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Introduction: The COVID-19 pandemic has caused severe disruption of healthcare services worldwide and interrupted patients’ access to essential services. During the first lockdown, many healthcare services were shut to all but emergencies. In this study, we aimed to determine the immediate and long-term indirect impact of COVID-19 health services utilisation on hepatocellular cancer (HCC) outcomes. Methods: A prospective cohort study was conducted from 1 March 2020 until 30 June 2020, correlating to the first wave of the COVID-19 pandemic. Patients were enrolled from tertiary hospitals in the UK and Germany with dedicated HCC management services. All patients with current or past HCC who were discussed at a multidisciplinary meeting (MDM) were identified. Any delay to treatment (DTT) and the effect on survival at one year were reported. Results: The median time to receipt of therapy following MDM discussion was 49 days. Patients with Barcelona Clinic Liver Cancer (BCLC) stages-A/B disease were more likely to experience DTT. Significant delays across all treatments for HCC were observed, but delay was most marked for those undergoing curative therapies. Even though severe delays were observed in curative HCC treatments, this did not translate into reduced survival in patients. Conclusion: Interruption of routine healthcare services because of the COVID-19 pandemic caused severe delays in HCC treatment. However, DTT did not translate to reduced survival. Longer follow is important given the delay in therapy in those receiving curative therapy.

Immune checkpoint blockade trials have yet to produce a robust anti-cancer response in prostate cancer patients as a monotherapy due to the immunosuppressed prostate cancer tumour immune microenvironment. ST3Gal1 and other sialyltransferases are implicated in cancer and immune suppression by synthesizing sialoglycans, which act as ligands for Siglec receptors. These checkpoints are important for the immune response. However, it’s unclear how the synthesis of Siglec ligands is regulated, and little is known about the role of sialoglycan-Siglec-axis in prostate cancer’s evasion of anti-tumour immunity. We report that ST3Gal1 levels negatively correlate with androgen signalling in prostate tumours. Utilising syngeneic mouse models, we demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion. Using mouse models, patient samples andin vitromodels we show that ST3Gal1 synthesises sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. For the first time we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. Importantly, we show that these interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.

Introduction: The COVID-19 pandemic has caused severe disruption of healthcare services worldwide and interrupted patients’ access to essential services. During the first lockdown, many healthcare services were shut to all but emergencies. In this study, we aimed to determine the immediate and long-term indirect impact of COVID-19 health services utilisation on hepatocellular cancer (HCC) outcomes. Methods A prospective cohort study was conducted from March 1, 2020, until June 30, 2020 correlating to the first wave of the COVID-19 pandemic. Patients were enrolled from tertiary hospitals in the UK and Germany with dedicated HCC management services. All patients with current or past HCC who were discussed at a multidisciplinary meeting (MDM) were identified. Any delay to treatment (DTT) and the effect on survival at 1 year were reported. Results The median time to receipt of therapy following MDM discussion was 49 days. Patients with Barcelona Clinic Liver Cancer (BCLC) stages-A/B disease were more likely to experience DTT. Significant delays across all treatments for HCC were observed but delay was most marked for those undergoing curative therapies. Even though severe delays were observed in curative HCC treatments, this did not translate in reduced survival in patients. Conclusion Interruption of routine healthcare services because of the COVID-19 pandemic caused severe delays in HCC treatment. However, DTT did not translate to reduced survival. Longer follow is important given the delay to therapy in those receiving curative therapy.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c-Rel in HCC.Histological and transcriptional studies confirmed expression of c-Rel in human patients with HCC, but low c-Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo, global (RelHepatocyte c-Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c-Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.

Background Patients with chronic kidney disease (CKD) are more prone to severe infection. Vaccination is a key strategy to reduce this risk. Some studies suggest vaccine efficacy may be reduced in patients with CKD, despite preserved maintenance of long-term responses to some pathogens and vaccines. Here, we investigated immune responses to 2 vaccines in patients with CKD to identify predictors of immunological responsiveness. Methods Individuals >65 years old, with or without nondialysis CKD (n = 36 and 29, respectively), were vaccinated with a nonadjuvanted seasonal influenza vaccine (T-dependent) and Pneumovax23 (23-valent pneumococcal polysaccharide [PPV23], T-independent). Humoral responses were measured at baseline, day 28, and 6 months. Lymphocyte subset and plasma cell/blast analyses were performed using flow cytometry. Cytomegalovirus (CMV) serotyping was assessed by enzyme-linked immunosorbent assay. Results Only modest responsiveness was observed to both vaccines, independent of CKD status (25% adequate response in controls vs. 12%–18% in the CKD group). Unexpectedly, previous immunization with PPV23 (median 10-year interval) and CMV seropositivity were associated with poor PPV23 responsiveness in both study groups (P < .001 and .003, respectively; multivariable linear regression model). Patients with CKD displayed expanded circulating populations of T helper 2 and regulatory T cells, which were unrelated to vaccine responses. Despite fewer circulating B cells, patients with CKD were able to mount a similar day 7 plasma cell/blast response to controls. Conclusion Patients with nondialysis CKD can respond similarly to vaccines as age- and sex-matched healthy individuals. CKD patients display an immune signature that is independent of vaccine responsiveness. Prior PPV23 immunization and CMV infection may influence responsiveness to vaccination. Clinical Trials Registration. NCT02535052, Patients with nondialysis Chronic Kidney Disease (CKD) can mount similar responses to vaccination as controls. Subtle changes in lymphocyte phenotype are seen in CKD when controlled for effect of Cytomegalovirus (CMV). Latent CMV infection and previous PPV23 vaccination are associated with poorer vaccine responses.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and usually occurs in the context of chronic liver disease. Due to its increasing incidence and high mortality, HCC is a major public health concern. The improved prevention and treatment of chronic hepatitis infection, combined with the recent epidemic of the metabolic syndrome, has led to non-alcoholic fatty liver disease (NAFLD) becoming a rapidly growing cause of HCC. NAFLD is now the leading of cause of HCC in many developed countries and is predicted to become much more common worldwide. The rise of NAFLD presents major challenges for the screening, diagnosis and treatment of HCC. Current HCC screening programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently, NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies, including type 2 diabetes mellitus (T2DM), obesity, cardiovascular disease and cerebrovascular disease. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and transarterial chemoembolization (TACE) may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective. This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Further studies are needed to evaluate the effectiveness of current treatment strategies in NAFLD-HCC. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.

Objective: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Design Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Results: neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1(+) dendritic cell activation and CD8(+) T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8(+) T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8(+) T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. Conclusion: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC., Cancer Research UK (CRUK); Newcastle Experimental Cancer Medicine Centre; Accelerator Award; Fondazione AIRC; MRC program; AstraZeneca; Wellcome Trust; Newcatle University Faculty of Medical Sciences; WE Harker Foundation; Ministry of Economy and Competitiveness (MINECO) (MICINN); Fundació Universitària Agustí Pedro i Pons; Instituto de Salud Carlos III (ISCIII); European Union (EU); European Social Fund; German Research Foundation (DFG); Fulbright España; National Institutes of Health (NIH); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute; Fundación Científica de la Asociación Española Contra el Cáncer; Generalitat de Catalunya; Sara Borrell Fellowship

The success of atezolizumab plus bevacizumab treatment contributed to a shift in systemic therapies for hepatocellular carcinoma (HCC) towards combinations that include cancer immunotherapeutic agents. Thus far, the principal focus of cancer immunotherapy has been on interrupting immune checkpoints that suppress antitumour lymphocytes. As well as lymphocytes, the HCC environment includes numerous other immune cell types, among which neutrophils are emerging as an important contributor to the pathogenesis of HCC. A growing body of evidence supports neutrophils as key mediators of the immunosuppressive environment in which some cancers develop, as well as drivers of tumour progression. If neutrophils have a similar role in HCC, approaches that target or manipulate neutrophils might have therapeutic benefits, potentially including sensitization of tumours to conventional immunotherapy. Several neutrophil-directed therapies for patients with HCC (and other cancers) are now entering clinical trials. This Review outlines the evidence in support of neutrophils as drivers of HCC and details their mechanistic roles in development, progression and metastasis, highlighting the reasons that neutrophils are well worth investigating despite the challenges associated with studying them. Neutrophil-modulating anticancer therapies entering clinical trials are also summarized.

HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.

Background and aims: Lenvatinib is an effective drug in advanced HCC. Its combination with the anti-PD1 (programmed cell death protein 1) immune checkpoint inhibitor, pembrolizumab, has generated encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed to explore the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti-PD1. Approach and results: We generated three syngeneic models of HCC in C57BL/6J mice (subcutaneous and orthotopic) and randomized animals to receive placebo, lenvatinib, anti-PD1, or combination treatment. Flow cytometry, transcriptomic, and immunohistochemistry analyses were performed in tumor and blood samples. A gene signature, capturing molecular features associated with the combination therapy, was used to identify a subset of candidates in a cohort of 228 HCC patients who might respond beyond what is expected for monotherapies. In mice, the combination treatment resulted in tumor regression and shorter time to response compared to monotherapies (P < 0.001). Single-agent anti-PD1 induced dendritic and T-cell infiltrates, and lenvatinib reduced the regulatory T cell (Treg) proportion. However, only the combination treatment significantly inhibited immune suppressive signaling, which was associated with the TGFß pathway and induced an immune-active microenvironment (P < 0.05 vs. other therapies). Based on immune-related genomic profiles in human HCC, 22% of patients were identified as potential responders beyond single-agent therapies, with tumors characterized by Treg cell infiltrates, low inflammatory signaling, and VEGFR pathway activation. Conclusions: Lenvatinib plus anti-PD1 exerted unique immunomodulatory effects through activation of immune pathways, reduction of Treg cell infiltrate, and inhibition of TGFß signaling. A gene signature enabled the identification of ~20% of human HCCs that, although nonresponding to single agents, could benefit from the proposed combination.

Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease. publishedVersion

BackgroundNorthern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region.ObjectiveTo assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region.DesignWe prospectively audited our service for the first year of the pandemic (March 2020–February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019–February 2020).ResultsWe observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection.ConclusionThe pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.

Daniel Geh,1,* Fahd A Rana,2,* Helen L Reeves1,3 1Northern Institute for Cancer Research, Newcastle University Medical School, Newcastle upon Tyne, UK; 2The Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK; 3The Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK *These authors contributed equally to this work Abstract: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and usually occurs in people with liver cirrhosis. Both the incidence and mortality of HCC are increasing worldwide, making it a growing public health issue. HCC diagnosed at an early stage has a far better prognosis than HCC diagnosed at a late stage, mainly because early stage HCC can be treated with potentially curative therapies such as resection and transplantation. This makes surveillance for HCC in patients with liver cirrhosis an important strategy in improving outcomes. Serial measurements of serum alpha fetoprotein (AFP) and abdominal ultrasound (US) are the established methods of surveillance. Surveillance using a combination of these techniques has reasonable sensitivity and specificity and reduces mortality from HCC by varying degrees, depending on the patient population. However, there are potential harms. The main harms result from false-positive and false-negative results. False-positive results commit patients to undergo further, potentially invasive and ultimately unnecessary diagnostic testing – which has both financial and emotional costs. False-negative results can have devastating consequences for patients who later present with more advanced HCC. Obesity is increasingly prevalent and reduces the sensitivity of US in detecting HCC. Obesity-associated non-alcoholic fatty liver disease (NAFLD) presents an additional challenge, where HCC can develop in the absence of cirrhosis. As surveillance with US and AFP is not cost-effective in NAFLD without cirrhosis, it is not advocated. These aspects will be reviewed. Keywords: hepatocellular carcinoma, liver cirrhosis, surveillance, NAFLD, screening

Introduction Experts are able to predict and differentiate between neoplastic and non-neoplastic colonic polyps with high accuracy and meet the PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) thresholds. However, this has not been replicated in non-experts and cannot be currently recommended in clinical practice. The aim of this randomised trial was to establish the optimum method of training to increase the diagnostic accuracy of diminutive/small colonic polyp histological prediction by trainee gastroenterologists. Methods Gastroenterology trainees from the Midlands, UK, reviewed 78 videos (48 i-Scan-OE+30 NBI) of diminutive/small polyps. Participants were randomised to computer-based learning or didactic training. The 78 videos (randomised order) were re-assessed. The NICE (NBI International Colorectal Endoscopic) classification and SIMPLE (Simplified Identification Method for Polyp Labelling during Endoscopy) classification systems were used to classify diminutive/small polyps (figure 1). Results 16 trainees (12 gastroenterology trainees and 4 naive endoscopists) were randomised to receive either self-training (n=8) or didactic training (n=8). A higher proportion of high confidence predictions of polyps were made by the self-training group vs didactic group when using the SIMPLE classification 77.1% vs. 69.9% (p Conclusions Self-learning for the prediction of diminutive/small polyp histology is a method of training that can achieve results similar to the more labour intensive and expensive didactic training. The availability of adequate self-learning teaching modules that teach how to differentiate neoplastic vs non-neoplastic colonic polyps with high accuracy could enable more widespread implementation of optical diagnosis in clinical practice.