Imperial College London

DrRohiniSharma

Faculty of MedicineDepartment of Surgery & Cancer

Reader in Clinical Pharmacology & Medical Oncology
 
 
 
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Contact

 

+44 (0)20 3313 3059r.sharma Website

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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160 results found

Han G, Berhane S, Toyoda H, Bettinger D, Elshaarawy O, Chan AWH, Kirstein M, Mosconi C, Hucke F, Palmer D, Pinato DJ, Sharma R, Ottaviani D, Jang JW, Labeur TA, van Delden OM, Pirisi M, Stern N, Sangro B, Meyer T, Fateen W, García-Fiñana M, Gomaa A, Waked I, Rewisha E, Aithal GP, Travis S, Kudo M, Cucchetti A, Peck-Radosavljevic M, Takkenberg RB, Chan SL, Vogel A, Johnson PJet al., 2019, Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach., Hepatology, ISSN: 0270-9139

The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological response (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) was also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A new pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. Median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, etiology, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared to existing models (the HAP score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. Conclusion: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.

Journal article

Stickel F, Lutz P, Buch S, Nischalke HD, Silva I, Rausch V, Fischer J, Weiss KH, Gotthardt D, Rosendahl J, Marot A, Elamly M, Krawczyk M, Casper M, Lammert F, Buckley TW, McQuillin A, Spengler U, Eyer F, Vogel A, Marhenke S, von Felden J, Wege H, Sharma R, Atkinson S, Franke A, Nehring S, Moser V, Schafmayer C, Spahr L, Lackner C, Stauber RE, Canbay A, Link A, Valenti L, Grove JI, Aithal GP, Marquardt JU, Fateen W, Zopf S, Dufour J-F, Trebicka J, Datz C, Deltenre P, Mueller S, Berg T, Hampe J, Morgan MYet al., 2019, Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers., Hepatology, ISSN: 0270-9139

BACKGROUND & AIMS: Carriage of rs738409:G in patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with PNPLA3 rs738409:G. This study explores the risk-associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including: 1,031 with alcohol-related cirrhosis and HCC; 1,653 with alcohol-related cirrhosis without HCC; 2,588 alcohol misusers with no liver disease; and 899 healthy controls. Genetic associations with the risks for alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for both cirrhosis (OR 0.79 [95% CI 0.72-0.88], p=8.13×10-6) and HCC (OR 0.77 [95% CI 0.68-0.89], p=2.27×10-4), while carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR 1.70 [95% CI 1.54-1.88], p=1.52x10-26) and HCC (OR 1.77 [95% CI 1.58-1.98], p=2.31×10-23). These associations remained significant after adjusting for age, sex, body mass index, type II diabetes mellitus and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women but the protective effect against the subsequent development of HCC was only observed in men (p=1.72×10-4; ORallelic, 0.75; 95% CI, 0.64-0.87). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of

Journal article

Sharma R, Wang WM, Yusuf S, Evans J, Ramaswami R, Wernig F, Frilling A, Mauri F, Al-Nahhas A, Aboagye EO, Barwick TDet al., 2019, 68Ga-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours, Radiotherapy and Oncology, ISSN: 0167-8140

PURPOSE: [177Lu]DOTATATE prolongs progression free survival (PFS) in metastatic neuroendocrine tumours (NETs). However, objective response rate is low. This, coupled with long duration of therapy and expense suggest need for better selection. We aim to assess whether baseline [68Ga]DOTATATE-PET/CT parameters, and whether response assessment by PET accurately predicts clinical outcome to [177Lu]DOTATATE. EXPERIMENTAL DESIGN: Retrospective study of patients receiving [177Lu]DOTATATE was conducted. Patients were followed 3-monthly until disease progression. Four [68Ga]DOTATATE-PET parameters (single lesion SUVmax, tumour to spleen and liver SUV ratios, and SUVmax-av using up to five target lesions in multiple organ sites) were determined at baseline and follow-up. The association between these PET parameters either at baseline, or any changes following treatment, and PET response criteria (PERCIST and modified PERCIST) to predict PFS were determined. Patients were followed 3-monthly until disease progression. Response was determined using RECIST 1.1. Baseline SSTR2 expression was assessed and compared with PET parameters. RESULTS: 55 patients with metastatic NETs were identified predominantly small bowel (N = 18) and pancreatic (N = 8) in origin. 16 were low grade, 15 intermediate and 3 high grade. Response to PRRT (N = 47): partial response (PR) 28%, stable disease (SD) 60% progressive disease (PD) 13%. Response to PRRT predicted PFS: PR 71.8 months (95%CI: not achieved), SD 29.1 months (95%CI: 15.2-43.1), and PD 9.7 months (95%CI: 0-21.02). Baseline, single lesion SUVmax predicted both response and PFS with SUV cut-off of 13.0 giving high sensitivity and specificity. Tumoural SUVmax correlated with SSTR2 expression, Spearman's rho - 0.69, p < 0.01. CONCLUSIONS: Baseline single lesion SUVmax and SUVmax-av predicts response to [177Lu]DOTATATE. Objective response following PRRT defines a subset of patients with markedly improved PFSBaseline SUVmax 13.0 defines a thre

Journal article

Trousil S, Lee P, Edwards RJ, Maslen L, Lozan-Kuehne JP, Ramaswami R, Aboagye EO, Clarke S, Liddle C, Sharma Ret al., 2019, Altered cytochrome 2E1 and 3A P450-dependent drug metabolism in advanced ovarian cancer correlates to tumour-associated inflammation, British Journal of Pharmacology, Vol: 176, Pages: 3712-3722, ISSN: 0007-1188

Background and PurposePrevious work has focussed on changes in drug metabolism caused by altered activity of CYP3A in the presence of inflammation and, in particular, inflammation associated with malignancy. However, drug metabolism involves a number of other P450s, and therefore, we assessed the effect of cancer‐related inflammation on multiple CYP enzymes using a validated drug cocktail.Experimental ApproachPatients with advanced stage ovarian cancer and healthy volunteers were recruited. Participants received caffeine, chlorzoxazone, dextromethorphan, and omeprazole as in vivo probes for CYP1A2, CYP2E1, CYP2D6, CYP3A, and CYP2C19. Blood was collected for serum C‐reactive protein and cytokine analysis.Key ResultsCYP2E1 activity was markedly up‐regulated in cancer (6‐hydroxychlorzoxazone/chlorzoxazone ratio of 1.30 vs. 2.75), while CYP3A phenotypic activity was repressed in cancer (omeprazole sulfone/omeprazole ratio of 0.23 vs. 0.49). Increased activity of CYP2E1 was associated with raised serum levels of IL‐6, IL‐8, and TNF‐α. Repression of CYP3A correlated with raised levels of serum C‐reactive protein, IL‐6, IL‐8, and TNF‐α.Conclusions and ImplicationsCYP enzyme activity is differentially affected by the presence of tumour‐associated inflammation, affecting particularly CYP2E1‐ and CYP3A‐mediated drug metabolism, and may have profound implications for drug development and prescribing in oncological settings.

Journal article

Chambers E, Byrne C, Rugyendo A, Morrison D, Preston T, Tedford C, Bell J, Thomas L, Akbar A, Riddell N, Sharma R, Thursz M, Manousou P, Frost Get al., 2019, The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease, Diabetes, Obesity and Metabolism, Vol: 21, Pages: 372-376, ISSN: 1462-8902

The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non‐alcoholic fatty liver disease (NAFLD). Eighteen adults were randomised to receive 20g/day of an inulin‐propionate ester (IPE), designed to deliver propionate to the colon, or an inulin‐control for 42‐days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between groups (P=0.082), however IHCL significantly increased within the inulin‐control group (20.9±2.9 to 26.8±3.9%; P=0.012; n=9), which was not observed within the IPE group (22.6±6.9 to 23.5±6.8%; P=0.635; n=9). The predominant SCFA from colonic fermentation of inulin is acetate, which in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate‐mediated increase in IHCL.

Journal article

Howell J, Atkinson SR, Pinato DJ, Knapp S, Ward C, Minisini R, Burlone ME, Leutner M, Pirisi M, Büttner R, Khan SA, Thursz M, Odenthal M, Sharma Ret al., 2019, Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma, European Journal of Cancer, Vol: 116, Pages: 56-66, ISSN: 0959-8049

BACKGROUND: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.

Journal article

Bettinger D, Pinato DJ, Schultheiss M, Sharma R, Rimassa L, Pressiani T, Burlone ME, Pirisi M, Kudo M, Park JW, Buettner N, Neumann-Haefelin C, Boettler T, Abbasi-Senger N, Alheit H, Baus W, Blanck O, Gerum S, Guckenberger M, Habermehl D, Ostheimer C, Riesterer O, Tamihardja J, Grosu AL, Thimme R, Brunner TB, Gkika Eet al., 2019, Stereotactic body radiation therapy as an alternative treatment for patients with hepatocellular carcinoma compared to sorafenib: a propensity score analysis, Liver Cancer, Vol: 8, Pages: 281-294, ISSN: 2235-1795

Background and Aims: Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. Methods: We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. Results: Median OS of SBRT patients was 18.1 (10.3–25.9) months compared to 8.8 (8.2–9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8–23.2) months compared to 9.6 (8.6–10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. Conclusions: In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.

Journal article

Pinato D, Mauri F, Spina P, Cain O, Siddique A, Goldin R, Victor S, Pizio C, Akarca A, Boldorini RL, Mazzucchelli L, Black J, Shetty S, Marafioti T, Sharma Ret al., 2019, Clinical implications of heterogeniety in PD-L1 immuno-histochemical detection in hepatocellular carcinoma: the Blueprint-HCC study, British Journal of Cancer, ISSN: 0007-0920

Programmed cell death ligand-1 immunohistochemical detection (PD-L1 IHC) is a putative predictor of response to PD-1/PD-L1-targeted checkpoint inhibitors. However, there is no gold standard assay in hepatocellular carcinoma (HCC). We evaluated 5 PD-L1 IHC assay platforms (E1LN3, 28-8, 22c3, SP263 and SP142) in 100 HCCs reporting PD-L1 expression in malignant (M) and tumour-infiltrating immune cells (TICs) and non-tumorous cirrhotic tissues (NTICs). We found substantial inter-assay heterogeneity in detecting PD-L1 expression in M (R2 = 0.080–0.921), TICs (Cohen’s  κ = 0.175–0.396) and NTICs (κ = 0.004–0.505). Such diversity may impact on the reliability and reproducibility of PD-L1 IHC assays as a predictor of response to immune checkpoint inhibitors.

Journal article

Flynn MJ, Sayed AA, Sharma R, Siddique A, Pinato DJet al., 2019, Challenges and opportunities in the clinical development of immune checkpoint inhibitors for hepatocellular carcinoma, Hepatology, Vol: 69, Pages: 2258-2270, ISSN: 0270-9139

After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPI) has been shown to be effective in advanced hepatocellular carcinoma (HCC). The clinical development of novel ICPIs continues at a rapid pace, with more than 50 clinical trials of immunotherapeutic agents registered as of May 2018 for this indication. The development of ICPI is particularly challenging in patients with HCC, a population with unique features which impact on safety and efficacy of immune-modulating therapies. In this review, we discuss the biologic foundations supporting the development of ICPI across the advancing stages of HCC, focusing in particular on the proposal of a rational positioning of ICPI across the various Barcelona-Clinic Liver Cancer stages of the disease. Translational studies should guide adequate prioritisation of those therapeutic agents and combination strategies which are most likely to achieve patient benefit based on solid mechanistic and clinical justifications.

Journal article

Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, Brandstetter J, Dragicevic M, Eroe J, Del Valle AE, Flechl M, Fruehwirth R, Ghete VM, Hrubec J, Jeitler M, Krammer N, Kraetschmer I, Liko D, Madlener T, Mikulec I, Rad N, Rohringer H, Schieck J, Schoefbeck R, Spanring M, Spitzbart D, Taurok A, Waltenberger W, Wittmann J, Wulz C-E, Zarucki M, Chekhovsky V, Mossolov V, Gonzalez JS, De Wolf EA, Di Croce D, Janssen X, Lauwers J, Pieters M, Van Haevermaet H, Van Mechelen P, Van Remortel N, Abu Zeid S, Blekman F, D'Hondt J, De Clercq J, Deroover K, Flouris G, Lontkovskyi D, Lowette S, Marchesini I, Moortgat S, Moreels L, Python Q, Skovpen K, Tavernier S, Van Doninck W, Van Mulders P, Van Parijs I, Beghin D, Bilin B, Brun H, Clerbaux B, De Lentdecker G, Delannoy H, Dorney B, Fasanella G, Favart L, Goldouzian R, Grebenyuk A, Kalsi AK, Lenzi T, Luetic J, Postiau N, Starling E, Thomas L, Vander Velde C, Vanlaer P, Vannerom D, Wang Q, Cornelis T, Dobur D, Fagot A, Gul M, Khvastunov I, Poyraz D, Roskas C, Trocino D, Tytgat M, Verbeke W, Vermassen B, Vit M, Zaganidis N, Bakhshiansohi H, Bondu O, Brochet S, Bruno G, David P, Delaere C, Delcourt M, Francois B, Giammanco A, Krintiras G, Lemaitre V, Magitteri A, Piotrzkowski K, Saggio A, Marono MV, Wertz S, Zobec J, Alves FL, Alves GA, Correa Martins M, Correia Silva G, Hensel C, Moraes A, Pol ME, Rebello Teles P, Belchior Batista Das Chagas E, Carvalho W, Chinellato J, Coelho E, Da Costa EM, Da Silveira GG, De Jesus Damiao D, De Oliveira Martins C, Fonseca De Souza S, Malbouisson H, Matos Figueiredo D, Melo De Almeida M, Mora Herrera C, Mundim L, Nogima H, Prado Da Silva WL, Sanchez Rosas LJ, Santoro A, Sznajder A, Thiel M, Tonelli Manganote EJ, Torres Da Silva De Araujo F, Vilela Pereira A, Ahuja S, Bernardes CA, Calligaris L, Fernandez Perez Tomei TR, Gregores EM, Mercadante PG, Novaes SF, Padula S, Aleksandrov A, Hadjiiska R, Iaydjiev P, Marinov A, Misheva M, Rodozov M, Shopova M, Sultanov G, Dimitrov A, Litov Let al., 2019, Search for W Boson Decays to Three Charged Pions, Publisher: AMER PHYSICAL SOC

Working paper

Gkika E, Brunner T, Abbasi-Senger N, Alheit H, Baus W, Blanck O, Gerum S, Guckenberger M, Habermehl D, Ostheimer C, Riesterer O, Tamihardja J, Pinato DJ, Rimassa L, Pressiani T, Schultheiss M, Sharma R, Burlone ME, Pirisi M, Kudo M, Park JW, Neumann-Haefelin C, Grosu A, Thimme R, Bettinger Det al., 2019, SBRT compared to sorafenib in locally advanced hepatocellular carcinoma: a propensity score analysis, 38th Annual Meeting of the European-Society-for-Radiotherapy-and-Oncology (ESTRO), Publisher: ELSEVIER IRELAND LTD, Pages: S423-S423, ISSN: 0167-8140

Conference paper

Hajiev S, Pinato DJ, Ramaswami R, Black JM, Arizumi T, Pirisi M, Kudo M, Sharma Ret al., 2019, Sorafenib starting dose impacts on survival in the elderly population with hepatocellular cancer, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E621-E621, ISSN: 0168-8278

Conference paper

Evans J, Pinato D, Ward C, Thursz M, Sharma Ret al., 2019, Longitudinal monitoring of cell-free DNA predicts for transarterial chemo-embolization failure in hepatocellular carcinoma, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E362-E362, ISSN: 0168-8278

Conference paper

Pinato DJ, Goldin RD, Mineo T, Siddique A, Akarca A, Marafioti T, Avellini C, Toniutto P, Mauri F, Sharma Ret al., 2019, Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E374-E375, ISSN: 0168-8278

Conference paper

Samani A, Pinato DJ, Bettinger D, Kaplan DE, Sharma Ret al., 2019, Sorafenib use in patients with HCC on a background of non-alcoholic fatty liver disease, International Liver Congress / 54th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: E621-E621, ISSN: 0168-8278

Conference paper

Pinato D, Brown MW, Trousil S, Aboagye E, Beaumont J, Zhang H, Coley HM, Mauri F, Sharma Ret al., 2019, Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma., British Journal of Cancer, Vol: 120, Pages: 512-521, ISSN: 0007-0920

Background: Aberrant activation of Axl is implicated in the progression of HCC. We explored biologic significance and preclinical efficacy of Axl inhibition as a therapeutic strategy in sorafenib-naïve and resistant HCC.Methods: We evaluated Axl expression in sorafenib-naïve and resistant (SR) clones of epithelial (HuH7) and mesenchymal origin (SKHep-1) using antibody arrays and confirmed tissue expression. We tested the effect of Axl inhibition with RNA-interference and pharmacologically with R428 on a number of phenotypic assays. Results: Axl mRNA overexpression in cell lines (n=28) and RNA-seq tissue datasets (n=373) correlated with epithelial-to-mesenchymal transition (EMT). Axl was overexpressed in HCC compared to cirrhosis and normal liver. We confirmed sorafenib-resistance to be associated with EMT and enhanced motility in both HuH7-SR and SKHep-1-SR cells documenting a 4-fold increase in Axl phosphorylation as an adaptive feature of chronic sorafenib treatment in SKHep-1-SR cells. Axl inhibition reduced motility and enhanced sensitivity to sorafenib in SKHep-1SR cells. In patients treated with sorafenib (n=40) circulating Axl levels correlated with shorter survival.Conclusions: Suppression of Axl-dependent signaling influences the transformed phenotype in HCC cells and contributes to adaptive resistance to sorafenib, providing a pre-clinical rationale for the development of Axl inhibitors as a measure to overcome sorafenib resistance.

Journal article

Black J, Atkinson S, Singh A, Evans J, Sharma Ret al., 2019, The inflammation-based index can predict response and improve patient selection in NETs treated with PRRT: a pilot study, Journal of Clinical Endocrinology and Metabolism, Vol: 104, Pages: 285-292, ISSN: 0021-972X

BackgroundPeptide Receptor Radionuclide Therapy (PRRT) is an effective treatment for certain patients with metastatic neuroendocrine tumours (NETs). Tumour response is highly variable; no biomarker in clinical practice has been demonstrated to reliably predict outcome. The Inflammation-Based Index (IBI), derived from serum C-reactive protein and albumin levels, predicts survival and response to treatment in patients in a number of cancer types and was therefore explored in this setting.Materials and MethodsClinico-pathological data from patients undergoing PRRT for metastatic NETs were collected at baseline and during treatment. The primary endpoint was progression free survival (PFS) with a secondary endpoint of overall survival (OS). Cox regression analysis tested associations between baseline variables and their dynamic changes, and PFS and OS. Decision curve analysis (DCA) was used to determine the net benefit associated with a treatment strategy determined by the baseline IBI and non-response to PRRT.ResultsFifty-five patients were recruited. Baseline IBI >0 was associated with inferior PFS (HR 14.2 (95% CI 5.25-38.5), p<0.001) and OS (p<0.001). Multivariate analysis confirmed an independent association between IBI and PFS (p=0.001). DCA indicated a net clinical benefit at risk thresholds between 0.03 and 0.58.ConclusionBaseline IBI score and its dynamic change through treatment are associated with both PFS and OS. At a risk threshold equivalent to the currently accepted rate of non-response to therapy, implementation of this easily derived score could avoid a significant number of futile treatments. These findings should be validated in additional independent cohorts.

Journal article

Black JRM, Atkinson SR, Singh A, Evans J, Sharma Ret al., 2018, Markers of the systemic inflammatory response can predict response and improve patient selection in Neuroendocrine Tumours treated with Peptide Radionuclide Receptor Therapy, 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S60-S60, ISSN: 1619-7070

Conference paper

Tan T, Shen L, Hajiev S, Mak L-Y, Sharma R, Goh BBG, Chang J, Yuen M-F, Pinato DJ, Tan C-Ket al., 2018, Development and external international validation of a therapy-independent HCC survival prediction score from a cohort of 1270 patients, Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) / Liver Meeting, Publisher: Wiley, Pages: 551A-551A, ISSN: 0270-9139

Conference paper

Lavdas I, Rockall AG, Daulton E, Kozlowski K, Honeyfield L, Aboagye EO, Sharma Ret al., 2018, Histogram analysis of apparent diffusion coefficient from whole-body diffusion-weighted MRI to predict early response to chemotherapy in patients with metastatic colorectal cancer: preliminary results, CLINICAL RADIOLOGY, Vol: 73, ISSN: 0009-9260

Journal article

Pinato DJ, Pai M, Reccia I, Patel M, Giakoustidis A, Karamanakos G, Rushd A, Jamshaid S, Oldani A, Grossi G, Pirisi M, Tait P, Sharma Ret al., 2018, Preliminary qualification of a novel, hypoxic-based radiologic signature for trans-arterial chemoembolization in hepatocellular carcinoma., BMC Cancer, Vol: 18, ISSN: 1471-2407

BACKGROUND: Survival advantage following trans-arterial chemoembolization (TACE) is variable in patients with hepatocellular carcinoma (HCC). We combined pre-TACE radiologic features to derive a novel prognostic signature in HCC. METHODS: A multi-institutional dataset of 98 patients was generated from two retrospective cohorts from United Kingdom (65%) and Italy (36%). The prognostic impact of a number baseline imaging parameters was assessed and factors significant on univariate analysis were combined to create a novel radiologic signature on multivariable analyses predictive of overall survival (OS) following TACE. RESULTS: Median OS was 15.4 months. Tumour size > 7 cm (p < 0.001), intra-tumour necrosis (ITN) (p = 0.02) and arterial ectatic neovascularisation (AEN) (p = 0.03) emerged as individual prognostic factors together with radiologic response (p < 0.001) and elevated alpha-fetoprotein (AFP) (p = 0.01). Combination of tumour size > 7 cm, ITN and AEN identified patients with poor prognosis (p < 0.001). CONCLUSIONS: We identified a coherent signature based on commonly available imaging biomarkers likely to be reflective of differential patterns of relative hypoxia and neovascularisation. Large tumours displaying AEN and ITN are characterised by a shorter survival after TACE.

Journal article

Pinato DJ, Mauri FA, Spina P, Cain O, Siddique A, Goldin RDet al., 2018, Quantitative comparison of PD-L1 immunohistochemical assays in hepatocellular carcinoma: The Blueprint-HCC study, ASCO-SITC Clinical Immuno-Oncology Symposium, Publisher: American Society of Clinical Oncology, ISSN: 0732-183X

Conference paper

Pinato DJ, Sharma R, Citti C, Platt H, Ventura-Cots M, Allara E, Chen T-Y, Dalla Pria A, Jain M, Minguez B, Kikuchi L, West EK, Merli M, Kaplan DE, Hasson H, Marks K, Nelson M, Nunez M, Aytaman A, Bower M, Brau Net al., 2017, The albumin-bilirubin grade uncovers the prognostic relationship between hepatic reserve and immune dysfunction in HIV-associated hepatocellular carcinoma, Alimentary Pharmacology and Therapeutics, Vol: 47, Pages: 95-103, ISSN: 0269-2813

Background:Hepatocellular carcinoma (HCC) is a leading cause of liver-related mortality in people living with HIV, where co-infection with hepatotropic viruses accelerates the course of chronic liver disease.Aim:To evaluate whether the albumin-bilirubin (ALBI) grade, a more accurate marker of liver dysfunction in HCC, might identify patients with progressive liver dysfunction in the context of HIV/hepatitis co-infection.Methods:Using uni- and multi-variable analyses, we studied the albumin-bilirubin grade as a predictor of overall survival (OS) in a large, multi-center cohort of patients with HIV-associated HCC recruited from 44 centres in 9 countries within the Liver Cancer in HIV study group. Patients who underwent liver transplantation were excluded.Results:A total of 387 patients, predominantly HCV co-infected (78%) with balanced representation of all Barcelona Clinic Liver Cancer (BCLC) stages (A = 33%, B = 18%, C = 37%, D = 12%) were recruited. At HCC diagnosis, 84% had been on anti-retrovirals for a median duration of 8.8 years. The albumin-bilirubin grade identified significant differences in median survival of 97 months for grade 1 (95% CI 13-180 months), 17 months for grade 2 (95% CI 11-22 months) and 6 months for grade 3 (95% CI 4-9 months, P < .001). A more advanced albumin-bilirubin grade correlated with lower CD4 counts (464/373/288 cells/mm3 for grades 1/2/3) and higher HIV viraemia (3.337/8.701/61.845 copies/mL for grades 1/2/3, P < .001).Conclusions:In this large, multi-center retrospective study, the albumin-bilirubin grade highlights the interplay between liver reserve and immune dysfunction as prognostic determinants in HIV-associated HCC.

Journal article

Kumar N, Khamri W, Sadiq F, Pop OT, Mukherjee S, Dhar A, Sharma R, Khan SA, Thursz MR, Antoniades CG, Khakoo Set al., 2017, Circulating Natural Killer cells in Hepatocellular Carcinoma are hypofunctional with an exhausted phenotype, 68th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Publisher: WILEY, Pages: 355A-355A, ISSN: 0270-9139

Conference paper

Pinato DJ, Black J, Trousil S, Dina R, Trivedi P, Mauri F, Sharma Ret al., 2017, Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: relationship with the hypoxic response, immune evasion and malignant behaviour., OncoImmunology, Vol: 6, ISSN: 2162-4011

Background: The hypoxic response underlies the pathogenesis and malignant behaviour of PCC/PGL. Regulation of PD-1 receptor-ligand signalling, a therapeutically actionable driver of the anti-tumour immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Methods: Tissue microarrays sections including consecutive cases diagnosed between 1983-2011 were stained for PD-L1 & 2, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). We explored the biologic significance of PD ligands expression using gene set enrichment analysis (GSEA) on The Cancer Genome Atlas (TCGA) for PCC/PGL (n=184). Results: In total, 100 patients, 10% malignant, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Median follow-up was 4.7 years. We found PD-L1 expression in 18% of PCC/PGL, which was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. PD-L2 expression (16%) strongly correlated with CI, VI, N and malignant behaviour (p<0.05) and was associated with stronger Hif-1a and CaIX immunolabeling (p<0.01). PD-L2 was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1-9.2, p=0.02). GSEA on TGCA samples confirmed enrichment of transcripts involved in hypoxia and anti-cancer immunity.Conclusions: We report for the first time PD ligands expression in PCC/PGL with a distinctive prognostic, clinico-pathologic and immuno-biologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumours.

Journal article

Khan SA, McClements S, Reccia I, Evans J, Pai M, Sharma Ret al., 2017, The next generation of hepatocellular cancer experts: what do they think?, Hepatic Oncology, Vol: 3, Pages: 213-215, ISSN: 2045-0923

Journal article

Sharma R, Wang WM, Evans J, Yusuf S, AL-Nahhas A, Mauri F, Barwick T, Aboagye Eet al., 2017, 68Ga-DOTATATE PET/CT to predict response to peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NETs), ASCO, Publisher: American Society of Clinical Oncology, ISSN: 0732-183X

Conference paper

Pinato DJ, Victor S, Spina P, Trivedi P, Pirisi M, Burlone M, Black JM, Minisini R, Leutner M, Boldorini R, Mauri FA, Sharma Ret al., 2017, Intra-tumour heterogeneity in the regulation of immune-tolerogenic pathways in primary and metastatic hepatocellular carcinoma (HCC)., 53rd Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Pinato DJ, Black JM, Trousil S, Dina R, Trivedi P, Mauri FA, Sharma Ret al., 2017, Programmed cell death ligands expression in pheochromocytomas (PCC) and paragangliomas (PGL): Relationship with the hypoxic response and malignant behaviour., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Citti C, Pinato D, Ventura-Cots M, Platt H, Merli M, Minguez B, Pria AD, Sharma R, Marcus S, Nelson M, Bower M, Mazzaferro V, Brau Net al., 2017, Liver transplantation for human immunodeficiency virus-Infected patients with hepatocellular carcinoma, International Liver Congress / 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver, Publisher: Elsevier, Pages: S216-S216, ISSN: 0168-8278

Conference paper

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