Publications
246 results found
Pinato DJ, D'Alessio A, Fulgenzi CAM, et al., 2024, Safety and preliminary efficacy of pembrolizumab following trans-arterial chemoembolization for hepatocellular carcinoma: the PETAL phase Ib study., Clin Cancer Res
BACKGROUND: TACE may prime adaptive immunity and enhance immunotherapy efficacy. PETAL evaluated safety, preliminary activity of TACE plus pembrolizumab and explored mechanisms of efficacy. METHODS: Patients with liver-confined HCC were planned to receive up to 2 rounds of TACE followed by pembrolizumab 200 mg every 21 days commencing 30-days post-TACE until disease progression or unacceptable toxicity for up to 1 year. Primary endpoint was safety, 21-days dose-limiting toxicities (DLT) from pembrolizumab initiation. Secondary endpoints included progression-free survival (PFS) and evaluation of tumour and host determinants of response. RESULTS: Fifteen patients were included in the safety and efficacy population: 73% had non-viral cirrhosis, median age was 72 years. Child-Pugh (CP) class was A in 14 patients. Median tumour size was 4 cm. Ten patients (67%) received pembrolizumab after 1 TACE, 5 patients after 2 (33%). Pembrolizumab yielded no synergistic toxicity nor DLTs post-TACE. Treatment-related adverse events occurred in 93% of patients most commonly skin rash (40%), fatigue and diarrhoea (27%). After a median follow-up of 38.5 months, objective response rate (ORR) 12 weeks post-TACE was 53%. PFS rate at 12 weeks was 93% and median PFS was 8.95 months (95%CI 7.30-NA). Median duration of response was 7.3 months (95%CI: 6.3-8.3). Median OS was 33.5 months (95%CI: 11.6-NA). Dynamic changes in peripheral T-cell subsets, circulating tumour DNA, serum metabolites and in stool bacterial profiles highlight potential mechanisms of action of multi-modal therapy. CONCLUSIONS: TACE plus pembrolizumab was tolerable with no evidence of synergistic toxicity, encouraging further clinical development of immunotherapy alongside TACE.
Dubash S, Barwick TD, Kozlowski K, et al., 2024, Somatostatin receptor imaging with [18F]FET-bAG-TOCAPET/CT and [68Ga]Ga-DOTA-peptide PET/CT in patientswith neuroendocrine tumors: a prospective, phase 2comparative study, The Journal of Nuclear Medicine, Vol: 65, Pages: 416-422, ISSN: 0161-5505
There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-βAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-βAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-βAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6–180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-βAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-βAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-βAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-βAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in rout
Murphy R, Chander G, Martinez M, et al., 2023, Study protocol of LANTana: A phase Ib study to investigate epigenetic modification of somatostatin receptor-2 with ASTX727 to improve therapeutic outcome with [177Lu]Lu-DOTA-TATE in patients with metastatic neuroendocrine tumours, United Kingdom, BMJ Open, Vol: 13, ISSN: 2044-6055
Introduction: Suitability for peptide receptor radionuclide therapy (PRRT) for neuroendocrine neoplasia (NENs) depends on presence of somatostatin receptor-2 (SSTR2) determined by [68Ga]Ga-DOTA-peptide-positron emission tomography (PET). Some patients have low or no uptake on [68Ga]Ga-DOTA-peptide-PET, precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression. Demethylating agents increase uptake on PET imaging in vivo such that tumours previously negative on PET become positive, correlating with a dose dependent increase in tumoural SSTR2 expression. LANTana will determine whether treatment with the demethylating agent, ASTX727, results in re-expression of SSTR2 using [68Ga]Ga-DOTA-peptide-PET to image epigenetic modification of the SSTR2 locus, allowing subsequent PRRT.Methods and analysis: 27 participants with a histologic diagnosis of NEN (Ki67<55%) with no or low uptake on baseline [68Ga]Ga-DOTA-TATE-PET/CT will be recruited. Patients will receive 5 days of ASTX727 (fixed dose 35mg decitabine + 100mg cedazuridine). [68Ga]Ga-DOTA-peptide-PET/CT will be repeated day 8+2; where there is significant uptake greater than liver in most lesions, PRRT will be administered. Primary objective is to determine re-expression of SSTR2 on PET imaging. Tolerability, progression free survival, overall response and quality of life will be assessed. Methylation in peripheral blood mononuclear cells and tumoral methylation will be evaluated. Ethics and dissemination: LANTana has ethical approval from Leeds West Research Ethics Committee (REC Reference: 21/YH/0247).Sponsored by Imperial College London and funded by Advanced Accelerator Applications pharmaceuticals. Results will be presented at conferences and submitted to peer-reviewed journals for publication and will be available on ClinicalTrials.gov.Trial registration numbers: EUDRACT number: 2020-003800-15, NCT05178693
Vithayathil M, D'Alessio A, Fulgenzi CAM, et al., 2023, Impact of body mass index in patients receiving atezolizumab plus bevacizumab for hepatocellular carcinoma, HEPATOLOGY INTERNATIONAL, Vol: 17, Pages: 904-914, ISSN: 1936-0533
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- Citations: 3
De Souza S, Kahol de Jong J, Perone Y, et al., 2023, Impact of COVID-19 on 1-year survival outcomes in hepatocellular carcinoma: a multicenter cohort study, Cancers (Basel), Vol: 15, Pages: 1-10, ISSN: 2072-6694
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.
D'Alessio A, Fulgenzi C, Scheiner B, et al., 2023, The ALBI grade refines prognostic prediction in advanced hepatocellular cancer and enables risk stratification for bleeding events following atezolizumab plus bevacizumab, Publisher: ELSEVIER, Pages: S575-S575, ISSN: 0168-8278
Fulgenzi C, D'Alessio A, Scheiner B, et al., 2023, Feasibility of systemic anti-cancer therapy as an alternative to best supportive care in patients with advanced HCC and Child-Pugh B liver dysfunction, Publisher: ELSEVIER, Pages: S586-S586, ISSN: 0168-8278
Vithayathil M, Vaidyanathan A, Ocal O, et al., 2023, Application of deep learning auto-segmentation and unsupervised machine learning in developing a radiomic prognostic score to predict disease recurrence post radiofrequency ablation for hepatocellular carcinoma, Publisher: ELSEVIER, Pages: S576-S576, ISSN: 0168-8278
Qurashi M, Stafford N, Al-Rubaiy L, et al., 2023, A pilot study to improve the uptake of hepatocellular carcinoma surveillance, Publisher: ELSEVIER, Pages: S864-S864, ISSN: 0168-8278
McNamara MG, Swain J, Craig Z, et al., 2023, NET-02: a randomised, non-comparative, phase II trial of nal-IRI/5-FU or docetaxel as second-line therapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma, ECLINICALMEDICINE, Vol: 60
Fessas P, Scheiner B, D'Alessio A, et al., 2023, PETAL protocol: a phase Ib study of pembrolizumab after transarterial chemoembolization in hepatocellular carcinoma, FUTURE ONCOLOGY, ISSN: 1479-6694
Hamill V, Gelson W, MacDonald D, et al., 2023, Delivery of biannual ultrasound surveillance for individuals with cirrhosis and cured hepatitis C in the UK, LIVER INTERNATIONAL, Vol: 43, Pages: 917-927, ISSN: 1478-3223
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- Citations: 2
Leineweber CG, Rabehl M, Pietzner A, et al., 2023, Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma, FRONTIERS IN PHARMACOLOGY, Vol: 14
Lu H, George J, Eslam M, et al., 2023, Discriminatory changes in circulating metabolites as a predictor of hepatocellular cancer in patients with MAFLD, Liver Cancer, Vol: 12, Pages: 19-31, ISSN: 2235-1795
Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC. Methods: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC. Results: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721–0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793–0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09–1.83, p < 0.01). Conclusion: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.
Jesuthasan A, McColgan P, Sharma R, et al., 2023, Anti-amphiphysin associated paraneoplastic diencephalitis secondary to a thymic neuroendocrine tumour, NEUROLOGICAL SCIENCES, Vol: 44, Pages: 745-748, ISSN: 1590-1874
Buch S, Innes H, Lutz PL, et al., 2023, Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study, Gut, Vol: 72, Pages: 381-391, ISSN: 0017-5749
OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.
Huang J, Sigon G, Mullish BH, et al., 2023, Applying Lipidomics to Non-Alcoholic Fatty Liver Disease: A Clinical Perspective, Nutrients, Vol: 15, ISSN: 2072-6643
The prevalence of Non-alcoholic fatty liver disease (NAFLD) and associated complications, such as hepatocellular carcinoma (HCC), is growing worldwide, due to the epidemics of metabolic risk factors, such as obesity and type II diabetes. Among other factors, an aberrant lipid metabolism represents a crucial step in the pathogenesis of NAFLD and the development of HCC in this population. In this review, we summarize the evidence supporting the application of translational lipidomics in NAFLD patients and NAFLD associated HCC in clinical practice.
Leineweber CG, Rabehl M, Pietzner A, et al., 2023, Corrigendum: Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma., Front Pharmacol, Vol: 14, ISSN: 1663-9812
[This corrects the article DOI: 10.3389/fphar.2023.1124214.].
Wu YL, Fulgenzi CAM, D'Alessio A, et al., 2022, Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Biomarkers in Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab, CANCERS, Vol: 14
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- Citations: 13
Evans JS, Beaumont J, Braga M, et al., 2022, Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy, European Journal of Cancer, Vol: 176, Pages: 110-120, ISSN: 0959-8049
BackgroundSomatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification.MethodsThe effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo.ResultsPyrosequencing of cell lines illustrated differential methylation indices – BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign −3.75,p < 0.01).ConclusionGuadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.
Fulgenzi CAM, Cheon J, D'Alessio A, et al., 2022, Reproducible safety and efficacy of atezolizumab plus bevacizumab for HCC in clinical practice: Results of the AB-real study, EUROPEAN JOURNAL OF CANCER, Vol: 175, Pages: 204-213, ISSN: 0959-8049
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- Citations: 15
Vithayathil M, D'Alessio A, Fulgenzi CAM, et al., 2022, Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma, Liver International, Vol: 42, Pages: 2538-2547, ISSN: 1478-3223
Background and AimsCombination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC.Methods191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment-related adverse events (trAEs) were evaluated.ResultsThe elderly (n = 116) had higher rates of non-alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p = .02) with less portal vein thrombosis (31.9 vs. 54.7%, p = .002), with fewer patients presenting with BCLC-C stage disease (50.9 vs. 74.3%, p = .002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65–2.02 p = .63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54–1.92; p = .72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p = .27) and DCR (77.5% vs. 66.1%; p = .11) compared to younger patients. Atezolizumab-related (40.5% vs. 48.0%; p = .31) and bevacizumab-related (44.8% vs. 41.3%; p = .63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity-related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients.ConclusionsAtezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC.
Craig Z, Swain J, Sharma R, et al., 2022, Health-related quality of life (HRQoL) in patients (pts) with progressive, poorly differentiated, extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) enrolled in NET-02: A phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy, Quality Care Symposium of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 293-293, ISSN: 0732-183X
Huang J, Forlano R, Wang D, et al., 2022, A specific lipidomic fingerprint is associated with the development of nalfd-associated hcc in an animal model, EASL NAFLD summit 2022
Huang J, Forlano R, Wang D, et al., 2022, Anti-pd-1 treatment affects lipidomic profile in an animal model of NAFLD-HCC, EASL NAFLD summit 2022
De Souza S, De Jong JK, Jones R, et al., 2022, Impact of COVID-19 pandemic on clinical outcomes in hepatocellular carcinoma: A multicentre cohort study, Annual Meeting of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S870-S871, ISSN: 0923-7534
Howell J, Samani A, Mannan B, et al., 2022, Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study, THERAPEUTIC ADVANCES IN GASTROENTEROLOGY, Vol: 15, ISSN: 1756-283X
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- Citations: 2
Sharma R, Slater S, Evans J, et al., 2022, ArTisaN trial protocol: a single Centre, open-label, phase II trial of the safety and efficacy of TheraSphere selective internal radiation therapy (SIRT) in the treatment of inoperable metastatic (liver) neuroendocrine neoplasia (NENs), BMC CANCER, Vol: 22
Fulgenzi CAM, D'Alessio A, Ogunbiyi O, et al., 2022, Novel immunotherapy combinations in clinical trials for hepatocellular carcinoma: will they shape the future treatment landscape?, EXPERT OPINION ON INVESTIGATIONAL DRUGS, Vol: 31, Pages: 681-691, ISSN: 1354-3784
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- Citations: 7
U MRA, Shen EY-L, Cartlidge C, et al., 2022, Optimised systematic review tool: Application to candidate biomarkers for the diagnosis of hepatocellular carcinoma, Cancer Epidemiology, Biomarkers and Prevention, Vol: 31, Pages: 1261-1274, ISSN: 1055-9965
This review aims to develop an appropriate review tool for systematically collating metabolites that are dysregulated in disease and applies the method to identify novel diagnostic biomarkers for hepatocellular carcinoma (HCC). Studies that analysed metabolites in blood or urine samples where HCC was compared with comparison groups (healthy, pre-cirrhotic liver disease, cirrhosis) were eligible. Tumour tissue was included to help differentiate primary and secondary biomarkers. Searches were conducted on Medline and EMBASE. A bespoke 'risk-of-bias' tool for metabolomic studies was developed adjusting for analytical quality. Discriminant metabolites for each sample type were ranked using a weighted score accounting for the direction and extent of change and the risk of bias of the reporting publication. A total of 84 eligible studies were included in the review (54 blood, 9 urine and 15 tissue), with six studying multiple sample types. High-ranking metabolites, based on their weighted score, comprised energy metabolites, bile acids, acylcarnitines and lysophosphocholines. This new review tool addresses an unmet need for incorporating quality of study design and analysis to overcome the gaps in standardisation of reporting of metabolomic data. Validation studies, standardised study designs and publications meeting minimal reporting standards are crucial for advancing the field beyond exploratory studies.
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