The Collateral Impact of the COVID-19 Pandemic on HPV-positive Oropharyngeal Cancer Diagnosis

Purpose We aim to assess the potential impact of the COVID-19 pandemic on diagnostic delays in HPV-positive oropharyngeal cancer (OPC), and to describe their underlying reasons. Methods All HPV+ OPC referred to a tertiary cancer centre and diagnosed between June-December 2019 (Pre-Pandemic cohort) vs June-December 2020 (Pandemic cohort) were reviewed. TNM classification, gross-tumor-volumes (GTV) and intervals between sign/symptom onset and treatment initiation were compared between the cohorts. Reasons for delay (>6 months from onset of signs/symptoms to a positive biopsy of the primary tumor, or a delay specifically mentioned in the patient chart) in establishing the diagnosis were recorded per clinician's documentation, and categorized as COVID-related or non-COVID-related. Results A total of 157 consecutive HPV+ OPC patients were identified (Pre-Pandemic: 92;Pandemic: 65). Compared to the Pre-Pandemic cohort, Pandemic cohort patients had a higher proportion of N2-N3 (32% vs 15%, p=0.019) and stage III (38% vs 23%, p=0.034) disease at presentation. The differences in proportions with >6 months delay from symptom onset to establishing the diagnosis (29% vs 20%, p=0.16) or to first treatment (49% vs 38%, p=0.22) were not statistically different. 47% of diagnostic delays in the Pandemic cohort were potentially attributable to COVID-19. Conclusion We observed a collateral impact of the COVID-19 pandemic on HPV+ OPC care through more advanced stage at presentation and a non-significant but numerically longer interval to diagnosis. This could adversely impact patient outcomes and future resource allocation. Both COVID-19-related or unrelated factors contribute to diagnostic delay. Tailored interventions to reduce delays are warranted.

The collateral impact of the COVID-19 pandemic on HPV-positive oropharyngeal cancer diagnosis.

PURPOSE: We aim to assess the potential impact of the COVID-19 pandemic on diagnostic delays in HPV-positive oropharyngeal cancer (OPC), and to describe their underlying reasons. METHODS: All HPV + OPC referred to a tertiary cancer centre and diagnosed between June-December 2019 (Pre-Pandemic cohort) vs June-December 2020 (Pandemic cohort) were reviewed. TNM classification, gross-tumor-volumes (GTV) and intervals between sign/symptom onset and treatment initiation were compared between the cohorts. Reasons for delay (>6 months from onset of signs/symptoms to a positive biopsy of the primary tumor, or a delay specifically mentioned in the patient chart) in establishing the diagnosis were recorded per clinician's documentation, and categorized as COVID-related or non-COVID-related. RESULTS: A total of 157 consecutive HPV + OPC patients were identified (Pre-Pandemic: 92; Pandemic: 65). Compared to the Pre-Pandemic cohort, Pandemic cohort patients had a higher proportion of N2-N3 (32 % vs 15 %, p = 0.019) and stage III (38 % vs 23 %, p = 0.034) disease at presentation. The differences in proportions with > 6 months delay from symptom onset to establishing the diagnosis (29 % vs 20 %, p = 0.16) or to first treatment (49 % vs 38 %, p = 0.22) were not statistically different. 47 % of diagnostic delays in the Pandemic cohort were potentially attributable to COVID-19. CONCLUSION: We observed a collateral impact of the COVID-19 pandemic on HPV + OPC care through more advanced stage at presentation and a non-significant but numerically longer interval to diagnosis. This could adversely impact patient outcomes and future resource allocation. Both COVID-19-related and unrelated factors contribute to diagnostic delays. Tailored interventions to reduce delays are warranted.

Antigenic mapping reveals sites of vulnerability on α-HCoV spike protein.

Understanding the antigenic signatures of all human coronaviruses (HCoVs) Spike (S) proteins is imperative for pan-HCoV epitopes identification and broadly effective vaccine development. To depict the currently elusive antigenic signatures of α-HCoVs S proteins, we isolated a panel of antibodies against the HCoV-229E S protein and characterized their epitopes and neutralizing potential. We found that the N-terminal domain of HCoV-229E S protein is antigenically dominant wherein an antigenic supersite is present and appears conserved in HCoV-NL63, which holds potential to serve as a pan-α-HCoVs epitope. In the receptor binding domain, a neutralizing epitope is captured in the end distal to the receptor binding site, reminiscent of the locations of the SARS-CoV-2 RBD cryptic epitopes. We also identified a neutralizing antibody that recognizes the connector domain, thus representing the first S2-directed neutralizing antibody against α-HCoVs. The unraveled HCoVs S proteins antigenic similarities and variances among genera highlight the challenges faced by pan-HCoV vaccine design while supporting the feasibility of broadly effective vaccine development against a subset of HCoVs.

Multiple Death Pathways of Neutrophils Regulate Alveolar Macrophage Proliferation.

Alveolar macrophage (AM) proliferation and self-renewal play an important role in the lung tissue microenvironment. However, the impact of immune cells, especially the neutrophils, on AM homeostasis or function is not well characterized. In this study, we induced in vivo migration of neutrophils into bronchoalveolar lavage (BAL) fluid and lung using CXCL1, and then co-cultured these with AMs in vitro. Neutrophils in the BAL (BAL-neutrophils), rather than neutrophils of bone marrow (BM-neutrophils), were found to inhibit AM proliferation. Analysis of publicly available data showed high heterogeneity of lung neutrophils with distinct molecular signatures of BM- and blood-neutrophils. Unexpectedly, BAL-neutrophils from influenza virus PR8-infected mice (PR8-neutrophils) did not inhibit the proliferation of AMs. Bulk RNA sequencing further revealed that co-culture of AMs with PR8-neutrophils induced IFN-α and -γ responses and inflammatory response, and AMs co-cultured with BAL-neutrophils showed higher expression of metabolism- and ROS-associated genes; in addition, BAL-neutrophils from PR8-infected mice modulated AM polarization and phagocytosis. BAL-neutrophil-mediated suppression of AM proliferation was abrogated by a combination of inhibitors of different neutrophil death pathways. Collectively, our findings suggest that multiple cell death pathways of neutrophils regulate the proliferation of AMs. Targeting neutrophil death may represent a potential therapeutic strategy for improving AM homeostasis during respiratory diseases.

Opportunities and challenges to the use of neutralizing monoclonal antibody therapies for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in a substantial global public healthcare crisis, leading to the urgent need for effective therapeutic strategies. Neutralizing antibodies (nAbs) are a potential treatment for COVID-19. This article provides a brief overview of the targets and development of nAbs against COVID-19, and it examines the efficacy of nAbs as part of both outpatient and inpatient treatments based on emerging clinical trial data. Assessment of several promising candidates in clinical trials highlights the potential of nAbs to be an effective therapeutic to treat COVID-19 in outpatient settings. Nevertheless, the efficacy of nAbs treatment for hospitalized patients varies. In addition, this review identifies challenges to ending the COVID-19 pandemic, including concerns over nAbs development and clinical use. Resistant variants significantly threaten the availability of nAb-based therapeutics. This review also discusses other approaches that may improve the clinical benefit of neutralizing mAbs.

A novel social distancing analysis in urban public space: A new online spatio-temporal trajectory approach.

Social distancing in public spaces plays a crucial role in controlling or slowing down the spread of coronavirus during the COVID-19 pandemic. Visual Social Distancing (VSD) offers an opportunity for real-time measuring and analysing the physical distance between pedestrians using surveillance videos in public spaces. It potentially provides new evidence for implementing effective prevention measures of the pandemic. The existing VSD methods developed in the literature are primarily based on frame-by-frame pedestrian detection, addressing the VSD problem from a static and local perspective. In this paper, we propose a new online multi-pedestrian tracking approach for spatio-temporal trajectory and its application to multi-scale social distancing measuring and analysis. Firstly, an online multi-pedestrian tracking method is proposed to obtain the trajectories of pedestrians in public spaces, based on hierarchical data association. Then, a new VSD method based on spatio-temporal trajectories is proposed. The proposed method not only considers the Euclidean distance between tracking objects frame-by-frame but also takes into account the discrete Fréchet distance between trajectories, hence forms a comprehensive solution from both static and dynamic, local and holistic perspectives. We evaluated the performance of the proposed tracking method using the public dataset MOT16 benchmark. We also collected our own pedestrian dataset "SCU-VSD" and designed a multi-scale VSD analysis scheme for benchmarking the performance of the social distancing monitoring in the crowd. Experiments have demonstrated that the proposed method achieved outstanding performance on the analysis of social distancing.

Shufeng Jiedu, a promising herbal therapy for moderate COVID-19:Antiviral and anti-inflammatory properties, pathways of bioactive compounds, and a clinical real-world pragmatic study.

BACKGROUND: Shufeng Jiedu capsules (SFJDC), a patented herbal drug composed of eight medicinal plants, is used for the treatment of different viral respiratory tract infectious diseases. Based on its antiviral, anti-inflammatory and immunoregulatory activity in acute lung injury, SFJDC might be a promising candidate for the treatment of COVID-19. PURPOSE: To evaluate the antiviral and anti-inflammatory properties and to discover the mechanism of action of SFJDC as a potential drug for the treatment of COVID-19. Furthermore, the study should determine the clinical effectiveness of SFJDC for the treatment of COVID-19. DESIGN: We analyzed the antiviral and anti-inflammatory effects of SFJDC in a HCoV-229E mouse model on lung index, virus load in the lung, the release of cytokines, and on T- and B-lymphocytes. The mechanism of action was further investigated by network analysis. Additionally, we investigated data from a clinical pragmatic real-world study for patients with confirmed COVID-19, to evaluate the clinical effect of SFJDC and to determine the best time to start the treatment. RESULTS: SFJDC significantly reduced the virus load in the lung of HCoV-229E mice (from 1109.29 ± 696.75 to 0 ± 0 copies/ml), decreased inflammatory factors IL-6, IL-10, TNF-α, and IFN-γ in the lung, and increased the amount of CD4+ and CD8+ cells in the blood compared to the model group. Network analysis revealed that SFJDC reduces the activity of NFκB via several signaling pathways. Quercetin, wogonin, and polydatin bind directly to the main protease (Mpro) of SARS-CoV-2. Clinical data showed that SFJDC, added to standard antiviral therapy (AVD), significantly reduced the clinical recovery time of COVID-19 and fatigue (from 3.55 ± 4.09 to 1.19 ± 2.28 days) as well as cough (from 5.67 ± 5.64 to 3.47 ± 3.75) days compared to AVD alone. SFJDC therapy was significantly more effective when used within the first 8 days after the onset of symptoms. CONCLUSION: SFJDC might be a promising drug for the treatment of COVID-19, but large-scale randomized, double-blinded, placebo-controlled clinical trials are needed to complement the real-world evidence. It might be beneficial to start SFJDC treatment as early as possible in suspected cases of COVID-19.

Hypofractionated radiotherapy alone with 2.4 Gy per fraction for head and neck cancer during the COVID-19 pandemic: The Princess Margaret experience and proposal.

BACKGROUND: The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT-hypo) during the COVID-19 pandemic. METHODS: HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT-hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT-acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005-2017 were included. Locoregional control (LRC) and distant control (DC) after RT-hypo, RT-acc, and CCRT were compared for various subgroups. RESULTS: The study identified 994 human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT-hypo, RT-acc, and CCRT, respectively) and 1045 HPV- HNSCC cases (with 263, 451, and 331 receiving RT-hypo, RT-acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy-alone patients were older. The median follow-up was 4.6 years. RT-hypo, RT-acc, and CCRT produced comparable 3-year LRC and DC for HPV+ T1-2N0-N2a disease (seventh edition of the TNM system [TNM-7]; LRC, 94%, 100%, and 94%; P = .769; DC, 94%, 100%, and 94%; P = .272), T1-T2N2b disease (LRC, 90%, 94%, and 97%; P = .445; DC, 100%, 96%, and 95%; P = .697), and T1-2N2c/T3N0-N2c disease (LRC, 89%, 93%, and 95%; P = .494; DC, 89%, 90%, and 87%; P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88%; P = .677), DC was significantly lower with RT-hypo or RT-acc versus CCRT (67%, 65%, and 87%; P = .005). For HPV- HNSCC, 3-year LRC and DC were similar with RT-hypo, RT-acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100%; P = .320; DC, 99%, 98%, and 100%; P = .446); however, RT-hypo and RT-acc had significantly lower LRC in stage III (76%, 69%, and 91%; P = .006), whereas DC rates were similar (92%, 85%, and 90%; P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT-acc (62%) but not RT-hypo (80%) or CCRT (92%; RT-hypo vs CCRT: P = .270; RT-acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT-hypo or RT-acc in stage IV (73%, 65%, and 66%; P = .336). CONCLUSIONS: It is proposed that RT-hypo be considered in place of CCRT for HPV+ T1-T3N0-N2c (TNM-7) HNSCCs, HPV- T1-T2N0 HNSCCs, and select stage III HNSCCs during the COVID-19 outbreak.