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Bachner M.,ACR ITR VIEnna CEADDP | Loriot Y.,Institute Gustave Roussy | Gross-goupil M.,Institute Gustave Roussy | Zucali P.A.,Instituto Clinico Humanitas IRCCS | And 18 more authors.
Annals of Oncology | Year: 2012

Background: 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients.Patients and methods: FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome.Results: One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P = 0.032).Conclusion: Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | Karolinska Institutet, University of British Columbia, University of Basel, University of Surrey and 5 more.
Type: Journal Article | Journal: Molecular oncology | Year: 2016

Metastasis is the primary cause of death in prostate cancer (PCa) patients. Small nucleolar RNAs (snoRNAs) have long been considered housekeeping genes with no relevance for cancer biology. Emerging evidence has challenged this assumption, suggesting that snoRNA expression is frequently modulated during cancer progression. Despite this, no study has systematically addressed the prognostic and functional significance of snoRNAs in PCa. We performed RNA Sequencing on paired metastatic/non-metastatic PCa xenografts derived from clinical specimens. The clinical significance of differentially expressed snoRNAs was further investigated in two independent primary PCa cohorts (131 and 43 patients, respectively). The snoRNA demonstrating the strongest association with clinical outcome was quantified in PCa patient-derived serum samples and its functional relevance was investigated in PCa cells via gene expression profiling, pathway analysis and gene silencing. Our comparison revealed 21 differentially expressed snoRNAs in the metastatic vs. non-metastatic xenografts. Of those, 12 were represented in clinical databases and were further analyzed. SNORA55 emerged as a predictor of shorter relapse-free survival (results confirmed in two independent databases). SNORA55 was reproducibly detectable in serum samples from PCa patients. SNORA55 silencing in PCa cell lines significantly inhibited cell proliferation and migration. Pathway analysis revealed that SNORA55 expression is significantly associated with growth factor signaling and pro-inflammatory cytokine expression in PCa. Our results demonstrate that SNORA55 up-regulation predicts PCa progression and that silencing this non-coding gene affects PCa cell proliferation and metastatic potential, thus positioning it as both a novel biomarker and therapeutic target.


Fizazi K.,University Paris - Sud | Scher H.I.,Sloan Kettering Cancer Center | Molina A.,Janssen Research and Development | Logothetis C.J.,University of Texas M. D. Anderson Cancer Center | And 14 more authors.
The Lancet Oncology | Year: 2012

Background: Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Methods: Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. Findings: Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). Interpretation: This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Funding: Janssen Research & Development. © 2012 Elsevier Ltd.


Motzer R.J.,Sloan Kettering Cancer Center | Porta C.,University of Pavia | Vogelzang N.J.,Comprehensive Cancer Centers of Nevada | Sternberg C.N.,San Camillo and Forlanini Hospitals | And 17 more authors.
The Lancet Oncology | Year: 2014

Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding: Novartis Pharmaceuticals Corporation. © 2014 Elsevier Ltd.


Crea F.,Cancer Agency Cancer Research Center | Watahiki A.,Cancer Agency Cancer Research Center | Watahiki A.,Vancouver General Hospital | Quagliata L.,University of Basel | And 16 more authors.
Oncotarget | Year: 2014

Metastatic prostate cancer (PCa) is still an incurable disease. Long non-coding RNAs (lncRNAs) may be an overlooked source of cancer biomarkers and therapeutic targets. We therefore performed RNA sequencing on paired metastatic/nonmetastatic PCa xenografts derived from clinical specimens. The most highly upregulated transcript was LOC728606, a lncRNA now designated PCAT18. PCAT18 is specifically expressed in the prostate compared to 11 other normal tissues (p<0.05) and up-regulated in PCa compared to 15 other neoplasms (p<0.001). Cancer-specific up-regulation of PCAT18 was confirmed on an independent dataset of PCa and benign prostatic hyperplasia samples (p<0.001). PCAT18 was detectable in plasma samples and increased incrementally from healthy individuals to those with localized and metastatic PCa (p<0.01). We identified a PCAT18-associated expression signature (PES), which is highly PCa-specific and activated in metastatic vs. primary PCa samples (p<1E-4, odds ratio >2). The PES was significantly associated with androgen receptor (AR) signalling. Accordingly, AR activation dramatically up-regulated PCAT18 expression in vitro and in vivo. PCAT18 silencing significantly (p<0.001) inhibited PCa cell proliferation and triggered caspase 3/7 activation, with no effect on nonneoplastic cells. PCAT18 silencing also inhibited PCa cell migration (p<0.01) and invasion (p<0.01). These results position PCAT18 as a potential therapeutic target and biomarker for metastatic PCa.


Robinson C.A.,University of British Columbia | Fyles G.,Cancer Agency Sindi Ahluwalia Hawkins Center for the Southern Interior | McKenzie M.,Cancer Agency Vancouver Cancer Center
Journal of Cancer Education | Year: 2015

Despite evidence that Goals of Care (GOC) discussions should occur early in the disease trajectory, the majority occur close to end of life. In a pilot, oncologists routinely initiated GOC discussions with all patients in their everyday ambulatory practice. Following the pilot, 9 of 12 eligible oncologists participated in semi-structured interviews about their experiences. Analysis resulted in the identification of seven principles of good GOC discussions embedded in the oncologists’ interviews, four barriers to engaging in GOC discussions and foundational education needs. Participants believed that the appropriate trigger for a GOC discussion is a diagnosis of advanced cancer, not simply a diagnosis of cancer, and supported the importance of selective and strategic targeting of GOC discussions. The findings have informed the development of an education-based model for culture change within a province-wide cancer care system. © 2015 American Association for Cancer Education


PubMed | University of British Columbia, Cancer Agency Vancouver Cancer Center and Cancer Agency Sindi Ahluwalia Hawkins Center for the Southern Interior
Type: | Journal: Journal of cancer education : the official journal of the American Association for Cancer Education | Year: 2015

Despite evidence that Goals of Care (GOC) discussions should occur early in the disease trajectory, the majority occur close to end of life. In a pilot, oncologists routinely initiated GOC discussions with all patients in their everyday ambulatory practice. Following the pilot, 9 of 12 eligible oncologists participated in semi-structured interviews about their experiences. Analysis resulted in the identification of seven principles of good GOC discussions embedded in the oncologists interviews, four barriers to engaging in GOC discussions and foundational education needs. Participants believed that the appropriate trigger for a GOC discussion is a diagnosis of advanced cancer, not simply a diagnosis of cancer, and supported the importance of selective and strategic targeting of GOC discussions. The findings have informed the development of an education-based model for culture change within a province-wide cancer care system.


Macfarlane R.J.,Cancer Agency Vancouver Cancer Center | Chi K.N.,Cancer Agency Vancouver Cancer Center | Chi K.N.,University of British Columbia
Urologic Clinics of North America | Year: 2010

This article reviews the concepts and rationale behind targeted agents that are currently in clinical testing for patients with castration resistant prostate cancer (CRPC). Advances in our understanding of the molecular mechanisms underlying prostate cancer progression has translated into a variety of treatment approaches. Agents targeting androgen receptor activation and local steroidogenesis, angiogenesis, apoptosis, chaperone proteins, the insulinlike growth factor pathway, RANK ligand, endothelin receptors, and Src family kinases are entering, or have recently completed, accrual to phase III trials for patients with CRPC. There has also been interest generated by data from early-phase studies evaluating multitargeted tyrosine kinase inhibitors, agents effecting signal transduction pathways, and novel cytotoxics. © 2010 Elsevier Inc. All rights reserved.


MacFarlane R.J.,Cancer Agency Vancouver Cancer Center | Chi K.N.,Cancer Agency Vancouver Cancer Center | Chi K.N.,University of British Columbia
Current Oncology | Year: 2010

Prostate cancer (PCa) is the most common non-skin cancer diagnosed in North America, and it affects 1 in 6 men. Patients with recurrent or metastatic PCa will inevitably develop castration-resistant disease after an initial period of hormone responsiveness. The standard first-line treatment for men with castration-resistant PCa (CRPC) is docetaxel, but further treatment options are limited. This review summarizes the research being conducted in CRPC, with specific regard to immunotherapy and to novel targeted therapies directed against the androgen axis, vascular endothelial growth factor, chaperone proteins, the phosphoinositide 3 kinase/Akt/phosphatase and tensin homolog/mammalian target of rapamycin pathway, and endothelin-1. © 2010 Multimed Inc.


PubMed | University of British Columbia, Cancer Agency Vancouver Cancer Center and Vancouver Prostate Center
Type: Journal Article | Journal: Small (Weinheim an der Bergstrasse, Germany) | Year: 2016

Circulating tumor cells (CTCs) offer tremendous potential for the detection and characterization of cancer. A key challenge for their isolation and subsequent analysis is the extreme rarity of these cells in circulation. Here, a novel label-free method is described to enrich viable CTCs directly from whole blood based on their distinct deformability relative to hematological cells. This mechanism leverages the deformation of single cells through tapered micrometer scale constrictions using oscillatory flow in order to generate a ratcheting effect that produces distinct flow paths for CTCs, leukocytes, and erythrocytes. A label-free separation of circulating tumor cells from whole blood is demonstrated, where target cells can be separated from background cells based on deformability despite their nearly identical size. In doping experiments, this microfluidic device is able to capture >90% of cancer cells from unprocessed whole blood to achieve 10(4) -fold enrichment of target cells relative to leukocytes. In patients with metastatic castration-resistant prostate cancer, where CTCs are not significantly larger than leukocytes, CTCs can be captured based on deformability at 25 greater yield than with the conventional CellSearch system. Finally, the CTCs separated using this approach are collected in suspension and are available for downstream molecular characterization.

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