Effects of Different Anticoagulation Doses on Moderate-to-Severe COVID-19 Pneumonia With Hypoxemia.

Background COVID-19 is a prothrombotic disease that can cause thromboembolism and microthrombi, which could lead to multiorgan failure and death. Since COVID-19 is a relatively new disease, there are guidelines for anticoagulation dosing for COVID-19 patients without consensus on the dosing. We studied the effects of different doses of anticoagulation in hospitalized patients with COVID-19 pneumonia and hypoxemia on any differences in need for high-flow oxygen, mechanical ventilation, and mortality. We also analyzed the patient population who benefited most from anticoagulation. Methodology We performed a retrospective chart review of all patients who were admitted with the diagnosis of COVID-19 infection with positive polymerase chain reaction, pneumonia (confirmed either by chest X-ray or CT chest), and hypoxemia (oxygen saturation of <94%, while on room air). These patients were studied for outcomes (the need for high-flow oxygen, the requirement for mechanical ventilation, and overall mortality) for different doses of anticoagulation (prophylactic, escalated, and therapeutic). Results The sample consists of 132 subjects, predominantly males (116, 87%), with a mean age of 59 years and a standard deviation of 15. About one-third of the participants had diabetes, and more than 50% had hypertension. Additionally, 27 (20.3%) had a history of heart disease, and 70 (53%) of the subjects were admitted to the intensive care unit (ICU) at some point during the study. Among those admitted to the ICU, about 11 (8%) subjects required mechanical ventilation and 16 (12%) passed away during the study. Those who died had higher use of high-flow oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation and had a longer stay on mechanical ventilation. There was no significant difference in mortality or need for mechanical ventilation for any strategy of anticoagulation. Conclusions Different doses of anticoagulation did not show any statistically significant relationship between the need for mechanical ventilation and mortality. More patients on high-flow oxygen had received escalated doses of anticoagulation as compared to those who were not on high-flow oxygen. Anticoagulation levels did not have any statistically significant effect on overall survival of patients.

Role of tumor infiltrating lymphocytes and spatial immune heterogeneity in sensitivity to PD-1 axis blockers in non-small cell lung cancer.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) reflect adaptive antitumor immune responses in cancer and are generally associated with favorable prognosis. However, the relationships between TILs subsets and their spatial arrangement with clinical benefit from immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) remains less explored. METHODS: We used multiplexed quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8+ cytotoxic T cells, CD4+ helper T cells and CD20+ B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes in a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI. The analysis of full-face tumor biopsies including numerous fields of view allowed a detailed spatial analysis and assessment of tumor immune heterogeneity using a multiparametric quadratic entropy metric (Rao's Q Index (RQI)). RESULTS: TILs were preferentially located in the stromal tissue areas surrounding tumor-cell nests and CD8+ T cells were the most abundant subset. Higher density of stromal CD8+ cytotoxic T cells was significantly associated with longer survival, and this effect was more prominent in programmed death ligand-1 (PD-L1) positive cases. The role of baseline T cell infiltration to stratify PD-L1 expressing cases was confirmed measuring the T cell receptor-burden in an independent NSCLC cohort studied with whole-exome DNA sequencing. High levels of LAG-3 on T cells or elevated RQI heterogeneity index were associated with worse survival in the cohort. CONCLUSION: Baseline T cell density and T cell exhaustion marker expression can stratify outcomes in PD-L1 positive patients with NSCLC treated with ICI. Spatial immune heterogeneity can be measured using the RQI and is associated with survival in NSCLC.

Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors.

Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.

Clinical and Pathology Findings Associate Consistently with Larger Glomerular Volume.

Background Glomerular volume increases when demand exceeds nephron supply, which may lead to glomerulosclerosis. It is unclear if determinants of glomerular volume are consistent between populations that differ by severity of comorbidities.Methods We studied kidney biopsy specimens from living kidney donors (n=2453) and patients who underwent radical nephrectomy for a renal tumor (n=780). We scanned specimen sections into high-resolution digital images, manually traced glomerular profiles, and calculated mean glomerular volumes using the Weibel-Gomez stereologic formula (separately for nonsclerosed glomeruli and globally sclerosed glomeruli). We then assessed the relationship of glomerular volume with age, clinical characteristics, and nephrosclerosis on biopsy specimen.Results Compared with kidney donors, patients with tumors were older and more frequently men, obese, diabetic, or hypertensive, had more glomerulosclerosis and interstitial fibrosis on biopsy specimen, and had 12% larger nonsclerosed glomeruli (P<0.001). In both populations, male sex, taller height, obesity, hypertension, and proteinuria associated with larger nonsclerosed glomeruli to a similar extent. In patients with tumors, diabetes, glomerulosclerosis >25%, and interstitial fibrosis >25% also associated with larger nonsclerosed glomeruli. Independent clinical predictors of larger nonsclerotic glomeruli were family history of ESRD, male sex, taller height, obesity, diabetes, and proteinuria. After adjustment for these characteristics, nonsclerotic glomerular volume did not differ between populations and was stable up to age 75 years, after which it decreased with age. Many of these findings were also evident with globally sclerotic glomerular volume.Conclusions Characteristics associated with glomerular volume are consistent between patient populations with low and high levels of comorbidity.