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

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

195 results found

Fulgenzi CAM, D'Alessio A, Ogunbiyi O, Demirtas CO, Gennari A, Cortellini A, Sharma R, Pinato DJet al., 2022, Novel immunotherapy combinations in clinical trials for hepatocellular carcinoma: will they shape the future treatment landscape?, EXPERT OPINION ON INVESTIGATIONAL DRUGS, ISSN: 1354-3784

Journal article

Sharma R, Pillai A, Marron TU, Fessas P, Saeed A, Jun T, Dharmapuri S, Szafron D, Naqash AR, Gampa A, Wang Y, Khan U, Muzaffar M, Lee C-J, Lee P-C, Bulumulle A, Paul S, Bettinger D, Hildebrand H, Yehia M, Pressiani T, Kaseb A, Huang Y-H, Ang C, Kudo M, Nishida N, Personeni N, Rimassa L, Pinato DJet al., 2022, Patterns and outcomes of subsequent therapy after immune checkpoint inhibitor discontinuation in HCC, HEPATOLOGY COMMUNICATIONS

Journal article

D'Alessio A, Weinmann A, Galle PR, Fulgenzi CAM, Bettinger D, Bengsch B, Vogel A, Balcar L, Scheiner B, Navaid M, Naqash AR, Personeni N, Pressiani T, Sharma R, Pinter M, Cortellini A, Rimassa L, Pinato DJet al., 2022, Real-world use of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Öcal O, Schinner R, Schütte K, de Toni EN, Loewe C, van Delden O, Vandecaveye V, Gebauer B, Zech CJ, Sengel C, Bargellini I, Gasbarrini A, Sangro B, Pech M, Malfertheiner P, Ricke J, Seidensticker M, SORAMIC study groupet al., 2022, Early tumor shrinkage and response assessment according to mRECIST predict overall survival in hepatocellular carcinoma patients under sorafenib., Cancer Imaging, Vol: 22

BACKGROUND: The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. METHODS: Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; ≥20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. RESULTS: The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22-0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS ≥ 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. CONCLUSION: OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC.

Journal article

Muhammed A, Fulgenzi CAM, Dharmapuri S, Pinter M, Balcar L, Scheiner B, Marron TU, Jun T, Saeed A, Hildebrand H, Muzaffar M, Navaid M, Naqash AR, Gampa A, Ozbek U, Lin J-Y, Perone Y, Vincenzi B, Silletta M, Pillai A, Wang Y, Khan U, Huang Y-H, Bettinger D, Abugabal YI, Kaseb A, Pressiani T, Personeni N, Rimassa L, Nishida N, Di Tommaso L, Kudo M, Vogel A, Mauri FA, Cortellini A, Sharma R, D'Alessio A, Ang C, Pinato DJet al., 2022, The Systemic Inflammatory Response Identifies Patients with Adverse Clinical Outcome from Immunotherapy in Hepatocellular Carcinoma, CANCERS, Vol: 14

Journal article

Hashimoto A, Sarker D, Reebye V, Jarvis S, Sodergren MH, Kossenkov A, Sanseviero E, Raulf N, Vasara J, Andrikakou P, Meyer T, Huang K-W, Plummer R, Chee CE, Spalding D, Pai M, Khan S, Pinato DJ, Sharma R, Basu B, Palmer D, Ma Y-T, Evans J, Habib R, Martirosyan A, Elasri N, Reynaud A, Rossi JJ, Cobbold M, Habib NA, Gabrilovich DIet al., 2021, Upregulation of C/EBP alpha Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer, CLINICAL CANCER RESEARCH, Vol: 27, Pages: 5961-5978, ISSN: 1078-0432

Journal article

Demirtas CO, 'Alessio A, Rimassa L, Sharma R, Pinato DJet al., 2021, ALBI grade: Evidence for an improved model for liver functional estimation in patients with hepatocellular carcinoma, JHEP REPORTS, Vol: 3

Journal article

Abdelmalak R, Lythgoe MP, Evans J, Flynn M, Waters J, Webb A, Pinato DJ, Sharma Ret 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

Journal article

Sharma R, Lythgoe MP, Slaich B, Patel Net al., 2021, Exploring the epigenome in gastroenteropancreatic neuroendocrine neoplasias, Cancers, Vol: 13, Pages: 1-18, ISSN: 2072-6694

Gastroenteropancreatic neuroendocrine neoplasias are a diverse group of neoplasms with different characteristics in terms of site, biological behaviour and metastatic potential. In comparison to other cancers, they are genetically quiet, harbouring relatively few somatic mutations. It is increasingly becoming evident that epigenetic changes are as relevant, if not more so, as somatic mutations in promoting oncogenesis. Despite significant tumour heterogeneity, it is obvious that DNA methylation, histone and chromatin modifications and microRNA expression profiles are distinctive for GEP-NEN subtypes and may correlate with clinical outcome. This review summarises existing knowledge on epigenetic changes, identifying potential contributions to pathogenesis and oncogenesis. In particular, we focus on epigenetic changes pertaining to well-differentiated neuroendocrine tumours, which make up the bulk of NENs. We also highlight both similarities and differences within the subtypes of GEP-NETs and how these relate and compare to other types of cancers. We relate epigenetic understanding to existing treatments and explore how this knowledge may be exploited in the development of novel treatment approaches, such as in theranostics and combining conventional treatment modalities. We consider potential barriers to epigenetic research in GEP-NENs and discuss strategies to optimise research and development of new therapies.

Journal article

Lo SH, Sharma R, Costentin CE, Aggio D, Shergill S, Colaone F, Brennan VK, Straccia VA, Agirrezabal I, Lloyd AJet al., 2021, Patient preferences for advanced hepatocellular carcinoma treatment: a multicountry stated preference study, Future Oncology, Vol: 17, Pages: 4275-4287, ISSN: 1479-6694

The present study aimed to explore patient preferences for attributes of advanced hepatocellular carcinoma (HCC) treatments. A stated preference survey was completed by 150 patients with HCC living in Europe. Overall survival (OS) was the most important attribute, closely followed by risk of diarrhea and hypertension, and other adverse event (AE) risks. Patients were willing to trade OS to reduce AE risks. While less important than OS and AEs, patients also preferred shorter waiting times, and one-off administration of selective internal radiation therapy and oral tablets over intravenous infusions. Although patients placed the most value on extending OS, they were willing to forego OS to avoid risk of treatment-related AEs, to maintain their quality of life.

Journal article

Sharma R, Lo S, Aggio D, Colaone F, Agirrezabal I, Straccia V, Brennan V, Shergill S, Lloyd A, Costentin Cet al., 2021, Caring for more than survival: A survey of patient preferences in advanced hepatocellular carcinoma, 23rd ESMO World Congress on Gastrointestinal Cance, Publisher: ELSEVIER, Pages: S141-S141, ISSN: 0923-7534

Conference paper

Pinato DJ, Cortellini A, Balcells C, Killmer S, Talbot T, Thomas R, Sayed AA, Allara E, Tait P, Ross P, Young AM, Cole T, Goldin RD, Ward C, Akarca A, Blanco JM, Marafioti T, Keun H, Siskos A, Marchesi J, Bengsch B, Sharma Ret 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

Conference paper

Sharma R, Lu H, George J, Eslam M, Villanueva A, Ward C, Reeves HL, McCain M, Chambers E, Sands C, Maslen L, Lewis M, Ramaswami Ret al., 2021, Discriminatory changes in circulating lipid and small molecule metabolites in patients with MAFLD associated hepatocellular cancer, Publisher: ELSEVIER, Pages: S490-S490, ISSN: 0168-8278

Conference paper

Pinato D, Cortellini A, Sukumaran A, Cole T, Pai M, Habib N, Spalding D, Sodergren M, Martinez M, Dhillon T, Tait P, Thomas R, Ward C, Kocher H, Yip V, Slater S, Sharma Ret al., 2021, PRIME-HCC: Phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma, BMC Cancer, Vol: 21, ISSN: 1471-2407

BackgroundAfter liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209–040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3–4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC.MethodsThe study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC.DiscussionThe results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcom

Journal article

Sharma R, Aval LM, 2021, Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224

Journal article

Win Z, Weiner J, Listanco A, Patel N, Sharma R, Greenwood A, Maertzdorf J, Mollenkopf H-J, Pizzoferro K, Cole T, Bodinham CL, Kaufmann SHE, Denoel P, Del Giudice G, Lewis DJMet al., 2021, Systematic evaluation of kinetics and distribution of muscle and lymph node activation measured by F-18-FDG- and C-11-PBR28-PET/CT imaging, and whole blood and muscle transcriptomics after immunization of healthy humans with adjuvanted and unadjuvanted vaccines, Frontiers in Immunology, Vol: 11, Pages: 1-16, ISSN: 1664-3224

Systems vaccinology has been applied to detect signatures of human vaccine induced immunity but its ability, together with high definition in vivo clinical imaging is not established to predict vaccine reactogenicity. Within two European Commission funded high impact programs, BIOVACSAFE and ADITEC, we applied high resolution positron emission tomography/computed tomography (PET/CT) scanning using tissue-specific and non-specific radioligands together with transcriptomic analysis of muscle biopsies in a clinical model systematically and prospectively comparing vaccine-induced immune/inflammatory responses. 109 male participants received a single immunization with licensed preparations of either AS04-adjuvanted hepatitis B virus vaccine (AHBVV); MF59C-adjuvanted (ATIV) or unadjuvanted seasonal trivalent influenza vaccine (STIV); or alum-OMV-meningococcal B protein vaccine (4CMenB), followed by a PET/CT scan (n = 54) or an injection site muscle biopsy (n = 45). Characteristic kinetics was observed with a localized intramuscular focus associated with increased tissue glycolysis at the site of immunization detected by 18F-fluorodeoxyglucose (FDG) PET/CT, peaking after 1–3 days and strongest and most prolonged after 4CMenB, which correlated with clinical experience. Draining lymph node activation peaked between days 3–5 and was most prominent after ATIV. Well defined uptake of the immune cell-binding radioligand 11C-PBR28 was observed in muscle lesions and draining lymph nodes. Kinetics of muscle gene expression module upregulation reflected those seen previously in preclinical models with a very early (~6hrs) upregulation of monocyte-, TLR- and cytokine/chemokine-associated modules after AHBVV, in contrast to a response on day 3 after ATIV, which was bracketed by whole blood responses on day 1 as antigen presenting, inflammatory and innate immune cells trafficked to the site of immunization, and on day 5 associated with activated CD4+ T cells. These observat

Journal article

Hajiev S, Allara E, Motedayen-Aval L, Arizumi T, Bettinger D, Pirisi M, Rimassa L, Pressiani T, Personeni N, Giordano L, Kudo M, Thimme R, Park J-W, Taddei TH, Kaplan DE, Ramaswami R, Pinato DJ, Sharma Ret al., 2021, Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study (vol 124, pg 407, 2021), BRITISH JOURNAL OF CANCER, Vol: 124, Pages: 1611-1611, ISSN: 0007-0920

Journal article

Howell J, Samani A, Mannan B, Hajiev S, Aval LM, Abdelmalak R, Tam VC, Bettinger D, Thimme R, Taddei TH, Kaplan DE, Seidensticker M, Sharma Ret al., 2021, Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: An international cohort study., Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Aboagye E, Sharma R, Inglese M, Dubash S, Lu H, Pinato D, Patel N, Chung A, Sanghera C, Tait A, Mauri F, Crum W, Barwick Tet al., 2020, Monitoring response to transarterial chemoembolization in hepatocellular carcinoma using 18F-Fluorothymidine Positron Emission Tomography, The Journal of Nuclear Medicine, Vol: 61, Pages: 1743-1748, ISSN: 0161-5505

Accurate disease monitoring is essential following transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) due to potential for profound adverse event and large variation in survival outcome. Post-treatment changes on conventional imaging can confound determination of residual/recurrent disease, magnifying the clinical challenge. Based on increased expression of thymidylate synthase (TYMS), thymidine kinase-1 (TK-1) and SLC29A1 (Equilibrative nucleoside transporter 1, ENT1) in HCC compared with liver tissue, we conducted a proof of concept study evaluating the efficacy of 18F-fluorothymidine (18F-FLT)-PET to assess response to TACE. As previous PET studies in HCC have been hampered by high background liver signal, we investigated if a temporal-intensity voxel-clustering (“Kinetic Spatial Filtering”) (KSF) improved lesion detection. Methods: A tissue microarray (TMA) was built from 36 HCC samples and matched surrounding cirrhotic tissue and was stained for thymidine kinase-1 (TK-1). A prospective study was conducted; eighteen patients with a diagnosis of HCC by American Association for the Study of Liver Diseases criteria (AALSD) who were eligible to treatment with TACE were enrolled. Patients underwent baseline conventional imaging and dynamic 18F-FLT-PET/KSF followed by TACE. Repeat imaging was performed 6-8 weeks post TACE. PET parameters were compared with modified-Response Evaluation in Solid Tumours (mRECIST) enhancement-based criteria. Results: Cancer Genome Atlas analysis revealed increased RNA expression of TYMS, TK-1 and SLC29A1 in HCC. TK-1 protein expression was significantly higher in HCC (p<0.05). The sensitivity of 18F-FLT-PET for baseline HCC detection was 73% (SUVmax of 9.7 ± 3.0; tumour to liver ratio of 1.2 ± 0.3). Application of KSF did not improve lesion detection. Lesion response following TACE by mRECIST criteria was 58% (14 patients with 24 lesions). A 30% reduction in mean 18F-FLT-PET uptake was o

Journal article

Schuette K, Schinner R, Fabritius MP, Moeller M, Kuhl C, Iezzi R, Ocal O, Pech M, Peynircioglu B, Seidensticker M, Sharma R, Palmer D, Bronowicki J-P, Reimer P, Malfertheiner P, Ricke Jet al., 2020, Impact of Extrahepatic Metastases on Overall Survival in Patients with Advanced Liver Dominant Hepatocellular Carcinoma: A Subanalysis of the SORAMIC Trial, LIVER CANCER, Vol: 9, Pages: 771-786, ISSN: 2235-1795

Journal article

Hajiev S, Allara E, Motedayen-Aval L, Arizumi T, Bettinger D, Pirisi M, Rimassa L, Pressiani T, Personeni N, Giordano L, Kudo M, Thimme R, Park J-W, Taddei TH, Kaplan DE, Ramaswami R, Pinato DJ, Sharma Ret al., 2020, Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study, BRITISH JOURNAL OF CANCER, Vol: 124, Pages: 407-413, ISSN: 0007-0920

Journal article

Motedayen Aval L, Pease JE, Sharma R, Pinato DJet al., 2020, Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy, Journal of Clinical Medicine, Vol: 9, ISSN: 2077-0383

Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a 'cold' tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

Journal article

Lythgoe M, Julve M, Pinato D, Sharma Ret al., 2020, "Regorafenib therapy for hepatocellular carcinoma in a HIV-1 infected patient: a case report", Liver Cancer International, Vol: 1, Pages: 51-54, ISSN: 2642-3561

Journal article

Sharma R, Pinato DJ, 2020, Management of Hepatocellular CAncer in the time of SARS-CoV-2, Liver International, Vol: 40, Pages: 1823-1825, ISSN: 1478-3223

As COVID-19 the disease caused by SARS-CoV-2 continues to have a profound impact on global health, there have been a number of guidelines recently published addressing the management of patients with liver disease during the COVID-19 pandemic including the recently published EASL-ESCMID Position Paper, guidelines issued by the International Liver Cancer Association and the American Association for the Study of Liver Diseases (1-3). All publications present a sound discussion regarding the challenges face by both patients and clinicians alike in the management of chronic liver disease in the setting of this ongoing pandemic.

Journal article

Sarker D, Plummer R, Meyer T, Sodergren MH, Basu B, Chee CE, Huang K-W, Palmer DH, Ma YT, Evans TRJ, Spalding DRC, Pai M, Sharma R, Pinato DJ, Spicer J, Hunter S, Kwatra V, Nicholls JP, Collin D, Nutbrown R, Glenny H, Fairbairn S, Reebye V, Voutila J, Dorman S, Andrikakou P, Lloyd P, Felstead S, Vasara J, Habib R, Wood C, Saetrom P, Huber HE, Blakey DC, Rossi JJ, Habib Net al., 2020, MTL-CEBPA, a small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label, phase I trial, Clinical Cancer Research, Vol: 26, Pages: 3936-3946, ISSN: 1078-0432

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Journal article

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., 2020, Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach, Hepatology, Vol: 72, Pages: 198-212, 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., 2020, Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers, Hepatology, Vol: 72, Pages: 88-102, 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, Hajiev S, Aval LM, Bettinger D, Arizumi T, Pirisi M, Rimassa L, Personeni N, Pressiani T, Giordano L, Kudo M, Thimme R, Park J-W, Taddei TH, Kaplan DE, Ramaswami R, Pinato DJ, Allara Eet al., 2020, An international cohort study investigating the impact of age on clinical outcome in patients with hepatocellular carcinoma treated with sorafenib., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X

Conference paper

Sharma R, Valls PO, Inglese M, Dubash S, Chen M, Gabra H, Montes A, Challapalli A, Arshad M, Tharakan G, Chambers E, Cole T, Lozano-Kuehne JP, Barwick TD, Aboagye EOet al., 2020, [18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 1239-1251, ISSN: 0340-6997

BACKGROUND: Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. PATIENTS AND METHODS: We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. RESULTS: Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. CONCLUSIONS: Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti

Journal article

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