Efficacy and safety of tixagevimab/cilgavimab as passive immunisation against COVID-19 infections in patients with hematological malignancies.

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3% males; 91% triple vaccinated), 25.8% had a COVID-19 breakthrough infection (76% mild) compared to 43.9% in the control group. Patients with chronic lymphocytic leukaemia (CLL)/lymphoma were at highest risk of a COVID-19 infection (OR = 2.21; 95% CI 1.05-4.65; p = 0.037). After immunisation, a steep increase in median antibody levels (1193.4BAU/ml, IQR 0-2318.94) was observed in 67.8%, followed by a rapid decrease between T1 and T2 (465.95BAU/ml, IQR 0-1900.65.3) with the greatest declines in CLL/lymphoma (848.7BAU/ml, IQR 0-1949.6, p = 0.026). Side-effects occurred in 21.2% (CTCAE I/II). These real-world data indicate that S/RBD antibodies respond rapidly after passive immunisation in all hematological patients without safety concerns. Given the rapid decline in S/RBD antibodies, early booster immunisations should be considered for future scenarios in this vulnerable group.

Cell-free circulating RAS mutation concentrations significantly impact the survival of metastatic colorectal cancer patients.

PURPOSE: RAS mutations are predictors of an adverse outcome in EGFR-targeted therapies and have been proposed as prognostic biomarkers of survival in metastatic colorectal cancer (mCRC). The analysis of circulating tumor DNA from plasma samples, known as liquid biopsies, has indicated that the RAS mutation status may change over time, potentially affecting patients' prognosis. To further evaluate the clinical validity of RAS mutation retesting using liquid biopsies, we prospectively investigated the impact of the circulating quantitative RAS mutation status on the course of mCRC. METHODS: The present study included 81 consecutively recruited patients with mCRC. We used targeted next-generation sequencing of circulating cell-free DNA to determine and quantify plasma RAS mutation status. RESULTS: Patients with a RAS mutation detected by liquid biopsy (37%; n = 30) were at increased risk of death during the follow-up period compared to RAS wild-type patients. Patients with evidence of a RAS mutation in the primary tumor but a putative RAS mutation loss in plasma (28%; n = 11) showed a prolonged survival compared to patients with a preserved RAS mutation status. Also, circulating RAS mutation concentrations significantly affected the outcome: The mortality risk of patients with a high RAS mutation concentration increased fivefold compared to subjects with a putative RAS mutation loss or low RAS mutation concentration. CONCLUSION: Our results emphasize the clinical value of circulating RAS mutations in managing mCRC.

Correlation between the level of evidence and the class of recommendations concerning the pharmacological aspects of the Guidelines of the European Society of Cardiology.

Background The reliability of the recommendations affecting the clinical decisions is being continuously weighed in everyday practice (Gershlick, 2018). The objective of our study was to assess the consistency of the evidence behind the recommendations. Methods We narrowed our focus on the pharmacotherapeutic aspects of the most recent 38 European Society of Cardiology guidelines and analyzed the correlation between the level of evidence (LoE) classified as A, B and C and the class of recommendations (CoR) subdivided into I, IIa, IIb and III. Results Contrary to the majority of recommendations based on a LoE C (43,0%), fewer recommendations were proposed on heavily evidence-supported LoE A (23.8%), which percentage increased with subsequent updates of the guidelines. The most common recommendation was CoR I (44,9%), while the least common recommendation was CoR III (9,2%). While a similar share of A (39,1%) and C (30,1%) LoE shaped the CoR I nearly half (48,8%) of the CoR III were based on LoE C. Conversely, the overwhelming majority of the recommendations within the scope of LoE A were indisputably strong and classified as CoR I (73,7%). Conclusion The pharmacological aspects of the ESC guidelines are predominantly based on LoE C. A greater number of pharmacological recommendations are based on LoE A in comparison to the general ones. Various constraints significantly skew the credibility due to paucity of scientific data. A more nuanced approach is needed, as the guidelines cannot completely substitute the clinical experience and the patient-centered approach in shaping the optimal therapeutic outcome.

Circulating syndecan-1 and glypican-4 predict 12-month survival in metastatic colorectal cancer patients.

Cell surface syndecans and glypicans play important roles in the development and prognosis of colorectal cancer (CRC). Their soluble forms from proteoglycan shedding can be detected in blood and have been proposed as new prognostic biomarkers in several cancer entities. However, studies on circulating syndecan-1 (SDC1) and glypican-4 (GPC4) in CRC are limited. We, therefore, evaluated the impact of plasma SDC1 and GPC4 on the prognosis of metastatic (m)CRC patients. The present study included 93 patients with mCRC. The endpoints were progression-free survival (PFS) and overall survival (OS) at 12 months. SDC1 and GPC4 levels were measured in plasma using enzyme-linked immunosorbent assays. Plasma levels of SDC1 and GPC4 were significantly correlated. Significant correlations of these two markers were also found with carcinoembryonic antigen (CEA). Kaplan-Meier curve analyses indicated that PFS and OS probabilities significantly decreased with increasing levels of SDC1 and GPC4, respectively. Multivariable Cox regression analyses showed that both markers were significantly associated with PFS and OS independently from clinicopathological characteristics including CEA. Respective adjusted hazard ratios (HR) together with corresponding 95% confidence intervals for one standard deviation change of SDC1 were 1.32 [1.02-1.84] for PFS and 1.48 [1.01-2.15] for OS. Adjusted HRs [95% confidence intervals] of GPC4 were 1.42 [1.07-1.89] for PFS and 2.40 [1.51-3.81] for OS. Results from area under the receiver operating characteristic curve analyses suggest that GPC4 and SDC1 add additional prognostic values to CEA for OS. In conclusion, we showed significant associations of circulating SDC1 and GPC4 with poor survival of mCRC patients.

SARS-CoV-2 RBD-specific and NP-specific antibody response of healthcare workers in the westernmost Austrian state Vorarlberg: a prospective cohort study.

OBJECTIVES: Austria, and particularly its westernmost federal state Vorarlberg, developed an extremely high incidence rate during the COVID-19 pandemic. Healthcare workers (HCWs) worldwide are known to have an increased risk of contracting the disease within the working environment and, therefore, the seroprevalence in this population is of particular interest. We thus aimed to analyse SARS-CoV-2-specific antibody dynamics in Vorarlberg HCWs. DESIGN: Prospective cohort study of HCWs including testing at three different time points for the prevalence of anti-SARS-CoV-2 IgG antibodies specific for nucleocapsid protein (NP) and receptor-binding domain (RBD). SETTING: All five state hospitals of Vorarlberg. PARTICIPANTS: A total of 395 HCWs, enrolled in June 2020 (time point 1 (t1)), 2 months after the end of the first wave, retested between October and November at the beginning of the second wave (time point 2 (t2)) and again at the downturn of the second wave in January 2021 (time point 3 (t3)). MAIN OUTCOMES: We assessed weak and strong seropositivity and associated factors, including demographic and clinical characteristics, symptoms consistent with COVID-19 infection, infections verified by reverse transcription PCR (RT-PCR) and vaccinations. RESULTS: At t1, 3% of HCWs showed strong IgG-specific responses to either NP or RBD. At t2, the rate had increased to 4%, and at t3 to 14%. A strong response was found to be stable for up to 10 months. Overall, only 55% of seropositive specimen had antibodies against both antigens RBD and NP; 29% had only RBD-specific and 16% only NP-specific antibodies. Compared with the number of infections found by RT-PCR, the number of HCWs being seropositive was 38% higher. CONCLUSION AND RELEVANCE: Serological testing based on only one antigen implicates the risk of missing infections; thus, the set of antigens should be broadened in the future. The seroprevalence among participating HCWs was comparable to the general population in Austria. Nevertheless, in view of undetected infections, monitoring and surveillance should be reconsidered.

SARS-CoV-2-related mortality and treatment delays for cancer patients in Austria : Findings of a multicentric nationwide study.

BACKGROUND: Cancer patients infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have an increased risk of mortality. Here, we investigated predictive factors for coronavirus disease 2019 (COVID-19) associated mortality in patients with neoplastic diseases treated throughout Austria. METHODS: In this multicentric nationwide cohort study, data on patients with active or previous malignant diseases and SARS-CoV­2 infections diagnosed between 13 March 2020 and 06 April 2021 were collected. Collected data included the stage of the malignant disease and outcome parameters 30 days after the diagnosis of SARS-CoV­2 infection. RESULTS: The cohort consisted of 230 individuals of which 75 (32.6%) patients were diagnosed with hematologic malignancies and 155 (67.4%) with solid tumors. At a median follow-up of 31 days after COVID-19 diagnosis, 38 (16.5%) patients had died due to COVID-19. Compared to survivors, patients who died were older (62.4 vs. 71.4 years, p < 0.001) and had a higher ECOG performance status (0.7 vs. 2.43, p < 0.001). Furthermore, higher neutrophil counts (64.9% vs. 73.8%, p = 0.03), lower lymphocyte counts (21.4% vs. 14%, p = 0.006) and lower albumin levels (32.5 g/l vs. 21.6 g/l, p < 0.001) were observed to be independent risk factors for adverse outcomes. No association between mortality and systemic antineoplastic therapy was found (p > 0.05). In 60.6% of the patients, therapy was postponed due to quarantine requirements or hospital admission. CONCLUSION: Mortality of Austrian cancer patients infected with SARS-CoV­2 is comparable to that of other countries. Furthermore, risk factors associated with higher mortality were evident and similar to the general population. Treatment delays were frequently observed.

Efficacy and safety of heterologous booster vaccination with Ad26.COV2.S after BNT162b2 mRNA COVID-19 vaccine in haemato-oncological patients with no antibody response.

Patients with haemato-oncological malignancies are one of the high-risk groups for a severe course in case of COVID-19 infections. Furthermore, vaccination results in significantly lower response rates in haematological malignancies and lower antibody levels in patients with solid cancer. We investigated efficacy and safety of a heterologous booster vaccination with Ad26.COV2.S DNA vector vaccine in haemato-oncological patients without antibody response after double-dose BNT162b2 messenger (m-)RNA COVID-19 vaccine. A total of 32 haemato-oncological non-responders to double-dose BNT162b2 received a heterologous booster vaccination with Ad26.COV2.S. Blood samples were assessed directly before the vaccination (T0) and four weeks after (T1). Safety assessment was performed using a standardised questionnaire. The overall response rate was 31%, with a mean (SD) antibody titre of 693·79 (1 096·99) binding activity units (BAU)/ml. Patients with chronic lymphocytic leukaemia or lymphoma showed a significantly lower response rate (P = 0·048). Adverse events were reported in 29·6% of patients, of which 7·1% were graded as severe, including grade III and IV events following the Common Terminology Criteria of Adverse Events (CTCAE). The heterologous booster vaccination with Ad26.COV2.S led to a serological response in nine out of 29 patients without response after double-dose BNT162b2. Furthermore, the vaccination was safe in our cohort, leading to mainly mild local and systemic reactions. Overall, this vaccination regimen should be further evaluated to increase the response rate in the highly vulnerable population of haemato-oncological patients.

Serological SARS-CoV-2 antibody response, potential predictive markers and safety of BNT162b2 mRNA COVID-19 vaccine in haematological and oncological patients.

Haemato-oncological patients are at risk in case of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Currently, vaccination is the best-evaluated preventive strategy. In the present study, we aimed to assess serological response, predictive markers, and safety of BNT162b2 in haemato-oncological patients. A total of 259 haemato-oncological patients were vaccinated with two 30 µg doses of BNT162b2 administered 21 days apart. Serological response was assessed by ELECSYS® Anti-SARS-CoV-2-S immunoassay before vaccination, and at 3 and 7 weeks after the first dose (T1, T2). Safety assessment was performed. At T2 spike protein receptor binding domain (S/RBD) antibodies were detected in 71·4% of haematological and in 94·5% of oncological patients (P < 0·001). Haematological patients receiving systemic treatment had a 14·2-fold increased risk of non-responding (95% confidence interval 3·2-63·3, P = 0·001). Subgroups of patients with lymphoma or chronic lymphocytic leukaemia were at highest risk of serological non-response. Low immunoglobulin G (IgG) level, lymphocyte- and natural killer (NK)-cell counts were significantly associated with poor serological response (P < 0·05). Vaccination was well tolerated with only 2·7% of patients reporting severe side-effects. Patients with side-effects developed a higher S/RBD-antibody titre compared to patients without side-effects (P = 0·038). Haematological patients under treatment were at highest risk of serological non-response. Low lymphocytes, NK cells and IgG levels were found to be associated with serological non-response. Serological response in oncological patients was encouraging. The use of BNT162b2 is safe in haemato-oncological patients.