Ricky A SharmaUniversity of Oxford | OX · Department of Oncology
Ricky A Sharma
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119
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Publications (119)
Purpose
To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemo-embolization in patients with resectable liver malignancies.
Methods
The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years, had resectable he...
Objective
To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE).
Methods
A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepa...
Aim
This is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pC...
Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibito...
Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncoge...
The purpose of this study was to establish the dose-response relationship of selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer (mCRC), when informed by radiobiological sensitivity parameters derived from mCRC cell lines exposed to yttrium-90 (90Y). Methods: 23 mCRC patients with liver metastases refractory to...
Purpose
To use a novel segmentation methodology based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to define tumour subregions of liver metastases from colorectal cancer (CRC), to compare these with histology, and to use these to compare extracted pharmacokinetic (PK) parameters between tumour subregions.
Materials and Methods...
373
Background: Initial results of the NEOSCOPE trial comparing pre-operative CarPac vs OxCap based chemoradiotherapy (CRT) in patients with adenocarcinoma of the oesophagus or oesophagogastric junction showed comparable toxicity and improvement in pathological complete response (pCR) in favour of the CarPacRT. Here we report survival after a media...
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer arising from the bile ducts with a need for earlier diagnosis and a greater range of treatment options. KRAS/NRAS mutations are common in ICC tumours and 6–32% of patients also have isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations associated with metabolic changes. This fe...
BACKGROUND
Radioembolization, also known as trans-arterial radio-embolization (TARE) or Selective Internal Radiation Therapy (SIRT) with Yttrium-90 (90Y) resin microspheres is a well-studied treatment modality for patients with primary and secondary liver tumours and is used in clinical practice. Large-scale prospective observational data on the ap...
Background:
Radioembolization, also known as transarterial radioembolization or selective internal radiation therapy with yttrium-90 (90Y) resin microspheres, is an established treatment modality for patients with primary and secondary liver tumors. However, large-scale prospective observational data on the application of this treatment in a real-...
Background:
Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and is also a treatment option for patients with liver metastases from colorectal cancer. However, TACE is not a curative treatment, and tumor progression occurs in more than half of the patients tr...
The FOXFIRE (5-Fluorouracil, OXaliplatin and Folinic acid ± Interventional Radio-Embolisation) clinical trial combined systemic chemotherapy (OxMdG: Oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radio-embolisation) using yttrium-90 resin microspheres in the first-line management for liver-dominant me...
BACKGROUND
Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and is also a treatment option for patients with liver metastases from colorectal cancer. However, TACE is not a curative treatment, and tumor progression occurs in more than half of the patients trea...
Background:
Colorectal cancer is one of the most common cancers and causes of cancer-related death. Up to approximately 70% of patients with metastatic colorectal cancer (mCRC) have metastases to the liver at initial diagnosis. Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after firs...
BACKGROUND
Colorectal cancer is one of the most common cancers and causes of cancer-related death. Up to approximately 70% of patients with metastatic colorectal cancer (mCRC) have metastases to the liver at initial diagnosis. Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after first-...
Liver metastasis from breast cancer is associated with poor prognosis and is a major cause of early morbidity and mortality. When liver resection is not feasible, minimally invasive directed therapies are considered to attempt to prolong survival. Selective internal radiation therapy (SIRT) with yttrium-90 microspheres is a liver-directed therapy t...
Purpose:
Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relati...
Selective internal radiation therapy (SIRT) with microspheres labelled with the β-emitter yttrium-90 (Y-90) enables targeted delivery of radiation to hepatic tumors. SIRT is primarily used to treat inoperable primary or metastatic liver tumors. Eligible patients have usually been exposed to a variety of systemic anticancer therapies, including cyto...
Background:
Data suggest selective internal radiotherapy (SIRT) in third-line or subsequent therapy for metastatic colorectal cancer has clinical benefit in patients with colorectal liver metastases with liver-dominant disease after chemotherapy. The FOXFIRE, SIRFLOX, and FOXFIRE-Global randomised studies evaluated the efficacy of combining first-...
3507
Background: The FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG) randomized studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer (mCRC) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres in patients with liver metastases. The studies were designed for prospective, comb...
Selective internal radiation therapy (SIRT or radioembolisation) by intraarterial injection of radioactive yttrium-90 ((90) Y)-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source so that its effects are...
646Background: Tumour heterogeneity is a key determinants of cancer resistance. Serial sampling of cell free (cf)DNA may detect evolving somatic mutations. Monitoring cancers after therapies e.g. selective internal radiation therapy (SIRT) require new biomarkers as RECIST imaging was developed to assess response to chemotherapy and may not reflect...
With the advent of novel treatment strategies to help widen the therapeutic window for patients with oligometastatic cancer, improved biomarkers are needed to reliably define patients who can benefit from these treatments. Multimodal imaging is one such option and should be optimised to comprehensively assess metastatic sites, disease burden, and r...
How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor resp...
Rectal tumour segmentation in dynamic contrast-enhanced MRI (DCE-MRI) is a challenging task, and an automated and consistent method would be highly desirable to improve the modelling and prediction of patient outcomes from tissue contrast enhancement characteristics – particularly in routine clinical practice. A framework is developed to automate D...
3
Background: NEOSCOPE compared toxicity and efficacy of 2 pre-op CRT regimens. Methods: Eligibility: Resectable ACA of the oesophagus/GOJ ≥ T3 and/or ≥ N1. Randomisation: 1:1 to OXCAP-CRT (oxaliplatin 85 mg/m2 Day 1,15,29; capecitabine 625 mg/m2 bd on days of RT) or CarPac-CRT (Carboplatin AUC2; paclitaxel 50 mg/m2 Day 1,8,15,22,29); concurrent RT...
The routine use of ¹⁸F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography scans for staging and assessment of treatment response for cancer has resulted in a large number of thyroid abnormalities being detected as incidental findings (“incidentalomas”). Since most PET/CT scans are performed in the setting of a known nonthyroi...
There is considerable excitement about the clinical potential of PARP inhibitors (PARPi), based on highly publicised results from several clinical trials. In this chapter, we will demonstrate that PARP inhibition is not a generic strategy for treating cancer in non-selected patients and that the most promising results involve accurate patient selec...
PARP Inhibitors for Cancer Therapy provides a comprehensive overview of the role of PARP—poly ADP ribose polymerase—in cancer therapy. The volume covers the history of the discovery of PARP and its role in DNA repair. Additionally, it describes the discovery of the PARP family, and includes a discussion of other DNA maintenance-associated PARPs. As...
Objectives
Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management.Methods
Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presen...
Delineation of hepatic tumours is challenging in CT due to limited inherent tissue contrast, leading to significant intra-/inter-observer variability. Perfusion CT (pCT) allows quantitative assessment of enhancement patterns in normal and abnormal liver. This study aims to develop a semi-automated perfusion analysis toolkit that classifies hepatic...
As the options for systemic treatment of malignant melanoma (MM) increase, the need to develop biomarkers to identify patients who might benefit from cytotoxic chemotherapy becomes more apparent. In preclinical models, oxaliplatin has activity in cisplatin-resistant cells. In this study, we have shown that oxaliplatin forms inter-strand cross-links...
45 Background: Patients with operable esophageal adenocarcinoma have a poor prognosis (median survival <2 years). We aimed to discover novel prognostic and predictive biomarkers to be validated as tools for patient selection for optimal neo-adjuvant therapy. Methods: Protein levels of XPF, MUS81, Cyclins A, B1, D1 and E, and Ki67 were assessed by r...
491 Background: Nelfinavir, an inhibitor of AKT in the PI3-kinase pathway, is a radiosensitizer which increases tumor blood flow and reduces hypoxia in preclinical models. We conducted a pilot study of nelfinavir before and during hypofractionated pelvic radiotherapy (RT) in patients with rectal cancer to evaluate the safety of the combination, cha...
Dynamic contrast-enhanced MRI is a dynamic imaging technique that is now widely used for cancer imaging. Changes in tumour microvasculature are typically quantified by pharmacokinetic modelling of the contrast
uptake curves. Reliable pharmacokinetic parameter estimation depends on the measurement of the arterial input function, which can be obtaine...
The commonest cause of death from advanced colorectal cancer is disease progression of hepatic metastases. Radiotherapy is an important treatment modality in locally advanced colorectal cancer. Radioembolisation (RE) is a technique for administering resin or glass microspheres that contain yttrium-90 to unresectable primary or secondary hepatic mal...
Background Knowledge that liver tumours preferentially take their blood supply from the arterial blood supply rather than the portal venous system can be used for local delivery of treatment or for embolisation to cut off the blood supply to tumours.
Aims To present histological evaluation of malignant and non-malignant hepatic tissue of one such t...
DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of
pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells
demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0...
Abstract Apart from surgical approaches, the treatment of cancer remains largely underpinned by radiotherapy and pharmacological agents that cause damage to cellular DNA, which ultimately causes cancer cell death. DNA polymerases, which are involved in the repair of cellular DNA damage, are therefore potential targets for inhibitors for improving t...
e13587
Background: Oxaliplatin is first-line chemotherapy for colorectal, gastric, and esophageal cancers. Aim was to identify key determinants of oxaliplatin sensitivity and optimise these biomarkers to select patients for chemotherapy. Methods: High-throughput screening of oxaliplatin sensitivity was performed in a Schizosaccharomyces pombe delet...
Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy treatments. This article comprehensively reviews the current clinical evidence for oxaliplatin-based chemo-radiotherapy that may improve local control and survival. In order to understand how clinical studies shou...
The cellular genome is constantly subject to DNA damage caused by endogenous factors or exogenously by damaging agents such as ionizing radiation or various anticancer agents. The base excision repair (BER) enzyme, DNA polymerase β, and the polymerases involved in translesion synthesis (TLS) have been shown to contribute to cellular tolerance and r...
The cellular genome is constantly subject to DNA damage caused by endogenous factors or exogenously by damaging agents such as ionizing radiation or various anticancer agents. The base excision repair (BER) enzyme, DNA polymerase β, and the polymerases involved in translesion synthesis (TLS) have been shown to contribute to cellular tolerance and r...
Primary Liver Tumors
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver; its incidence is increasing worldwide. It ranks as the sixth most common tumor and third most common cause of cancer-related mortality (1,2). Primary liver tumors include HCC and intrahepatic cholangiocarcinoma. Surgical resection is preferred ov...
Ionising radiation, and most chemotherapeutic agents currently used to treat cancer, target DNA to cause cytotoxicity. The
cellular response to DNA damage is a complex set of intra-cellular processes involving multiple DNA repair pathways, leading
either to cell death or to survival if the lesions are repaired or bypassed. Thus, the multiple and re...
Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors are tested for these tumours in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thiog...
The commonest cause of death from advanced colorectal cancer is disease progression of hepatic metastases. A number of technologies are in clinical development to improve local control of liver metastases and potentially improve overall survival. Radio-embolization (RE) is a technique for administering resin or glass microspheres that contain yttri...
Although the liver possesses a dual blood supply, arterial vessels deliver only a small proportion of blood to normal parenchyma, but they deliver the vast majority of blood to primary and secondary cancers of the liver. This anatomical discrepancy is the basis for intra-arterial brachytherapy of liver cancers using radioactive microspheres, termed...
Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thiog...
Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) is activated by DNA single-strand breaks (SSB) or at stalled replication forks to facilitate DNA repair. Inhibitors of PARP efficiently kill breast, ovarian, or prostate tumors in patients carrying hereditary mutations in the homologous recombination (HR) genes BRCA1 or BRCA2 through synthetic lethality....
We thank Dr. Vente and colleagues for clarification that they used 'any response' (AR) as an end point in their meta-analysis.¹ We apologize for this error in our discussion of their study.
The majority of patients with advanced colorectal cancer die from hepatic metastases caused by disease progression; therefore, several novel technologies are in clinical development to potentially improve local control of liver disease. Radioembolization is a technique for administering radiotherapy internally to unresectable primary or secondary h...
Base excision repair (BER) is the major cellular pathway involved in removal of endogenous/spontaneous DNA lesions. Here, we study the mechanism that controls the steady-state levels of BER enzymes in human cells. By fractionating human cell extract, we purified the E3 ubiquitin ligase Mule (ARF-BP1/HectH9) as an enzyme that can ubiquitylate DNA po...
Sensitive and reliable methods are required for the assessment of oxidative DNA damage, which can result from reactive oxygen species that are generated endogenously from cellular metabolism and inflammatory responses, or by exposure to exogenous agents. The development of a liquid chromatography/tandem mass spectrometry (LC/MS/MS) selected reactio...
DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during tumour development can ma...
Curcumin is a natural polyphenol used in ancient Asian medicine. Since the first article referring to the use of curcumin to treat human disease was published in The Lancet in 1937, >2,600 research studies using curcumin or turmeric have been published in English language journals. The mechanisms implicated in the inhibition of tumorigenesis by cur...
Intracellular reactive oxygen species (ROS) may cause oxidative DNA damage, resulting in the formation of adducts such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and the cyclic pyrimidopurinone N-1, N(2) malondialdehyde-2'-deoxyguanosine (M(1)dG). These adducts have been associated with carcinogenesis, genomic instability and clonal evolutio...
Most commonly used cancer therapies, particularly ionizing radiation and certain classes of cytotoxic chemotherapies, cause cell death by damaging DNA. Base excision repair (BER) is the major system responsible for the removal of corrupt DNA bases and repair of DNA single strand breaks generated spontaneously and induced by exogenous DNA damaging f...
To standardize the indications, techniques, multimodality treatment approaches, and dosimetry to be used for yttrium-90 (Y90) microsphere hepatic brachytherapy.
Members of the Radioembolization Brachytherapy Oncology Consortium met as an independent group of experts in interventional radiology, radiation oncology, nuclear medicine, medical oncology...
Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)--containing the beta-emitter, yttrium-90--into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy,...
Curcuma spp. contain turmerin, essential oils, and curcuminoids, including curcumin. Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is regarded as the most biologically active constituent of the spice turmeric and it comprises 2-8% of most turmeric preparations. Preclinical data from animal models and phase I clinical studi...
Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-l...
The natural polphenol, curcumin, retards the growth of intestinal adenomas in the Apc(Min+) mouse model of human familial adenomatous polyposis. In other preclinical models, curcumin downregulates the transcription of the enzyme cyclooxygenase-2 (COX-2) and decreases levels of two oxidative DNA adducts, the pyrimidopurinone adduct of deoxyguanosine...
When compared to a reference population, several large epidemiological studies with long-term follow-up have reported a three- to five-fold increased risk of neoplasia amongst patients who have received organ transplants, with an incidence curve that rises in a linear fashion with time. The relationship between the immune system and cancer is compl...
Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from curcumin's potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signalling pathways at...
Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a reduction of levels of the oxidative DNA adduct 3-(2-deoxy-beta-di-erythro-pentafuranosyl)-pyr[1,2-alpha]-purin-10(3H)one (M(1)G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hy...
Over the last decade, epidemiological, experimental and clinical studies have implicated oxidative stress in the development and progression of prostate cancer. Oxidative stress may be linked to the effects of androgens, anti-oxidant systems and the pre-malignant condition, high-grade prostatic intraepithelial neoplasia. Cyclooxygenase-2 activity h...
Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E(2) (PGE(2)) production, or suppression of oxidative DNA adduct (M(1)G) formation. We designed a dose-escalation...