Enabling mRNA medicine for brain tumors

mRNA is a new class of drugs that has the potential to revolutionize the treatment of brain tumors. Thanks to the COVID-19 mRNA vaccines and numerous therapy-based clinical trials, it is now clear that lipid nanoparticles (LNPs) are a clinically viable means to deliver RNA therapeutics. However, LNP-mediated mRNA delivery to brain tumors remains elusive. Over the past decade, numerous studies have shown that tumor cells communicate with each other via small extracellular vesicles, which are around 100 nm in diameter and consist of lipid bilayer membrane similar to synthetic lipidbased nanocarriers. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain tumors without undue toxicity. We synthesized LNPs using four components similar to the formulation used in the mRNA COVID19 vaccines (Moderna and Pfizer): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. For the in vitro screen, we tested ten classes of helper lipids based on their abundance in extracellular vesicle membranes, commercial availability, and large-scale production feasibility while keeping rest of the LNP components unchanged. The transfection kinetics of GFP mRNA encapsulated in LNPs and doped with 16 mol% of helper lipids was tested using GL261, U87 and SIM-A9 cell lines. Several LNP formations resulted in stable transfection (upto 5 days) of GFP mRNA in all the cell lines tested in vitro. The successful LNP candidates (enabling >80% transfection efficacy) were then tested in vivo to deliver luciferase mRNA to brain tumors via intrathecal administration in a syngeneic glioblastoma (GBM) mouse model, which confirmed luciferase expression in brain tumors in the cortex. LNPs were then tested to deliver Cre recombinase mRNA in syngeneic GBM mouse model genetically modified to express tdTomato under LoxP marker cassette that enabled identification of LNP targeted cells. mRNA was successfully delivered to tumor cells (70-80% transfected) and a range of different cells in the tumor microenvironment, including tumor-associated macrophages (80-90% transfected), neurons (31- 40% transfected), neural stem cells (39-62% transfected), oligodendrocytes (70-80% transfected) and astrocytes (44-76% transfected). Then, LNP formulations were assessed for delivering Cas9 mRNA and CD81 sgRNA (model protein) in murine syngeneic GBM model to enable gene editing in brain tumor cells. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~94% of brain tumor cells in vivo. In conclusion, we have developed a library of safe LNPs that can transfect GBM cells in vivo with high efficacy. This technology can potentially be used to develop novel mRNA therapies for GBM by delivering single or multiple mRNAs and holds great potential as a tool to study brain tumor biology.

Mechanism of interferon induction by cannabidiol (CBD) and analogues in lung cancer cells

CBD, an FDA approved drug for epilepsy, may have therapeutic potential for other diseases and is currently being tested for efficacy in cancer-related clinical trials. As the literature about CBD, especially in vitro reports, is often contradictory, increasing our understanding of its specific action on a molecular level will allow to determine whether CBD can become a useful therapy or exacerbates specific cancers in a context-dependent manner. Due to its relative lipophilicity, CBD is challenging to dispense at therapeutic concentrations;therefore, one goal is to identify cannabinoid congeners with greater efficacy and reduced drug delivery challenges. We recently showed that CBD activates interferons as a mechanism of inhibiting SARS-CoV-2 replication in lung carcinoma cells. As factors produced by the innate immune system, interferons have been implicated in both pro-survival and growth arrest and apoptosis signaling in cancer. Here we show that CBD induces interferon production and interferon stimulated genes (ISGs) through a mechanism involving NRF2 and MAVS in lung carcinoma cells. We also show that CBDV, which differs from CBD by 2 fewer aliphatic tail carbons, has limited potency, suggesting that CBD specifically interacts with one or more cellular proteins rather than having a non-specific effect. We also identified other CBD-related cannabinoids that are more effective at inducing ISGs. Taken together, these results characterize a novel mechanism by which CBD activates the innate immune system in lung cancer cells and identify related cannabinoids that have possible therapeutic potential in cancer treatment.

Heterologous prime-boost viral vector vaccines for the treatment of a P1A-expressing BGL-1 glioblastoma model

Glioblastoma is an extremely aggressive and difficult cancer to treat, which may partly be due to its limited ability to induce T-cell responses. However, combining viral vector vaccines with other therapies to generate tumor-specific T cells may provide a meaningful benefit to patients. Here, we investigated whether heterologous prime-boost vaccination with chimpanzee-derived adenoviral vector ChAdOx1 and modified vaccinia Ankara (MVA) vaccines could generate therapeutically effective CD8+ T-cell responses against a model antigen P1A, a mouse homolog of human tumorassociated Melanoma Antigen GenE (MAGE)-type antigens, expressed by a BGL-1 mouse glioblastoma cell line. We demonstrated that heterologous prime-boost vaccination with ChAdOx1/MVA vaccines targeting P1A generated a high magnitude of CD8+ T cells specific for the P1A35-43 epitope presented by the MHC class I molecule H-2Ld . Prophylactic vaccination with ChAdOx1/MVA-P1A significantly prolonged the survival of syngeneic mice subcutaneously challenged with P1A-expressing BGL-1 tumors. Furthermore, different vaccination schedules significantly impact the magnitude of antigen-specific CD8+ T-cell responses and may impact protective efficacy. However, the substantial induction of myeloid-derived suppressor cells (MDSCs) by this tumor model presents a significant challenge in the therapeutic setting. Future work will investigate the efficacy of this vaccination strategy on intracranial P1A-expressing BGL-1 models.

The temporal evolution in disease phenotype of COVID-19 hospitalisation, intensive care and case fatality rates in cancer patients across the United Kingdom (UKCCP)

Background: People living with cancer are reported to be at increased risk of hospitalization and death following infection with acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is proposed to be dependent on a combination of intrinsic patient and cancer factors such as cancer subtype, and emerging SARS-CoV-2 variants with differing pathogenicity. However, COVID-19 phenotype evolution across the pandemic from 2020 has not yet been systematically evaluated in cancer patients. Method(s): This study is a population-scale real-world evaluation of Coronavirus outcomes in the United Kingdom for cancer patients from 1st November 2020-31st August 2022. The cancer cohort comprises individuals from Public Health England's national cancer dataset, excluding individuals less than 18 years old. Case-outcome rates, including hospitalization, intensive care and casefatality rates were used to assess the evolution in disease phenotype of COVID-19 in cancer patients. Multivariable logistic regression models were fitted to compare risk of Coronavirus outcomes in the cancer cohort relative to the non-cancer population during the Omicron wave in 2022. Result(s): The cancer cohort comprised of 198,819 positive SARS-CoV-2 tests from 127,322 individual infections. Coronavirus case-outcome rates were evaluated by reference to 18,188,573 positive tests from 15,801,004 individual infections in the non-cancer population. From 2020 to 2022, the SARS-CoV-2 disease phenotype became less severe in both patients with cancer and the non-cancer population, though cancer patients remain at higher risk. In 2022, the relative risk of Coronavirus hospital admission, inpatient hospitalization, intensive care admission and mortality in cancer patients was 3.02x, 2.10x, 2.53x and 2.54x compared to the non-cancer population following multivariable adjustment, respectively. Higher risk of hospital admission and inpatient hospitalization were associated with receipt of B/T cell antibody and/or targeted therapy which also corresponded with an increased risk of Coronavirus mortality. Conclusion(s): The disease phenotype of SARS-CoV-2 in cancer patients in 2022 has evolved significantly from the disease phenotype in 2020. Direct effects of the virus in terms of SARS-CoV-2 hospitalization, intensive care and case fatality rates have fallen significantly over time. However, relative to the general population, people living with cancer and hematological malignancies remain at elevated risk. In order to mitigate the indirect effects of the SARS-CoV-2 pandemic in terms of disruption to cancer care, there should be increased focus on preventative measures. Used in conjunction with vaccination and early treatment programs, this will maximize quality of life for those with cancer during the ongoing pandemic and ensure the best cancer outcomes.

Immunotherapy: SYNERGISTIC PERITONEAL ANTI-TUMOR EFFECT OF ALLOCETRAOTS, A CELLULAR IMMUNE-THERAPY, IN COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS/CHEMOTHERAPY, THROUGH IN-VIVO REPROGRAMMING OF MACROPHAGES AND DENDRITIC CELLS

Background & Aim: Immune checkpoint inhibitors (ICI) revolutionized solid tumor treatment, however, in many tumors only partial response is achieved. Allocetra-OTS has an immune modulating effect on macrophages and dendritic cells and showed an excellent safety profile in patients including patients with sepsis and Covid-19. Here we investigated the anti-tumoral effect of Allocetra-OTS cellular therapy, in peritoneal solid tumor animal models. Methods, Results & Conclusion(s): Allocetra-OTS is manufactured from enriched mononuclear fractions and induced to undergo early apoptosis. Balb/c mice were inoculated intraperitoneally (IP) with AB12 (mesothelioma) with pLenti-PGK-V5-Luc-Neo and treated with anti- CTLA4 with or without Allocetra-OTS. Mice were monitored daily for clinical score and weekly using IVIS (Fig.1). Kaplan-Meier log rank test was done for survival. For Allocetra-OTS preparation, enriched mononuclear fractions were collected by leukapheresis from healthy eligible human donors and induced to undergo early apoptosis. Anti- CTLA4 standalone therapy significantly improved survival (Fig.2) from mean 34+/-9 to 44.9 +/-20 days. However, OTS standalone therapy was non-inferior and improved survival to 52.3 +/-20 days. Anti-CTLA4 + Allocetra-OTS combination therapy, ameliorated survival to 86.7+/-20 days with complete cancer remission in 60-100% of mice. Similar anti- tumoral effects of Allocetra-OTS were seen in mesothelioma model in a combination therapy with either anti-PD1 or cisplatin and using anti-PD1 in ID8 ovary cancer model. Based on single cell analysis confirmed by flow cytometry and pathology, the mechanism of action seems to be related or at least associated with an increase in f/480high peritoneal macrophages and a decrease in recruited macrophages, and to f/480high infiltration of the tumor. However, further studies are needed to confirm these observations. During IP tumor progression, Allocetra-OTS as a standalone therapy or in combination with ICI, or cisplatin, significantly reduced tumor size and resulted in complete remission in up to 100% treated mice. Similar results were obtained in ID8 ovary cancer. Based on excellent safety profile in > 50 patients treated in prior clinical trials for sepsis and Covid-19, Phase I/II clinical trial of Allocetra-OTS plus chemotherapy has started and three patient already recruited. A second phase I/II clinical trial of Allocetra- OTS plus anti-PD1, as a second- and third-line therapy in various cancers, was initiated in Q1 2023. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

Impact of COVID-19 on Delivery of Cancer Care: Real-World Insights from Community Oncology Research Evaluations (CORE)

Objectives: The COVID-19 pandemic has disrupted healthcare delivery for patients with cancer. This research assessed the impact of COVID-19 on the delivery of cancer care in the US during the pandemic and evaluated emerging treatment trends in the post-COVID-19 setting. Method(s): A series of Community Oncology Research Evaluations (CORE) meetings were conducted across the US between December 2021 and May 2022. During these meetings, community oncologists undertook a survey focused on the impact of COVID-19 in the community-practice setting. Result(s): 242 community oncologists participated in the survey. Over 80% of the physicians estimated that up to 20% of patients with cancer have gone undiagnosed due to their reluctance to visit a healthcare provider during the pandemic. More than half (51%) of community oncologists reported a decrease of up to 50% in in-office patient visits versus before COVID-19, with most physicians (71%) indicating that some delivery of care changed to a virtual setting in up to 20% of patients. Most physicians (86%) reported no change in their willingness to assess new therapies. Most common strategies to manage cancer during the pandemic included the use of telemedicine for stable patients receiving oral chemotherapy (55%), use of extended dosing schedules (39%), and switching route of chemotherapy administration from intravenous to oral or subcutaneous (38%). Once COVID-19 is under control, these strategies are expected to remain in place. Nearly half of the community oncologists (48%) plan to continue using telemedicine for managing disease in stable patients receiving oral chemotherapy, over a quarter intend to continue using extended dosing schedules, and 19% plan to use oral or subcutaneous chemotherapy when appropriate. Conclusion(s): COVID-19 had a detrimental impact on cancer diagnosis and delivery of therapy. Community oncologists reported a seemingly permanent shift in care patterns including telemedicine, extended dosing schedules, and switching chemotherapy administration route.Copyright © 2023

Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen

Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (>= 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-offlight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Result(s): We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICIinsensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusion(s): Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer.

Scientific debrief: cirrhosis

Globally, hepatitis C (26%), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from nonalcoholic fatty liver disease (8%) is small but increasing. Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acuteon-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure, Cardiovascular alterations including portal hypertension trigger the formation of portocaval shunts and varices. Systemic under filling and arterial hypotension is compensated by vasoconstriction but might decline into a state of aggravated portal hypertension and cirrhotic cardiomyopathy, leading to a hyperdynamic state, microvascular dysfunction and reduced organ perfusion culminating in decompensation. The immune system is dysfunctional showing a contrary co-existence of immune paralysis and immune overstimulation leading to secondary infections and inflammatory response syndrome aggravating cardiovascular alterations but also initiating tissue injury and metabolic alteration. This transition from compensated to decompensated cirrhosis is characterised by the occurrence of ascites, variceal bleeding and/or hepatic encephalopathy or organ failures (in the case of ACLF. Precipitating events for ACLF vary between Western countries (bacterial infection, alcohol intake) and Eastern countries (flare of HBV, superimposed HAV or HEV). In the majority of patients, systemic inflammation is a major driver of progression from compensated to decompensated cirrhosis. Once the first episode of AD develops, systemic inflammation follows a chronic course, with transient periods of aggravation due to proinflammatory precipitants or bursts of bacterial translocation resulting in repeated episodes of AD. The multistate model describing the clinical outcomes of decompensated cirrhosis has been well validated. State 3 is defined by the occurrence of variceal bleeding alone, state 4 by any single non-bleeding event, state 5 by any 2 or more events and the late decompensate state by any event with organ failures either with or without ACLF. 5-year mortality across states from 3 to 5 is in the order of, respectively: 20%, 30%, 88%. With late decompensation mortality ranges between 60 and 80% at 1 year. Cirrhosis is increasingly common and morbid. Optimal utilisation of therapeutic strategies to prevent and control the complications of cirrhosis are central to improving clinical and patient-reported outcomes. Aetiology-focused therapies that can prevent cirrhosis and its complications. These include anti-viral therapies, psychopharmacological therapy for alcohol-use disorder, management of hepatic encephalopathy (HE), ascites, hepatorenal syndrome, non-pain symptoms of cirrhosis including pruritis, muscle cramps, sexual dysfunction and fatigue, and reduce the risk of hepatocellular carcinoma. New disease-modifying agents are expected to be identified in the next few years by systematic drug repurposing and the development of novel molecules currently undergoing pre-clinical or early clinical testing. COVID-19 continues to pose a significant healthcare challenge throughout the world. Comorbidities including diabetes and hypertension are associated with a significantly higher mortality risk. Cirrhosis is associated with an increased risk of all-cause mortality in COVID-19 infection compared to non-cirrhotic patients. Patients with cirrhosis should be considered for targeted public health interventions to prevent COVID-19 infection, such as shielding and prioritisation of vaccination.

Every breath: the benefits of a lung cancer support group

Introduction: Cancer support groups provide valuable peer support for patients, carers and families. Lung cancer is the biggest cause of UK cancer deaths, but few local support groups exist due to patients' social vulnerabilities and stigma. A need was identified for a support group in Bromley, South East London. The COVID pandemic provided additional challenges to meet and support others. Method(s): The group was initiated by patients and the lung Clinical Nurse Specialist (CNS). Patients and relatives were invited to participate in a "lung cancer awareness" hospital stand. Sharing experiences was hugely beneficial leading to a regular meeting outside hospital. Patients established aims to provide: A voice for people living with lung cancer A sense of community, belonging and purpose A reason for hope The group is inclusive to patients, families and bereaved relatives. It survived the pandemic as an online community. Result(s): Every breath support group has been invaluable and feedback highlights the importance of a safe space to be understood. It successfully achieved its aims and continues to grow, with over 60 active members. It is recognised as the Bromley Mayors Charity of the year. Group members provide patient representation to local NHS Integrated Care Networks, and patient perspectives educating health professionals. Examples of group member feedback: "Every Breath has been like a family to me... This group have helped me find peace in the unknown." "Lung Cancer is the dirty cancer ... we are here to help support those in need and ... to change the perception of Lung Cancer" Conclusion(s): Every Breath support group offers a model for lung cancer support. Patients and CNS team have reached out to other areas to support establishing groups. Peer support has huge psychosocial benefits and should be available to every lung cancer patient and their family. Disclosure: No significant relationships.Copyright © 2023 Elsevier B.V.

Immune-Viral Dynamics Modeling of the Basis for Individual Variation in Covid-19

Background: Viral dynamics models provide mechanistic insights into viral disease and therapeutic interventions. A detailed, mechanistic model of COVID-19 was developed and fit to data from molnupiravir (MOV) trials to characterize the SARS-CoV-2 viral dynamics in MOV-treated and untreated participants and describe the basis for variation across individuals. Method(s): An Immune-Viral Dynamics Model (IVDM) incorporating mechanisms of viral infection, viral replication, and induced innate and adaptive immune response described the dynamics of viral load (VL) from pooled data from MOV Phase 2 and 3 trials (N=1958). Population approaches were incorporated to estimate variation across individuals and to conduct an extensive covariate analysis. Nineteen parameters in a system of five differential equations described SARS-CoV-2 viral dynamics in humans. Six population parameters were successfully informed through fitting to observed trial data while the remaining parameters were fixed based on literature values or calibrated via sensitivity analysis. Result(s): Final viral dynamics and immune response parameters were all estimated with high certainty and reasonable inter-individual variabilities. The model captured the viral load profiles across a wide range of subpopulations and predicted lymphocyte dynamics without using this data to inform the parameters, suggesting inferred immune response curves from this model were accurate. This mechanistic representation of COVID-19 disease indicated that the processes of cellular infection, viral production, and immune response are in a time-varying, non-equilibrium state throughout the course of infection. MOV mechanism of action was best described as an inhibitory process on the infectivity term with estimated AUC50 of 10.5 muM*hr. Covariates identified included baseline viral load on infectivity and age, baseline disease severity, viral clade, baseline viral load, and diabetes on immune response parameters. Greater variation was identified for immune parameters than viral kinetic parameters. Conclusion(s): These findings show that the variation in the human response (e.g., immune response) is more influential in COVID-19 disease than variations in the virus kinetics. The model indicates that immunocompromised patients (due to HIV, organ transplant, active cancer, immunosuppressive therapies) develop an immune response to SARS-CoV-2, albeit more slowly than in immunocompetent, and MOV is effective in further reducing viral loads in the immunocompromised.

Using ex vivo bioengineered lungs to model pathologies and screening therapeutics

Introduction: More than 8 million lives are claimed annually by various respiratory diseases including lung cancer. While therapeutics is the first line of defence, treatment failure always remains challenging and research studies face a lag of transition from preclinical to clinical phase. This is partly due to the inadequate representation of the preclinical models in clinical trials. In this proof-of-concept study, we sought to use an ex-vivo model to identify lung pathologies and therapeutically screen them in a rodent model. Method(s): Briefly, the heart-lung tissues were extracted and decellularized using a detergent-based decellularization technique. Subsequently, lungs were seeded and cultured (6-10 days) with human cell lines: BEAS-2B, A549, and Calu3, demonstrating healthy lung, cancerous state, and congenital pathologies (cystic fibrosis), respectively. By altering the cultural conditions and exploiting the unique characteristics of these cell lines, we were able to model a variety of novel pathological models in ex vivo, such as advanced-stage solid tumours and the primary phase of infection via SARS-COV2. We also validated the above-mentioned observations by histology and immunofluorescence staining. Another novel part of our study includes a qualitative screening of efficacy and impact of important Therapeutics (anti-neoplastic)- Cisplatin and Wogonin, in our cancer models. Result(s): Using A549 and BEAS-2B cells, we were able to model different stages of Non-small cell lung cancer, qualitatively validated the resemblance to clinical samples and monitor the impact of different therapeutics on these models. The qualitative assessment also demonstrated different levels of cell death depending on the efficacy of the drugs. Contribution to research : Collectively this study demonstrates the remarkable versatility and strength of the ex vivo model in representing important lung pathologies and screening therapeutics in the preclinical phase.

Evolution of Clinical Trials in Oncohematology in a Reference Center: Does It Worth a Dedicated Structure?

Introduction: As part of the reorganization of our outpatient activity in onco-hematology (OH), questions were raised about the relevance of dedicating a specific structure to clinical research in this field. These questions arise all the more so as the proportion of OH clinical trials (CT) in our center has increased from 10% to 45% of all CT between 2000 and 2020. The aim of this study is to assess the evolution of this activity and thus to consider the interest of such a structure. Material(s) and Method(s): A retrospective data review of new CT related to OH in our center from 2016 to 2021 was performed. The evolution of 3 key indicators was assessed: distribution of OH CT among all CT, main OH indications and preferred routes of administration. Results and discussion: Over the period 2016-2021, OH CT represented an average of 32% of newly activated CT corresponding to 34% in 2016 and 48% in 2021 (approximately 90 CT start each year for a total of 420 CT in our center). A short decrease was observed in 2019 and 2020, 25% and 24% respectively, probably related to Covid-19. In terms of sterile preparations, OH represented steadily more than 60% of our activity over the period. The main indications were lymphomas (30%), acute myeloid leukemias (AML - 19%), myelodysplastic syndromes (12%) and CT related to transplant center (12%) in steady distribution overtime. Only new CT in myeloma increased from 7% to 18% in relation with increased subcutaneous (SC) use of daratumumab. Regarding preferred routes of administration, an increased trend in oral and SC routes is observed (respectively 53% and 7% in 2016 vs. 69%and 28% in 2021). The increasing use of SC intensified in 2017 as part of the arrival of AML treatments combining azacitidine (SC) with venetoclax (oral). New CT using the intravenous route decreased from 70% in 2016 to 51% in 2021 even if bispecific antibodies araised in 2021. Focusing in 2021, 1359 visits (772 in day hospital for protocol chemotherapy and 597 for oral treatment) were observed, i.e. 6 patients per day. Conclusion(s): This review showed OH's activity growth in our center. The increasingly frequent use of SC and oral routes requires that patients be fully informed and trained about their own management. In this context, a pharmacist has its place and could best inform patients about the adverse effects of new complex therapies (antibodies, targeted therapy). A unique place, organized and dedicated to clinical research in OH, would allow patients benefiting from a structured and exhaustive support as well as meeting all the healthcare professionals involved and finally ensuring the conditions for optimal care.

Modeling a public-private grant initiative to address breast cancer care disparities at the community level

Background: Breast cancer disparities between Black and White women have persisted in the US, with breast cancer death rates 40% higher in Black women compared to White women (American Cancer Society Cancer Facts & Figures for African American/Black People 2022-2024). Education and interventions at the community level can potentially reduce racial gaps, particularly in curbing late-stage diagnoses that disproportionately affect Black women with breast cancer. Together, the American Cancer Society (ACS) and Pfizer Global Medical Grants (Pfizer) developed a collaborative model to support health systems in engaging communities to reduce breast cancer disparities between Black and White women. This collaboration aimed to identify novel interventions and provide foundational support for these communities to advance their work in bridging the gap in breast cancer disparities. Method(s): This collaborative grant program divided project responsibilities, in which Pfizer provided funding and ACS provided project oversight and technical support. An advisory committee provided input on the areas of most need, impact and project direction. Funding applicants were required to partner with local organizations to implement evidence-based initiatives for education and/or quality improvement within the respected community. The grant award selection committee comprised of experts in the field, including breast cancer survivors and individuals from racial/ethnic minority groups. In response to a Request for Proposals, over 100 applications were systematically reviewed based on the National Cancer Institute grant selection process. The committee selected 9 grantees with innovative proposals addressing breast cancer disparities for Black women along the cancer-care continuum. Bi-annual progress reports were used to measure progress, with a final report to mark projects' impact and reach. The COVID-19 pandemic presented numerous obstacles during the project period and the ability to convene with partners virtually through web-based sessions helped to foster opportunities for collaboration and knowledge sharing among leaders in cancer disparities research. Result(s): The projects occurred from January 2020 to June 2022, with no-cost extensions given to accommodate COVID-19 pandemic delays. During this period grantees successfully completed project goals in one of three areas: screening, identifying areas of need and education. Approximately 10,000 patients and 200 healthcare professions were impacted among three projects focused on increasing mammography efforts in Black women during the project period. Three projects incorporated surveys and focus groups to identify novel areas for intervention/need and interviewed over 350 patients and over 60 health care professionals. The remaining three grantee projects that focused on education successfully implemented advertisement campaigns and lecture series to target patients and healthcare professionals. The projects selected under this model independently completed their goals within the project period while also laying a foundation to continue work in reducing disparities along the cancer care continuum with their enhanced community partner relations. Additionally, the project period also provided opportunities for external collaborations and discussion among all grantees through 8 ACS-coordinated online sessions and 3 summits. Conclusion(s): Projects selected by the public-private grant initiative model can enhance community relationships and provide infrastructure to continue work along the cancer care continuum. We believe this collaborative competitive grant program can be used for future efforts to address breast cancer and other health disparities at the community level. Similar collaborative funding projects related to prostate and pan-tumor disparities have been launched and are currently ongoing.

European Cancer Summit 2022 submission for HPV Action NetworkHPV SCREENING FOR CERVICAL CANCER USING THE SELF-SAMPLING MODEL IN UKRAINE DURING THE WAR

Background: The Covid pandemic and the war created the conditions for the growth of cancer in Ukraine. Violence against women and mass migration of the population have increased the risk of HPV infection in the population, which may provoke a surge in the incidence of cervical cancer shortly (1). Method(s): In the front-line city of Zaporizhzhia (eastern Ukraine), HPV screening for cervical cancer was organized using the Self-sampling model from the first weeks of the war. Women aged 25-60 were offered to take part in the screening at the refugee reception centre where they received humanitarian assistance. For Self-sampling, the Swedish test Qvintip Aprovix AB (2) was used. Screening participants returned the test through volunteers to a certified PCR laboratory, where they tested viral DNA for six oncogenic HPV strains. Women received a response with further recommendations for monitoring and treatment via SMS or email. The organization and financing of screening in Ukraine during the war were taken over by the charitable foundation "World Against Cancer". Result(s): Consent for HPV screening was obtained from 180 women. A positive result of HPV testing was obtained in 12 (6.7%) women. Systematic analysis of screening results and the use of "Test and treat" tactics is the subject of our further research. Conclusion(s): Due to the small number of participants in the program and the short follow-up period, it is not yet possible to conclude the impact of the war on the risk of developing cervical cancer in Ukrainian women. Our pilot study showed that the Self-sampling model is the most optimal for HPV screening in a military conflict. However, this model can only be applied after the end of active hostilities in the region and the low probability of a missile and bomb strike on the city, when relative stability sets in after the phase of a humanitarian catastrophe. This model of cancer prevention can also be used during the mass migration of refugees in the aftermath of environmental disasters as part of a program of humanitarian assistance to the population.Copyright © 2023

Reducing face-to-face visits for skin cancer assessment using patient-led teledermatology: a retrospective review of experience with the My Skin Selfie platform

Teledermatology has made massive progress throughout the COVID-19 pandemic, but significant debates are emerging about the correct way to use technology and deliver services in a nonpandemic future where all face-to-face (F2F) options will be available again. Some very fixed views are emerging, and it is important that future national guidelines are both evidence-based and pragmatic. Improvements in phone camera technology allow patients to take high-quality skin images. Adequate assessment of moles does require dermoscopy, but many other skin lesions can be accurately triaged without it, as was commonplace until relatively recently. There is now extensive literature confirming the ability to make safe and secure diagnoses of skin cancers using teledermatology. Debates around the optimal uses of teledermatology are now in progress. We report retrospective data from two pilot studies, for basal cell carcinoma (BCC) and 2-week wait (2WW), using patient-led skin images taken using the MySkinSelfie app and viewed on the MySkinSelfie web portal. The aim was to evaluate the number of F2F visits that had been prevented. In each pilot, patients were initially referred by their general practitioner in the usual way, without images. The BCC pilot was conducted prepandemic. Patients were sent a letter inviting them to submit images. Once images had been received, they were booked into a telephone clinic for assessment. In total, 288 patients were invited and 76 submitted images. Thirty-two (42%) needed further F2F review, 37 (49%) were booked for a surgical procedure, five (6%) were prescribed a cream and two (3%) lesions resolved. The 2WW pilot was conducted during the pandemic. Patients referred on a 2WW pathway were telephoned by administration staff and invited to submit images followed by a telephone consultation. In total, 1385 were invited and 704 submitted images. Two hundred and sixty-five (37 6%) needed further F2F review, 170 (24 1%) were booked for a surgical procedure, 219 (31 1%) were discharged and 50 (7 1%) received a cream. The agreement between diagnosis via digital images of nonpigmented skin lesions and a final diagnosis was 83%. Compared with a standard F2F model, 58% (BCC) and 62% (2WW) avoided a first F2F appointment, providing benefits for patients' travel time, infection risk and missed time at work for patients and carers. A larger prospective study is now needed to document image quality, diagnostic concordance and health economic effects with more precision.

Quercetin potentially suppresses renal fibrosis in patients with COVID-19 under hypoxic state

Introduction: Renal fibrosis is a main outcome of acute kidney injury in COVID-19 survivors, which is emerging as a global public health concern. Lung damage in the COVID-19 patients leads to acute and chronic hypoxia, which results in inflammation, epithelial-mesenchymal transformation, and fibrosis in kidney. Quercetin is an abundant flavonoid in plant materials. Previous studies indicate that quercetin alleviates the decline of renal function, suppress epithelial to mesenchymal transformation in renal tubules, and reduce fibrosis. The study aimed to explore potential targets of quercetin on treating renal fibrosis in patients with COVID-19-induced hoxpia. Method(s): Gene/protein targets related to COVID-19, renal fibrosis, or quercetin were searched from ten databases, and Cytoscape 3.8.2 was then used to construct the protein-protein interaction network and to identify the core targets. The Metascape platform was used for bioconcentration analysis, while AutoDock Vina was used as the primary molecular docking tool. In vitro, the combination model of hypoxia- and transforming growth factor-beta (TGF-beta)- treated human proximal tubule epithelial cells (HK2 cells) was applied to determine the reno-protective effect of quercetin. Result(s): The network analysis showed that quercetin targeted on TGF-beta pathway in treating COVID-19 induced renal fibrosis. In the intersection PPI network, 115 targets were obtained, and gene enrichment analysis was conducted on 109 key nodes. Molecular docking analysis revealed that quercetin could spontaneously bind to eight targets on the TGF-beta pathway, and the binding energy of TGF-beta1 was 29.82 kJ/mol. The in vitro experiment further showed that quercetin significantly suppressed fibrosis in TGF-beta and hypoxia treated HK2 cells in a dose dependent manner by inhibiting TGF-beta/Smad3 pathway. Conclusion(s): Quercetin could attenuate renal fibrosis in patients with COVID-19 by suppressing TGF-beta/Smad3 pathway. No conflict of interestCopyright © 2023

Determinants of severe COVID-19 infection in Patients with Breast Cancer from a Community Oncology Practice in Brazil

Purpose: The SARS-CoV-2 pandemic was declared a global public health emergency. Determinants of mortality in the general population are now clear, but specific data on patients with breast cancer (BC) remain limited, particularly in developing nations. Material(s) and Method(s): We conducted a longitudinal, multicenter cohort study in patients with BC and confirmed SARS-CoV-2 infection. The primary end point was the proportion of patients on treatment for severe SARS-CoV-2 infection (defined as need for hospitalization) or early death (within 30 days of diagnosis). Data were evaluated sequentially in the following way: i) univariate Fisher's exact test;ii) multivariable logistic regression analysis;and iii) multivariable logistic regression. In items i and ii only those with P< 0.1 are considered significant and in stage iii only those with p< 0.05 were the final significant variables. We divided patients' data into three major variable domains: a) signs and symptoms;b) comorbidities;and c) tumor and treatment characteristics;in item ii each variable domain was tested separately, finally, in item iii the significant variables of all domains were tested together and we called it the integrative step. Result(s): From April 2020 to June 2021, 413 patients with BC and COVID-19 were retrospectively registered, of which 288 (70%) had an identified molecular subtype and 273 (66%) had stage information. Most patients were on active systemic therapy or radiotherapy (73.2%), most of them in the curative setting (69.5%). The overall rate of severe SARS-CoV-2 was 19.7% (95% CI, 15.3-25.1). In the integrative multivariate analysis, factors associated with severe infection were metastatic setting, chronic pain, acute dyspnea, and cardiovascular comorbidities. Recursive partitioning modeling used acute dyspnea, metastatic setting, and cardiovascular comorbidities to predict nonprogression to severe infection, yielding a negative predictive value of 84.9% (95% CI, 78.9%-88.3%). Conclusion(s): The rate of severe COVID-19 in patients with BC is influenced by prognostic factors that partially overlap with those reported in the general population. High-risk patients should be considered candidates to active preventive measures to reduce the risk of infection, close monitoring in the case of exposure or SARS-CoV-2 -related symptoms and prophylactic treatment once infected.

21st International Congress of Cytology with the ASC 70th Annual Scientific Meeting

The proceedings contain 158 papers. The topics discussed include: use of cumulative sum in the assessment of diagnostic competency of cytopathology fellows;what's up in Whatsapp - telecytopathology experience connecting rural districts of Punjab to a tertiary care center in India;ballistic gel model for ultrasound-guided fine needle aspiration: a cost-effective method for simulation training;science, medicine, and cytology: a pilot program of the ASC diversity equity and inclusion (DEI) committee;comparison of low-cost phantoms for ultrasound guided fine needle aspiration biopsy teaching;deep learning algorithm for malignant pleural fluids cytology;application of international system for reporting serous fluid cytology (ISRSFC) in effusion samples - a prospective study;evaluation of 'crowd wisdom' in biliary brush cytology;characterization of the cellular composition of malignant pleural effusion specimens for clinical applications: preliminary study;and diagnostic criteria for COVID-19 pneumonia in broncho-alveolar lavage specimens.

COVID-19 severity prediction based on patient risk factors and number of vaccines received

Background: Vaccines are highly effective in preventing severe disease and death from COVID-19, and new medications that can reduce disease severity have been approved. However, many countries are facing limited supply of vaccine doses and medications. Research question: A model estimating the probabilities for hospitalisation and mortality according to individual risk factors and vaccine doses received could help prioritise vaccination and yet scarce medications to maximise lives saved and reduce the burden on hospitalisation facilities. Method(s): Electronic health records from 101,034 individuals infected with SARS-CoV-2, since the beginning of the pandemic and until 30 November 2021, were extracted from a national healthcare organization in Israel. Logistic regression models were built to estimate the risk for subsequent hospitalization and death based on the number of BNT162b2 mRNA vaccine doses received and few major risk factors (age, sex, body mass index, hemoglobin A1C, kidney function, and presence of hypertension, pulmonary disease or malignancy). Result(s): The models built predicts the outcome of newly infected individuals with remarkable accuracy: area under the curve was 0.889 for predicting hospitalisation, and 0.967 for predicting mortality. Even when a breakthrough infection occurs, receiving three vaccination doses significantly reduces the risk of hospitalization by 66% (OR = 0.336) and death by 78% (OR = 0.220). Conclusion(s): The models enable rapid identification of individuals at high risk for hospitalisation and death when infected. These patients can be prioritised to receive booster vaccination and the yet scarce medications. A calculator based on these models is made public: http://covidest.web.app.

Imaging tumor-infiltrating CD8+ T-cells in non-small cell lung cancer patients upon neo-adjuvant treatment with durvalumab

Aim/Introduction: Immune checkpoint inhibitors (ICI), like targeting programmed death receptor ligand 1 (PD-L1), have revolutionized anti-cancer treatments, including non-small cell lung cancer (NSCLC) [1, 2]. Assessment of PD-L1 expression on tumor biopsies is current practice, but there is a need for additional biomarkers correlating to the complex mechanism of action of ICI. The presence of tumorinfiltrating CD8+ T-cells (TILs) is a robust biomarker associated with immune therapy success [3]. Tools to track TILs in patients during ICI treatment allow further development of immune-oncology drugs. Material(s) and Method(s): This ongoing single-center prospective study (NCT03853187) includes patients with histologically proven T1b-3N0-1M0 NSCLC eligible for resection. Exclusion criteria are previous anti-cancer therapy and known immune disorders or suppression. Patients receive two courses neo-adjuvant durvalumab (750mg Q2W), after which TIL imaging is performed. Cohort 1 underwent apheresis and magnetic-activated cells sorting to isolate 100 x10e6 autologous CD8+ T-cells for cell labeling with 111In-oxine. Re-injection was followed by 4h post-injection (p.i.) planar imaging, 70h p.i. SPECT imaging, standard-of-care surgery and 78h p.i. uSPECT of the resected lobe. Patients in cohort 2 (ongoing) receive 1.5mg 89Zr-Df-crefmirlimab followed by PET/CT 24h p.i. Result(s): In cohort 1, 8/10 patients underwent apheresis and TIL imaging;one procedure was withdrawn due to COVID-19 restrictions and one due to unsuccessful T-cell isolation. Yield ranged 240-714 x10e6 CD8+ T-cells, purity 84%-97% and cell viability 92%-100%. Labeling efficacy of 100 x10e6 cells for re-injection ranged 42%-64% and injected activity 22,4-36,7 MBq In-111.TIL imaging was completed by 4/5 patients in cohort 2, one subject discontinued neo-adjuvant treatment due to post-obstruction pneumonia.Tumor-to-bloodpool were determined to quantify specific TIL accumulation in the tumor. Our results favor quantification of T-cells on PET over SPECT given its higher sensitivity and spatial resolution. Correlation of imaging findings with density of CD8+ T-cells in the resected tumor is currently ongoing. Conclusion(s): We implemented two methods for tracking CD8+ T-cells in earlystage NSCLC patients after neo-adjuvant durvalumab treatment. Although ex vivo cell labeling perhaps more specifically targets migrating TILs into the tumor, 89Zr-Df-crefmirlimab has the potential to also target residing cells. Quantitative correlation with presence of TILs in the resected tumor will help to determine the role of these imaging tools in the development of immune-oncology drugs.