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1.  Patient‐reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life 
Lane, Athene | Metcalfe, Chris | Young, Grace J. | Peters, Tim J. | Blazeby, Jane | Avery, Kerry N. L. | Dedman, Daniel | Down, Liz | Mason, Malcolm D. | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Bonnington, Sue | Bradshaw, Lynne | Cooper, Debbie | Elliott, Emma | Herbert, Pippa | Holding, Peter | Howson, Joanne | Jones, Mandy | Lennon, Teresa | Lyons, Norma | Moody, Hilary | Plumb, Claire | O'Sullivan, Tricia | Salter, Liz | Tidball, Sarah | Thompson, Pauline | Adam, Tonia | Askew, Sarah | Atkinson, Sharon | Baynes, Tim | Blaikie, Jan | Brain, Carole | Breen, Viv | Brunt, Sarah | Bryne, Sean | Bythem, Jo | Clarke, Jenny | Cloete, Jenny | Dark, Susan | Davis, Gill | De La Rue, Rachael | Denizot, Jane | Dewhurst, Elspeth | Dimes, Anna | Dixon, Nicola | Ebbs, Penny | Emmerson, Ingrid | Ferguson, Jill | Gadd, Ali | Geoghegan, Lisa | Grant, Alison | Grant, Collette | Gray, Catherine | Godfrey, Rosemary | Goodwin, Louise | Hall, Susie | Hart, Liz | Harvey, Andrew | Hoult, Chloe | Hawkins, Sarah | Holling, Sharon | Innes, Alastair | Kilner, Sue | Marshall, Fiona | Mellen, Louise | Moore, Andrea | Napier, Sally | Needham, Julie | Pearse, Kevin | Pisa, Anna | Rees, Mark | Richards, Elliw | Robson, Lindsay | Roxburgh, Janet | Samuel, Nikki | Sharkey, Irene | Slater, Michael | Smith, Donna | Taggart, Pippa | Taylor, Helen | Taylor, Vicky | Thomas, Ayesha | Tomkies, Briony | Trewick, Nicola | Ward, Claire | Walker, Christy | Williams, Ayesha | Woodhouse, Colin | Wyber, Elizabeth | Aning, Jonathan | Bollina, Prasad | Catto, Jim | Doble, Andrew | Doherty, Alan | Durkan, Garett | Gillatt, David | Hughes, Owen | Kocklebergh, Roger | Kouparis, Anthony | Kynaston, Howard | Leung, Hing | Mariappan, Param | McNeill, Alan | Paez, Edgar | Paul, Alan | Persad, Raj | Powell, Philip | Prescott, Stephen | Rosario, Derek | Rowe, Edward | Schwaibold, Hartwig | Tulloch, David | Wallace, Mike | Bahl, Amit | Benson, Richard | Beresford, Mark | Ferguson, Catherine | Graham, John | Herbert, Chris | Howard, Grahame | James, Nick | Law, Alastair | Loughrey, Carmel | McClaren, Duncan | Patterson, Helen | Pedley, Ian | Robinson, Angus | Russell, Simon | Staffurth, John | Symonds, Paul | Thanvi, Narottam | Vasanthan, Subramaniam | Wilson, Paula | Appleby, Helen | Ash, Dominic | Aston, Dean | Bolton, Steven | Chalmers, Graham | Conway, John | Early, Nick | Geater, Tony | Goddall, Lynda | Heymann, Claire | Hicks, Deborah | Jones, Liza | Lamb, Susan | Lambert, Geoff | Lawrence, Gill | Lewis, Geraint | Lilley, John | MacLeod, Aileen | Massey, Pauline | McQueen, Alison | Moore, Rollo | Penketh, Lynda | Potterton, Janet | Roberts, Neil | Showler, Helen | Slade, Stephen | Steele, Alasdair | Swinscoe, James | Tiffany, Marie | Townley, John | Treeby, Jo | Wilkinson, Joyce | Williams, Lorraine | Wills, Lucy | Woodley, Owain | Yarrow, Sue | Bhattarai, Selina | Deshmukh, Neeta | Dormer, John | Fernando, Malee | Goepel, John | Griffiths, David | Grigor, Ken | Mayer, Nick | Oxley, Jon | Robinson, Mary | Varma, Murali | Warren, Anne | Brindle, Lucy | Davis, Michael | Khazragui, Hanan | Noble, Sian | Taylor, Hilary | Tazewell, Marta | Turner, Emma | Wade, Julia | Walsh, Eleanor | Baker, Susan | Bellis‐Sheldon, Elizabeth | Bougard, Chantal | Bowtell, Joanne | Brewer, Catherine | Burton, Chris | Charlton, Jennie | Christoforou, Nicholas | Clark, Rebecca | Coull, Susan | Croker, Christine | Currer, Rosemary | Daisey, Claire | Delaney, Gill | Donohue, Rose | Drew, Jane | Farmer, Rebecca | Fry, Susan | Haddow, Jean | Hale, Alex | Halpin, Susan | Harris, Belle | Hattrick, Barbara | Holmes, Sharon | Hunt, Helen | Jackson, Vicky | Johnson, Donna | Le Butt, Mandy | Leworthy, Jo | Liddiatt, Tanya | Martin, Alex | Mauree, Jainee | Moore, Susan | Moulam, Gill | Mutch, Jackie | Nash, Alena | Parker, Kathleen | Pawsey, Christopher | Purdie, Michelle | Robson, Teresa | Smith, Lynne | Snoeck, Jo | Stenton, Carole | Steuart‐Feilding, Tom | Sully, Chris | Sutton, Caroline | Torrington, Carol | Wilkins, Zoe | Williams, Sharon | Wilson, Andrea | Grant, Adrian | Roberts, Ian | Ashby, Deborah | Cowan, Richard | Fayers, Peter | Mellon, Killian | N'Dow, James | O'Brien, Tim | Sokhal, Michael | Baum, Michael | Adolfson, Jan | Albertsen, Peter | Dearnaley, David | Schroeder, Fritz | Roberts, Tracy | Zietman, Anthony
Bju International  2016;118(6):869-879.
To present the baseline patient‐reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external‐beam conformal radiotherapy for localized prostate cancer and to compare results with other populations.
Materials and Methods
A total of 1643 randomized men, aged 50–69 years and diagnosed with clinically localized disease identified by prostate‐specific antigen (PSA) testing, in nine UK cities in the period 1999–2009 were included. Validated PROMs for disease‐specific (urinary, bowel and sexual function) and condition‐specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire‐Urinary Incontinence [ICIQ‐UI], 2001 onwards; the International Continence Society short‐form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12‐item short‐form health survey [SF‐12]; EuroQol quality‐of‐life survey, the EQ‐5D‐3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men's age at biopsy and PSA testing time points for selected measures.
A total of 1438 participants completed biopsy questionnaires (88%) and 77–88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65–70 years), whilst urinary bother and physical health were somewhat worse than in younger men (49–54 years, all P < 0.001). Bowel health, urinary function and depression were unaltered by age, whilst mental health and anxiety were better in older men (P < 0.001). Only minor differences existed in mental or physical health, anxiety and depression between PSA testing and biopsy assessments.
The ProtecT trial baseline PROMs response rates were high. Symptom frequencies and generic quality of life were similar to those observed in populations screened for prostate cancer and control subjects without cancer.
PMCID: PMC5113698  PMID: 27415448
prostate cancer; treatment; functional status; quality of life; protect trial; ISRCTN 20141297
2.  Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial 
The Lancet. Oncology  2016;17(8):1047-1060.
Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.
CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.
Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.
Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.
Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.
PMCID: PMC4961874  PMID: 27339115
3.  Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286 
Tenorio, Allan R. | Chan, Ellen S. | Bosch, Ronald J. | Macatangay, Bernard J. C. | Read, Sarah W. | Yesmin, Suria | Taiwo, Babafemi | Margolis, David M. | Jacobson, Jeffrey M. | Landay, Alan L. | Wilson, Cara C. | Mellors, John W. | Keshavarzian, Ali | Rodriguez, Benigno | Aziz, Mariam | Presti, Rachel | Deeks, Steven | Ebiasah, Ruth | Myers, Laurie | Borowski, LuAnn | Plants, Jill | Palm, David A. | Weibel, Derek | Putnam, Beverly | Lindsey, Elizabeth | Player, Amy | Albrecht, Mary | Kershaw, Andrea | Sax, Paul | Keenan, Cheryl | Walton, Patricia | Baum, Jane | Stroberg, Todd | Hughes, Valery | Coster, Laura | Kumar, Princy N. | Yin, Michael T. | Noel-Connor, Jolene | Tebas, Pablo | Thomas, Aleshia | Davis, Charles E. | Redfield, Robert R. | Sbrolla, Amy | Flynn, Teri | Davis, Traci | Whitely, Kim | Singh, Baljinder | Swaminathan, Shobha | McGregor, Donna | Palella, Frank | Aberg, Judith | Cavanagh, Karen | Santana Bagur, Jorge L. | Flores, Olga Méndez | Fritsche, Janice | Sha, Beverly | Slamowitz, Debbie | Valle, Sandra | Tashima, Karen | Patterson, Helen | Harber, Heather | Para, Michael | Eaton, Molly | Maddox, Dale | Currier, Judith | Cajahuaringa, Vanessa | Luetkemeyer, Annie | Dwyer, Jay | Fichtenbaum, Carl J. | Saemann, Michelle | Ray, Graham | Campbell, Thomas | Fischl, Margaret A. | Bolivar, Hector | Oakes, Jonathan | Chicurel-Bayard, Miriam | Tripoli, Christine | Weinman, D. Renee | Adams, Mary | Hurley, Christine | Dunaway, Shelia | Storey, Sheryl | Klebert, Michael | Royal, Michael
The Journal of Infectious Diseases  2014;211(5):780-790.
Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART).
Methods. HIV-positive adults receiving ART for ≥96 weeks with undetectable viremia for ≥48 weeks and CD4+ T-cell counts <350 cells/mm3 were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD14 were measured at baseline and at weeks 2, 4, and 8. Wilcoxon rank sum tests compared changes between arms.
Results. Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8+T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P = .03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD14, there were no significant changes within the rifaximin arm.
Conclusions. In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8+T-cell activation.
Trial registration number. NCT01466595.
PMCID: PMC4334803  PMID: 25214516
HIV; immune nonresponders to ART; microbial translocation; immune activation; inflammation; rifaximin
4.  Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial 
The Lancet. Oncology  2015;16(16):1605-1616.
Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.
The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b–T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.
2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4–64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.
The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.
Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.
PMCID: PMC4664817  PMID: 26522334
5.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
6.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 number, NCT00638690.)
PMCID: PMC3471149  PMID: 21612468
7.  Lip, a Human Gene Detected by Transfection of DNA From a Human Liposarcoma Encodes a Protein With Homology to Regulators of Small G Proteins 
Sarcoma  1998;2(1):35-44.
Purpose/Method. Transfection experiments have been used to identify activated oncogenes in a wide variety of tumour types. Here we describe the use of transfection experiments utilizing DNA from a human pleomorphic liposarcoma to identify a novel gene, designated lip which maps to chromosome 19.
Results. lip was expressed in all sarcoma cell lines examined and a wide variety of normal tissues. Sequencing of cDNAs prepared from transcripts of the normal lip gene indicates that lip is predicted to encode a 966 amino acid protein with a region of homology to proteins such as vav, dbl, lbc and ect-2 which act as GDP–GTP exchange factors for the RAS superfamily of small GTP-binding proteins, and the N-terminal 830 amino acids are identical to the recently identified gene p115-RhoGEF, an exchange factor for RHOA. In transfectants, lip has undergone a rearrangement which results in C-terminal truncation of the predicted LIP protein. However, we failed to detect this alteration in the primary liposarcoma used in the original transfection experiments, or in other sarcoma specimens examined.
Discussion. When considered together, these observations suggest that transforming lip sequences represent an alternatively spliced form of p115-RhoGEF that is activated for transformation by C-terminal truncation during transfection, and is not widely involved in sarcoma development.
PMCID: PMC2395381  PMID: 18521231
8.  Amplification and Over-Expression of the MDM2 Gene in Human Soft Tissue Tumours 
Sarcoma  1997;1(1):17-22.
Purpose. Amplification of genetic sequences on chromosome 12q13 is frequently found in soft tissue tumours. However, for the MDM2 gene, over-expression of the MDM2 protein has not always been shown to accompany gene amplification, raising the possibility that amplification of genetic sequences targets alternative genes on chromosome 12q13 for over-expression. To investigate this discrepancy, we have examined 129 soft tissue tumours for amplification of the MDM2 gene using Southern analysis, and 39 of these tumours were also examined by immunohistochemical staining for MDM2 over-expression.
Results. Gene amplification was identified in 14/114 (12.3%) of the malignant tumours, but was not identified in any of the benign tumours; 21/39 (54%) of the malignant tumours also demonstrated MDM2 over-expression. Within this group the MDM2 gene was over-expressed in every tumour in which the gene amplification was found, and over-expression in the absence of gene amplification was also found in an additional 10 tumours.
Discussion. These data demonstrate a clear correlation between the presence of MDM2 amplification and MDM2 over-expression, and provide persuasive evidence therefore that the amplification of genetic sequences on chromosome 12q13 in soft tissue sarcomas targets the MDM2 gene for over-expression. These data also indicate that alternative mechanisms may contribute to MDM2 over-expression within some tumours.
PMCID: PMC2373578  PMID: 18521196

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