Intravesical administration of durvalumab to patients with high risk non muscle invasive bladder cancer after BCG failure. A phase II trial by the Hellenic GU Cancer Group

Introduction & Objectives: Patients with high risk non muscle invasive bladder cancer (NMIBC) who experience BCG failure have limited bladder preserving treatment options as radical cystectomy currently represents the standard therapeutical approach. Systematic immunotherapy (IO) has changed the landscape in advanced bladder cancer and is currently being investigated in NMIBC. Based on the hypothesis that intravesical administration will not be related with severe adverse events, we evaluated the role of intravesically administered durvalumab in NMIBC patients after BCG failure. Material(s) and Method(s): An open label, single-arm, multi-center, phase II clinical trial was conducted. A run-in phase had the objective to determine the maximum tolerated dose (MTD) of durvalumab and to exclude a detrimental effect on disease relapse by this strategy. Durvalumab was administered for a total of 6 instillations per patient at consecutive levels of 500, 750 and 1000 mg. Phase II has as primary end point the 1-year high-grade-relapse-free (HGRF)-rate. Secondary endpoints included toxicity, and high-grade progression-free rat at 1, 3 and 6 months after treatment. Result(s): Thirty patients were enrolled (run in phase: 9, phase II: 21). One patient withdrew consent prior to receiving study treatment, so 29 patients were included in efficacy and toxicity analyses. Mean age was 66.5 years. MTD of durvalumab was set at 1000 mg as no dose related toxicities (DLTs) occurred at any level studied. Three of 9 patients included in the run-in phase (33.3%) were tumor free one month after the last durvalumab instillation, therefore, the null hypothesis was rejected by the futility analysis. Western blot showed that durvalumab remained stable in urine during instillation. One patient died from Covid-19, 3 months after the last durvalumab administration. All patients concluded at least 1 year follow up. One-year HGRF rate was 34.6%. HGRF rates at 1, 3 and 6 months was 73%, 65.3% and 50% respectively. Five patients (17%) experienced a T2 or above disease relapse. Five out of the six patients who received 500mg or 750mg of durvalumab relapsed within 1 year. When efficacy analyses were restricted to patients receiving 1000mg of durvalumab, 1-year HGRF rate was 35%. Interestingly, 2 out of 2 patients with only CIS disease at baseline experienced a tumor complete response, which was durable and was maintained at least for a year. No severe adverse events were noted. The most common adverse event was Grade 1 hematuria. Conclusion(s): Intravesical IO using durvalumab was proved to be feasible with an excellent safety profile. Oncological results seem to be promising and comparable with other bladder preserving strategies in BCG failure with the advantage of a better safety profile. Further study of intravesical IO in high-risk patients with NMIBC after BCG failure is warranted.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Impaired endothelial glycocalyx, vascular dysfunction and myocardial deformation four months after COVID-19 infection are partially improved at twelve months

Introduction: COVID-19 patients present impaired subclinical markers of cardiovascular and endothelial function. Subclinical myocardial and vascular dysfunction during COVID-19 disease have been associated with worse outcomes and higher mortality risk. Purpose: We investigated the effect of COVID-19 infection on markers of endothelial, vascular and myocardial function at four and twelve months after the infection Methods: We recruited 70 patients who were examined in a dedicated post-COVID-19 outpatient clinic during a scheduled follow-up visit at four and twelve months after a confirmed COVID-19 infection and 70 healthy individuals with similar clinical characteristics. At four and twelve months we measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow-mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV) and central systolic blood pressure (cSBP), (v) global left and right ventricular longitudinal strain (GLS), (vi) myocardial global work index (GWI) global constructive work (GCW), global wasted work (GWW) and the myocardial global work efficiency (GWE) and v) malondialdehyde (MDA), an oxidative stress marker. Results: At four months, COVID-19 patients displayed higher values of PBR5–25 compared to control group (p<0.001) which increased at twelve months (p<0.001). FMD, PWV and cSBP values were similar between 4 and 12 months (p>0.05 for all the comparisons) and higher than those in controls (p<0.001, p=0.057, p=0.003 respectively). At four months, COVID-19 patients presented impaired CFR and LVGLS values which were improved at twelve months (p=0.002, p=0.069 respectively), though remained impaired compared to controls (p=0.003 for all the comparisons). At four months, COVID-19 patients had impaired RVGLS values which were significantly improved at twelve months (p=0.001,) and showed no statistically significant difference compared to controls (p>0.05). COVID-19 patients at four months display higher myocardial wasted work and decreased myocardial efficiency compared to controls (p=0.01, p=0.006 respectively). There was a modest improvement in GWW and GWE at twelve months,(p=0.043, p=0.001, respectively);however, these markers remained impaired compared to controls (p>0.05). At four months, MDA was higher in COVID-19 patients compared to control group and significantly decreased at twelve months (p<0.001);however, these values remain higher than in controls (p=0.002) (Table 1). Conclusions: SARS-CoV-2 causes endothelial and cardiovascular dysfunction which are partially restored at twelve months after the infection. Funding Acknowledgement: Type of funding sources: None.Table 1

SARS-CoV-2 is associated withabnormal biomarkers of oxidative stress,and endothelial function linked with cardiovascular dysfunction four months after the infection

Introduction: COVID-19 infection has been associated with increase arterial stiffness, endothelialdysfunction, and impairment in coronary and cardiac performance. Inflammation and oxidative stress have beensuggested as possible pathophysiological mechanisms leading to vascular and endothelial deregulation afterCOVID-19 infection. Purpose: The objective of our study is to evaluate premature alterations in arterial stiffness, endothelial,coronary, and myocardial function markers four months after SARS-CoV-2 infection. Methods: In a case-control prospective study, we included 70 patients 4 months after COVID-19 infection, 70 age- and sex-matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow-mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV) and central systolic blood pressure (cSBP), (v) global left and right ventricular longitudinal strain (GLS), (vi) malondialdehyde (MDA), an oxidative stress marker, thrombomodulin and von Willebrand factor as endothelial biomarkers. Results: COVID-19 patients had similar CFR and FMD with hypertensives (2.48±0.41 vs 2.58±0.88, p=0.562, 5.86±2.82% vs 5.80±2.07%, p=0.872 respectively) but lower values than controls (3.42±0.65, p=0.0135, 9.06±2.11%, p=0.002 respectively). Compared to controls, both COVID-19 and hypertensives had greater PBR5–25 (2.07±0.15μm and 2.07±0.26μm p=0.8 vs 1.89±0.17μm, p=0.001), higher PWV, (12.09±2.50 vs 11.92±2.94, p=0.7 vs 10.04±1.80m/sec, p=0.036) increased cSBP (128.43±17.39 vs 135.17±16.83 vs 117.89±18.85) and impaired LV and RV GLS (−19.50±2.56% vs −19.23±2.67%, p=0.864 vs −21.98±1.51%, p=0.020 and −16.99±3.17% vs −18.63±3.20%, p=0.002 vs −20.51±2.28%, p<0.001). MDA and thrombomodulin were higher in COVID-19 patients than both hypertensives and controls (10.67±2.75 vs 1.76±0.30, p=0.003 vs 1.01±0.50nmole/L, p=0.001 and 3716.63±188.36 vs 3114.46±179.18, p=0.017 vs 2590.02±156.51pg/ml, p<0.001). COVID-19 patients displayed similar vWF values with hypertensives but higher compared with healthy controls (4018.03±474.31 vs 3756.65±293.28 vs 2079.33±855.10 ng/ml, p=0.718 and p=0.016 respectively). Conclusions: SARS-CoV-2 infection is associated with oxidative stress, endothelial and vascular dysfunction, which are linked to impaired longitudinal myocardial deformation 4 months after COVID-19 infection. Funding Acknowledgement: Type of funding sources: None.

Association of COVID-19 with impaired endothelial glycocalyx, vascular function and myocardial efficiency four months after infection

Aims: SARS-CoV-2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers four months after COVID-19 infection. Methods: In a case-control prospective study, we included 100 patients four months after COVID-19 infection, 50 age- and sex-matched healthy individuals. We measured a) pulse wave velocity (PWV), b) flow-mediated dilation (FMD) of brachial artery, c) coronary Flow Reserve (CFR) by Doppler echocardiography d) left ventricular (LV) global longitudinal strain (GLS), e) left ventricular myocardial work index, constructive work, wasted work and work efficiency and e) von-Willenbrand factor and thrombomodulin as endothelial biomarkers. Results: COVID-19 patients had lower CFR and FMD values than controls (2.39 ± 0.39 vs 3.31 ± 0.59, p = 0.0122, 5.12 ± 2.95% vs 8.12 ± 2.23%, p = 0.006 respectively). Compared to controls, COVID-19 patients had higher PWV (PWVc-f 12.32 ± 2.44 vs 10.11 ± 1.85 m/sec, p = 0.033) and impaired LV GLS (-19.11 ± 2.14% vs -20.41 ± 1.61%, p = 0.001). Compared to controls, COVID-19 patients had higher myocardial work index, and wasted work (2067.7 ± 325.9 mmHg% vs 1929.4 ± 312.7 mmHg%, p = 0.026, 104.6 ± 58.9 mmHg% vs 75.1 ± 52.6 mmHg%, p = 0.008, respectively), while myocardial efficiency was lower (94.8 ± 2.5% vs 96.06 ± 2.3%, p = 0.008). and thrombomodulin were higher in COVID-19 patients than controls (3716.63 ± 188.36 vs 2590.02 ± 156.51pg/ml, p < 0.001). MDA was higher in COVID-19 patients than controls (10.55 ± 2.45 vs 1.01 ± 0.50 nmole/L, p = 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress markers. Myocardial work efficiency was related with PWV (F=-0.309, p = 0.016) and vWillenbrand (F=-0.541, p = 0.037). Myocardial wasted work was related with PWV (F = 0.255, p = 0.047) and vWillenbrand (F = 0.610, p = 0.016). Conclusions: SARS-CoV-2 may cause vascular dysfunction, followed by a waste of cardiac work, in order to compensate for increased arterial stiffness 4 months after infection.

Association of COVID-19 with impaired endothelial glycocalyx, coronary flow and longitudinal strain four months after infection

Aims: SARS-CoV-2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers four months after COVID-19 infection. Methods: In a case-control prospective study, we included 100 patients four months after COVID-19 infection, 50 age- and sex-matched healthy individuals. We measured a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), b) flow-mediated dilation (FMD), c) coronary Flow Reserve (CFR) by Doppler echocardiography d) pulse wave velocity (PWV) e) global left (LV) and right (RV) ventricular longitudinal strain (GLS), f) malondialdehyde (MDA), an oxidative stress marker, von-Willenbrand factor and thrombomodulin as endothelial biomarkers. Results: COVID-19 patients had lower CFR and FMD values than controls (2.39 ± 0.39 vs 3.31 ± 0.59, p = 0.0122, 5.12 ± 2.95% vs 8.12 ± 2.23%, p = 0.006 respectively). Compared to controls, COVID-19 had greater PBR5-25 (2.11 ± 0.14μm vs 1.87 ± 0.16μm, p = 0.002), higher PWV (PWVc-f 12.32 ± 2.44 vs 10.11 ± 1.85 m/sec, p = 0.033) and impaired LV and RV GLS (-19.11 ± 2.14% vs -20.41 ± 1.61%, p = 0.001 and -16.45 ± 3.33% vs -20.11 ± 2.48%, p < 0.001). MDA and thrombomodulin were higher in COVID-19 patients than controls (10.55 ± 2.45 vs 1.01 ± 0.50 nmole/L, p = 0.001 and 3716.63 ± 188.36 vs 2590.02 ± 156.51pg/ml, p < 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress and endothelial dysfunction markers. Conclusions: SARS-CoV-2 may cause endothelial and vascular dysfunction linked to.

COVID-19 patients present impaired endothelial glycocalyx, vascular dysfunction and myocardial deformation resembling those observed in hypertensives four months after infection

Background/Introduction: COVID-19 infection has been associated with increase arterial stiffness, endothelial dysfunction, and impairment in coronary and cardiac performance. Inflammation and oxidative stress have been suggested as possible pathophysiological mechanisms leading to vascular and endothelial deregulation after COVID-19 infection. Purpose: The objective of our study is to evaluate premature alterations in arterial stiffness, endothelial, coronary, and myocardial function markers four months after SARS-CoV-2 infection. Methods: We conducted a case-control prospective study, including 70 patients four months after COVID-19 infection, 70 age- and sex-matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness b) flow-mediated dilation (FMD), c) coronary Flow Reserve (CFR) by Doppler echocardiography d) pulse wave velocity (PWV) and central systolic (SBP) e) global LV longitudinal strain (GLS) by speckle tracking imaging and f) malondialdehyde (MDA) as oxidative stress marker. Results: COVID-19 patients had similar CFR and FMD with hypertensives (2.48±0.41 vs 2.58±0.88, p=0.562, 5.86±2.82% vs 5.80±2.07%, p=0.872 respectively), but lower CFR and FMD than controls (3.42±0.65, p=0.0135 9.06±2.11%, p=0.002 respectively) Both COVID-19 and hypertensive group had greater PBR than controls (PBR5-25: 2.07±0.15 μm and 2.07±0.26 μm p=0.8 vs 1.89±0.17 μm, p=0.001). COVID-19 patients and hypertensives had higher PWV and central SBP than controls (PWVcf 12.09±2.50 and 11.92±2.94, p=0.7 vs 10.04±1.80 m/sec, p=0.036). COVID-19 patients and hypertensives had impaired values of GLS compared to controls (-19.50±2.56% and -19.23±2.67%, p=0.864 vs -21.98±1.51%, p=0.020). Increased PBR5-25 was associated with increased SBP central which in turn was related with impaired GLS (p<0.05). MDA was found increased in COVID-19 patients compared to both hypertensives and controls (10.67±2.75 vs 1.76±0.30, p=0.003 vs 1.01±0.50 nmole/L, p=0.001). Conclusions: SARS-CoV-2 may cause impaired coronary microcirculatory, endothelial and vascular deregulation which remain four months after initial infection and are associated with reduced cardiac performance. The 10-fold increase of MDA compared to healthy individuals four months after COVID-19 infection indicate oxidative stress as possible pathophysiological mechanism.

A Phase II Study on the Use of Convalescent Plasma for the Treatment of Severe COVID-19- A Propensity Score-Matched Control Analysis

COVID-19 is a global pandemic associated with increased morbidity and mortality. Convalescent plasma (CP) infusion is a strategy of potential therapeutic benefit. We conducted a multicenter phase II study to evaluate the efficacy and safety of CP in patients with COVID-19, grade 4 or higher. To evaluate the efficacy of CP, a matched propensity score analysis was used comparing the intervention (n = 59) to a control group (n = 59). Sixty patients received CP within a median time of 7 days from symptom onset. During a median follow-up of 28.5 days, 56/60 patients fully recovered and 1 patient remained in the ICU. The death rate in the CP group was 3.4% vs. 13.6% in the control group. By multivariate analysis, CP recipients demonstrated a significantly reduced risk of death [HR: 0.04 (95% CI: 0.004-0.36), p: 0.005], significantly better overall survival by Kaplan-Meir analysis (p < 0.001), and increased probability of extubation [OR: 30.3 (95% CI: 2.64-348.9), p: 0.006]. Higher levels of antibodies in the CP were independently associated with significantly reduced risk of death. CP infusion was safe with only one grade 3 adverse event (AE), which easily resolved. CP used early may be a safe and effective treatment for patients with severe COVID-19 (trial number NCT04408209).

Demographic and clinical features of critically ill patients with COVID-19 in Greece: The burden of diabetes and obesity.

AIMS: The aim of the study was to investigate the association between type-2 diabetes mellitus, other underlying diseases and obesity with the outcomes of critically ill Covid-19 patients in Greece. METHODS: In this retrospective observational multi-centre study, data and outcomes of 90 RNA 2109-nCoV confirmed critically ill patients from 8 hospitals throughout Greece, were analysed. All reported information stand through April 13th 2020. RESULTS: The median age of the patients was 65.5 (IQR 56-73), majority were male (80%) and obesity was present in 34.4% of patients most prevalent to younger than 55 years. Hypertension was the prevailing comorbidity (50%), followed by cardiovascular diseases (21.1%) and type-2 diabetes (18.9%). At admission, common symptoms duration had a median of 8 (IQR 5-11) days. A 13.3% of the patients were discharged, 53.4% were still in the ICUs and 28.9% deceased who were hospitalised for fewer days than the survivors [6 (IQR 3-9) vs. 9 (IQR 7-14.5) respectively]. Aging was not a risk factor but diabetes deteriorates the outcomes. Obesity poses a suggestive burden as it was more notable in deceased versus survivors. CONCLUSIONS: Type 2 diabetes and obesity may have contributed to disease severity and mortality in COVID-19 critically ill patients in Greece.