Effectiveness of 80% vs 30–35% fraction of inspired oxygen in patients undergoing surgery: an updated systematic review and meta-analysis

Background In 2016, the World Health Organization (WHO) strongly recommended the use of a high fraction of inspired oxygen (FiO2) in adult patients undergoing general anaesthesia to reduce the risk of surgical site infection (SSI). Since then, further trials have been published, trials included previously have come under scrutiny, and one article was retracted. We updated the systematic review on which the recommendation was based. Methods We performed a systematic literature search from January 1990 to April 2018 for RCTs comparing the effect of high (80%) vs standard (30–35%) FiO2 on the incidence of SSI. Studies retracted or under investigation were excluded. A random effects model was used for meta-analyses; the sources of heterogeneity were explored using meta-regression. Results Of 21 RCTs included, six were newly identified since the publication of the WHO guideline review; 17 could be included in the final analyses. Overall, no evidence for a reduction of SSI after the use of high FiO2 was found [relative risk (RR): 0.89; 95% confidence interval (CI): 0.73–1.07]. There was evidence that high FiO2 was beneficial in intubated patients [RR: 0.80 (95% CI: 0.64–0.99)], but not in non-intubated patients [RR: 1.20 (95% CI: 0.91–1.58); test of interaction; P=0.048]. Conclusions The WHO updated analyses did not show definite beneficial effect of the use of high perioperative FiO2, overall, but there was evidence of effect of reducing the SSI risk in surgical patients under general anaesthesia with tracheal intubation. However, the evidence for this beneficial effect has become weaker and the strength of the recommendation needs to be reconsidered

Safety of 80% vs 30–35% fraction of inspired oxygen in patients undergoing surgery: a systematic review and meta-analysis

Background: Evidence-based guidelines from the World Health Organization (WHO) have recommended a high (80%) fraction of inspired oxygen (FiO2) to reduce surgical site infection in adult surgical patients undergoing general anaesthesia with tracheal intubation. However, there is ongoing debate over the safety of high FiO2. We performed a systematic review to define the relative risk of clinically relevant adverse events (AE) associated with high FiO2. Methods: We reviewed potentially relevant articles from the WHO review supporting the recommendation, including an updated (July 2018) search of EMBASE and PubMed for randomised and non-randomised controlled studies reporting AE in surgical patients receiving 80% FiO2 compared with 30–35% FiO2. We assessed study quality and performed meta-analyses of risk ratios (RR) comparing 80% FiO2 against 30–35% for major complications, mortality, and intensive care admission. Results: We included 17 moderate–good quality trials and two non-randomised studies with serious-critical risk of bias. No evidence of harm with high FiO2 was found for major AE in the meta-analysis of randomised trials: atelectasis RR 0.91 [95% confidence interval (CI) 0.59–1.42); cardiovascular events RR 0.90 (95% CI 0.32–2.54); intensive care admission RR 0.93 (95% CI 0.7–1.12); and death during the trial RR 0.49 (95% CI 0.17–1.37). One non-randomised study reported that high FiO2 was associated with major respiratory AE [RR 1.99 (95% CI 1.72–2.31)]. Conclusions: No definite signal of harm with 80% FiO2 in adult surgical patients undergoing general anaesthesia was demonstrated and there is little evidence on safety-related issues to discourage its use in this population

Een bronzen hielbijl uit Emmen

A Bronze Age palstave found at EmmenIn 2019, a Bronze Age palstave was found in a field west of Emmen by a father-and-son team of metal detectorists. In agreement with the landowner, the find was reported to PAN. During the process of conservation, the opportunitypresented itself to study the alloy using pXRF analysis. This suggested that the copper ores used in the bronze alloy ultimately derived from Swiss or Slovakian mines, but that the metal was cast locally into a form well-known in the sandy regions of the Low Countries. A review of the find in its topographical and cultural context indicated that it – like various other items in the Bronze Age – had been deposited in (the margin of) wetland parts of the landscape, not far from a contemporaneous settlement

Endoglin and squamous cell carcinomas

Despite the fact that the role of endoglin on endothelial cells has been extensively described, its expression and biological role on (epithelial) cancer cells is still debatable. Especially its function on squamous cell carcinoma (SCC) cells is largely unknown. Therefore, we investigated SCC endoglin expression and function in three types of SCCs; head and neck (HNSCC), esophageal (ESCC) and vulvar (VSCC) cancers. Endoglin expression was evaluated in tumor specimens and 14 patient-derived cell lines. Next to being expressed on angiogenic endothelial cells, endoglin is selectively expressed by individual SCC cells in tumor nests. Patient derived HNSCC, ESCC and VSCC cell lines express varying levels of endoglin with high interpatient variation. To assess the function of endoglin in signaling of TGF-β ligands, endoglin was overexpressed or knocked out or the signaling was blocked using TRC105, an endoglin neutralizing antibody. The endoglin ligand BMP-9 induced strong phosphorylation of SMAD1 independent of expression of the type-I receptor ALK1. Interestingly, we observed that endoglin overexpression leads to strongly increased soluble endoglin levels, which in turn decreases BMP-9 signaling. On the functional level, endoglin, both in a ligand dependent and independent manner, did not influence proliferation or migration of the SCC cells. In conclusion, these data show endoglin expression on individual cells in the tumor nests in SCCs and a role for (soluble) endoglin in paracrine signaling, without directly affecting proliferation or migration in an autocrine manner.</p

Endoscopic screening of the upper gastrointestinal tract for second primary tumors in patients with head and neck cancer in a Western country

Background: Patients with head and neck squamous cell carcinoma (HNSCC) relatively frequent develop second primary tumors (SPTs) in the esophagus. Endoscopic screening could lead to timely detection of SPTs in early stages and therefore improves the survival. Methods: We performed a prospective endoscopic screening study in patients with HNSCC in a Western country. Patients with curably treated HNSCC diagnosed January 2017 to July 2021 were included. Routine imaging for HNSCC consisted of flexible transnasal endoscopy with PET/CT or MRI-scan, depending on primary HNSCC location. Screening was performed synchronously(&lt;6 months) or metachronously (≥6 months) after HNSCC diagnosis. The primary outcome was prevalence of SPTs, defined as presence of esophageal high-grade dysplasia or squamous cell carcinoma. Results: We included 202 patients (81% male, mean age 65 years) and performed 250 screening endoscopies. HNSCC was located in the oropharynx(32%), hypopharynx(26%), larynx(22%), and oral cavity(19%). Endoscopic screening was performed within 6 months(34%), 6 months to 1 year(8%), 1 to 2 years(34%), and 2 to 5 years(24%) after HNSCC diagnosis. We detected 11 SPTs in 10 patients(5.0%, 95%CI: 2.4-8.9%) during synchronous(6/85) and metachronous screening(5/165). Most SPTs were detected in early stages(91%) and treated with curative intent with endoscopic resection(80%). No SPTs in screened patients were detected with routine imaging for HNSCC before endoscopic screening. Conclusion: In 5% of patients with HNSCC, an SPT was detected with endoscopic screening. Endoscopic screening should be considered in a selection of HNSCC patients to detect early-stage SPTs, based on highest SPT-risk and life expectancy depending on HNSCC and comorbidities.</p

Screening for synchronous esophageal second primary tumors in patients with head and neck cancer

Patients with head and neck squamous cell carcinoma (HNSCC) have an increased risk of developing esophageal second primary tumors (ESPTs). We aimed to determine the incidence, stage, and outcome of synchronous ESPTs in patients with HNSCC in a Western population. We performed a prospective, observational, and cohort study. Patients diagnosed with HNSCC in the oropharynx, hypopharynx, any other sub-location in combination with alcohol abuse, or patients with two synchronous HNSCCs, between February 2019 and February 2020 underwent screening esophagogastroduodenoscopy (EGD). ESPT was defined as presence of esophageal squamous cell carcinoma (ESCC) or high grade dysplasia (HGD). Eighty-five patients were included. A lesion suspected for ESPT was detected in 14 of 85 patients, which was pathologically confirmed in five patients (1 ESCC and 4 HGD). The radiotherapy field was extended to the esophagus in two of five patients, HGD was treated with endoscopic resection in three of five patients. None of the ESPTs were detected on MRI and/or CT-scan prior to EGD. Of the remaining nine patients, three had low grade dysplasia on histology whereas the other six patients had benign lesions. Incidence of synchronous ESPT was 5.9% in our cohort of HNSCC patients. All ESPTs were diagnosed at an early stage and treated with curative intent. We recommend that screening for synchronous ESPTs should be considered in a selected group of patients with HNSCC

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRAS^G12C-Mutated NSCLC Treated With Sotorasib

Introduction: For patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression. Methods: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1. Results: Pretreatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior progression-free survival (hazard ratio [HR] 2.13 [95% confidence interval [CI]: 1.06–4.30], p = 0.031) and overall survival (HR 2.61 [95% CI: 1.16–5.91], p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 [95% CI: 1.65–7.74], p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations. Conclusions: Our data suggest detectable pretreatment KRASG12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.</p

From registration to publication: A study on Dutch academic randomized controlled trials

Introduction: Registration of clinical trials has been initiated in order to assess adherence of the reported results to the original trial protocol. This study aimed to investigate the publication rates, timely dissemination of results, and the prevalence of consistency in hypothesis, sample size, and primary endpoint of Dutch investigator-initiated randomized controlled clinical trials (RCTs). Methods: All Dutch investigator-initiated RCTs with a completion date between December 31, 2010, and January 1, 2012, and registered in the Trial Register of The Netherlands database were included. PubMed was searched for the publication of these RCT results until September 2016, and the time to the publication date was calculated. Consistency in hypothesis, sample size, and primary endpoint compared with the registry data were assessed. Results: The search resulted in a total of 168 Dutch investigator-initiated RCTs. In September 2016, the results of 129 (77%) trials had been published, of which 50 (39%) within 2 years after completion of accrual. Consistency in hypothesis with the original protocol was observed in 108 (84%) RCTs; in 71 trials (55%), the planned sample size was reached; and 103 trials (80%) presented the original primary endpoint. Consistency in all three parameters was observe