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1.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-336111

ABSTRACT

Objective: We quantified changes in dispensing of common medicines proposed for “repurposing” due to their perceived benefits as therapeutic or preventive for COVID-19 in Australia, a country with relatively low COVID-19 incidence in the first year of the pandemic. Methods: We performed an interrupted time series analysis and cross-sectional study using nationwide dispensing claims data (January 2017-November 2020). We focused on six subsidised medicines proposed for re-purposing: hydroxychloroquine, azithromycin, ivermectin, colchicine, corticosteroids, and calcitriol (Vitamin D analogue). We quantified changes in monthly dispensing and initiation trends during COVID-19 (March-November 2020) using autoregressive integrated moving average models (ARIMA) and compared characteristics of initiators in 2020 and 2019. Results: In March 2020, we observed a 99% (95%CI 96%-103%) increase in hydroxychloroquine dispensing (of which approximately 22% attributable to new use), and a 199% increase (95%CI 184%-213%) in initiation, with a shift towards prescribing by general practitioners (42% in 2020 vs 25% in 2019) rather than specialists. These increases subsided following regulatory restrictions on prescribing to relevant specialties. There was a small but sustained increase in ivermectin dispensing over multiple months, with a 80% (95%CI 42%-118%) increase in initiation in May 2020 following its first identification as potentially disease-modifying in April. Other than increases in March related to stockpiling, we observed no increases in initiation of calcitriol or colchicine during COVID-19. Dispensing of corticosteroids and azithromycin remained lower than expected in April through November 2020. Conclusions: While most increases in dispensing observed early on during COVID-19 were temporary and appear to be related to stockpiling among existing users, we did observed increases in initiation of hydroxychloroquine and ivermectin and a shift in prescribing patterns which may be related to media hype around these medicines. A quick response by regulators can help limit inappropriate repurposing to lessen the impact on medicine supply and patient harms.

2.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-336024

ABSTRACT

Background: Continued SARS-CoV-2 infections and COVID-19-related hospitalizations highlight the need for effective anti-viral treatments in the outpatient setting. In a descriptive interim analysis of the phase 1/2 portion of a double-blind phase 1/2/3 trial in COVID-19 outpatients conducted between June 16, 2020 and September 4, 2020, REGEN-COV® (casirivimab plus imdevimab) antibody combination reduced SARS-CoV-2 viral load versus placebo. Methods: This final phase 1/2 analysis comprises 799 outpatients, including 275 from the previous descriptive analysis (group-1) and 524 from phase 2 (group-2). Patients were randomized (1:1:1) to placebo, REGEN-COV 2400mg, or REGEN-COV 8000mg. Prespecified hierarchical analyses of virologic endpoints were performed in group-2. The proportion of patients with ≥1 COVID-19-related medically attended visit (MAV) through day 29 was assessed in group-1+2. Efficacy was assessed in patients confirmed SARS-CoV-2-positive by baseline nasopharyngeal RT-qPCR. Safety was assessed in all treated patients. Results: Data from 799 outpatients enrolled from June 16, 2020 to September 23, 2020 are reported. Time-weighted average daily reduction in viral load through day 7 was significantly greater in the REGEN-COV combined 2400mg+8000mg group versus placebo in patients with baseline viral load >107 copies/mL (prespecified primary endpoint): -0.68 log10 copies/ml (95% CI, -0.94 to -0.41;P<.0001). This reduction was - 0.73 (P<.0001) and -0.36 (P=.0003) log10 copies/mL in serum antibody-negative patients and in the overall population, respectively. REGEN-COV reduced the proportion of patients with ≥1 COVID-19-related MAV versus placebo (2.8% [12/434] REGEN-COV combined dose group versus 6.5% [15/231] placebo;P=.024;relative risk reduction [RRR]=57%);in patients with ≥1 risk factor for hospitalization, the treatment effect was more pronounced (RRR=71%). Adverse events were similar across groups. Conclusions: In COVID-19 outpatients enrolled prior to the widespread circulation of delta and omicron variants, treatment with REGEN-COV significantly reduced viral load and COVID-19-related MAVs.

3.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-335579

ABSTRACT

Background: The impact of chronic health conditions (CHC) on serostatus post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is unknown. Methods: We assessed serostatus post-SARS-CoV-2 vaccination among fully vaccinated participants recruited between April 2021 through August 2021 in 18 years and older residents of Jefferson County, Kentucky, USA. Serostatus was determined by measuring SARS-CoV-2 Spike protein specific immunoglobulin (Ig) G (Spike IgG) antibodies via enzyme-linked immunoassay (ELISA) in peripheral blood samples. Results: Of the 5,178 fully vaccinated participants, 51 were seronegative and 5,127 were seropositive. Chronic kidney disease (CKD) (OR=13.49;95% CI: 4.88–37.3;P<0.0001) and autoimmune disease (OR=11.34;95% CI: 5.21–24.69;P<0.0001) showed highest association with negative serostatus in fully vaccinated participants. The absence of any CHC was strongly associated with positive serostatus (OR=0.37;95% CI: 0.19–0.73;P=0.003). The risk of negative serostatus increased in the presence of two CHCs (OR=2.82;95% CI: 1.14–7) to three or more CHCs (OR=4.52;95% CI: 1.68–12.14). Similarly, use of 2 or more CHC related medications was significantly associated with seronegative status (OR=6.08;95%: 2.01–18.35). Conclusions: Presence of any CHC, especially CKD or autoimmune disease, increased the likelihood of seronegative status among individuals who were fully vaccinated to SAR-CoV-2. This risk increased with a concurrent increase in number of comorbidities, especially with multiple medications. Absence of any CHC was protective and increased the likelihood of a positive serological response post-vaccination. These results will help develop appropriate guidelines for booster doses and targeted vaccination programs.

4.
Frontiers in Pharmacology ; 13, 2022.
Article in English | EMBASE | ID: covidwho-1822399

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a positive-strand RNA virus, and has rapidly spread worldwide as a pandemic. The vaccines, repurposed drugs, and specific treatments have led to a surge of novel therapies and guidelines nowadays;however, the epidemic of COVID-19 is not yet fully combated and is still in a vital crisis. In repositioning drugs, natural products are gaining attention because of the large therapeutic window and potent antiviral, immunomodulatory, anti-inflammatory, and antioxidant properties. Of note, the predominant curcumoid extracted from turmeric (Curcuma longa L.) including phenolic curcumin influences multiple signaling pathways and has demonstrated to possess anti-inflammatory, antioxidant, antimicrobial, hypoglycemic, wound healing, chemopreventive, chemosensitizing, and radiosensitizing spectrums. In this review, all pieces of current information related to curcumin-used for the treatment and prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through in vitro, in vivo, and in silico studies, clinical trials, and new formulation designs are retrieved to re-evaluate the applications based on the pharmaceutical efficacy of clinical therapy and to provide deep insights into knowledge and strategy about the curcumin’s role as an immune booster, inflammatory modulator, and therapeutic agent against COVID-19. Moreover, this study will also afford a favorable application or approach with evidence based on the drug discovery and development, pharmacology, functional foods, and nutraceuticals for effectively fighting the COVID-19 pandemic.

5.
Natural Product Communications ; 17(4), 2022.
Article in English | EMBASE | ID: covidwho-1822124

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) has posed a serious threat to human health and there is an urgent need for drug development. In this study, we explored the potential mechanisms underlying the efficacy of polydatin against COVID-19. Methods: A combined approach of network pharmacology, molecular docking, and experimental verification were employed in this study. Potential targets of polydatin for treating COVID-19 were obtained from multiple drug and disease databases. Protein–protein interaction and enrichment analyses were performed to predict the potential mechanism of action of polydatin against COVID-19. The binding potential of polydatin and key targets was evaluated through molecular docking. Furthermore, experimental methods including flow cytometry and luciferase assay were used to validate the results of computational analyses. Results: The main diseases identified as polydatin targets included metabolic diseases, lung diseases, inflammation, infectious diseases, and tumors. Polydatin may be used to treat COVID-19 through interventions that alter the immune and inflammatory responses, including IL-17 signaling pathway, T-cell activation, cytokines and inflammatory response, lipopolysaccharide-mediated signaling pathway, as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) innate immunity evasion and cell-specific immune response. Polydatin can potentially bind to the target proteins related to COVID-19, such as SARS-CoV-2 Mpro, RdRp, and human angiotensin-converting enzyme 2 (ACE2), while directly exerting its regulatory or therapeutic functions. The experimental results showed that polydatin decreased the infectivity of the SARS-CoV-2 spike pseudovirus in HEK293T-ACE2 cells. Accordingly, polydatin may retard the entry of SARS-CoV-2 into cells by competitively binding to human ACE2. Conclusion: The potential targets and signaling pathways of polydatin against COVID-19 were preliminarily identified. The findings may benefit the development and application of polydatin as a treatment for COVID-19.

6.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821960

ABSTRACT

Introduction and Objectives Novel SARS-CoV-2 virus has been implicated in prompting a bold immune response that leads to severe Coronavirus disease 2019 (COVID-19). Recent studies have shown that SARSCoV-2-infected monocytes and macrophages are stimulated to produce an overabundance of pro-inflammatory cytokines and chemokines to generate a cytokine storm. Cytokines in excess can contribute to local tissue inflammation and the pathogenesis of COVID-19. However, the mechanism by which SARS-CoV-2 signal macrophage-derived inflammatory response remains unclear. In the present study, we used RAW 264.7 cells, a wellcharacterized macrophage model, to study the in vitro effects of SARS-CoV-2 on reactive oxygen species (ROS) production and its potential role in the signal transduction of cytokine production. Methods The effect of SARS-CoV-2 on ROS and cytokine generation in macrophages was assessed by treating RAW 264.7 cells with SARS-CoV-2 heat inactivated virus (0-20 million viral particles) or recombinant proteins for 24 hours. 2',7'-Dichlorodihydrofluorescein (2',7'-DCF) fluorescence analysis was utilized to quantify ROS generation within the RAW 264.7 macrophage cell line. Cell culture medium was sampled to quantify the levels of tumor necrosis factor (TNF) using enzyme-linked immunosorbent assay (ELISA). To assess the effects of SARS-CoV-2 on mitochondrial function, cells were treated with SARS-CoV-2 heat inactivated virus (0-20 million viral particles) for 24 hrs. Mitochondria-derived superoxide was measured using the MitoSOX™ red mitochondrial superoxide indicator. Results Treatment of RAW 264.7 cells with inactivated SARS-CoV-2 viral particles or recombinant proteins stimulated ROS production. Mitochondria-derived superoxide and hydrogen peroxide production were increased in response to inactivated SARS-CoV-2 viral particles and recombinant protein exposure. The increased ROS generation is linked to macrophage activation induced by SARS-CoV-2 exposures. Along with the ROS generation, increased TNF production was observed. Conclusions The results of this study suggest that both SARS-CoV-2 viral proteins and heat-inactivated viral particle exposures cause significant generation of ROS and cytokines by RAW 264.7 cells. ROS generation and the subsequent cytokine release apparently play a significant role in the pathogenesis associated with the SARS-CoV-2 viral infection. The imbalanced cellular defense system against oxidative stress commonly associated with aging could explain the increased occurrence of more severe SARS-CoV-2 illness in seniors and in patients with underlying health conditions. Based on the results from this study, we propose that antioxidants such as N-acetyl-L-cysteine, resveratrol, or Vitamin E in combination with antiinflammatory drug could be used to control excess ROS and cytokines in patients with severe COVID-19.

7.
Chinese Journal of Evidence-Based Medicine ; 22(4):438-443, 2022.
Article in Chinese | EMBASE | ID: covidwho-1818644

ABSTRACT

Objective To systematically review the impact of ACEI/ARB (angiotensin converting enzyme inhibitor/angiotensin receptor antagonist) treatment on the clinical outcomes of Chinese patients with COVID-19 infections. Methods PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, WanFang Data, and VIP databases were electronically searched to collect cohort studies on the impact of the treatment with ACEI/ARB on the clinical outcomes of Chinese patients with COVID-19 infections from January 2020 to January 2022. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of the included studies. Then, meta-analysis was performed using RevMan 5.3 software. Results A total of 17 cohort studies involving 4 912 subjects were included. The results of meta-analysis showed that patients who were prescribed ACEI/ARB had shorter hospital stays (SMD=-0.28, 95%CI -0.46 to -0.11, P=0.002) and a lower mortality rate (OR=0.47, 95%CI 0.36 to 0.62, P<0.000 01) than patients who did not take ACEI/ARB. Conclusion Current evidence shows that the use of ACEI/ARB drugs can improve the clinical prognosis of Chinese patients with COVID-19 infections. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.

8.
Blood Purification ; 50(SUPPL 1):20, 2021.
Article in English | EMBASE | ID: covidwho-1816960

ABSTRACT

Background: Until the present time, the effect of hemoperfusion to mitigate inflammatory response and improve outcome in severe COVID-19 is still unknown. Therefore, we aimed to investigate the effects of early HA-330 hemoperfusion in combination with standard therapy in severe COVID-19 patients. Methods: We conducted a single center, prospective cohort study on patients who diagnosed with severe COVID-19 patients and admitted to ICU. Patients in hemoperfusion group (defined as patients who were treated with hemoperfusion therapy at least 3 sessions in combination with standard therapy) were compared with the control group (defined as patients who received standard treatment alone or received less than 3 sessions of hemoperfusion therapy). We assessed C-reactive protein, oxygenation assessment (PaO2 and ratio of PaO2/FiO2) , severity scoring of lung infiltration on the chest x-ray (CXR RALE score) and organ failure score (SOFA score) daily. Those were defined as a primary outcome. The secondary outcomes were ventilator free day, hospital mortality and 28-day mortality. All outcome was adjusted by regression analysis to reduce the confounders due to some difference in baseline characteristics. Results: Between April 7,2021 and May 31,2021, a total number of 29 severe and critical COVID-19 confirmed patients were enrolled. Fifteen patients were defined as hemoperfusion group and 14 were control group. The median of C-reactive protein and SOFA score at the baseline (the day after severe pneumonia diagnosis or before hemoperfusion) in hemoperfusion and control groups were comparable, 96.79 mg/L and 87.3 mg/L, p=0.53, 3.53 ± 0.99 VS 4.3 ±1.89, p=0.15, respectively. Clinical improvement associated with decreased SOFA score and improvement of CXR RALE score were found in hemoperfusion group compared to control group (p=0.008 and p=0.005, respectively). The 28-day mortality rate was significantly lower in hemoperfusion group compared to control group (6.67 % vs 85.71 %, p<0.001) and adjusted HR of death was 0.017 (95 % CI = 0.008-0.351, p=0.008) Conclusion: In severe COVID-19 patients, the addition of at least 3 sessions of hemoperfusion therapy to standard COVID-19 therapy seemed to improve severity of organ failure, CXR severity score, ventilator-free day and reduced the mortality rate.

9.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816928

ABSTRACT

Background: To understand the impact of the COVID-19 pandemic on National Health Services (NHS) cancer service delivery, care and patients, we examined the impact of changes in cancer service delivery, treatment intensity and delay by evaluating oncological outcomes of genitourinary (GU) cancer patients receiving systemic anticancer treatment (SACT) during 1st March and 8th July 2020. Methods: We used data from patients with GU cancers (i.e. prostate, urothelial, kidney and testicular) treated with SACT at Guy's Cancer Centre during the first wave of the COVID-19 pandemic in the UK: demographics (sex, age, ethnicity, ECOG performance status (PS), comorbidities, smoking history, socio-economic status (SES)) and disease characteristics (stage, treatment type and setting, lines of treatment), as well as results from SARS-CoV-2 PCR testing. Classification of COVID-19 severity was based on the World Health Organisation (WHO) guidelines. Results: A total of 457 GU cancer patients received SACT during the study period: 68% prostate cancer, 23% renal cancer, 7% urothelial cancer, 2% testicular cancer. Mean age was 69 years (SD: 11.2). 91% were males, 82% were classified as low SES and out of the 291 patients we had ethnicity data on 199 (68%) were White British. The majority of patients had a PS of 1 and 95% of all patients had stage IV disease and hence received palliative SACT, with 58% being in the second line setting. Half of the patients received hormone therapy, 17% received chemotherapy, 20% received targeted therapy, 13% received immunotherapy (IO) and 1% received combination IO and targeted treatment. Only 5 (1%) patients tested SARS-CoV-2 positive: 2 had prostate cancer, 2 renal and 1 bladder cancer. Mean age was 66 years (SD: 5.6). They were all male, 2 White British, 1 Black African and 2 of unknown ethnicity and were all classified as low SES. Average PS was 2. Of these 5 patients 3 had at least two comorbidities (i.ehypertension, diabetes mellitus, renal impairment, frailty) and were receiving multiple medications. All had stage IV disease and received palliative SACT. 3 were on hormone therapy alone and 2 on chemotherapy. 2 of the patients presented symptoms within less than 7 days from PCR diagnosis, 1 within 7 to 14 days and 1 after 14 days. All 5 COVID-19 positive patients required hospitalization, 4 suffered severe pneumonia, 1 died from COVID-19 and 2 died from cancer related causes. In comparison, the mortality rate for the COVID-19 negative patients was 3.3%. Conclusion: Despite the impact of COVID-19 in health provision, a large number of our GU patients at Guy's Cancer Centre safely received SACT. Our results suggest that the continuation of SACT during the COVID-19 pandemic did not increase the risk of COVID-19 in our patient cohort (SARS-CoV-2 infection rate: 1%). Of note, the infection rate was lower than observed in a similar study in our centre for gastrointestinal cancer patients (SARS-CoV-2 infection rate: 3.4%). In light of the above, decisions against SACT or SACT intensity should carefully be evaluated.

10.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816927

ABSTRACT

Introduction Treatment of B-lineage lymphoma with B-cell depleting immunotherapy causes B-cell aplasia and impairs immune response. Case studies have reported patients treated with anti-CD20 therapy who suffered from persistent Covid-19. We aimed to assess the incidence, risk factors and long-term outcomes of persistent Covid-19 in patients with lymphoma. Patients and methods This retrospective multicentric study was conducted in 16 French hospitals. All adult patients with lymphoma who were admitted for Covid-19 in March and April 2020 were included. Persistent Covid-19 was defined as persisting severe Covid-19 symptoms requiring in-hospital stay for >30 days. Patients who re-experienced severe Covid-19 symptoms after initial improvement, requiring repeated hospitalizations for a total in-hospital length of stay >30 days were added to the persistent Covid-19 cases. Results One hundred eleven patients were included. Thirty days after admission for Covid-19, 24 patients had died, 55 had been definitively discharged from hospital, 31 were still hospitalized and 1 was later rehospitalized for Covid-19 recurrence. The incidence of persistent Covid-19 was 32/111 (29%). Patients with persistent Covid-19 had a median age of 64 years (range, 43-87) and 63% were male. Twenty-two patients (69%) had at least one significant comorbidity. None of the patients with T-cell (n=8) lymphoma or classical Hodgkin's disease (n=8) experienced persistent Covid-19. In the 32 patients with persistent Covid-19, the median time between first admission and final discharge was 58 days (range, 31-235) and the median duration of Covid-19 symptoms was 83 days (range, 32-237). Eight patients received corticosteroids and 9 convalescent plasma: all patients recovered from their symptoms, except one. Overall, 9 patients with persistent Covid-19 died (27%). After a median follow-up of 191 days (range, 3-260), the 6-month overall survival was 69% (95% CI 60-78%) for the whole cohort. In multivariate analysis, administration of anti-CD20 monoclonal antibody within 12 months before admission to hospital for Covid-19 was both associated with decreased overall survival (HR 2.13, 95% CI 1.03-4.44, p = 0.043) and prolonged in-hospital stay (HR 1.97, 95% CI 1.24-3.13, p = 0.004). The two other significant factors associated with decreased overall survival and prolonged in-hospital stay: age ≥ 70 years and refractory or relapsed lymphoma. Conclusion Patients with B-cell non-Hodgkin lymphoma hospitalized for Covid-19 have a high incidence of prolonged evolution of SARS-CoV-2 infection. Administration of anti-CD20 therapy within the last 12 months is one of the main risk factors for longer in-hospital stay and death of Covid-19. The risk of persistent Covid-19 was also higher in patients older than 70 years or with refractory or relapsed disease. These findings may contribute to guide the management of lymphoma patients during the Covid-19 pandemic.

11.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816906

ABSTRACT

The ability to control the proliferation and cell death by inhibiting specific target kinase offers the opportunity to apply targeted therapies in the treatment of cancer. It has been found that (S)-valine-thiazole-derived compounds such as NEOS-223 are effective inhibitors of one or more of these kinases. NEOS 223 was developed, synthesized, and tested in the NCI 60 human tumor cell-screening panel demonstrating inhibition of colon (-53%), melanoma (-41%), and breast cancers (-9%). Microsomal clearance was determined in mouse, rat, dog, and human, and analyzed by LC-MS/MS by percent of parent material. IC50 values for CYP inhibition of >10 μM were calculated for 1A2, 2C19, and 3A4 with IC50 values of 4.86, 4.31, and 7.84 μM for 2C9 and 2D6. Microsomal clearance was high in all species with clearance rates ranging from 69-136 mL/min/kg. Plasma protein binding was determined by Rapid Equilibrium Dialysis in mice, rats, dogs, and humans. High plasma protein binding (>70%) was observed across all species. Based on the NCI results several cell lines were assayed in an MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) to determine cell viability in the presence of NEOS-223 resulting in <20% viability in colon, breast, melanoma, pancreatic and prostate human cancer cell lines at a 10 uM concentration. Maximum tolerated dose studies were conducted by both intraperitoneal and oral administration in mice. NEOS-223 delivered up to 80 mg/kg was well tolerated. Minimal or no toxicity was observed in acute and repeat dose animal studies. Pharmacokinetics of oral administration demonstrated adequate systemic exposure at therapeutic levels in mice, rats, and dogs. Preliminary in vivo mouse xenograft studies were performed on colon (COLO 205, HT-29 red FLUC), breast (MDA-Sumathi Chittamuru;Timothy M. Murphy;Sara A. Little;Andrew A. Taylor;Roseanne Wexler;Laxman Desai MB-468), melanoma (M-14), pancreatic (PANC-1), and prostate (PC3) human cancer cells with significant tumor inhibition observed compared to positive control agent groups with twice daily dosing of NEOS-223. In addition, a five-day pilot oral toxicity study in rats with dose range-finding studies and a 28-day repeat dose toxicity study performed in both rats and dogs provided favorable results. NEOS-223 has demonstrated active in vitro activity along with a favorable safety profile. in vivo efficacy resulted in inhibition of growth of multiple cell line. As a novel effective structure possibly targeting multiple kinases and transporters in one hybrid molecule, NEOS-223 may be a preferred monotherapy or combined therapy for multiple cancers. If upon further development, this drug is effective in humans, it would advance clinical practice and could improve current therapy significantly.

12.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816897

ABSTRACT

Background: The COVID-19 pandemic has influenced treatment decisions in cancer patients. There is increasing evidence that not all oncology patients are at increased risk of COVID-19 infection or death. This study aimed to look at rate of SARS-CoV-2 infection and mortality in patients with skin malignancies receiving systemic anti-cancer therapy (SACT) during the pandemic in Guy's Cancer Centre. Methods: All patients with skin cancer receiving SACT at Guy's Cancer Centre between March 1st and May 31st 2020 were included. Demographic data: sex, age, socio-economic status (SES), ethnicity, comorbidities, medications and smoking history were collected along with cancer characteristics: cancer type, stage, treatment paradigm, modality and line. COVID-19 infection was confirmed by PCR and severity defined by the World Health Organisation classification. Patients with radiological or clinical diagnoses alone were excluded. Results: Of 116 skin cancer patients on SACT over the 3-month period, 89% had Melanoma, 5% Kaposi's Sarcoma (KS), 3% Squamous Cell, 2% Merkel Cell, 1% Basal Cell Carcinoma and 1% Angiosarcoma. 53% were male and 78% were of low SES. 62% were being treated with palliative intent and 70% of these were on first line palliative treatment. The median age was 57.6 years in COVID-19 positive patients (n=3) compared to 60.3 years in the negative group (n=113). 58.6% received immunotherapy, 28.4% targeted therapy, 7.8% chemotherapy and 4.3% combined treatment. Of the 3 patients (2.6%) with confirmed COVID-19 infection, the two patients with KS were receiving liposomal doxorubicin hydrochloride and the other paclitaxel chemotherapy and the patient with Melanoma was receiving encorafenib and binimetinib. All COVID-19 positive patients were of low SES, 2 females and 1 male. There was a low rate of co-morbidities with hypertension in 1 COVID-19 positive patient and none in the negative group. All 3 confirmed COVID-19 patients developed severe pneumonia and were diagnosed within 7 days of the onset of symptoms. There were no COVID related deaths and one disease-related death in the negative cohort. Conclusion: There was a low rate of COVID-19 infection in the 116 skin cancer patients on SACT (2.6%) with 60% of patients on immunotherapy. All 3 confirmed cases had severe pneumonia with no COVID-19 related deaths (0%);2 were receiving chemotherapy and 1 on targeted therapy. Patients on treatment were encouraged to shield between hospital attendances during this period which may account for the reduced rate of SARS-CoV-2 infection. This data supports the emerging observations that immunotherapy does not confer an increased risk of severe COVID-19 infection in cancer patients. This observation is confounded by the relatively young age and low co-morbidity rates in the cohort which may have contributed to the low infection and mortality rate.

13.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816887

ABSTRACT

Background: The provision of cancer services has been strongly impacted by the outbreak of SARS-CoV-2. Our Cancer Centre in South-East London treats about 8,800 patients annually (incl. 4,500 new diagnoses) and is one of the largest Comprehensive Cancer Centres in the UK. The first COVID-19 positive cancer patient was reported on 29 Feb 2020. Whilst we are dealing with the second wave of COVID-19, it is important to further evaluate safety of cancer treatments whilst balancing risks of COVID-19 infection and complications. Methods: Using descriptive statistics, we report on the patient/tumour characteristics as well as short-term clinical outcomes of those patients undergoing radical treatment (i.e. systemic anticancer treatment (SACT), surgery, or radiotherapy (RT)) for their cancer during the first wave as to help establish the clinical guidelines for the management of cancer patients in a SARS-CoV-2 epidemic. Results: Between March-July 2020, 1,553 patients underwent surgery, 1,125 received SACT, and 814 had RT. Compared to the same period in 2019, there was a decrease of 28% for surgery, 15% for SACT, and 10% for radiotherapy. Whilst surgery was performed on more male patients (58%), more women received SACT (75%) and RT (58%). The age distribution was similar between treatment arms, with the majority of patients aged 50 to 80 years. The most common tumour types were breast (21%), thoracic (20%), and urological (29%) for surgical treatment;breast (49%), gastrointestinal (18%), and gynaecological (10%) for SACT;and breast (40%), urology (25%), and head & neck (11%) for RT. Within SACT, 36% received combination therapy, 35% received systemic chemotherapy, 23% targeted therapy, 5% immunotherapy, and 2% biological therapy. In terms of oncological outcomes, outcomes were similar to pre-COVID-19 times;with 6 deaths at 30 days (<1%) for surgical patients and 36 readmissions (2%), 10 deaths (<1%) for SACT patients, and 52% of RT delivered with radical intent (which was the same in 2019). The COVID-19 infection rates for our patients were very low: 12 patients were positive pre-surgery (1%), 7 post-surgery (<1%), 17 SACT patients (2%) and 3 RT patients (<1%). No COVID-19 related deaths were registered for the surgical, SACT and RT patients. Conclusion: Whilst there was a decline in overall radical treatment, likely due to a delay in cancer diagnoses, those who did undergo their treatment were treated in a safe COVID-19 managed environment. Our findings highlight that cancer patients should have the confidence to attend hospitals and be reassured of the safety measurements taken.

14.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816884

ABSTRACT

The COVID-19 pandemic brought with it TX changes for many patients (pts) with AMEL, as it did for other pts with cancer. The long-term impacts of mandated area lockdowns, social distancing, medical society guidelines, and patient preference will not be fully understood for some time. The first step to learning from the pandemic is to assess how AMEL care was rendered in 2020. We performed a retrospective analysis of systemic TX for AMEL in KPNC, an integrated community healthcare system with approximately 4 million pts and about 150 de novo diagnoses of AMEL annually. We performed a chart review of pts with AMEL who were treated with standard of care systemic therapy, either immune-checkpoint inhibitors (ICI) or BRAF/MEK inhibitors (BRAF/MEKi), from January 1 to March 15, 2020, as a control group, and between March 15 and May 20, during the first wave of the COVID-19 pandemic in California with follow-up through November 4, 2020. Between January 1 and March 15, 26 pts started palliative ICI of whom 11 started combination PD1 (PD1i) and CTLA4 inhibitors. Among 15 pts who started on single-agent PD1i, 14 pts received short-interval TX (SIT), while 1 started long-interval TX (LIT). All 21 pts who started perioperative PD1i pre-pandemic, started on SIT. Between March 15 and May 20, 21 pts started palliative ICI, of whom only 3 started combination TX. Among pts who started palliative single-agent PD1i 40% started on LIT in this initial phase of the pandemic. 27 pts started perioperative ICI during this time. We found 3 started with neoadjuvant therapy and 78% started on LIT. Among 78 pts who were already on palliative single-agent ICI at the start of the COVID-19 pandemic, 15% remained on SIT and 24% changed to LIT. Sixteen pts (21%) also interrupted palliative ICI between March 15 and April 15 after a median time on TX of 45 weeks and for 63% the cited reason for interruption on chart review was the COVID 19 pandemic. Three of these pts who stopped ICI changed to BRAF/MEKi, the remainder continue in active follow-up as of November 2020. Among 72 pts already receiving perioperative ICI in March 2020, 19% remained on SIT, 35% changed to LIT, and 11% were already on LIT. 39% of pts interrupted perioperative ICI after a median time of 20 weeks on TX and 46% of these cited COVID 19 as the reason for interruption. Three pts have since resumed peri-operative TX, but the others remain in active follow-up off therapy. Between 3/15 and 5/30/2020, we noted a 325% increase in pts started on BRAF/MEKi;69% of pts received therapy for palliative intent. The start of the COVID-19 pandemic saw many different changes in AMEL TX in KPNC, with increased use of single-agent ICI, LIT, and oral therapy, in line with public health guidance, oncology societal guidelines and patient preference. It will be important to assess the long-term outcomes relating to these changes, including the impact of early discontinuation of ICI, to help guide future Melanoma care during and after the pandemic.

15.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816879

ABSTRACT

The main causative agent for the global pandemic of COVID-19 is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Developing therapeutic strategies to stop the virus is the hour of need. According to the recent clinical reports, it is seen that an androgen-regulated host cell serine protease TMPRSS2 acts on the spike protein of the SARS-CoV-2 virus which interacts with the host angiotensin-converting enzyme 2 (ACE2) and enters the host cell to cause the infection. Reports also suggest that TMPRSS2 is regulated by androgen present in prostate cells and it is highly expressed in PCa patients. Our lab has recently synthesized a new cisplatin prodrug which is a conjugate of lauric acid and cisplatin that potentially works very effectively in various androgen dependent and independent prostate cancer (PCa) cells. The cisplatin prodrug unlike other conventional platinum drugs is involved in inhibition of one of the major metabolic pathways of the PCa cells. Preliminary results show that, the prodrug in combination with the anti-androgen bicalutamide has an increased inhibition on the expression of TMPRSS2 in androgen dependent PCa and lung carcinoma cells along with down-regulation of some the lipogenic enzymes in-vitro. Here, we propose that the prodrug inhibits one of the mitochondrial metabolic pathways making the PCa cells sensitive towards cisplatin-based chemotherapy along with reducing the expression of TMPRSS2. Once completed, our work will provide an inside story of cisplatin prodrug mediated alteration of lipogenesis of cells in PCa tumor microenvironment resulting in a platform that has the potential to reduce the burden of cancer aggressiveness in both androgen dependent and independent PCa and also can be used as a potent chemotherapeutic agent against COVID-19.

16.
Case Reports in Cardiology ; 2022, 2022.
Article in English | EMBASE | ID: covidwho-1816872

ABSTRACT

Background. Currently, the literature regarding the management of COVID-19 induced cardiomyopathy with reduced ejection fraction is limited. In this case report, we present the first documented case of COVID-19 induced myocardial stunning leading to severely reduced LV systolic function that was reversed by the administration of corticosteroids and tocilizumab. Case Summary. A 39-year-old female with well controlled systemic hypertension, tested positive for SARS-CoV-2 RNA and underwent self-isolation for 14 days. Patient presented to our facility a month later with one-week history of progressively worsening generalized body aches, chills, fever, watery diarrhea, nausea with associated mild dry nonproductive cough, shortness of breath and nonspecific chest pain. Initial labs demonstrated that she was COVID-19 positive, elevated troponin (4.295 ng/ml), and elevated BNP (2,291 pg/ml). Her initial Transthoracic echocardiography demonstrated an Left ventricular ejection fraction (LVEF) of 20-25% with apical akinesis. After administration of tocilizumab and corticosteroids, patient demonstrated interval improvement with LVEF improving to 50-55% within days. Her labs confirmed these findings with improved troponin (0.858 ng/ml) and BNP (209 pg/ml). Discussion. This case demonstrates that it can be safe and efficacious to use tocilizumab and corticosteroids in patients with COVID-19 induced cardiomyopathy. These finding suggest that cytokine storm is the predominant mechanism by which COVID-19 induced cardiomyopathy occurs. Additional studies are required to determine the role of corticosteroids and tocilizumab in management of this condition.

17.
Wound Repair and Regeneration ; 30(2):A56-A57, 2022.
Article in English | EMBASE | ID: covidwho-1816664

ABSTRACT

Background: Antiviral and anti-inflammatory activity of a unique solution of Ag released from Acticoat was tested in standard lab and animal models. Clinical effects of nebulized inhalation of the Ag solution in ventilated patients with MDR bacterial pneumonia, TENS, and COVID-19 were assessed. Methods: Ag release kinetics was determined using integration of absorption spectra at 350-650 nm. Inactivation of hHSV1 and SARSCoV- 2 by the Ag solution, colloidal silver, or stable silver nanoparticles was assessed using the ASTM E1052-20 protocol for antiviral testing of agents in solution. Rat lungs infected for 24 hours with Pseudomonas aeruginosa were treated with lavage of silver solution, tobramycin, or water, and rat survival and lung histology were assessed at 48 hours. Anti-inflammatory activity of the Ag solution was assessed using a pig contact dermatitis model. Eight patients, six with burn wounds who developed MDR pneumonia, one with burns who developed COVID-19, and one with TENS, all of whom were placed on ventilators, were treated with nebulized inhalation of the Ag solution and clinical parameters were measured. Results: Silver species (Ag0, Ag+, Ag3+) were rapidly released from the nanocrystalline silver dressing into distilled water at RT, reaching 50% saturation at 24 hours and 90% saturation at 48 hours with a concentration of γ400 mg/mL. The Ag solution inactivated hHSV1 by 4-logs and 5-logs at 4 and 24 hours, and inactivated 1-log and 6-logs of SARS-CoV-2 after 4 and 24 hours, respectively. Neither a colloidal silver product nor a stable Ag nanoparticle product inactivated hHSV1 or SARS-Cov-2 viruses. Lavage of infected rat lungs with the Ag solution prevented death and preserved normal lung tissue histology. Silver nitrate or tobramycin treatments did not prevent death, and massive inflammation and lung tissue destruction was observed histologically. The Ag solution was highly anti-inflammatory in the pig contact dermatitis model. Nebulized inhalation of the Ag solution via ventilator rapidly reversed clinical parameters in all six patients with MDR pneumonia, in the TENS patient, and the COVID-19-infected burn patient. Chest x-rays showed no evidence of silver deposits in lung tissues of any treated patients. Conclusions: Nebulized inhalation of a unique solution of Ag species released from the nanocrystalline silver wound dressing appears to be a highly effective new treatment for patients with MDR pneumonia, TENS, and COVID-19 due to its unique triple combination of antimicrobial, anti-inflammatory, and anti-viral actions.

18.
Respirology ; 27(SUPPL 1):73, 2022.
Article in English | EMBASE | ID: covidwho-1816629

ABSTRACT

Introduction: The induction of regulatory T cells (Tregs) is indicated as a potential therapeutic strategy in inflammatory lung diseases including, asthma, viral-induced pneumonia, viral-induced acute lung injury (ALI), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and SARSCoV- 2-induced ALI. We previously identified that components of the bacteria Streptococcus pneumoniae (T + P) are able to increase Tregs to suppress experimental allergic airways disease, however, this mechanism of suppression and therapy has not been examined in ALI. Methods: We established a murine model of ALI using aerosolized LPS (100 μg/ml) in BALB/c mice. ALI was measured by the presence of neutrophils in the airways up to 96 hours post-exposure, and Tregs and dendritic cells were assessed by flow cytometry. To assess the therapeutic of T + P in ALI and the mechanisms involved, the combination was administered prior to LPS exposure in the absence or presence of anti-CD25. Results: Treatment with T + P significantly reduced total airway inflammation and suppressed the neutrophil chemokine C-X-C motif chemokine ligand 1 (Cxcl1) compared to Saline+LPS alone in experimental ALI. The numbers of Tregs were reduced in experimental ALI model and were restored by T + P treatment. Depletion of Tregs with anti- CD25 confirmed that the suppressive effects of T + P on ALI was through the induction of Tregs. Conclusion: Treatment with S. pneumoniae components T + P suppresses neutrophilic inflammation in ALI through immunoregulatory mechanisms that involve Tregs and may be a novel treatment for ALI including in COVID-19.

19.
Journal of Aerosol Medicine and Pulmonary Drug Delivery ; 35(2):A7, 2022.
Article in English | EMBASE | ID: covidwho-1815947

ABSTRACT

The work led to the formulation of a powder of calcium phosphate coated liposomes containing cyclosporine A (CsA). The formulation was designed to reduce the dose of CsA to be administered following lung transplantation. Potentially this formulation can be used also to contain the inflammatory process due to SARS-CoV-2. Calcium phosphate (CaP) is a material found in bones and teeth and considered non-toxic and biocompatible and this coating could reduce the recognition by alveolar macrophages and increase the cell uptake. Moreover, CaP is insoluble at physiological pH (7.4), while it solubilizes easily at pH below 5. This could favor drug release in the cell after pinocytosis and in inflamed tissues, while reducing drug release at physiological pH [1]. The liposomes produced were evaluated in terms of size, surface charge and drug loading. The presence of the CaP coating was verified by calcium titration, variation of the zeta potential and by cryogenic transmission electron microscopy (cryo-TEM). The highest loading was obtained in the formulation containing CsA at 7% (w/w). Cholesterol was added to liposomes at two different concentrations in order to improve the stability of the nanostructure and reduce the drug leakage. However, cholesterol did not bring any improvement to the formulation. The inhalation powder produced by spray drying with the best aerosolization performance (fine particle fraction of coated liposomes powder 33.69 - 1.6% and 50.50- 0.6% for the uncoated liposomes powder) was obtained using a 1:3 weight ratio between liposomes and excipients using mannitol as bulking agent and 15% L-leucine. Key Message: This work aimed to develop a respirable dry powder for inhalation containing CsA for the local treatment of lung immune diseases. CsA was efficiently loaded into CaP-coated liposomes and transformed into a respirable powder by spray-drying. The inhaled immunosuppressive product would offer multiple advantages related to drug deposition at the target site. Furthermore, the coating of the liposomes governs the release of the drug which will occur only at only at biological acidic conditions.

20.
Journal of Aerosol Medicine and Pulmonary Drug Delivery ; 35(2), 2022.
Article in English | EMBASE | ID: covidwho-1812570

ABSTRACT

The proceedings contain 58 papers. The topics discussed include: assessment of aerosol drug delivery during the escalation of treatment for a simulated COVID-19 adult patient;development of a prototype of an aerosolization device for dry powders to improve in vitro cell-based assays in the context of lung delivery;surface acoustic wave nebulization for targeted inhalation drug delivery to central and peripheral airways;nasal-pampa: a novel in vitro tool for prediction of intranasal drug permeability;in vitro and in vivo evaluations of the tolerance of a new and innovative anti-tuberculosis drug combination by inhalation;transport of local anesthetic lidocaine across a pharyngeal air-liquid interface cell model;and the quantitative assessment of vape devices as novel pulmonary drug delivery systems using fluorine-18 radiolabeled drug molecules.

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