tinyIFD: A High-Throughput Binding Pose Refinement Workflow Through Induced-Fit Ligand Docking.

A critical step in structure-based drug discovery is predicting whether and how a candidate molecule binds to a model of a therapeutic target. However, substantial protein side chain movements prevent current screening methods, such as docking, from accurately predicting the ligand conformations and require expensive refinements to produce viable candidates. We present the development of a high-throughput and flexible ligand pose refinement workflow, called "tinyIFD". The main features of the workflow include the use of specialized high-throughput, small-system MD simulation code mdgx.cuda and an actively learning model zoo approach. We show the application of this workflow on a large test set of diverse protein targets, achieving 66% and 76% success rates for finding a crystal-like pose within the top-2 and top-5 poses, respectively. We also applied this workflow to the SARS-CoV-2 main protease (Mpro) inhibitors, where we demonstrate the benefit of the active learning aspect in this workflow.

Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2.

Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we design a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibits PLpro with kinact/KI = 9,600 M-1 s-1, achieves sub-µM EC50 values against three SARS-CoV-2 variants in mammalian cell lines, and does not inhibit a panel of human deubiquitinases (DUBs) at >30 µM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validates our design strategy and establishes the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.

COVID-19 and indications for delivery: a prospective cohort study

Objective: Studies have shown that COVID-19 affects intrapartum management, resulting in higher rates of cesarean delivery. However, it is unknown if COVID-19 infection increases rates of medically indicated deliveries. The primary objective was to determine if there are differences in medical indications for delivery in COVID-19 positive patients. Study design: This is a prospective cohort study of patients admitted for delivery at an urban obstetrical unit from April-November 2020 where patients were tested for COVID-19 following admission. Baseline demographics, labor and delivery information, and outcomes were recorded, and composite maternal and neonatal outcomes were compared between COVID-19 positive and negative patients using Fisher's exact tests and a Poisson regression analysis to adjust for confounders. Result(s): 545 deliveries were included, with 56 (10.33%) COVID-19 positive and 486 (89.67%) negative patients. There were no differences in rate of medical indications for delivery. There was a higher rate of cesarean delivery in the COVID-19 positive group (46.43% versus 31.28%, p=.034), although there was no difference in indications for cesarean delivery. Additionally, for COVID-19 positive patients, there were higher rates of preterm births (p=.014) but no increase in preterm labor. There was an increase in composite adverse neonatal outcomes (p= <0.05), but not composite adverse maternal outcomes. Conclusion(s): Despite an increase in cesarean delivery, there was no difference in medical indications for delivery in COVID-19 patients. Although there was an increase in composite adverse neonatal outcomes, this may be attributed to an increase in admission of exposed newborns to the neonatal intensive care unit. Disclosure: No [Formula presented] Copyright © 2022

Evaluation of the impact of an oncology urgent care clinic on preventable emergency department visits

Background: OP-35 is a publicly reported quality metric aimed at reducing preventable emergency department (ED) visits and hospitalizations in patients with cancer on chemotherapy. During the COVID- 19 surge, one academic medical center opened the Respiratory Emergent Evaluation Service (REES) Unit, an urgent care clinic for patients with cancer and symptoms of COVID-19. In addition to preventing potential COVID-19 exposures in the clinic, this oncology-staffed urgent care evaluated patients who may have otherwise presented to the ED. We investigated the association between the REES urgent care clinic and patient ED evaluations for OP-35 diagnoses. Method(s): This single center retrospective analysis included patients with cancer receiving infusion and oral chemotherapy who presented to the ED within 30 days of treatment. ED visits occurred between 1/2019-12/2021, including when the REES unit was open (3/2020-6/2021). Preventable ED visits were defined as having one of ten primary diagnoses, which have been identified by OP-35. Of these, COVID-related diagnoses included fever, pneumonia, sepsis, neutropenia and diarrhea. Interrupted time series analyses were utilized to investigate the association between the REES unit opening and preventable ED visits. Result(s): 3,107 patients on chemotherapy were assessed in the ED from 1/2019-12/2021. Per week, there were 19.9 ED visits, 39.7% of which were for OP-35 diagnoses. When the REES unit opened, there was a 30% (95% CI -53% to -7%) reduction in preventable ED visits, corresponding to 2.62 (95% CI -4.61 to -0.63) fewer preventable ED evaluations per week. The primary driver of this reduction were presentations for COVID- related diagnoses, as there were 38% (95% CI -76% to -0.3%) fewer preventable ED visits weekly. During this period, there were approximately 6.9 patient visits per week to the REES unit. Conclusion(s): The introduction of an oncology urgent care clinic focusing on patients with symptoms of COVID-19 was associated with a reduction in potentially preventable ED visits. This analysis demonstrates the potential value of oncology urgent care clinics in reducing ED overcrowding and decreasing OP-35 related evaluations, which has patient experience, infection exposure and financial implications.

Impact of the COVID-19 Pandemic in Treating Breast Cancer (BC) Patients Receiving Systemic Anti-cancer Treatment (SACT): The Guy's Cancer Centre Experience

Purpose: The COVID-19 pandemic transformed cancer care, with oncologists trying to balance the benefits of SACT against the risk of COVID-19 infection and mortality. Our study compares the demographic and treatment characteristics of BC patients treated at Guy’s Cancer Centre during the first wave of the pandemic with the same period in 2019. Methods: We conducted a retrospective analysis of all BC patients who received SACT from 1 March 2020 until 31 May 2020 and compared the demographic (age, ethnicity, socioeconomic and performance status), cancer (stage) and SACT characteristics (type, intent and line of treatment) with those from the same period in 2019. Results: In 2020, 571 BC patients received SACT during the study period, compared with 595 in 2019. Demographic characteristics were equally balanced between both years. The cancer stage, type of treatment and treatment paradigm were also similar (stage I–III: 49.8% versus 50.9%;chemotherapy: 29.8% versus 30.8%;palliative treatment: 49.9% versus 46.6%, in 2020 and 2019, respectively). However, a larger proportion of patients received first-line palliative treatment in 2020 compared with 2019 (38.6% versus 14.8%). The overall mortality rate was 3.15% in 2020 versus 4.36% in 2019. 11 BC patients were diagnosed with COVID-19 in 2020. From these patients, 10 were receiving chemotherapy and 7 were treated with palliative intent. 9 patients developed severe pneumonia and there was 1 COVID-19-related death. Conclusion: Our study shows that there were no significant differences in patient characteristics during the first wave of the pandemic, compared with a similar period in 2019, although numerically fewer patients were treated in 2020 and there was a focus on first-line palliative treatment, rather than subsequent lines. Moreover, it demonstrated that SACT during the pandemic was relatively safe. However, this study might not reflect the decrease in the number of new referrals owing to the pandemic.

Clinical and demographic characteristics associated with shorter time to COVID-19 death

Introduction: Cancer patients have been considered a high-risk population in the COVID-19 pandemic. We previously investigated risk of COVID-19 death in COVID-19 positive cancer patients during a median follow-up of 134 days, and identified the following risk factors: male sex, age >60 years, Asian ethnicity, hematological cancer type, cancer diagnosis for >2.5 years, patients presenting with fever or dyspnea, and high levels of ferritin and C-reactive protein (CRP). Here, we further investigate which factors are associated with a COVID-19 related death within 7 days of diagnosis. Methods: Using data from Guy's Cancer Centre and one of its partner trusts (King's College Hospital), we included 306 cancer patients with a confirmed COVID-19 diagnosis (February 29th-July 31st 2020). 72 patients had a COVID-19 related death (24%) of whom 35 died within 7 days (50%). Cox proportional hazards regression was used to identify which factors were associated with a COVID-19 related death <7 days of diagnosis. Results: Of the 72 cancer patients who had a COVID-19 related death, the mean age was 72 years (Standard Deviation (SD) 14). A total of 53 (74%) patients were men. 37 (52%) had a hematological cancer type, 47 (65%) had stage IV cancer, and 42 (58%) had been diagnosed with cancer more than 24 months before COVID-19 related death. In the group of patients who died within 7 days of diagnosis (n= 35), mean age was 73 years (SD 13.96), 24 (68%) were men, 20 (57%) had a hematological cancer type, 26 (74%) had stage IV cancer, and 24 (68%) had been diagnosed with cancer >24 months before COVID-19 diagnosis. Factors associated with COVID-19 related death <7 days of diagnosis were: hematological cancer (Hazard Ratio (HR): 2.74 (95% Confidence Interval (CI): 1.21-6.22)), 2-5 yrs since cancer diagnosis (HR: 4.81 (95%CI: 1.47-15.69)), and >5 yrs since cancer diagnosis (HR: 4.41 (95%CI: 1.38-14.06)). Additionally, patients who presented with dyspnea had increased risk of COVID-19 related death <7 days compared to asymptomatic patients (HR: 5.25 (95%CI 2.14-12.89)). CRP levels in the third tercile (146-528 mg/L) as compared to the first were also associated with increased risk of an early death due to COVID-19. Conclusion: From all the factors identified in our previous COVID-19 related death analysis, only hematological cancer type, a longer-established cancer diagnosis (2-5 years and more than 5 years), dyspnea at time of diagnosis and high levels of CRP were indicative of an early COVID-19 related death (within 7 days of diagnosis) in cancer patients.

The impact of COVID-19 in the cancer population stratified by age: A real-world data study from Guy's Cancer Center

Background It is widely accepted that advancing age is associated with worse COVID-19 outcomes. However, there is insufficient data analyzing the impact of COVID-19 in the older cancer population. The aim of the study is to establish if age has an influence on severity and mortality of COVID-19 in cancer patients. Methods We reviewed 306 oncology patients with PCR-confirmed COVID-19 from Guy's Cancer Centre and its partner Trust King's College Hospital, between 29 February - 31 July 2020. Demographic and tumor characteristics in relation to COVID-19 severity and death were assessed with logistic and Cox proportional hazards regression models, stratified by age (≤65 and >65 years). Severity of COVID-19 was classified by World Health Organization (WHO) grading. Results A total of 135 patients were aged ≤65 years (44%) and 171 aged >65 (56%). Severe COVID-19 presentation was seen in 27% of those aged ≤65 and 30% of those aged >65. The COVID-19 mortality rate was 19% in those aged ≤65 and 27% in those aged >65. In the older cohort, there was an increased incidence of severe disease in Caucasian ethnicity compared to the younger cohort (55% vs 43%) and compared to severe disease in Black and Asian ethnicities. There were increased co-morbidities in the older cohort including hypertension (54% vs 32%), diabetes (30% vs 12%) with increased rate of poly-pharmacy (62% vs 40%) compared to the younger cohort. In terms of cancer characteristics in the older cohort, there was a higher rate of patients with cancer for more than 2 years (53% vs 32%) and performance status of 3 (22% vs 6%). In terms of severity, Asian ethnicity [OR: 3.1 (95% CI: 0.88-10.96) p=0.64] had greater association with increasing COVID-19 severity in those aged >65. Interestingly, there were no positive associations between number of co-morbidities, treatment paradigm or performance status with severity of disease in the older group. The risk of mortality was greater in the elderly cohort with hematological cancer types [HR: 2.69 (1.31-5.53) p=0.85] and having cancer for more than 2 years [2.20 (1.09-4.42) p=0.28] compared to the younger cohort. Conclusions In our study we demonstrate that severity and mortality of COVID-19 did not significantly differ between the two age cohorts except in regards to Asian ethnicity, hematological malignancies and having cancer for more than 2 years. As expected, the older population had more co-morbidities and polypharmacy. Despite this, the incidence of severe COVID-19 was similar regardless of age. Further analyses for other geriatric presentations are ongoing to understand their interaction with COVID-19 in the cancer population.

Real world data analysis of patients with genitourinary cancers receiving systemic anticancer treatment during the COVID-19 pandemic at Guy's Cancer Centre: A single centre retrospective study in the UK

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.

The acute phase response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection as quantified by the OnCovid Inflammatory Score

We sought to determine parameters of the acute phase response, a feature of innate immunity activated by infectious noxae and cancer, deranged by Covid-19 and establish oncological indices' prognostic potential for patients with concomitant cancer and Covid-19. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive referrals of patients with cancer and Covid-19 aged 18 from the U.K., Spain, Italy, Belgium, and Germany. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values and the pre-established risk categorizations from literature utilized for the mGPS and PI. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of 1 comorbidity (52.1% TS, 49.8% VS), development of 1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P<0.0001) with a return to pre-Covid-19 diagnosis NLR, PNI, and mGPS categorizations following recovery (P<0.01). In the TS, higher mortality rates were associated with NLR>6 (44.6% vs 28%, P<0.0001), PNI<40 (46.6% vs 20.9%, P<0.0001), mGPS (50.6% for mGPS2 vs 30.4% and 11.4% for mGPS1 and 0, P<0.0001), and PI (50% for PI2 vs 40% for PI1 and 9.1% for PI0, P<0.0001). Findings were confirmed in the VS (P<0.001 for all comparisons). Patients in poor risk categories had shorter median overall survival [OS], (NLR>6 30 days 95%CI 1-63, PNI<40 23 days 95%CI 10-35, mGPS2 20 days 95%CI 8-32, PI2 23 days 95%CI 1-56) compared to patients in good risk categories, for whom median OS was not reached (P<0.001 for all comparisons). The PLR was not associated with survival. Analyses of survival in the VS confirmed the NLR (P<0.0001), PNI (P<0.0001), PI (P<0.01), and mGPS (P<0.001) as predictors of survival. In a multivariable Cox regression model including all inflammatory indices and pre-established prognostic factors for severe Covid-19 including sex, age, comorbid burden, malignancy status, and receipt of anti-cancer therapy at Covid-19 diagnosis, the PNI was the only factor to emerge with a significant hazard ratio [HR] in both TS and VS analysis (TS HR 1.97, 95%CI 1.19-3.26, P=0.008;VS HR 2.48, 95%CI 1.47- 4.20, P=0.001). We conclude that systemic inflammation drives mortality from Covid-19 through hypoalbuminemia and lymphocytopenia as measured by the PNI and propose the PNI as the OnCovid Inflammatory Score (OIS) in this context.

Factors affecting COVID-19 outcomes in cancer patients from Guy's Cancer Center and King's College Hospital

Background: The Coronavirus disease 2019 (COVID-19) pandemic continues to have a significant impact on the treatment of cancer patients. Understanding the clinical course, potential risk factors for severe infection and excess mortality, is essential to improve patient outcomes. We previously presented preliminary results from 156 SARS-CoV-2 positive cancer patients from Guy's Cancer Center, which suggested that increased COVID-19 mortality was associated with a diagnosis of cancer for over 2 years, Asian ethnicity and being on palliative treatment. Herein, we present an updated analysis using data from Guy's Cancer Centre and a partner Hospital Trust (King's College Hospital), with an increased number of patients and an extended follow up. Methods: We performed an analysis of all cancer patients who had a positive RT-PCR nasal/throat swab for SARS-CoV-2 infection at our Centers between 29th February and 31st July 2020. Associations between patients' demographics, clinical characteristics, and laboratory investigations with COVID-19 severity and mortality, were assessed using Logistic regression and Cox proportional hazards models. Results: 306 SARS-CoV-2 positive cancer patients were included in the analysis with a median follow up of 134 days (IQR 32-156). 184 (60%) were male and 217 (71%) were aged over 60 (mean age: 66). The most common malignancies were haematological (38%) and urological-gynaecological (20%). 218 (71%) had mild/moderate COVID-19 and 88 (29%) had severe disease. The overall COVID-related mortality rate was 24%;19% in solid and 32% in haematological cancers. Male sex [OR: 1.84 (95%CI:1.08-3.13)], Asian ethnicity [3.86 (1.20-12.36)], haematological cancer type [2.16 (1.18-3.95)], being diagnosed with cancer for 2-5 years [3.74 (1.80-7.78)] or ≥5 years [3.06 (1.50-6.26)] and a ferritin > 1964 mcg/l [54.92 (5.90-511.33)] were all associated with a risk of developing severe COVID-19 disease. Similarly, male sex [HR:1.97 (95%CI:1.15-3.38)], Asian ethnicity [3.42 (1. 59-7.35)], haematological cancer type [2.03 (1.16-3.56)] as well as a cancer diagnosis for >2-5 years [2.81 (1.41-5.59)] or ≥5 years [2.13 (1.06-4.27)] and a ferritin > 1964 mcg/l [16.11 (3.81-68.17)] were associated with an increased risk of death from COVID-19. Age >60 [2.14 (1.15-3.98)] and a raised CRP [4.10 (1.66-10.10)] were also associated with COVID-19 death. An inverse relationship was observed between a raised albumin and COVID-19 related death [0.12 (0.03- 0.51)]. Performance status and treatment paradigm were not associated with COVID-19 severity or mortality. Conclusions: This study further substantiates the evidence for an increased risk of severe COVID-19 infection and mortality for male and Asian patients with cancer, and those with haematological malignancies or with a diagnosis of cancer for over 2 years. These risk factors should be taken into account when making clinical decisions for cancer patients during the pandemic.

COVID-19 infection and mortality in patients with skin malignancies receiving systemic anti-cancer therapy (SACT): The Guy's Cancer Centre experience

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.

Radical cancer treatment is safe during COVID-19: The experience of a large London-based Comprehensive Cancer Centre

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.

Continuity of cancer care: The surgical experience of two large Cancer Hubs in London and Milan

Introduction: A better understanding of the reality for cancer patients during COVID-19 will help us readapt current predication models. To further inform future clinical guidelines, we need a deep dive into rich data sources from apex Cancer Centres. We report on the outcomes of cancer patients receiving radical surgery between March-September 2020 (as well as 2019) in the European Institute of Oncology (EIO) in Milan and the South East London Cancer Alliance (SELCA). Methods: IEO is one of the largest cancer hospitals in Italy. SELCA includes 3 major hospital trust, treating about 8,000 new cancer patients per annum. Both institutions implemented a COVID-19 minimal pathway, whereby patients were required to shield for 14 days prior to admission and were swabbed for COVID-19 within 3 days of surgery. Positive patients had surgery deferred until a negative swab. Surgical outcomes assessed were: ASA grade, surgery time, theatre time, ICU stay>24h, pneumonia, length of stay (LOS), and admissions. For COVID-19, we focused on infection rate and mortality. Results: At IEO the number of radical surgeries (270 for gynaecological, 339 for head and neck, 377 for thoracic, and 491 for urological cancers) declined by 6% as compared to the same period in 2019 (n=1477 vs 1560). The main decline was observed for thoracic surgery (377 vs 460, i.e. -18%). Age, sex, SES, ethnicity, comorbidities, and performance status were all comparable between both periods (e.g. 58% male, 38% aged 70+, 48% high SES, 15% with existing cardiovascular diseases). Readmissions were required for 39%, and <1% (n=9) developed COVID-19, of which only 1 had severe disease and died. 11 died of other causes during follow-up (1%). At SELCA, the number of radical surgeries (321 for breast, 129 for colorectal, 114 for gynaecological, 152 for head and neck, 92 for liver, 56 for plastics/skin, 305 for thoracic, 72 for upper gastrointestinal, and 312 for urology) declined by 29% (n=1553 vs 2182). Even though a different geographical setting, characteristics were fairly comparable with the IEO: 58% males, 30% aged 70+, 34% high SES, 16% with existing cardiovascular diseases. Readmissions were required for 22%, <1% (n=7) developed COVID-19, and none died from it. 19 died of other causes within 30 days (1%). Conclusion: Milan and London were both at the epicentre of the first COVID-19 wave. Whilst a decline in number of surgeries was observed, the implemented COVID-19 minimal pathways have shown to be safe for cancer patients requiring radical treatment, with limited complications and almost no COVID-19 infections.

Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor.

Inhibition of the SARS-CoV-2 main protease (Mpro) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of Mpro. Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 µM. Among these, four compounds with IC50 values around 1 µM were found. Interestingly, despite the large search space, the isoquinolone motif was conserved in each of these four strongest binders. Room-temperature X-ray structures of co-crystallized protein-inhibitor complexes were determined up to 1.9 Å resolution for two of these compounds as well as one of the stronger inhibitors in the original isoquinoline series, revealing essential interactions with the binding site and water molecules. Molecular dynamics simulations and quantum chemical calculations further elucidate the binding interactions as well as electrostatic effects on ligand binding. The results help explain the strength of this new non-covalent scaffold for Mpro inhibition and inform lead optimization efforts for this series, while demonstrating the effectiveness of a high-throughput computational approach to expanding a pharmacophore library.

COVID-19 Acute Care at Home: A Substitution for Hospitalization in Patients with Mild Symptoms

Background. Constraints on resources require healthcare systems to implement alternative and innovative means for delivering care. The COVID-19 pandemic amplified this issue throughout the world, leading to shortages of ventilators, hospital beds, and healthcare personnel. We report the results of an Acute Care at Home Program (ACHP) response to COVID-19, providing in-home hospital-level care to patients with mild symptoms, preserving in-hospital beds for more serious illness. Methods. Patients with COVID-19 were selected for ACHP after undergoing risk stratification for severe disease, including oxygen evaluation, time course of illness, and evaluation of comorbidities. Patients admitted to ACH met inpatient criteria, required oxygen supplementation of ≤4 liters, and received insurance approval. Services were provided consistent with best practice of inpatient care, including 24/7 provider availability via TeleMedicine, bedside care provided by paramedics and nurses, respiratory therapy, radiology and laboratory services, pulse oximetry monitoring, and administration of medications. Protocols existed for patient transfer to hospital in the event of clinical deterioration. Results. Our initial cohort included 62 patients enrolled October 1, 2020 - May 31, 2021. Of these, 57 patients were discharged successfully from ACHP. Patients presented with initial oxygen requirements of 0-4 liters. Average length-of-stay in ACHP was 5.4 days. Five patients required hospitalization after enrollment in ACHP;one subsequently expired, two were discharged home, one returned to ACHP after inpatient hospitalization, and one remains hospitalized. One additional patient that was successfully discharged home from ACHP was later readmitted and expired in a subsequent hospitalization. The patients that expired had significant immunocompromising conditions that may have contributed to their outcomes. Conclusion. ACHP can provide care equivalent to hospitalization for select COVID-19 patients. Immunocompromised hosts with COVID-19 may represent a subset of patients in which in-house hospitalization must be carefully considered, even with mild oxygen requirements. Health systems should consider ACHP as a substitution for hospitalization for COVID-19 patients with mild symptoms.

Creating Surveillance Data Infrastructure Using Laboratory Analytics: Leveraging Visiun and Epic Systems to Support COVID-19 Pandemic Response.

BACKGROUND: Pandemics are unpredictable and can rapidly spread. Proper planning and preparation for managing the impact of outbreaks is only achievable through continuous and systematic collection and analysis of health-related data. We describe our experience on how to comply with required reporting and develop a robust platform for surveillance data during an outbreak. MATERIALS AND METHODS: At Mount Sinai Health System, New York City, we applied Visiun, a laboratory analytics dashboard, to support main response activities. Epic System Inc.'s SlicerDicer application was used to develop clinical and research reports. We followed World Health Organization (WHO); federal and state guidelines; departmental policies; and expert consultation to create the framework. RESULTS: The developed dashboard integrated data from scattered sources are used to seamlessly distribute reports to key stakeholders. The main report categories included federal, state, laboratory, clinical, and research. The first two groups were created to meet government and state reporting requirements. The laboratory group was the most comprehensive category and included operational reports such as performance metrics, technician performance assessment, and analyzer metrics. The close monitoring of testing volumes and lab operational efficiency was essential to manage increasing demands and provide timely and accurate results. The clinical data reports were valuable for proper managing of medical surge requirements, such as healthcare workforce and medical supplies. The reports included in the research category were highly variable and depended on healthcare setting, research priorities, and available funding. We share a few examples of queries that were included in the designed framework for research projects. CONCLUSION: We reviewed here the key components of a conceptual surveillance framework required for a robust response to COVID-19 pandemics. We demonstrated leveraging a lab analytics dashboard, Visiun, combined with Epic reporting tools to function as a surveillance system. The framework could be used as a generic template for possible future outbreak events.

Development and outcomes of a virtual triage pathway for cancer diagnosis in vague symptom patients

Background: At the Rapid Access Diagnostic Unit at Guy's Hospital London, we review patients with vague symptoms that are concerning for malignancy. As part of our response to the COVID-19 pandemic, we developed a virtual triage pathway with the aim to reduce face-to-face appointments and prioritise resources towards patients with an underlying cancer diagnosis. Methods: Patients were triaged by clinicians based on a telephone consultation with the patient and history and blood tests provided in the referral. Those triaged as high risk were either directly booked for investigation ("straight-to-test") or booked for a face-to-face consultation for further history and examination. Low risk patients were either put on a watch-and-wait pathway with a telephone follow-up in 3-4 weeks or discharged back to the GP with a robust plan on symptom management. The patient outcomes were tracked and compared to the outcomes from the face-to-face assessment service used prior to the COVID-19 pandemic (Dec 2016-Feb 2020). Patients triaged as low risk and discharged were tracked to monitor for any subsequent cancer diagnoses. Results: There were 804 referrals triaged between March 2020-January 2021. 75% were triaged to a face-to-face assessment and 18% triaged straight-to-test. 4% were placed on the watch-and-wait pathway and 3% were returned to the GP with advice. In those triaged as high risk, 8.2% were diagnosed with cancer, 54% were diagnosed with a serious-benign condition and 38% with a non-serious or no condition. In the patients triaged as low risk and placed on the watch-and-wait pathway, 14% were brought in for a face-to-face assessment based on their follow-up telephone assessment. None of the patients on the watch-and-wait pathway were found to have a cancer diagnosis, 11% were diagnosed with a seriousbenign condition, and 89% were diagnosed with a non-serious or no condition. There was an overall cancer diagnosis rate of 7.6% compared with a pre-COVID-19 diagnosis rate of 6.6%. Conclusions: The virtual triage pathway effectively risk-assessed patients, with those triaged as high risk having an 8.2% cancer diagnosis rate compared to a 0% cancer diagnosis rate in those triaged as low risk. Furthermore, the virtual triage service had a higher cancer diagnosis rate compared to the pre-COVID-19 face-to-face assessment service. Therefore the virtual triage service provides an efficient pathway for cancer diagnosis in patients presenting with vague symptoms, reducing the number of face-to-face appointments and supporting management of low risk patients in the community.