High mortality among hospital-acquired COVID-19 infection in patients with cancer: A multicentre observational cohort study.

INTRODUCTION: Studies suggest that patients with cancer are more likely to experience severe outcomes from COVID-19. Therefore, cancer centres have undertaken efforts to care for patients with cancer in COVID-free units. Nevertheless, the frequency and relevance of nosocomial transmission of COVID-19 in patients with cancer remain unknown. The goal of this study was to determine the incidence and impact of hospital-acquired COVID-19 in this population and identify predictive factors for COVID-19 severity in patients with cancer. METHODS: Patients with cancer and a laboratory-confirmed diagnosis of COVID-19 were prospectively identified using provincial registries and hospital databases between March 3rd and May 23rd, 2020 in the provinces of Quebec and British Columbia in Canada. Patient's baseline characteristics including age, sex, comorbidities, cancer type and type of anticancer treatment were collected. The exposure of interest was incidence of hospital-acquired infection defined by diagnosis of SARS-CoV-2 ≥ 5 days after hospital admission for COVID-unrelated cause. Co-primary outcomes were death or composite outcomes of severe illness from COVID-19 such as hospitalisation, supplemental oxygen, intensive-care unit (ICU) admission and/or mechanical ventilation. RESULTS: A total of 252 patients (N = 249 adult and N = 3 paediatric) with COVID-19 and cancer were identified, and the majority were residents of Quebec (N = 233). One hundred and six patients (42.1%) received active anticancer treatment in the last 3 months before COVID-19 diagnosis. During a median follow-up of 25 days, 33 (13.1%) required admission to the ICU, and 71 (28.2%) died. Forty-seven (19.1%) had a diagnosis of hospital-acquired COVID-19. Median overall survival was shorter in those with hospital-acquired infection than that in a contemporary community-acquired population (27 days versus unreached, hazard ratio (HR) = 2.3, 95% CI: 1.2-4.4, p = 0.0006. Multivariate analysis demonstrated that hospital-acquired COVID-19, age, Eastern Cooperative Oncology Group status and advanced stage of cancer were independently associated with death. INTERPRETATION: Our study demonstrates a high rate of nosocomial transmission of COVID-19, associated with increased mortality in both univariate and multivariate analysis in the cancer population, reinforcing the importance of treating patients with cancer in COVID-free units. We also validated that age and advanced cancer were negative predictive factors for COVID-19 severity in patients with cancer.

Real-world direct healthcare costs of treating recurrent high-grade serous ovarian cancer with cytotoxic chemotherapy.

Aim: To describe the direct healthcare costs associated with repeated cytotoxic chemotherapy treatments for recurrent high-grade serous cancer (HGSC) of the ovaries. Patients & methods: Retrospective review of 66 women with recurrent stage III/IV HGSC ovarian cancer treated with repeated lines of cytotoxic chemotherapy in a Canadian University Tertiary Center. Results: Mean cost of treatment of first relapse was CAD$52,227 increasing by 38% for two, and 86% for three or more relapses with median overall survival of 36.0, 50.7 and 42.8 months, respectively. In-hospital care accounted for 71% and chemotherapy drugs accounted for 17% of the total costs. Conclusion: After the third relapse of HGSC, cytotoxic chemotherapy did not prolong survival but was associated with substantially increased healthcare costs.

Benefits of an abridged antibiotic protocol for treatment of gangrenous appendicitis.

BACKGROUND: We previously reported a validated, objective definition of gangrenous, nonperforated appendicitis. In this study, we compared a cohort of children with gangrenous appendicitis treated with abridged antibiotics (AA) to another treated with prolonged antibiotics (PA). METHODS: In 2012, our service changed its standard of care for gangrenous appendicitis from PA to AA. In PA, patients received postoperative triple antibiotics until ileus resolved, they were afebrile (<37.5°C) for 24hours, and achieved a normal WBC count. In AA, patients received two doses of postoperative triple antibiotics. A PA cohort during a 12-month period (February 2010-January 2011) was compared to an AA cohort during another 12-month period (April 2012-March 2013). RESULTS: Twenty patients were treated with AA and 38 patients with PA. AA patients had a significantly shorter overall length of stay (2.1±1.58 vs. 3.18±1.09days, p=0.003), as well as a significantly shorter postoperative stay (1.85±1.42 vs. 2.95±1.14days, p=0.002). There were no differences between the AA and PA cohorts in wound infections (0%), intraabdominal infections (0%), or appendicitis-related readmissions (0%). CONCLUSIONS: Abridged postoperative antibiotics for gangrenous appendicitis significantly shorten hospital stay without increasing complications.

Determinants of postoperative abscess occurrence and percutaneous drainage in children with perforated appendicitis.

PURPOSE: Postoperative abscesses after perforated appendicitis have no clear risk factors or indications for percutaneous drainage. Our study addressed these two issues. METHODS: A logistic regression model was used to delineate risk factors for postoperative abscess in children with perforated appendicitis treated during a recent 5-year period. Drainage of abscess was compared to antibiotic treatment. RESULTS: Postoperative abscess occurred in 42 (14.8%) of 284 patients. Higher WBC count, presence of bowel obstruction at presentation, diffuse peritonitis with a dominant abscess at surgery, and one specific surgeon were significantly associated with postoperative abscess, while fever or pain requiring narcotics at the time of abscess diagnosis was significantly associated with drainage. Compared to non-drainage, those drained had longer hospital stay including readmissions (15.9 ± 5.3 vs. 12.2 ± 4.6 days, p < 0.005) and less readmissions (9.5 vs. 33.3%, p = 0.06). Over the 5-year period, there was no increased trend in abscess occurrence (p = 0.56), but there was an increased trend in the use of percutaneous drainage (p = 0.02). CONCLUSIONS: The risk of a postoperative abscess can be predicted by specific clinical characteristics, surgical findings, and treatment-related factors. Percutaneous drainage was associated with longer hospital stays, but less readmissions.

T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.

Angiotensin (Ang) II induces hypertension by mechanisms mediated in part by adaptive immunity and T effector lymphocytes. T regulatory lymphocytes (Tregs) suppress T effector lymphocytes. We questioned whether Treg adoptive transfer would blunt Ang II-induced hypertension and vascular injury. Ten- to 12-week-old male C57BL/6 mice were injected IV with 3 ×10(5) Treg (CD4(+)CD25(+)) or T effector (CD4(+)CD25(-)) cells, 3 times at 2-week intervals, and then infused or not with Ang II (1 µg/kg per minute, SC) for 14 days. Ang II increased systolic blood pressure by 43 mm Hg (P<0.05), NADPH oxidase activity 1.5-fold in aorta and 1.8-fold in the heart (P<0.05), impaired acetylcholine vasodilatory responses by 70% compared with control (P<0.05), and increased vascular stiffness (P<0.001), mesenteric artery vascular cell adhesion molecule expression (2-fold; P<0.05), and aortic macrophage and T-cell infiltration (P<0.001). All of the above were prevented by Treg but not T effector adoptive transfer. Ang II caused a 43% decrease in Foxp3(+) cells in the renal cortex, whereas Treg adoptive transfer increased Foxp3(+) cells 2-fold compared with control. Thus, Tregs suppress Ang II-mediated vascular injury in part through anti-inflammatory actions. Immune mechanisms modulate Ang II-induced blood pressure elevation, vascular oxidative stress, inflammation, and endothelial dysfunction.

Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of eNOS and downregulation of SIRT1.

Hyperhomocysteinemia (HHcy) has been shown to induce endothelial dysfunction in part as a result of enhanced oxidative stress. Function and survival of endothelial progenitor cells (EPCs, defined as sca1(+) c-kit(+) flk-1(+) bone marrow-derived cells), which significantly contribute to neovascularization and endothelial regeneration, depend on controlled production of reactive oxygen species (ROS). Mice heterozygous for the gene deletion of methylenetetrahydrofolate reductase (Mthfr(+/-)) have a 1.5- to 2-fold elevation in plasma homocysteine. This mild HHcy significantly reduced the number of circulating EPCs as well as their differentiation. Mthfr deficiency was also associated with increased ROS production and reduced nitric oxide (NO) generation in Mthfr(+/-) EPCs. Treatment of EPCs with sepiapterin, a precursor of tetrahydrobiopterin (BH(4)), a cofactor of endothelial nitric oxide synthase (eNOS), significantly reduced ROS and improved NO production. mRNA and protein expression of eNOS and the relative amount of eNOS dimer compared with monomer were decreased by Mthfr deficiency. Impaired differentiation of EPCs induced by Mthfr deficiency correlated with increased senescence, decreased telomere length, and reduced expression of SIRT1. Addition of sepiapterin maintained cell senescence and SIRT1 expression at levels comparable to the wild type. Taken together, these results demonstrate that Mthfr deficiency impairs EPC formation and increases EPC senescence by eNOS uncoupling and downregulation of SIRT1.