Immunogenicity of BNT162b2 vaccine against the Alpha and Delta variants in immunocompromised patients with systemic inflammatory diseases

ObjectivesThe emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases.MethodsProspective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety.ResultsSixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses.ConclusionRituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411).

Preliminary results of single centre experience with the “release and perfuse technique” during aortic arch surgery.

Background and aim of the study To evaluate whether the release and perfuse technique implies a circulatory arrest time comparable with or shorter than those of standard Frozen Elephant Trunk technique in aortic arch surgery. Methods We retrospectively reviewed the records of patients who had undergone aortic arch repair with Release and Perfuse Technique (RPT) or standard Frozen Elephant Trunk (FET) at our Institution between January 2018 and May 2021. Primary endpoints were the comparison of circulatory arrest time, perioperative variables, and complications between two groups. A propensity score weighting approach was used for data analysis. Results A total of 41 patients underwent aortic arch surgery were analyzed:15 (37%) and 26 (63 %) in RPT and FET group, respectively. The use of RPT showed a significant shorter circulatory arrest times than FET: 9 min vs 58 min (P < 0.001), respectively. The median lactates peak in the first 24h post intervention was 2.6 for RPT group and 5.4 mmol/L for FET group, (P <0.0001). When compared with the FET, RPT is associated with significant reduction in the use of packed red blood cells (P <0.0001), fresh frozen plasma (P <0.0001), platelet concentrate (P <0.0001), and fibrinogen (P <0.004). The median ICU stay was 3 and 9 days (P = 0.011), whereas the median hospital stay was 12 and 18.5 days (P=0.004) in the RPT and FET groups, respectively. Thirty-day mortality and postoperative outcomes were comparable between the two groups. Conclusions Considering the anatomical limitations related to the use of this technique, the RPT appears to be safe, feasible, and effective in reducing the circulatory arrest time during aortic arch surgery. Nevertheless, further studies are required to demonstrate its safety and efficacy.

Avacopan, a Selective C5a Receptor Antagonist, for Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Avacopan, an orally administered C5a receptor (C5aR) antagonist, has been approved for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in Japan and the United States. In ADVOCATE Phase III clinical trial, patients with active MPA or GPA received either 30 mg avacopan twice daily or prednisone on a tapering schedule in combination with rituximab or cyclophosphamide (followed by azathioprine). The trial met its two primary endpoints: avacopan showed non-inferiority to prednisone for achieving remission at week 26 (avacopan, 72.3%; prednisone, 70.1%; p &lt; 0.001 for non-inferiority and p = 0.24 for superiority) and superiority for maintaining remission at week 52 (65.7% for avacopan, 54.9% prednisone, p &lt; 0.001 for non-inferiority and p = 0.007 for superiority). Of several key secondary endpoints tested, the glucocorticoid toxicity index (GTI)-cumulative worsening score and GTI-aggregate improvement score were significantly lower in the avacopan group than in the prednisone group at both weeks 26 and 52. Serious adverse events related and unrelated to the worsening vasculitis were reported at 10.2% and 37.3% in the avacopan group and at 14.0% and 39.0% in the prednisone group, respectively. Avacopan has set the stage for the semi-glucocorticoid-free or glucocorticoid-free treatment of MPA and GPA.

Surgery Versus Radiofrequency Ablation for Small Hepatocellular Carcinoma: a Randomized Controlled Trial (SURF-Trial)

Introduction: It remains unclear which of surgery or radiofrequency ablation (RFA) is the more effective treatment for small hepatocellular carcinoma (HCC). We aimed to compare survival between patients undergoing surgery (surgery group) and patients undergoing RFA (RFA group). Methods: We conducted a randomized controlled trial involving 49 institutions in Japan. Patients with Child-Pugh scores ≤ 7, largest HCC diameter ≤ 3 cm, and ≤ 3 HCC nodules were considered eligible. The co-primary endpoints were recurrence-free survival (RFS) and overall survival (OS). The current study reports the final result of RFS, and the follow-up of OS is still ongoing. Results: During 2009–2015, 308 patients were registered. After excluding ineligible patients, the surgery and RFA groups included 150 and 151 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range, 1.5–2.2 cm) in the surgery group and 1.8 cm (interquartile range, 1.5–2.3 cm) in the RFA group. The median procedure duration (274 versus 40 minutes, P<0.01) and the median duration of hospital stay (17 days versus 10 days, P<0.01) were longer in the surgery group than in the RFA group. RFS did not differ significantly between the groups as the median RFS was 3.5 (95% confidence interval [CI], 2.6–5.1) years in the surgery group and 3.0 (95% CI, 2.4–5.6) years in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; P=0.58). Discussion/Conclusion: Our study did not show which of surgery or RFA is the better treatment option for small HCC.

Neoadjuvant chemo-free combination of camrelizumab and apatinib for locally advanced resectable oral squamous cell carcinoma – A pilot study

Novel neoadjuvant therapy regimens are needed to improve the outcomes of patients with locally advanced resectable oral squamous cell carcinoma (OSCC). We conducted a prospective, open-label, single-arm trial (n = 21, NCT04393506) to determine the safety and feasibility of neoadjuvant camrelizumab (an anti-PD-1 antibody) plus apatinib (a VEGFR inhibitor) for locally advanced resectable OSCC. The primary endpoints were safety and major pathological response (MPR). Neoadjuvant camrelizumab plus apatinib was well-tolerated and the MPR rate was 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃ 10 had MPR. Additionally, patients achieving MPR showed more CD4+ T cell infiltration and a higher CD8+/FoxP3+ ratio than those without MPR (p < 0.05), and decreased CD31 and ɑ-SMA expression were observed after neoadjuvant therapy. Our findings demonstrate that neoadjuvant therapy with a chemo-free combination of camrelizumab and apatinib is safe and yields a promising MPR rate, supporting further trials.

Vitamin D Status and SARS-CoV-2 Infection and COVID-19 Clinical Outcomes

Background: Several studies suggest an association between serum 25-hydroxyvitamin D (25OHD) and the outcomes of Severe Acute Respiratory Syndrome Corona-Virus-2 (SARS-CoV-2) infection, in particular Coronavirus Disease-2019 (COVID-19) related severity and mortality. The aim of the present meta-analysis was to investigate whether vitamin D status is associated with the COVID-19 severity, defined as ARDS requiring admission to intensive care unit (ICU) or mortality (primary endpoints) and with the susceptibility to SARS-CoV-2 and COVID-19-related hospitalization (secondary endpoints).Methods: A search in PubMed, ScienceDirect, Web of Science, Google Scholar, Scopus, and preprints repositories was performed until March 31th 2021 to identify all original observational studies reporting association measures, or enough data to calculate them, between Vitamin D status (insufficiency &lt;75, deficiency &lt;50, or severe deficiency &lt;25 nmol/L) and risk of SARS-CoV-2 infection, COVID-19 hospitalization, ICU admission, or death during COVID-19 hospitalization.Findings: Fifty-four studies (49 as fully-printed and 5 as pre-print publications) were included for a total of 1,403,715 individuals. The association between vitamin D status and SARS-CoV2 infection, COVID-19 related hospitalization, COVID-19 related ICU admission, and COVID-19 related mortality was reported in 17, 9, 27, and 35 studies, respectively. Severe deficiency, deficiency and insufficiency of vitamin D were all associated with ICU admission (odds ratio [OR], 95% confidence intervals [95%CIs]: 2.63, 1.45–4.77; 2.16, 1.43–3.26; 2.83, 1.74–4.61, respectively), mortality (OR, 95%CIs: 2.60, 1.93–3.49; 1.84, 1.26–2.69; 4.15, 1.76–9.77, respectively), SARS-CoV-2 infection (OR, 95%CIs: 1.68, 1.32–2.13; 1.83, 1.43–2.33; 1.49, 1.16–1.91, respectively) and COVID-19 hospitalization (OR, 95%CIs 2.51, 1.63–3.85; 2.38, 1.56–3.63; 1.82, 1.43–2.33). Considering specific subgroups (i.e., Caucasian patients, high quality studies, and studies reporting adjusted association estimates) the results of primary endpoints did not change.Interpretations: Patients with low vitamin D levels present an increased risk of ARDS requiring admission to intensive care unit (ICU) or mortality due to SARS-CoV-2 infection and a higher susceptibility to SARS-CoV-2 infection and related hospitalization.

Novel hormonal agents for metastatic Castration-Resistant Prostate Cancer: comparing outcomes. A single-center retrospective study

Introduction: Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancerrelated deaths amongst men worldwide. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. Objective: To evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastatic prostate cancer in an academic center.Patients and methods: We retrospectively reviewed patients treated for castration-resistant prostate cancer with either abiraterone or enzulatamide between January 1, 2016 and December 31, 2019. The primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. Results: Enzalutamide had a higher biochemical response rate than abiraterone in patients with mCRPC (77.1% vs 58.1%, p = 0.016). Achieving a biochemical response was associated with a lower risk of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038). Conclusions: Enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical significance. Well-designed prospective studies are needed to elucidate the comparative efficacies of these agents.

The Efficacy of TACE Combined With Lenvatinib Plus Sintilimab in Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study

ObjectiveTo assess the efficacy and safety of transarterial Chemoembolization (TACE) combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma (HCC).Patients and MethodsThe data of patients with unresectable HCC administered a combination therapy with TACE and lenvatinib plus sintilimab were retrospectively assessed. Patients received lenvatinib orally once daily 2 weeks before TACE, followed by sintilimab administration at 200 mg intravenously on day 1 of a 21-day therapeutic cycle after TACE. The primary endpoints were objective response rate (ORR) and duration of response (DOR) by the modified RECIST criteria.ResultsMedian duration of follow-up was 12.5 months (95%CI 9.1 to 14.8 months). ORR was 46.7% (28/60). Median DOR in confirmed responders was 10.0 months (95%CI 9.0-11.0 months). Median progression-free survival (PFS) was 13.3 months (95%CI 11.9-14.7 months). Median overall survival (OS) was 23.6 months (95%CI 22.2-25.0 months).ConclusionsTACE combined with lenvatinib plus sintilimab is a promising therapeutic regimen in unresectable hepatocellular carcinoma.

Comparative Outcomes of Standard Perioperative Eye Drops, Intravitreal Triamcinolone Acetonide-Moxifloxacin, and Intracameral Dexamethasone-Moxifloxacin-Ketorolac in Cataract Surgery

Background: Since the advent of cataract surgery, topical eye drops have been the mainstay of postoperative prophylaxis and treatment. Due to factors such as high expenses and poor patient compliance, there has been a growing interest and acceptance of “dropless” alternatives. The purpose of this study is to compare the effectiveness of intravitreal triamcinolone acetonide-moxifloxacin and intracameral dexamethasone-moxifloxacin-ketorolac to a standard eye drop regimen in controlling postoperative inflammation, corneal edema, and intraocular pressure (IOP) among cataract patients.Methods: A retrospective longitudinal comparative study among 619 consecutive eyes receiving either a standard eye drop regimen, intraoperative triamcinolone acetonide-moxifloxacin or dexamethasone-moxifloxacin-ketorolac was performed between October 2016 and December 2020. Primary endpoints at postoperative day one (POD1), week one (POW1), and month one (POM1) included corneal edema, anterior chamber inflammation (ACI), and IOP.Results: Throughout the postoperative time points, there were no significant differences in corneal edema between intravitreal triamcinolone acetonide-moxifloxacin versus the standard eye drop therapy (OR [95%CI]: 1.09 [0.82, 1.45], P = .54) and intracameral dexamethasone-moxifloxacin-ketorolac versus the standard eye drop treatment (OR [95% CI]: 1.22 [0.89, 1.67], P = .22). The postoperative ACI severity was lower in the dexamethasone-moxifloxacin-ketorolac group compared to the triamcinolone acetonide-moxifloxacin group by 35% on postoperative day 1 (P = .01). The differences at subsequent postoperative time points were not statistically significant (P = .27 and P = 1.00 for POW1 and POM1 respectively). IOP at POM1 follow up visit was statistically significantly higher for the triamcinolone acetonide-moxifloxacin group [mean (±SD): 15.64 (4.26)] compared to the dexamethasone-moxifloxacin-ketorolac [mean (±SD): 14.16 (4.02)] (P < .01). There was no statistical difference in rates of CME (P = .16) and there were no cases of endophthalmitis.Conclusions: Intravitreal triamcinolone acetonide-moxifloxacin and intracameral dexamethasone-moxifloxacin-ketorolac demonstrate similar levels of efficacy to a standard eye drop regimen after cataract surgery. This study reinforces them as viable alternatives to traditional postoperative drops.

Effect of bisphosphonate on hip fracture in patients with osteoporosis or osteopenia according to age: a meta-analysis and systematic review

This meta-analysis and systematic review investigated the efficacy of bisphosphonates on the incidence of hip fracture (IHF) in patients of different ages with osteoporosis or osteopenia. We searched Web of Science, Embase, the Cochrane Database, and PubMed from inception to January 10, 2021, for trials reporting the effects of bisphosphonates on the IHF. We included only randomized, double-blind, placebo-controlled clinical trials. We pooled data using a random-effects meta-analysis with risk ratios (RRs) and reported 95% CIs. We also used the Cochran Q and I² statistics to assess the heterogeneity in the results of individual studies. The primary endpoints were the total numbers of people in the bisphosphonates and placebo groups and the numbers of IHFs during the follow-up periods. Bisphosphonates reduced the IHF with an overall effect (RR: 0.66; 95% CI: 0.56 to 0.77; zoledronic acid: RR: 0.60; 95% CI: 0.46 to 0.78; risedronate: RR: 0.74; 95% CI: 0.59 to 0.94, and alendronate: RR: 0.61; 95% CI: 0.40 to 0.95). The result of the heterogeneity assessment was I²=0, p=0.97. In all age groups (all ages, ≥55 years old, ≥65 years old), bisphosphonates reduced the IHF. In the ≥55 years old and ≥65 years old age groups, the RR and 95% CI were 0.63 and 0.43 to 0.93, and 0.60 and 0.44 to 0.81, respectively. Bisphosphonate reduced the IHF in the general population and all age groups (≥55 years old and ≥65 years old). Zoledronic acid, risedronate and alendronate reduced the IHF in osteoporosis or osteopenia populations. The association between bisphosphonate and the IHF does not appear to be influenced by age.