Thirty-day Postoperative Complications After Surgery For Metastatic Long Bone Disease Are Associated With Higher Mortality at 1 Year

BACKGROUND: The benefits of surgical treatment of a metastasis of the extremities may be offset by drawbacks such as potential postoperative complications. For this group of patients, the primary goal of surgery is to improve quality of life in a palliative setting. A better comprehension of factors associated with complications and the impact of postoperative complications on mortality may prevent negative outcomes and help surgeons in surgical decision-making. QUESTIONS/PURPOSES: (1) What is the risk of 30-day postoperative complications after surgical treatment of osseous metastatic disease of the extremities? (2) What predisposing factors are associated with a higher risk of 30-day complications? (3) Are minor and major 30-day complications associated with higher mortality at 1 year? METHODS: Between 1999 and 2016, 1090 patients with osseous metastatic disease of the long bones treated surgically at our institution were retrospectively included in the study. Surgery included intramedullary nailing (58%), endoprosthetic reconstruction (22%), plate-screw fixation (14%), dynamic hip screw fixation (2%), and combined approaches (4%). Surgery was performed if patients were deemed healthy enough to proceed to surgery and wished to undergo surgery. All data were retrieved by manually reviewing patients' records. The overall frequency of complications, which were defined using the Clavien-Dindo classification system, was calculated. We did not include Grade I complications as postoperative complications and complications were divided into minor (Grade II) and major (Grades III-V) complications. A multivariate logistic regression analysis was used to identify factors associated with 30-day postoperative complications. A Cox regression analysis was used to assess the association between postoperative complications and overall survival. RESULTS: Overall, 31% of the patients (333 of 1090) had a postoperative complication within 30 days. The following factors were independently associated with 30-day postoperative complications: rapidly growing primary tumors classified according to the modified Katagiri classification (odds ratio 1.6; 95% confidence interval, 1.1-2.2; p = 0.011), multiple bone metastases (OR 1.6; 95% CI, 1.1-2.3; p = 0.008), pathologic fracture (OR 1.5; 95% CI, 1.1-2.0; p = 0.010), lower-extremity location (OR 2.2; 95% CI, 1.6-3.2; p < 0.001), hypoalbuminemia (OR 1.7; 95% CI, 1.2-2.4; p = 0.002), hyponatremia (OR 1.5; 95% CI, 1.0-2.2; p = 0.044), and elevated white blood cell count (OR 1.6; 95% CI, 1.1-2.4; p = 0.007). Minor and major postoperative complications within 30 days after surgery were both associated with greater 1-year mortality (hazard ratio 1.6; 95% CI, 1.3-1.8; p < 0.001 and HR 3.4; 95% CI, 2.8-4.2, respectively; p < 0.001). CONCLUSION: Patients with metastatic disease in the long bones are vulnerable to postoperative adverse events. When selecting patients for surgery, surgeons should carefully assess a patient's cancer status, and several preoperative laboratory values should be part of the standard work-up before surgery. Furthermore, 30-day postoperative complications decrease survival within 1 year after surgery. Therefore, patients at a high risk of having postoperative complications are less likely to profit from surgery and should be considered for nonoperative treatment or be monitored closely after surgery. LEVEL OF EVIDENCE: Level III, therapeutic study

The Systemic Immune Response in COVID-19 Is Associated with a Shift to Formyl-Peptide Unresponsive Eosinophils

A malfunction of the innate immune response in COVID-19 is associated with eosinopenia, particularly in more severe cases. This study tested the hypothesis that this eosinopenia is COVID-19 specific and is associated with systemic activation of eosinophils. Blood of 15 healthy controls and 75 adult patients with suspected COVID-19 at the ER were included before PCR testing and analyzed by point-of-care automated flow cytometry (CD10, CD11b, CD16, and CD62L) in the absence or presence of a formyl peptide (fNLF). Forty-five SARS-CoV-2 PCR positive patients were grouped based on disease severity. PCR negative patients with proven bacterial (n = 20) or other viral (n = 10) infections were used as disease controls. Eosinophils were identified with the use of the FlowSOM algorithm. Low blood eosinophil numbers (&lt;100 cells/μL; p &lt; 0.005) were found both in patients with COVID-19 and with other infectious diseases, albeit less pronounced. Two discrete eosinophil populations were identified in healthy controls both before and after activation with fNLF based on the expression of CD11b. Before activation, the CD11bbright population consisted of 5.4% (CI95% = 3.8, 13.4) of total eosinophils. After activation, this population of CD11bbright cells comprised nearly half the population (42.21%, CI95% = 35.9, 54.1). Eosinophils in COVID-19 had a similar percentage of CD11bbright cells before activation (7.6%, CI95% = 4.5, 13.6), but were clearly refractory to activation with fNLF as a much lower percentage of cells end up in the CD11bbright fraction after activation (23.7%, CI95% = 18.5, 27.6; p &lt; 0.001). Low eosinophil numbers in COVID-19 are associated with refractoriness in responsiveness to fNLF. This might be caused by migration of fully functional cells to the tissue

Availability and reporting quality of external validations of machine-learning prediction models with orthopedic surgical outcomes: a systematic review

Background and purpose — External validation of machine learning (ML) prediction models is an essential step before clinical application. We assessed the proportion, performance, and transparent reporting of externally validated ML prediction models in orthopedic surgery, using the Transparent Reporting for Individual Prognosis or Diagnosis (TRIPOD) guidelines. Material and methods — We performed a systematic search using synonyms for every orthopedic specialty, ML, and external validation. The proportion was determined by using 59 ML prediction models with only internal validation in orthopedic surgical outcome published up until June 18, 2020, previously identified by our group. Model performance was evaluated using discrimination, calibration, and decision-curve analysis. The TRIPOD guidelines assessed transparent reporting. Results — We included 18 studies externally validating 10 different ML prediction models of the 59 available ML models after screening 4,682 studies. All external validations identified in this review retained good discrimination. Other key performance measures were provided in only 3 studies, rendering overall performance evaluation difficult. The overall median TRIPOD completeness was 61% (IQR 43–89), with 6 items being reported in less than 4/18 of the studies. Interpretation — Most current predictive ML models are not externally validated. The 18 available external validation studies were characterized by incomplete reporting of performance measures, limiting a transparent examination of model performance. Further prospective studies are needed to validate or refute the myriad of predictive ML models in orthopedics while adhering to existing guidelines. This ensures clinicians can take full advantage of validated and clinically implementable ML decision tools

Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML

Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid- or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (DMs), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE was a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of 1 allele via promoter methylation and concurrent overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission along with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DMs. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML

The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis

Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study

Background: Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak. Methods: PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342). Findings: Between March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6·3 mL/kg predicted bodyweight (IQR 5·7–7·1), PEEP was 14·0 cm H2O (IQR 11·0–15·0), and driving pressure was 14·0 cm H2O (11·2–16·0). Median respiratory system compliance was 31·9 mL/cm H2O (26·0–39·9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0–15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation. Interpretation: In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19. Funding: Amsterdam University Medical Centers, location Academic Medical Center