Publications
505 results found
Alexander J, Ibraheim H, Sheth B, et al., 2021, A MULTI-CENTRE STUDY OF INFLIXIMAB TREATMENT FOR CORTICOSTEROID-REFRACTORY CHECKPOINT INHIBITOR INDUCED ENTEROCOLITIS, Publisher: BMJ PUBLISHING GROUP, Pages: A22-A22, ISSN: 0017-5749
Pinato DJ, Marron TU, Mishra-Kalyani PS, et al., 2021, Treatment-related toxicity and improved outcome from immunotherapy in hepatocellular cancer: Evidence from an FDA pooled analysis of landmark clinical trials with validation from routine practice, EUROPEAN JOURNAL OF CANCER, Vol: 157, Pages: 140-152, ISSN: 0959-8049
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- Citations: 32
Fessas P, Naeem M, Pinter M, et al., 2021, Early Antibiotic Exposure Is Not Detrimental to Therapeutic Effect from Immunotherapy in Hepatocellular Carcinoma, LIVER CANCER, Vol: 10, Pages: 583-592, ISSN: 2235-1795
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- Citations: 23
Demirtas CO, 'Alessio A, Rimassa L, et al., 2021, ALBI grade: Evidence for an improved model for liver functional estimation in patients with hepatocellular carcinoma, JHEP REPORTS, Vol: 3
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- Citations: 40
Fulgenzi CAM, Talbot T, Murray SM, et al., 2021, Immunotherapy in Hepatocellular Carcinoma, CURRENT TREATMENT OPTIONS IN ONCOLOGY, Vol: 22, ISSN: 1527-2729
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- Citations: 22
Pinato D, Murray S, Forner A, et al., 2021, Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy., Journal for ImmunoTherapy of Cancer, Vol: 9, Pages: 1-9, ISSN: 2051-1426
Background: Modulation of adaptive immunity may underscore the efficacy of TACE. We evaluated the influence of TACE on T-cell function by phenotypic lymphocyte characterization in samples of patients undergoing surgery with (T+) or without (T-) prior-TACE treatment.Methods: We profiled intra-tumoural (IT), peri-tumoural (PT) and non-tumoural background tissue (NT) to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD1+ T-cells across T+ (n=58) and T- (n=61). We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples (n=24) evaluated in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163.Results: We analyzed 119 patients resected (n=25, 21%) or transplanted (n=94, 79%) for Child-Pugh A (n=65, 55%) and Barcelona Clinic Liver Cancer stage A (n=92, 77%) HCC. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD1+ and NT CD8+/PD1+ (p<0.001) compared to T-. Lower IT (p=0.005) and NT CD4+/FOXP3+ (p=0.03) predicted for improved recurrence-free survival. In a subset of samples (n=24), transcriptomic analysis revealed up-regulation of a pro-inflammatory response in T+. T+ samples were enriched for IRF2 expression (p=0.01), an interferon-regulated transcription factor implicated in cancer immune-evasion. T-cell clonality and expression of PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163 was similar in T+ versus T-.Conclusions: TACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant up-regulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumour microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.
Soosaipillai G, Wu A, Dettorre GM, et al., 2021, Specialist palliative and end-of-life care for patients with cancer and SARS-CoV-2 infection: a European perspective, Therapeutic Advances in Medical Oncology, Vol: 13, Pages: 1-17, ISSN: 1758-8340
Background: Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres. Methods: From the OnCovid repository (n=1,318), we analysed cancer patients aged ≥18 diagnosed with COVID-19 between 26th February and 22nd June 2020 who had complete specialist palliative care team (SPCT) data (SPCT+ referred; SPCT- not referred).Results: Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had >1 co-morbidity. 206 patients received SPCT input for symptom control (80.1%), psychological support (54.4%), and/or advance care planning (51%). SPCT+ patients had more DNACPR orders completed prior to (12.6% vs. 3.7%) and during admission (50% vs 22.1%, P<0.001), with more SPCT+ patients deemed suitable for treatment escalation (50% vs. 22.1%, P<0.001). SPCT involvement was associated with higher discharge rates from hospital for end-of-life care (9.7% vs. 0%, P<0.001). End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% vs. 47.1%) and benzodiazepines (82.9% vs. 41.2%) being used frequently for symptom control.Conclusions: SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCT for patients with cancer during the pandemic and should inform service planning for this population.
Greten TF, Abou-Alfa GK, Cheng A-L, et al., 2021, Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of hepatocellular carcinoma, JOURNAL FOR IMMUNOTHERAPY OF CANCER, Vol: 9
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- Citations: 34
Cortellini A, Bersanelli M, Pinato JD, et al., 2021, Response to letter entitled: Re: Predictive ability of a drug-based score in advanced non-small cell lung cancer patients receiving first-line immunotherapy, EUROPEAN JOURNAL OF CANCER, Vol: 155, Pages: 315-316, ISSN: 0959-8049
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- Citations: 1
Hulbert-Williams NJ, Leslie M, Hulbert-Williams L, et al., 2021, Evaluating the impact of COVID-19 on supportive care needs, psychological distress and quality of life in UK cancer survivors and their support network, EUROPEAN JOURNAL OF CANCER CARE, Vol: 30, ISSN: 0961-5423
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- Citations: 11
Schettini F, Giuliano M, Lambertini M, et al., 2021, Anthracyclines Strike Back: Rediscovering Non-Pegylated Liposomal Doxorubicin in Current Therapeutic Scenarios of Breast Cancer, CANCERS, Vol: 13
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- Citations: 7
Scheiner B, Pomej K, Kirstein MM, et al., 2021, Predicting the outcome of patients with hepatocellular carcinoma treated with immunotherapy - the CRAFITY score, Publisher: SPRINGER WIEN, Pages: 179-179, ISSN: 0043-5325
Abdelmalak R, Lythgoe MP, Evans J, et al., 2021, Exploration of novel prognostic markers in grade 3 neuroendocrine neoplasia, Cancers, Vol: 13, Pages: 1-12, ISSN: 2072-6694
Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified
Pardo O, Chrysostomou S, Roy R, et al., 2021, Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer, Science Translational Medicine, Vol: 13, ISSN: 1946-6234
Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.
Alexander J, Ibraheim H, Sheth B, et al., 2021, Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor induced enterocolitis treated with infliximab, Journal for ImmunoTherapy of Cancer, Vol: 9, Pages: 1-9, ISSN: 2051-1426
IntroductionImmune Checkpoint Inhibitors (CPI) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. MethodsWe conducted a multi-centre (six cancer centres), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with CTCAE grade 0 for diarrhoea at 12 weeks after IFX initiation. We also assessed cancer outcomes at one year using RECIST criteria.Results127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhoea CTCAE grade >2 and 115 (90.6%) required hospitalisation for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistical regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04-0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13-8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared to patients with IFX-responsive enterocolitis (37.5%; p=0.013).ConclusionThis is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Utilizing pre-defined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI-therapy.
Pinato DJ, Fessas P, Sapisochin G, et al., 2021, Perspectives on the neoadjuvant use of immunotherapy in hepatocellular carcinoma, Hepatology, Vol: 74, Pages: 483-490, ISSN: 0270-9139
Immune checkpoint inhibitor (ICI) therapy is an increasingly used treatment modality across the various stages of hepatocellular cancer (HCC). There is currently no standard peri-operative therapy for HCC, despite a high probability of recurrence. Emerging studies in a variety of tumors demonstrate significant pathologic and immune responses to neoadjuvant immunotherapy. Unlike kinase inhibitors and other targeted therapies, which demonstrated no benefit in the adjuvant setting and fail to induce significant responses, ICIs can induce radiologically appreciable reduction in disease burden, which make ICI combinations an appealing downstaging strategy in patients early or locally advanced disease. Additionally, induction of anti-tumor immunity in the pre-operative setting may induce protracted T-cell response that, in the post-operative phase, may be capable of eliminating micro-metastatic disease and prevent future recurrence. In this review, we discuss the rationale and clinical hurdles that underlie optimal integration of immunotherapy in the pre-operative setting, highlighting the positive impact on surgical and oncological outcomes in patients with early-stage HCC.
Fessas P, Naeem M, Marron TU, et al., 2021, Early antibiotic exposure delays disease progression following immune checkpoint inhibitor therapy for hepatocellular carcinoma: Evidence from an observational study., Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Dettorre GM, Dolly S, Loizidou A, et al., 2021, The acute phase response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection as quantified by the OnCovid Inflammatory Score., Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pinato DJ, Cortellini A, Balcells C, et al., 2021, A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL, Publisher: ELSEVIER, Pages: S245-S246, ISSN: 0168-8278
Scheiner B, Pomej K, Kirstein MM, et al., 2021, Predicting the outcome of patients with hepatocellular carcinoma treated with immunotherapy-the CRAFITY score, International Liver Congress, Publisher: ELSEVIER, Pages: S236-S238, ISSN: 0168-8278
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- Citations: 1
Possamai L, Gudd C, Au L, et al., 2021, Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis, Journal of Hepatology, Vol: 75, Pages: 177-189, ISSN: 0168-8278
Background & Aims: Checkpoint inhibitor-related hepatitis (CPI-Hep) is an emerging clinical challenge. We aimed to gain insights into the immunopathology of CPI-Hep by comprehensively characterising myeloid and lymphoid subsets.Methods: CPI-treated patients with or without related hepatitis (CPI-Hep; n = 22 and CPI-noHep; n = 7) were recruited. Phenotypic and transcriptional profiling of peripheral immune subsets was performed and compared with 19 healthy controls (HCs). In vitro monocyte-derived macrophages (MoMFs) were assessed for activation and cytokine production. CD163, CCR2, CD68, CD3, CD8 and granzyme B expression was assessed using immunohistochemistry/immunofluorescence (n = 4).Results: A significant total monocyte depletion was observed in CPI-Hep compared with HCs (p = 0.04), along with a proportionate increase in the classical monocyte population (p = 0.0002) and significant upregulation of CCR2, CD163 and downregulation of CCR7. Soluble CD163 levels were significantly elevated in CPI-Hep compared with HCs (p <0.0001). In vitro MoMFs from CPI-Hep showed enhanced production of pro-inflammatory cytokines. CD8+ T cells demonstrated increased perforin, granzyme B, ICOS and HLA-DR expression in CPI-Hep. Transcriptional profiling indicated the presence of activated monocyte and enhanced effector CD8+ T cell populations in CPI-Hep. Immunohistochemistry demonstrated co-localisation of CD8+/granzyme B+ T cells with CD68+CCR2+/CD68+CD163+ macrophages in CPI-Hep liver tissue.Conclusions: CPI-Hep is associated with activation of peripheral monocytes and an enhanced cytotoxic, effector CD8+ T cell phenotype. These changes were reflected by liver inflammation composed of CD163+/CCR2+ macrophages and CD8+ T cells.Lay summary: Some patients who receive immunotherapy for cancer develop liver inflammation, which requires cessation of cancer treatment. Herein, we describe ways in which the white blood cells of patients who develop liver inflammation differ from tho
Munoz-Martinez S, Sapena V, Forner A, et al., 2021, Early SARS-CoV-2-related mortality of liver cancer patients: Cancer stage matters, Publisher: ELSEVIER, Pages: S495-S496, ISSN: 0168-8278
Pinato DJ, Valeri N, Muhammed A, et al., 2021, Therapeutic targeting of VEGFR2 in HBV-associated hepatocellular carcinoma, LANCET GASTROENTEROLOGY & HEPATOLOGY, Vol: 6, Pages: S15-S16
Santini D, Zeppola T, Russano M, et al., 2021, PD-1/PD-L1 checkpoint inhibitors during late stages of life: an ad-hoc analysis from a large multicenter cohort, JOURNAL OF TRANSLATIONAL MEDICINE, Vol: 19
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- Citations: 10
Muñoz-Martínez S, Sapena V, Forner A, et al., 2021, Assessing the impact of COVID-19 on liver cancer management (CERO-19), JHEP Reports, Vol: 3, ISSN: 2589-5559
BACKGROUND: The coronavirus 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). This project has evaluated if the schedule of LC screening or procedures has been interrupted /delayed because of the COVID-19 pandemic. MATERIAL AND METHODS: An international survey evaluated the impact of COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. RESULTS: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia and Africa (73.7%, 17.1%, 5.3%, 2.6% and 1.3% per continent, respectively). Eighty-seven per cent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening program, 50% cancelled curative and/or palliative treatments for LC, and 44.0% cancelled the liver transplantation program. Forty-five out 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service prior to COVID-19 pandemic (n=19/37). CONCLUSION: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with LC. Modifications in screening, diagnostic and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision making.
Openshaw MR, Pinato DJ, Valeri N, 2021, Back from the Brink: EGFR Inhibition in Gastroesophageal Cancer, CLINICAL CANCER RESEARCH, Vol: 27, Pages: 2964-2966, ISSN: 1078-0432
Naqash AR, Kihn-Alarcon AJ, Stavraka C, et al., 2021, The role of gut microbiome in modulating response to immune checkpoint inhibitor therapy in cancer, Annals of Translational Medicine, Vol: 9, Pages: 1-11, ISSN: 2305-5839
Immunotherapy has led to a paradigm shift in the treatment of several cancers. There have been significant efforts to identify biomarkers that can predict response and toxicities related to immune checkpoint inhibitor (ICPI) therapy. Despite these advances, it has been challenging to tease out why a subset of patients benefit more than others or why certain patients experience immune-related adverse events (irAEs). Although the immune-modulating properties of the human gut bacterial ecosystem are yet to be fully elucidated, there has been growing interest in evaluating the role of the gut microbiome in shaping the therapeutic response to cancer immunotherapy. Considerable research efforts are currently directed to utilizing metagenomic and metabolic profiling of stool microbiota in patients on ICPI-based therapies. Dysbiosis or loss of microbial diversity has been associated with a poor treatment response to ICPIs and worse survival outcomes in cancer patients. Emerging data have shown that certain bacterial strains, such as Faecalibacterium that confer sensitivity to ICPI, also have a higher propensity to increase the risk of irAEs. Additionally, the microbiome can modulate the local immune response at the intestinal interface and influence the trafficking of bacterial peptide primed T-cells distally, influencing the toxicity patterns to ICPI. Antibiotic or diet induced alterations in composition of the microbiome can also indirectly alter the production of certain bacterial metabolites such as deoxycholate and short chain fatty acids that can influence the anti-tumor tolerogenesis. Gaining sufficient understanding of the exact mechanisms underpinning the interplay between ICPI induced anti-tumor immunity and the immune modulatory role gut microbiome can be vital in identifying potential avenues of improving outcomes to cancer immunotherapy. In the current review, we have summarized and highlighted the key emerging data supporting the role of gut microbiome in regu
Dettorre G, Patel M, Cortellini A, et al., 2021, The systemic pro-inflammatory response: targeting the dangerous liaison between COVID-19 and cancer, ESMO Open, Vol: 6, ISSN: 2059-7029
Inflammation is an established driver of severe SARS-CoV-2 infection and a mechanism linked to the increased susceptibility to fatal COVID-19 demonstrated by patients with cancer. As patients with cancer exhibit a higher level of inflammation compared to the general patient population, patients with cancer and COVID-19 may uniquely benefit from strategies targeted at overcoming the unrestrained pro-inflammatory response. Targeted and non-targeted anti-inflammatory therapies may prevent end-organ damage in SARS-CoV-2-infected patients with cancer and decrease mortality. Here, we review the clinical role of selective inhibition of pro-inflammatory interleukins, tyrosine kinase modulation, anti-TNF agents, and other non-targeted approaches including corticosteroids in their roles as disease-modulating agents in patients with COVID-19 and cancer. Investigation of these therapeutics in this highly vulnerable patient group is posited to facilitate the development of tailored therapeutics for this patient population, aiding the transition of systemic inflammation from a prognostic domain to a source of therapeutic targets.
Vogel A, Rimassa L, Sun H-C, et al., 2021, Comparative Efficacy of Atezolizumab plus Bevacizumab and Other Treatment Options for Patients with Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis, LIVER CANCER, Vol: 10, Pages: 240-248, ISSN: 2235-1795
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- Citations: 27
Pinato DJ, Scotti L, Gennari A, et al., 2021, Determinants of enhanced vulnerability to coronavirus disease 2019 in UK patients with cancer: a European study, EUROPEAN JOURNAL OF CANCER, Vol: 150, Pages: 190-202, ISSN: 0959-8049
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- Citations: 30
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