Publications
246 results found
Olmos D, Barker D, Sharma R, et al., 2011, Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies, CLINICAL CANCER RESEARCH, Vol: 17, Pages: 3420-3430, ISSN: 1078-0432
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- Citations: 126
Backshall A, Sharma R, Clarke SJ, et al., 2011, Pharmacometabonomic Profiling as a Predictor of Toxicity in Patients with Inoperable Colorectal Cancer Treated with Capecitabine, CLINICAL CANCER RESEARCH, Vol: 17, Pages: 3019-3028, ISSN: 1078-0432
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- Citations: 87
Contractor KB, Kenny L, Stebbing J, et al., 2011, [18F]-3'deoxy-3'-Fluorothymidine Positron Emission Tomography and Breast Cancer Response to Docetaxel, ISSN: 1078-0432
PURPOSE: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [18F]-3'deoxy-3'-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer.EXPERIMENTAL DESIGN: This was a prospective unblinded study in 20 patients with AJCC stage II-IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan two weeks after initiating the first or second cycle of docetaxel. PET variables were compared to anatomical response mid-therapy (after 3 cycles). RESULTS: Average and maximum tumor standardized uptake values at 60 min (SUV60,av and SUV60,max) normalized to body surface area ranged between 1.7 and 17.0, and 5.6 and 26.9 x 10-5 m2/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (p=0.0003 for SUV60,av and p=0.0002 for SUV60,max). Reduction in tumor SUV60,av was associated with target lesion size changes mid-therapy (Pearson R for SUV60,av=0.64; p=0.004) and predicted mid-therapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV60,av in responders were due at least in part, to reduced net intracellular trapping of FLT (rate constant Ki). Docetaxel significantly reduced Ki by 51.1% (+/-28.4%, p=0.0009).CONCLUSIONS: Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response mid-therapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non-FLT-PET response.
Hanna G, Lin SJ, Wertheimer MD, et al., 2011, Unresolved, atraumatic breast hematoma: post-irradiation or secondary breast angiosarcoma., Breast Dis, Vol: 33, Pages: 139-142
Post-irradiation or secondary angiosarcoma of the breast was first described in the 1980s in patients treated with breast conserving therapy for cancer. The primary management of radiation-induced breast angiosarcoma has focused on surgical resection with an emphasis on achieving negative tumor margins. While surgery remains a key component of treatment, novel therapeutic approaches have surfaced. Despite such advances in treatment, prognosis remains poor.
Sharma R, Pinato D, Wasan HS, et al., 2011, A novel inflammatory-based prognostic score in hepatocellular carcinoma, ASCO
Sharma R, Coombes C, Winick J, et al., 2010, DETECTION OF TUMOR ANGIOGENESIS IN SOLID TUMOURS VIA THE EXPRESSION OF αVβ3 INTEGRIN USING AN RGD PEPTIDE, [18F] FLUCICLATIDE, AND POSITRON EMISSION TOMOGRAPHY (PET) IMAGING, 35th European-Society-for-Medical-Oncology (ESMO) Congress, Publisher: OXFORD UNIV PRESS, Pages: 65-65, ISSN: 0923-7534
Contractor KB, Challapalli A, Sharma R, et al., 2010, Determination of pelvic node status in patients with high-risk localized or locally advanced prostate cancer by [<SUP>11</SUP>c]choline PET-CT, JOURNAL OF CLINICAL ONCOLOGY, Vol: 28, ISSN: 0732-183X
Barker D, Sharma R, McIndoe A, et al., 2010, An Unusual Case of Sex Cord Tumor With Annular Tubules With Malignant Transformation in a Patient With Peutz-Jeghers Syndrome, INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, Vol: 29, Pages: 27-32, ISSN: 0277-1691
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- Citations: 17
Olmos D, Allred A, Sharma R, et al., 2009, Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors., J Clin Oncol, Vol: 27
3536 Background: Polo-like kinase-1 (Plk1), part of a family of highly conserved serine-threonine kinases, has multiple roles in mitotic progression, is over-expressed and also associated with poor prognosis in some tumor types. GSK461364 is a potent and selective ATP-competitive inhibitor of Plk1 (Ki 2.2nM) with demonstrated antiproliferative activity in vitro and in vivo. METHODS: Adult patients (pts) with relapsed/refractory advanced solid tumors with performance status of 0-2 and adequate organ function were eligible. Sequential cohorts of 2-6 patients each received escalating doses of GSK461364 administered as a 4h intravenous infusion (Schedule [Sch] 1: D1,8,15 q28 or Sch 2: D1,2,8,9,15,16 q28). Primary objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSK461364. Secondary objectives included preliminary evaluation of anti-tumor activity. RESULTS: 27 pts (20 male, 7 female) were evaluated. Four dose levels, 50mg (n = 2), 100 mg (n = 3), 150 mg (n = 3) and 225 mg (n = 8) were evaluated in Sch 1. Three dose levels, 25 mg (n = 2), 50 mg (n = 2) and 100 mg (n = 7) were evaluated in Sch 2. Dose-limiting toxicities (DLTs) observed were Gr 4 sepsis, in Sch 1 at 225 mg dose, Gr 4 pulmonary embolism (PE) and Gr 4 neutropenia >7d in Sch 2, both at 100 mg dose. Other Sch 1 adverse events (AEs) with a maximum grade ≥3 were fatigue and anemia (both, n = 2), pleuritic pain, pelvic pain, abdominal discomfort, constipation, vomiting, neutropenia, and deep vein thrombosis (all, n = 1). Other Sch 2 AEs with a maximum grade ≥3 were PE, renal failure, thrombocytopenia, and catheter-related infection (all n = 1). The most common adverse events (AEs) regardless of attribution, Sch and dose level were phlebitis (n = 9), fatigue (n = 9), nausea (n = 7), anemia (n = 6), anorexia (n = 6), diarrhea (n = 6), and infusion site reaction (n = 5). Preliminary PK data indicate that AUC and Cmax were proportional across doses; mean values were
Olmos D, Allred A, Sharma R, et al., 2009, Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors, 45th Annual Meeting of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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- Citations: 11
Sharma R, Cunningham D, Smith P, et al., 2009, Inflammatory (B) symptoms are independent predictors of myelosuppression from chemotherapy in Non-Hodgkin Lymphoma (NHL) patients - analysis of data from a British National Lymphoma Investigation phase III trial comparing CHOP to PMitCEBO, BMC CANCER, Vol: 9, ISSN: 1471-2407
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- Citations: 19
Sharma R, Graham J, Mitchell H, et al., 2009, Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer, British Journal of Cancer, Vol: 100, Pages: 707-712, ISSN: 0007-0920
There is increasing evidence of the efficacy of dose-dense therapy in the management of platinum-resistant/refractory ovarian cancer. We report our experience of extended weekly carboplatin and paclitaxel in this population group. Twenty patients with platinum-resistant/refractory ovarian cancer received carboplatin AUC 3 and paclitaxel 70 mg m−2 on day 1, 8, 15 q 4 weekly for six planned cycles. Toxicity was assessed using Common Toxicity Criteria. Response was evaluated using radiological and CA125 criteria. Median age was 61 years (range 40–74 years). Median number of prior therapies is three (range 1–8). Response rate was 60% by radiological criteria (RECIST) and 76% by CA125 assessment. Grade 3 toxicities consisted of neutropenia (29% of patients) and anaemia (5%). One patient experienced grade 4 neutropenia. No grade 3/4 thombocytopaenia was reported. Fatigue, nausea and peripheral neuropathy were the most frequent non-hematological side effects. Median progression-free survival was 7.9 months and overall survival was 13.3 months. The dynamics of response to dose-dense therapy were as rapid as with front-line therapy within the same patient. This dose-dense regimen can be extended to at least 18 weekly cycles over 6 months and is well tolerated with high response rates in heavily pre-treated, platinum-resistant ovarian cancer. It forms a highly active and tolerable cytotoxic scaffold to which molecular-targeted therapies can be added in platinum-resistant ovarian cancer.
Goel S, Sharma R, Hamilton A, et al., 2009, LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women, COCHRANE DATABASE OF SYSTEMATIC REVIEWS, ISSN: 1469-493X
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- Citations: 18
Lose F, Duffy DL, Kay GF, et al., 2008, Skewed X chromosome inactivation and breast and ovarian cancer status: evidence for X-linked modifiers of BRCA1., J Natl Cancer Inst, Vol: 100, Pages: 1519-1529
BACKGROUND: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. METHODS: We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. RESULTS: The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P = .02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P = .005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] of br
Blagden S, Olmos D, Sharma R, et al., 2008, A phase I first-in-human study of the polo-like kinase 1-selective inhibitor, GSK461364, in patients with advanced solid tumors, 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 135-136, ISSN: 1359-6349
Blagden S, Olmos D, Sharma R, et al., 2008, Characterization of BI 6727, a novel Polo-like kinase inhibitor with a distinct pharmacokinetic profile and efficacy in a model of taxane-resistant colon cancer, 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 135-135, ISSN: 1359-6349
Sharma R, Zucknick M, London R, et al., 2008, Systemic inflammatory response predicts prognosis in patients with advanced-stage colorectal cancer, CLINICAL COLORECTAL CANCER, Vol: 7, Pages: 331-337, ISSN: 1533-0028
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- Citations: 89
Roxburgh P, Sharma R, Brooks A, et al., 2008, EXPERIENCE OF WEEKLY DOSE DENSE CARBOPLATIN AND PACLITAXEL IN PLATINUM RESISTANT OVARIAN CANCER, 33rd European-Society-for-Medical-Oncology Congress, Publisher: OXFORD UNIV PRESS, Pages: 212-212, ISSN: 0923-7534
Sharma R, Smith P, Cunningham D, et al., 2008, Use of inflammatory symptoms to predict worse myelosuppression in aggressive non-Hodgkin lymphoma (NHL): Reanalysis of British National Lymphoma Institute (BNLI) study of CHOP versus PMitCEBO with or without granulocyte colony stimulating factor, JOURNAL OF CLINICAL ONCOLOGY, Vol: 26, ISSN: 0732-183X
Morgan ET, Goralski KB, Piquette-Miller M, et al., 2008, Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer, DRUG METABOLISM AND DISPOSITION, Vol: 36, Pages: 205-216, ISSN: 0090-9556
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- Citations: 297
Sharma R, Kacevska M, London R, et al., 2008, Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies, BRITISH JOURNAL OF CANCER, Vol: 98, Pages: 91-97, ISSN: 0007-0920
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- Citations: 18
Gabra H, Stronach E, Sharma R, 2008, Molecular biology, Treatment of Cancer, Fifth Edition, Pages: 23-39, ISBN: 9781444115017
Molecular biology is no longer a revolution in medicine. It is now the very fabric of clinical practice and this is particularly so in the practice of oncology. Understanding of the molecular processes underlying cancer, whether for prevention, diagnosis, treatment or palliation, is essential for the practitioner. The purpose of this chapter is twofold: first, to describe the concepts and language underlying this discipline, and second, to integrate these concepts into a clinical overview of where molecular biology currently impacts cancer treatment.
Sharma R, Hook J, Kumar M, et al., 2008, Evaluation of an inflammation-based prognostic score in patients with advanced ovarian cancer, EUROPEAN JOURNAL OF CANCER, Vol: 44, Pages: 251-256, ISSN: 0959-8049
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- Citations: 64
Sharma R, Hoskins JM, Rivory LP, et al., 2008, Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients, Clin Cancer Res, Vol: 14, Pages: 817-825, ISSN: 1078-0432
PURPOSE: To evaluate the effect of thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR) genotypes on toxicity in patients treated with capecitabine for advanced colorectal cancer and to determine the effect of these polymorphisms on the pretreatment levels of serum folate and plasma homocysteine. EXPERIMENTAL DESIGN: Fifty-four patients with a diagnosis of metastatic colorectal cancer were treated with fixed-dose capecitabine. Germ line DNA from patients was genotyped for TYMS TSER, TSER*3G>C, and 3'-untranslated 6 bp insertion/deletion (3' untranslated region insertion/deletion), and MTHFR c.677C>T and c.1298A>C using PCRs and RFLP. Toxicity was graded by National Cancer Institute Common Toxicity Criteria version 2.0. Response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: MTHFR c.677C>T and c.1298A>C genotypes and diplotypes predicted for grade 2/3 toxicities, whereas the TYMS genotypes had no influence. MTHFR c.677 genotype tended to predict overall survival (P = 0.08). MTHFR c.677 influenced pretreatment homocysteine (P < 0.05) and serum folate levels (P < 0.05). Multivariate analysis suggests that MTHFR c.1298 is an independent predictor of toxicity. CONCLUSIONS: This study suggests that common genetic variation in MTHFR but not TYMS may be useful for predicting toxicity from capecitabine in patients with advanced colorectal cancer. In addition, MTHFR single nucleotide polymorphisms predicted serum folate and plasma homocysteine levels, and, combined, these factors may be important predictors of capecitabine-induced toxicity.
Sharma R, Hoskins JM, Rivory LP, et al., 2008, Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients, Clinical cancer research : an official journal of the American Association for Cancer Research, Pages: 817-825, ISSN: 1078-0432
PURPOSE: To evaluate the effect of thymidylate synthase (TYMS) and methylenetetrahydrofolate reductase (MTHFR) genotypes on toxicity in patients treated with capecitabine for advanced colorectal cancer and to determine the effect of these polymorphisms on the pretreatment levels of serum folate and plasma homocysteine. EXPERIMENTAL DESIGN: Fifty-four patients with a diagnosis of metastatic colorectal cancer were treated with fixed-dose capecitabine. Germ line DNA from patients was genotyped for TYMS TSER, TSER*3G>C, and 3'-untranslated 6 bp insertion/deletion (3' untranslated region insertion/deletion), and MTHFR c.677C>T and c.1298A>C using PCRs and RFLP. Toxicity was graded by National Cancer Institute Common Toxicity Criteria version 2.0. Response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: MTHFR c.677C>T and c.1298A>C genotypes and diplotypes predicted for grade 2/3 toxicities, whereas the TYMS genotypes had no influence. MTHFR c.677 genotype tended to predict overall survival (P = 0.08). MTHFR c.677 influenced pretreatment homocysteine (P < 0.05) and serum folate levels (P < 0.05). Multivariate analysis suggests that MTHFR c.1298 is an independent predictor of toxicity. CONCLUSIONS: This study suggests that common genetic variation in MTHFR but not TYMS may be useful for predicting toxicity from capecitabine in patients with advanced colorectal cancer. In addition, MTHFR single nucleotide polymorphisms predicted serum folate and plasma homocysteine levels, and, combined, these factors may be important predictors of capecitabine-induced toxicity.
Sharma R, Hamilton A, Beith J, 2008, LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women, COCHRANE DATABASE OF SYSTEMATIC REVIEWS, ISSN: 1469-493X
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- Citations: 41
Sharma R, Koller L, Barclay R, et al., 2007, Evaluation of the off-label usage of rituximab in a large teaching hospital in New South Wales, INTERNAL MEDICINE JOURNAL, Vol: 37, Pages: 569-571, ISSN: 1444-0903
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- Citations: 9
Li KM, Rivory LP, Hoskins J, et al., 2007, Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients., Br J Clin Pharmacol, Vol: 63, Pages: 67-74, ISSN: 0306-5251
AIMS: To investigate the relationship between changes in plasma deoxynucleoside concentrations and response and toxicity in patients treated with capecitabine. METHODS: Twenty-six patients received 2 g capecitabine twice daily orally for 2 weeks of a 3-week cycle. Blood samples were collected on day 0 (baseline), day 8, day 15 and day 22 of the first cycle for the determination of plasma thymidine (TdR) and deoxyuridine (UdR) concentrations. Patients were reviewed weekly during the first cycle, then 3-weekly for toxicity assessment. Response was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. RESULTS: The plasma UdR and UdR/TdR ratios were significantly elevated (P < 0.001) compared with baseline (49.3 +/- 20.8 nmol l(-1)) for the entire 3-week treatment period. In contrast, the plasma TdR concentrations of these patients were significantly reduced only on day 8 (P < 0.01) compared with baseline (12.1 +/- 3.83 nmol l(-1)), but returned gradually to basal levels by day 15. There were no significant correlations demonstrated between pretreatment or maximal post-treatment plasma nucleoside ratio and either toxicity or response. The TSER genotype frequencies of homozygous TSER*2, TSER*3 and heterozygous TSER*2/*3 were 7.7%, 42.3% and 50%, respectively. These preliminary data also indicate no direct relationship between thymidylate synthase (TS) genotype and plasma nucleoside levels. CONCLUSIONS: Capecitabine mimics continuous infusion of 5-FU to achieve sustained cellular TS inhibitory effects and suggests the antiproliferative mechanism of capectabine is at least partly due to TS inhibition through its active metabolite FdUMP. Although plasma UdR and TdR concentrations and the UdR/TdR ratio can provide some pharmacodynamic indication of TS inhibition, they are unlikely to predict therapeutic response or toxicity accurately following capecitabine treatment in cancer patients.
Sharma R, Koller L, Liddle C, et al., 2006, Retrospective evaluation of the use of rituximab in a renal transplant population, 24th Annual Scientific Meeting of the Transplantation-Society-of-Australia-and-New-Zealand, Publisher: BLACKWELL PUBLISHING, Pages: A11-A11, ISSN: 0818-9641
Sharma R, Rivory L, Beale P, et al., 2006, A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer., Br J Cancer, Vol: 94, Pages: 964-968, ISSN: 0007-0920
The purpose of this study was to evaluate the safety and activity of fixed-dose capecitabine in patients with advanced colorectal cancer and to correlate pretreatment plasma concentrations of homocysteine and serum and red cell folate with toxicity. Patients received capecitabine 2000 mg (4 x 500 mg tablets) twice daily on days 1-14 every 3 weeks. They were reviewed weekly during the first cycle and then three weekly for safety assessment. Eligibility criteria were advanced/metastatic colorectal cancer, < or = 2 prior chemotherapy regimens, ECOG performance status 0-2 and life expectancy >12 weeks. A total of 60 patients were enrolled and 55 were evaluable for efficacy. The median age was 72 years and 63% of patients had a performance status of 1 or 2. Confirmed tumour responses were reported in 15 patients (28%; 95% confidence interval (CI), 15.7-40.3%). The median time to disease progression was 4.9 months and median overall survival was 11.2 months. The median ratio of fixed dose to body surface area (BSA)-calculated dose was 88% (range 65-108%). Significant myelosuppression was not observed. Grade 2/3 treatment-related adverse events were diarrhoea (34%), fatigue (27%), stomatitis (15%) and hand-foot syndrome (22%). Dose reduction due to adverse events was required in 16 patients (29%) and multiple reductions in five patients (9%). There was no grade 3/4 haematological toxicity, any grade 4 adverse events or treatment-related deaths. Patients with higher pretreatment levels of serum folate experienced significantly greater toxicity (P = 0.02, CI: 1.0-1.2) during cycle 1 and over the entire treatment period (P = 0.04, CI: 1.0-1.3). Pretreatment homocysteine concentrations did not predict for toxicity. In conclusion, fixed-dose capecitabine appears to have similar efficacy and safety compared to the currently recommended dose schedule based on body surface area and simplifies drug administration. A high pretreatment folate may be predictive of increased toxi
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