mature B-cell lymphomas, to describe in synoptic tables the results they achieved and, finally, to draw future scenarios as we glimpse through the ongoing clinical trials. Characteristics and therapeutic efficacy are summarized for the currently approved mAbs [i.e., anti-Cluster of differentiation (CD) mAbs, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and bispecific antibodies] as well as for SMIs i.e., inhibitors of B-cell receptor signaling, proteasome, mTOR BCL-2 HDAC pathways. The biological disease profiling of B-cell lymphoma subtypes may foster the discovery of innovative drug strategies for improving survival outcome in lymphoid neoplasms, as well as the trade-offs between efficacy and toxicity. The hope for clinical advantages should carefully be coupled with mindful awareness of the potential pitfalls and the occurrence of uneven, sometimes severe, toxicities.

Background: Given the consistent antitumor activity and favorable toxicity profile in heavily pretreated patients, BDM represents a suitable platform for combination with target-based agents in the setting of recurrent HL. The anti-CD30 antibody-monomethyl auristatin E (MMAE) conjugate brentuximab vedotin (BV) appears a most valuable candidate by coupling an impressive clinical activity with the lack of serious overlapping toxicities with BDM. While the combination of BDM and BV is being evaluated in Phase II studies, no information is available as to possible mechanisms through which BDM may regulate the antitumor efficacy of BV towards HL cells. Methods: We evaluated the effects of acute and extended exposure to BDM on CD30 expression and sensitivity to the cytotoxic activity BV in the HL cell line L1236. Cells were cultured in the presence of BDM at its IC50 for different time points of acute exposure. Through continuous exposure to increasing concentrations (25.0, 50.0, 75.0, 100 micromol/L) of BDM, we then performed a serial in vitro selection for BDM-resistant (R) L1236 cell clones and determined their CD30 expression by flow cytometry, qRT-PCR, and Western analysis. Results: Acute exposure to BDM (48 to 72 hrs) of L1236 cells led to a sizeable upregulation of CD30 as shown by flow cytometry. This effect was unsustained since CD30 intensity returned to baseline levels upon culturing in BDM-free medium for one week. Expression of other surface antigens, i.e. HLA-DR, was unaffected by BDM while acute exposure to doxorubicin and other cytotoxic drugs did not modify the CD30 expression. We established four L1236-derived cell clones (R25, R50, R75 and R100) able to proliferate across the different concentrations of BDM with growth/viability curves superimposable to native cells. Clonal identity among clones and with parental cells was confirmed by sequencing of V3-21 (FR2/FR3) and JH3-JH4 Ig DNA regions. All R-clones displayed an up to 900% increase in CD30 median fluorescence intensity, relative to native L1236 cells (Figure 1A). The sustained CD30 upregulation was confirmed by qRT-PCR and Western blotting since R-clones expressed up to 10-fold higher levels of CD30-specific mRNA and CD30-specific 120 kDa components as compared to parental cells. To rule out a general upregulation of surface molecules as a result of the chronic exposure to BDM we evaluated the expression of other surface antigens. As opposed to CD30, HLA-DR and PDL-1 relative transcript levels and cell surface expression were significantly reduced in R-cells. Intriguingly, BDM-induced CD30 upregulation was specific to L1236 cells since extended exposure to BDM did not modify expression levels of CD30 in other lymphoma cell types (SUDHL1, JEKO). BDM-induced CD30 overexpression significantly enhanced the sensitivity of HL cells to the cytotoxic effects of BV. MTS assay showed the IC50 of R100 cells to BV shifted to 0.21 ± 0.06 mcg/mL (48 hrs) and 0.19 ± 0.05 mcg/mL (72 hrs) vs. 3.16 ± 0.75 mcg/mL (48 hrs) and 3.87 ± 0.68 mcg/mL (72 hrs) of parental cells, a 15- and 20-fold increase, respectively (p<0.001; Figure 1B). Finally, qRT-PCR studies disclosed that R-clones did not show any upregulation of the drug exporter MDR1 gene, involved in MMAE extrusion and BV resistance in HL cells, as compared to parental L1236 cells. Conclusions: Whileacute exposure to BDM induced a transient upregulation of CD30, extended exposure to the agent resulted in the selection of L1236 subclones with a stable overexpression of surface CD30 and reduced levels of HLA-DR and PDL-1. Upregulation of CD30 was associated with a significantly enhanced sensitivity to cytotoxic effects of BV. Translated into a clinical context these findings suggest that HL patients progressing upon BDM treatment may turn exquisitely sensitive to BV and prompt the exploration of a sequential treatment with BDM and BV in late and earlier disease phases. Results also provide a mechanistic insight as to the efficacy of the BDM-BV combination in HL, highlighting non-overlapping resistance pathways between BDM and MMAE. BDM-induced selection of CD30hi, HLA-DRlow/PDL-1low tumor cell clones might be relevant to the design of novel treatment strategies for HL based on the combination of BDM with BV and anti-PD1/PDL-1 antibodies. Figure 1. Expression of CD30 and HLA-DR in parental (L1236) and BDM-resistant (R) HL cells Figure 1. Expression of CD30 and HLA-DR in parental (L1236) and BDM-resistant (R) HL cells Figure 2. Sensitivity to BV of parental (L1236) and BDM-resistant (R100) HL cells Figure 2. Sensitivity to BV of parental (L1236) and BDM-resistant (R100) HL cells Disclosures Pinto: Takeda: Research Funding; Takeda, Celgene, Roche, TEVA: Honoraria.