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1. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Author

Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Adams L., Adlard J., Alfonso R., Ali S., Andrew A., Araujo L., Azam N., Ball D., Barker Q., Basevitch A., Benton B., Berlin C., Bermingham N., Biller L., Bloss A., Bradford M., Bradshaw N., Branson A., Brendler C., Brennan M., Bulman B., Burgess L., Cahill D., Callard A., Calvo Verges N., Cardoso M., Carter V., Catanzaro M., Chamberlain A., Chapman C., Chong M., Clark C., Clowes V., Cogley L., Cole T., Compton C., Conner T., Cookson S., Cornford P., Costello P., Coulier L., Davies M., Dechet C., DeSouza B., Devlin G., Douglas F., Douglas E., Dudakia D., Duncan A., Ellery N., Everest S., Freemantle S., Frydenberg M., Fuller D., Gabriel C., Gale M., Garcia L., Gay S., Genova E., George A., Georgiou D., Gisbert A., Gleeson M., Glover W., Gnanapragasam V., Goff S., Goldgar D., Goncalves N., Goodman S., Gorrie J., Gott H., Grant A., Gray C., Griffiths J., Gupwell K., Gurasashvili J., Hanslien E., Haraldsdottir S., Hart R., Hartigan C., Hawkes L., Heaton T., Henderson A., Henrique R., Hilario K., Hill K., Hulick P., Hunt C., Hutchings M., Ibitoye R., Inglehearn T., Ireland J., Islam F., Ismail S., Jacobs C., James D., Jenkins S., Jobson I., Johnstone A., Jones O., Josefsberg Ben-Yehoshua S., Kaemba B., Kaul K., Kemp Z., Kinsella N., Klehm M., Kockelbergh R., Kohut K., Kosicka-Slawinska M., Kulkarni A., Kumar P., Lam J., LeButt M., Leibovici D., Lim R., Limb L., Lomas C., Longmuir M., Lopez C., Magnani T., Maia S., Maiden J., Male A., Manalo M., Martin P., McBride D., McGuire M., McMahon R., McNally C., McVeigh T., Melzer E., Mencias M., Mercer C., Mitchell G., Mora J., Morton C., Moss C., Murphy M., Murphy D., Mzazi S., Nadolski M., Newlin A., Nogueira P., O'Keefe R., O'Toole K., O'Connell S., Ogden C., Okoth L., Oliveira J., Paez E., Palou J., Park L., Patel N., Paulo Souto J., Pearce A., Peixoto A., Perez K., Petelin L., Pichert G., Poile C., Potter A., Preitner N., Purnell H., Quinn E., Radice P., Rankin B., Rees K., Renton C., Richardson K., Risby P., Rogers J., Ruderman M., Ruiz A., Sajoo A., Salvatore N., Sands V., Sanguedolce F., Sattar A., Saunders K., Schofield L., Scott R., Searle A., Sehra R., Selkirk C., Shackleton K., Shanley S., Shaw A., Shevrin D., Shipman H., Sidat Z., Siguake K., Simon K., Smyth C., Snadden L., Solanky N., Solomons J., Sorrentino M., Stayner B., Stephenson R., Stoffel E., Thomas M., Thompson A., Tidey L., Tischkowitz M., Torokwa A., Townshend S., Treherne K., Tricker K., Trinh Q.-D., Tripathi V., Turnbull C., Valdagni R., Van As N., Venne V., Verdon L., Vitellaro M., Vogel K., Walker L., Watford A., Watt C., Weintroub I., Weiss S., Weissman S., Weston M., Wiggins J., Wise G., Woodhouse C., Yesildag P., Youngs A., Yurgelun M., Zollo F., Offman J., Kote-Jarai Z., Eeles R.A., Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Adams L., Adlard J., Alfonso R., Ali S., Andrew A., Araujo L., Azam N., Ball D., Barker Q., Basevitch A., Benton B., Berlin C., Bermingham N., Biller L., Bloss A., Bradford M., Bradshaw N., Branson A., Brendler C., Brennan M., Bulman B., Burgess L., Cahill D., Callard A., Calvo Verges N., Cardoso M., Carter V., Catanzaro M., Chamberlain A., Chapman C., Chong M., Clark C., Clowes V., Cogley L., Cole T., Compton C., Conner T., Cookson S., Cornford P., Costello P., Coulier L., Davies M., Dechet C., DeSouza B., Devlin G., Douglas F., Douglas E., Dudakia D., Duncan A., Ellery N., Everest S., Freemantle S., Frydenberg M., Fuller D., Gabriel C., Gale M., Garcia L., Gay S., Genova E., George A., Georgiou D., Gisbert A., Gleeson M., Glover W., Gnanapragasam V., Goff S., Goldgar D., Goncalves N., Goodman S., Gorrie J., Gott H., Grant A., Gray C., Griffiths J., Gupwell K., Gurasashvili J., Hanslien E., Haraldsdottir S., Hart R., Hartigan C., Hawkes L., Heaton T., Henderson A., Henrique R., Hilario K., Hill K., Hulick P., Hunt C., Hutchings M., Ibitoye R., Inglehearn T., Ireland J., Islam F., Ismail S., Jacobs C., James D., Jenkins S., Jobson I., Johnstone A., Jones O., Josefsberg Ben-Yehoshua S., Kaemba B., Kaul K., Kemp Z., Kinsella N., Klehm M., Kockelbergh R., Kohut K., Kosicka-Slawinska M., Kulkarni A., Kumar P., Lam J., LeButt M., Leibovici D., Lim R., Limb L., Lomas C., Longmuir M., Lopez C., Magnani T., Maia S., Maiden J., Male A., Manalo M., Martin P., McBride D., McGuire M., McMahon R., McNally C., McVeigh T., Melzer E., Mencias M., Mercer C., Mitchell G., Mora J., Morton C., Moss C., Murphy M., Murphy D., Mzazi S., Nadolski M., Newlin A., Nogueira P., O'Keefe R., O'Toole K., O'Connell S., Ogden C., Okoth L., Oliveira J., Paez E., Palou J., Park L., Patel N., Paulo Souto J., Pearce A., Peixoto A., Perez K., Petelin L., Pichert G., Poile C., Potter A., Preitner N., Purnell H., Quinn E., Radice P., Rankin B., Rees K., Renton C., Richardson K., Risby P., Rogers J., Ruderman M., Ruiz A., Sajoo A., Salvatore N., Sands V., Sanguedolce F., Sattar A., Saunders K., Schofield L., Scott R., Searle A., Sehra R., Selkirk C., Shackleton K., Shanley S., Shaw A., Shevrin D., Shipman H., Sidat Z., Siguake K., Simon K., Smyth C., Snadden L., Solanky N., Solomons J., Sorrentino M., Stayner B., Stephenson R., Stoffel E., Thomas M., Thompson A., Tidey L., Tischkowitz M., Torokwa A., Townshend S., Treherne K., Tricker K., Trinh Q.-D., Tripathi V., Turnbull C., Valdagni R., Van As N., Venne V., Verdon L., Vitellaro M., Vogel K., Walker L., Watford A., Watt C., Weintroub I., Weiss S., Weissman S., Weston M., Wiggins J., Wise G., Woodhouse C., Yesildag P., Youngs A., Yurgelun M., Zollo F., Offman J., Kote-Jarai Z., and Eeles R.A.

Abstract

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. Method(s): The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This

Published
2022

7. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Author

Teixeira M.R., Rhiem K., Izatt L., Tripathi V., Cardoso M., Foulkes W.D., Aprikian A., van Randeraad H., Davidson R., Longmuir M., Ruijs M.W.G., Adank M., Williams R., Andrews L., Murphy D.G., Halliday D., Walker L., Liljegren A., Carlsson S., Azzabi A., Jobson I., Morton C., Shackleton K., Snape K., Hanson H., Harris M., Tischkowitz M., Taylor A., Kirk J., Susman R., Chen-Shtoyerman R., Spigelman A., Pachter N., Ahmed M., Ramon y Cajal T., Zgajnar J., Brewer C., Gadea N., Brady A.F., van Os T., Gallagher D., Johannsson O., Donaldson A., Barwell J., Nicolai N., Friedman E., Obeid E., Greenhalgh L., Murthy V., Copakova L., Saya S., McGrath J., Cooke P., Ronlund K., Richardson K., Henderson A., Teo S.H., Arun B., Kast K., Dias A., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Eccles D.M., Tricker K., Eyfjord J., Falconer A., Foster C., Gronberg H., Hamdy F.C., Stefansdottir V., Khoo V., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A., Moynihan C., Rennert G., Suri M., Wilson P., Dudderidge T., Offman J., Kote-Jarai Z., Vickers A., Lilja H., Eeles R.A., Helderman van den Enden A.T.J.M., Page E.C., Bancroft E.K., Brook M.N., Assel M., Hassan Al Battat M., Thomas S., Taylor N., Chamberlain A., Pope J., Raghallaigh H.N., Evans D.G., Rothwell J., Maehle L., Grindedal E.M., James P., Mascarenhas L., McKinley J., Side L., Thomas T., van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Jensen T.D., Osther P.J.S., Helfand B.T., Genova E., Oldenburg R.A., Cybulski C., Wokolorczyk D., Ong K.-R., Huber C., Lam J., Taylor L., Salinas M., Feliubadalo L., Oosterwijk J.C., van Zelst-Stams W., Cook J., Rosario D.J., Domchek S., Powers J., Buys S., O'Toole K., Ausems M.G.E.M., Schmutzler R.K., Teixeira M.R., Rhiem K., Izatt L., Tripathi V., Cardoso M., Foulkes W.D., Aprikian A., van Randeraad H., Davidson R., Longmuir M., Ruijs M.W.G., Adank M., Williams R., Andrews L., Murphy D.G., Halliday D., Walker L., Liljegren A., Carlsson S., Azzabi A., Jobson I., Morton C., Shackleton K., Snape K., Hanson H., Harris M., Tischkowitz M., Taylor A., Kirk J., Susman R., Chen-Shtoyerman R., Spigelman A., Pachter N., Ahmed M., Ramon y Cajal T., Zgajnar J., Brewer C., Gadea N., Brady A.F., van Os T., Gallagher D., Johannsson O., Donaldson A., Barwell J., Nicolai N., Friedman E., Obeid E., Greenhalgh L., Murthy V., Copakova L., Saya S., McGrath J., Cooke P., Ronlund K., Richardson K., Henderson A., Teo S.H., Arun B., Kast K., Dias A., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Eccles D.M., Tricker K., Eyfjord J., Falconer A., Foster C., Gronberg H., Hamdy F.C., Stefansdottir V., Khoo V., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A., Moynihan C., Rennert G., Suri M., Wilson P., Dudderidge T., Offman J., Kote-Jarai Z., Vickers A., Lilja H., Eeles R.A., Helderman van den Enden A.T.J.M., Page E.C., Bancroft E.K., Brook M.N., Assel M., Hassan Al Battat M., Thomas S., Taylor N., Chamberlain A., Pope J., Raghallaigh H.N., Evans D.G., Rothwell J., Maehle L., Grindedal E.M., James P., Mascarenhas L., McKinley J., Side L., Thomas T., van Asperen C., Vasen H., Kiemeney L.A., Ringelberg J., Jensen T.D., Osther P.J.S., Helfand B.T., Genova E., Oldenburg R.A., Cybulski C., Wokolorczyk D., Ong K.-R., Huber C., Lam J., Taylor L., Salinas M., Feliubadalo L., Oosterwijk J.C., van Zelst-Stams W., Cook J., Rosario D.J., Domchek S., Powers J., Buys S., O'Toole K., Ausems M.G.E.M., and Schmutzler R.K.

Abstract

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. Objective(s): To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Design, setting, and participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at

Published
2019

8. Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations

Author

Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, Okoth, L, Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, and Okoth, L

Abstract

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support t

Published
2019

9. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers

Author

Page, EC, Bancroft, EK, Brook, MN, Assel, M, Al Battat, MH, Thomas, S, Taylor, N, Chamberlain, A, Pope, J, Ni Raghallaigh, H, Evans, DG, Rothwell, J, Maehle, L, Grindedal, EM, James, P, Mascarenhas, L, McKinley, J, Side, L, Thomas, T, van Asperen, C, Vasen, H, Kiemeney, LA, Ringelberg, J, Jensen, TD, Osther, PJS, Helfand, BT, Genova, E, Oldenburg, RA, Cybulski, C, Wokolorczyk, D, Ong, K-R, Huber, C, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oosterwijk, JC, van Zelst-Stams, W, Cook, J, Rosario, DJ, Domchek, S, Powers, J, Buys, S, O'Toole, K, Ausems, MGEM, Schmutzler, RK, Rhiem, K, Izatt, L, Tripathi, V, Teixeira, MR, Cardoso, M, Foulkes, WD, Aprikian, A, van Randeraad, H, Davidson, R, Longmuir, M, Ruijs, MWG, Helderman van den Enden, ATJM, Adank, M, Williams, R, Andrews, L, Murphy, DG, Halliday, D, Walker, L, Liljegren, A, Carlsson, S, Azzabi, A, Jobson, I, Morton, C, Shackleton, K, Snape, K, Hanson, H, Harris, M, Tischkowitz, M, Taylor, A, Kirk, J, Susman, R, Chen-Shtoyerman, R, Spigelman, A, Pachter, N, Ahmed, M, Ramon y Cajal, T, Zgajnar, J, Brewer, C, Gadea, N, Brady, AF, van Os, T, Gallagher, D, Johannsson, O, Donaldson, A, Barwell, J, Nicolai, N, Friedman, E, Obeid, E, Greenhalgh, L, Murthy, V, Copakova, L, Saya, S, McGrath, J, Cooke, P, Ronlund, K, Richardson, K, Henderson, A, Teo, SH, Arun, B, Kast, K, Dias, A, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Eccles, DM, Tricker, K, Eyfjord, J, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Stefansdottir, V, Khoo, V, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Rennert, G, Suri, M, Wilson, P, Dudderidge, T, Offman, J, Kote-Jarai, Z, Vickers, A, Lilja, H, Eeles, RA, Page, EC, Bancroft, EK, Brook, MN, Assel, M, Al Battat, MH, Thomas, S, Taylor, N, Chamberlain, A, Pope, J, Ni Raghallaigh, H, Evans, DG, Rothwell, J, Maehle, L, Grindedal, EM, James, P, Mascarenhas, L, McKinley, J, Side, L, Thomas, T, van Asperen, C, Vasen, H, Kiemeney, LA, Ringelberg, J, Jensen, TD, Osther, PJS, Helfand, BT, Genova, E, Oldenburg, RA, Cybulski, C, Wokolorczyk, D, Ong, K-R, Huber, C, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oosterwijk, JC, van Zelst-Stams, W, Cook, J, Rosario, DJ, Domchek, S, Powers, J, Buys, S, O'Toole, K, Ausems, MGEM, Schmutzler, RK, Rhiem, K, Izatt, L, Tripathi, V, Teixeira, MR, Cardoso, M, Foulkes, WD, Aprikian, A, van Randeraad, H, Davidson, R, Longmuir, M, Ruijs, MWG, Helderman van den Enden, ATJM, Adank, M, Williams, R, Andrews, L, Murphy, DG, Halliday, D, Walker, L, Liljegren, A, Carlsson, S, Azzabi, A, Jobson, I, Morton, C, Shackleton, K, Snape, K, Hanson, H, Harris, M, Tischkowitz, M, Taylor, A, Kirk, J, Susman, R, Chen-Shtoyerman, R, Spigelman, A, Pachter, N, Ahmed, M, Ramon y Cajal, T, Zgajnar, J, Brewer, C, Gadea, N, Brady, AF, van Os, T, Gallagher, D, Johannsson, O, Donaldson, A, Barwell, J, Nicolai, N, Friedman, E, Obeid, E, Greenhalgh, L, Murthy, V, Copakova, L, Saya, S, McGrath, J, Cooke, P, Ronlund, K, Richardson, K, Henderson, A, Teo, SH, Arun, B, Kast, K, Dias, A, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Eccles, DM, Tricker, K, Eyfjord, J, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Stefansdottir, V, Khoo, V, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, A, Moynihan, C, Rennert, G, Suri, M, Wilson, P, Dudderidge, T, Offman, J, Kote-Jarai, Z, Vickers, A, Lilja, H, and Eeles, RA

Abstract

BACKGROUND: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. OBJECTIVE: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. DESIGN, SETTING, AND PARTICIPANTS: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. RESULTS AND LIMITATIONS: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at

Published
2019

10. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition (vol 118, pg 266, 2018)

Author

Mikropoulos, C., Selkirk, C.G.H., Saya, S., Bancroft, E., Vertosick, E., Dadaev, T., Brendler, C., Page, E., Dias, A., Evans, D.G., Rothwell, J., Maehle, L., Axcrona, K., Richardson, K., Eccles, D., Jensen, T., Osther, P.J., Asperen, C.J. van, Vasen, H., Kiemeney, L.A., Ringelberg, J., Cybulski, C., Wokolorczyk, D., Hart, R., Glover, W., Lam, J., Taylor, L., Salinas, M., Feliubadalo, L., Oldenburg, R., Cremers, R., Verhaegh, G., Zelst-Stams, W.A. van, Oosterwijk, J.C., Cook, J., Rosario, D.J., Buys, S.S., Conner, T., Domchek, S., Powers, J., Ausems, M.G.E.M., Teixeira, M.R., Maia, S., Izatt, L., Schmutzler, R., Rhiem, K., Foulkes, W.D., Boshari, T., Davidson, R., Ruijs, M., Helderman-van den Enden, A.T.J.M., Andrews, L., Walker, L., Snape, K., Henderson, A., Jobson, I., Lindeman, G.J., Liljegren, A., Harris, M., Adank, M.A., Kirk, J., Taylor, A., Susman, R., Chen-Shtoyerman, R., Pachter, N., Spigelman, A., Side, L., Zgajnar, J., Mora, J., Brewer, C., Gadea, N., Brady, A.F., Gallagher, D., Os, T. van, Donaldson, A., Stefansdottir, V., Barwell, J., James, P.A., Murphy, D., Friedman, E., Nicolai, N., Greenhalgh, L., Obeid, E., Murthy, V., Copakova, L., McGrath, J., Teo, S.H., Strom, S., Kast, K., Leongamornlert, D.A., Chamberlain, A., Pope, J., Newlin, A.C., Aaronson, N., Ardern-Jones, A., Bangma, C., Castro, E., Dearnaley, D., Eyfjord, J., Falconer, A., Foster, C.S., Gronberg, H., Hamdy, F.C., Johannsson, O., Khoo, V., Lubinski, J., Grindedal, E.M., McKinley, J., Shackleton, K., Mitra, A.V., Moynihan, C., Rennert, G., Suri, M., Tricker, K., Moss, S., Kote-Jarai, Z., Vickers, A., Lilja, H., Helfand, B.T., Eeles, R.A., and IMPACT Study Collaborators

Published
2018

11. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Author

Mikropoulos, C., Selkirk, C.G.H., Saya, S., Bancroft, E., Vertosick, E., Dadaev, T., Brendler, C., Page, E., Dias, A., Evans, D.G., Rothwell, J., Maehle, L., Axcrona, K., Richardson, K., Eccles, D., Jensen, T., Osther, P.J., Asperen, C.J. van, Vasen, H., Kiemeney, L.A., Ringelberg, J., Cybulski, C., Wokolorczyk, D., Hart, R., Glover, W., Lam, J., Taylor, L., Salinas, M., Feliubadalo, L., Oldenburg, R., Cremers, R., Verhaegh, G., Zelst-Stams, W.A. van, Oosterwijk, J.C., Cook, J., Rosario, D.J., Buys, S.S., Conner, T., Domchek, S., Powers, J., Ausems, M.G.E.M., Teixeira, M.R., Maia, S., Izatt, L., Schmutzler, R., Rhiem, K., Foulkes, W.D., Boshari, T., Davidson, R., Ruijs, M., Helderman-van den Enden, A.T.J.M., Andrews, L., Walker, L., Snape, K., Henderson, A., Jobson, I., Lindeman, G.J., Liljegren, A., Harris, M., Adank, M.A., Kirk, J., Taylor, A., Susman, R., Chen-Shtoyerman, R., Pachter, N., Spigelman, A., Side, L., Zgajnar, J., Mora, J., Brewer, C., Gadea, N., Brady, A.F., Gallagher, D., Os, T. van, Donaldson, A., Stefansdottir, V., Barwell, J., James, P.A., Murphy, D., Friedman, E., Nicolai, N., Greenhalgh, L., Obeid, E., Murthy, V., Copakova, L., McGrath, J., Teo, S.H., Strom, S., Kast, K., Leongamornlert, D.A., Chamberlain, A., Pope, J., Newlin, A.C., Aaronson, N., Ardern-Jones, A., Bangma, C., Castro, E., Dearnaley, D., Eyfjord, J., Falconer, A., Foster, C.S., Gronberg, H., Hamdy, F.C., Johannsson, O., Khoo, V., Lubinski, J., Grindedal, E.M., McKinley, J., Shackleton, K., Mitra, A.V., Moynihan, C., Rennert, G., Suri, M., Tricker, K., Moss, S., Kote-Jarai, Z., Vickers, A., Lilja, H., Helfand, B.T., Eeles, R.A., and IMPACT Study Collaborators

Subjects
predictive model, prostate cancer, BRCA1, urologic and male genital diseases, genetic predisposition, BRCA2, PSA velocity
Abstract

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. Methods: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. Results: 1634 participants had >= 3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml(-1), PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P = 0.031) and BRCA2 status and PSAV (P = 0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. Conclusions: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Published
2018

13. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Author

Izatt L., Davidson R., Ruijs M., Helderman-Van Den Enden A.T., Andrews L., Walker L., Snape K., Henderson A., Jobson I., Lindeman G.J., Liljegren A., Harris M., Adank M.A., Kirk J., Taylor A., Susman R., Chen-Shtoyerman R., Pachter N., Spigelman A., Side L., Zgajnar J., Mora J., Brewer C., Gadea N., Brady A.F., Gallagher D., Van Os T., Donaldson A., Stefansdottir V., Barwell J., James P.A., Murphy D., Friedman E., Nicolai N., Greenhalgh L., Obeid E., Murthy V., Copakova L., McGrath J., Teo S.-H., Strom S., Kast K., Leongamornlert D.A., Chamberlain A., Pope J., Newlin A.C., Aaronson N., Ardern-Jones A., Bangma C., Castro E., Dearnaley D., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lubinski J., Grindedal E.M., McKinley J., Shackleton K., Mitra A.V., Moynihan C., Rennert G., Suri M., Tricker K., Moss S., Kote-Jarai Z., Vickers A., Lilja H., Helfand B.T., Eeles R.A., Mikropoulos C., Selkirk C.G.H., Saya S., Bancroft E., Vertosick E., Dadaev T., Brendler C., Page E., Dias A., Evans D.G., Rothwell J., Maehle L., Axcrona K., Richardson K., Eccles D., Jensen T., Osther P.J., Van Asperen C.J., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Hart R., Glover W., Lam J., Taylor L., Salinas M., Feliubadalo L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., Oosterwijk J.C., Cook J., Rosario D.J., Buys S.S., Conner T., Domchek S., Powers J., Ausems M.G., Teixeira M.R., Maia S., Schmutzler R., Rhiem K., Foulkes W.D., Boshari T., Izatt L., Davidson R., Ruijs M., Helderman-Van Den Enden A.T., Andrews L., Walker L., Snape K., Henderson A., Jobson I., Lindeman G.J., Liljegren A., Harris M., Adank M.A., Kirk J., Taylor A., Susman R., Chen-Shtoyerman R., Pachter N., Spigelman A., Side L., Zgajnar J., Mora J., Brewer C., Gadea N., Brady A.F., Gallagher D., Van Os T., Donaldson A., Stefansdottir V., Barwell J., James P.A., Murphy D., Friedman E., Nicolai N., Greenhalgh L., Obeid E., Murthy V., Copakova L., McGrath J., Teo S.-H., Strom S., Kast K., Leongamornlert D.A., Chamberlain A., Pope J., Newlin A.C., Aaronson N., Ardern-Jones A., Bangma C., Castro E., Dearnaley D., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lubinski J., Grindedal E.M., McKinley J., Shackleton K., Mitra A.V., Moynihan C., Rennert G., Suri M., Tricker K., Moss S., Kote-Jarai Z., Vickers A., Lilja H., Helfand B.T., Eeles R.A., Mikropoulos C., Selkirk C.G.H., Saya S., Bancroft E., Vertosick E., Dadaev T., Brendler C., Page E., Dias A., Evans D.G., Rothwell J., Maehle L., Axcrona K., Richardson K., Eccles D., Jensen T., Osther P.J., Van Asperen C.J., Vasen H., Kiemeney L.A., Ringelberg J., Cybulski C., Wokolorczyk D., Hart R., Glover W., Lam J., Taylor L., Salinas M., Feliubadalo L., Oldenburg R., Cremers R., Verhaegh G., Van Zelst-Stams W.A., Oosterwijk J.C., Cook J., Rosario D.J., Buys S.S., Conner T., Domchek S., Powers J., Ausems M.G., Teixeira M.R., Maia S., Schmutzler R., Rhiem K., Foulkes W.D., and Boshari T.

Abstract

Background:Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. Method(s):PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. Result(s):1634 participants had 3/43 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml -l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. Conclusion(s):PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Published
2018

14. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition (vol 118, pg 266, 2018)

Author

Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, R, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, MGEM, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van den Enden, ATJM, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA, Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, S-H, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, Eeles, RA, Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J, Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, R, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, MGEM, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van den Enden, ATJM, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA, Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, S-H, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, and Eeles, RA

Abstract

This corrects the article DOI: 10.1038/bjc.2017.429.

Published
2018

15. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Author

Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J (Jan), Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, Rogier, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, M, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van d Enden, A, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA (Muriel), Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, Van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, SH, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C.H., Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS (Christopher), Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, Eeles, RA, Mikropoulos, C, Selkirk, CGH, Saya, S, Bancroft, E, Vertosick, E, Dadaev, T, Brendler, C, Page, E, Dias, A, Evans, DG, Rothwell, J, Maehle, L, Axcrona, K, Richardson, K, Eccles, D, Jensen, T, Osther, PJ, van Asperen, CJ, Vasen, H, Kiemeney, LA, Ringelberg, J, Cybulski, C, Wokolorczyk, D, Hart, R, Glover, W, Lam, J (Jan), Taylor, L, Salinas, M, Feliubadalo, L, Oldenburg, Rogier, Cremers, R, Verhaegh, G, van Zelst-Stams, WA, Oosterwijk, JC, Cook, J, Rosario, DJ, Buys, SS, Conner, T, Domchek, S, Powers, J, Ausems, M, Teixeira, MR, Maia, S, Izatt, L, Schmutzler, R, Rhiem, K, Foulkes, WD, Boshari, T, Davidson, R, Ruijs, M, Helderman-van d Enden, A, Andrews, L, Walker, L, Snape, K, Henderson, A, Jobson, I, Lindeman, GJ, Liljegren, A, Harris, M, Adank, MA (Muriel), Kirk, J, Taylor, A, Susman, R, Chen-Shtoyerman, R, Pachter, N, Spigelman, A, Side, L, Zgajnar, J, Mora, J, Brewer, C, Gadea, N, Brady, AF, Gallagher, D, Van Os, T, Donaldson, A, Stefansdottir, V, Barwell, J, James, PA, Murphy, D, Friedman, E, Nicolai, N, Greenhalgh, L, Obeid, E, Murthy, V, Copakova, L, McGrath, J, Teo, SH, Strom, S, Kast, K, Leongamornlert, DA, Chamberlain, A, Pope, J, Newlin, AC, Aaronson, N, Ardern-Jones, A, Bangma, C.H., Castro, E, Dearnaley, D, Eyfjord, J, Falconer, A, Foster, CS (Christopher), Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lubinski, J, Grindedal, EM, McKinley, J, Shackleton, K, Mitra, AV, Moynihan, C, Rennert, G, Suri, M, Tricker, K, Moss, S, Kote-Jarai, Z, Vickers, A, Lilja, H, Helfand, BT, and Eeles, RA

Published
2018

16. Early development of infants with neurofibromatosis type 1: A case series

Author

Kolesnik, A, Jones, E, Garg, S, Green, J, Charman, T, Johnson, M, Baron-Cohen, S, Begum-Ali, J, Bolton, P, Cheung, C, Dafner, L, Davies, K, Elsabbagh, M, Fernandes, J, Fish, L, Gammer, I, Greensmith, M, Gliga, T, Kalwarowsky, S, Liew, M, Pasco, G, Pickles, A, Ribeiro, H, Salomone, E, Taylor, C, Tucker, L, Wass, S, Burkitt-Wright, E, Evans, D, Vassallo, G, Eelloo, J, West, S, Howard, E, Hupton, E, Huson, S, Lewis, L, Tricker, K, Dobbie, A, Drimer, R, Sharif, S, Baralle, D, Redman, C, Symth, C, Lam, W, Bradbury, A, Harrower, N, Quarrell, O, Bethell, H, Jones, R, Musson, S, Prem, C, Splitt, M, Horridge, K, Steiger, C, Jim, C, Kolesnik, Anna May, Jones, Emily Jane Harrison, Garg, Shruti, Green, Jonathan, Charman, Tony, Johnson, Mark Henry, Baron-Cohen, Simon, Begum-Ali, Jannath, Bolton, Patrick, Cheung, Celeste, Dafner, Leila, Davies, Kim, Elsabbagh, Mayada, Fernandes, Janice, Fish, Laurel, Gammer, Isobel, Greensmith, Marian, Gliga, Teodora, Kalwarowsky, Sarah, Liew, Michelle, Pasco, Greg, Pickles, Andrew, Ribeiro, Helena, Salomone, Erica, Taylor, Chloe, Tucker, Leslie, Wass, Sam, Burkitt-Wright, Emma, Evans, D. Gareth, Vassallo, Grace, Eelloo, Judith, West, Siobhan, Howard, Elizabeth, Hupton, Eileen, Huson, Sue, Lewis, Lauren, Tricker, Karen, Dobbie, Angus, Drimer, Ruth, Sharif, Saghira Malik, Baralle, Diane, Redman, Carolyn, Sharif, Saba, Symth, Carolyn, Lam, Wayne, Bradbury, Alyson, Harrower, Neil, Quarrell, Oliver, Bethell, Helen, Jones, Rachel, Musson, Susan, Prem, Catherine, Splitt, Miranda, Horridge, Karen, Steiger, Christine, Jim, Carly, Kolesnik, A, Jones, E, Garg, S, Green, J, Charman, T, Johnson, M, Baron-Cohen, S, Begum-Ali, J, Bolton, P, Cheung, C, Dafner, L, Davies, K, Elsabbagh, M, Fernandes, J, Fish, L, Gammer, I, Greensmith, M, Gliga, T, Kalwarowsky, S, Liew, M, Pasco, G, Pickles, A, Ribeiro, H, Salomone, E, Taylor, C, Tucker, L, Wass, S, Burkitt-Wright, E, Evans, D, Vassallo, G, Eelloo, J, West, S, Howard, E, Hupton, E, Huson, S, Lewis, L, Tricker, K, Dobbie, A, Drimer, R, Sharif, S, Baralle, D, Redman, C, Symth, C, Lam, W, Bradbury, A, Harrower, N, Quarrell, O, Bethell, H, Jones, R, Musson, S, Prem, C, Splitt, M, Horridge, K, Steiger, C, Jim, C, Kolesnik, Anna May, Jones, Emily Jane Harrison, Garg, Shruti, Green, Jonathan, Charman, Tony, Johnson, Mark Henry, Baron-Cohen, Simon, Begum-Ali, Jannath, Bolton, Patrick, Cheung, Celeste, Dafner, Leila, Davies, Kim, Elsabbagh, Mayada, Fernandes, Janice, Fish, Laurel, Gammer, Isobel, Greensmith, Marian, Gliga, Teodora, Kalwarowsky, Sarah, Liew, Michelle, Pasco, Greg, Pickles, Andrew, Ribeiro, Helena, Salomone, Erica, Taylor, Chloe, Tucker, Leslie, Wass, Sam, Burkitt-Wright, Emma, Evans, D. Gareth, Vassallo, Grace, Eelloo, Judith, West, Siobhan, Howard, Elizabeth, Hupton, Eileen, Huson, Sue, Lewis, Lauren, Tricker, Karen, Dobbie, Angus, Drimer, Ruth, Sharif, Saghira Malik, Baralle, Diane, Redman, Carolyn, Sharif, Saba, Symth, Carolyn, Lam, Wayne, Bradbury, Alyson, Harrower, Neil, Quarrell, Oliver, Bethell, Helen, Jones, Rachel, Musson, Susan, Prem, Catherine, Splitt, Miranda, Horridge, Karen, Steiger, Christine, and Jim, Carly

Abstract

Background: Prospective studies of infants at familial risk for autism spectrum disorder (ASD) have yielded insights into the earliest signs of the disorder but represent heterogeneous samples of unclear aetiology. Complementing this approach by studying cohorts of infants with monogenic syndromes associated with high rates of ASD offers the opportunity to elucidate the factors that lead to ASD. Methods: We present the first report from a prospective study of ten 10-month-old infants with neurofibromatosis type 1 (NF1), a monogenic disorder with high prevalence of ASD or ASD symptomatology. We compared data from infants with NF1 to a large cohort of infants at familial risk for ASD, separated by outcome at age 3 of ASD (n = 34), atypical development (n = 44), or typical development (n = 89), and low-risk controls (n = 75). Domains assessed at 10 months by parent report and examiner observation include cognitive and adaptive function, sensory processing, social engagement, and temperament. Results: Infants with NF1 showed striking impairments in motor functioning relative to low-risk infants; this pattern was seen in infants with later ASD from the familial cohort (HR-ASD). Both infants with NF1 and the HR-ASD group showed communication delays relative to low-risk infants. Conclusions: Ten-month-old infants with NF1 show a range of developmental difficulties that were particularly striking in motor and communication domains. As with HR-ASD infants, social skills at this age were not notably impaired. This is some of the first information on early neurodevelopment in NF1. Strong inferences are limited by the sample size, but the findings suggest implications for early comparative developmental science and highlight motor functioning as an important domain to inform the development of relevant animal models. The findings have clinical implications in indicating an important focus for early surveillance and remediation in this early diagnosed genetic disorder.

Published
2017

17. The relationship between social deprivation, disease outcome measures, and response to treatment in patients with stable, long-standing rheumatoid arthritis

Author

Harrison, M. J., Tricker, K. J., Davies, L., Hassell, A., Dawes, P., Scott, D. L., Knight, S., Davis, M., Mulherin, D., and Deborah Symmons

Abstract

OBJECTIVE: Patients with rheumatoid arthritis (RA) with lower socioeconomic status (SES) are known to have more severe disease, more comorbidity, and higher mortality. It is not known whether SES influences response to treatment in RA. We examined the relationship between area of residence (as a surrogate for SES) and baseline outcome measures and response to treatment, using data from the British Rheumatoid Outcome Study Group randomized controlled trial of aggressive versus symptomatic treatment of long-standing, stable RA. METHODS: A total of 466 patients from 5 centers were recruited to the trial. Baseline data included age, sex, smoking status, and comorbidity. Patients were assigned a Townsend score (a measure of social deprivation) according to their area of residence. Outcome measures including the Disease Activity Score (DAS28), Health Assessment Questionnaire, Medical Outcomes Study Short Form-36, and EuroQol (EQ5D) were recorded at the beginning and end of the 3 year trial. The baseline, 3 year values, and change data were examined by Townsend quintile adjusting for each treatment arm. RESULTS: Significant relationships between increasing social deprivation by area of residence and higher disease activity, higher pain, poorer physical function, poorer emotional aspects of mental health, and lower quality of life were found at baseline (adjusted for age, sex, disease duration, current smoking, treatment center, and treatment group). During the 3 year trial period, patients from the most deprived areas showed greater improvement, with statistically significant greater improvement on DAS28 (p = 0.041) and 28 tender joint count (p = 0.015). CONCLUSION: Area of residence is related to the severity of RA at recruitment and is a predictor of response in a clinical trial situation. The results suggest that measures of SES should be recorded for patients enrolled in clinical trials, longitudinal observational studies, and in the clinical setting.

Published
2005

20. Patients with stable long-standing rheumatoid arthritis continue to deteriorate despite intensified treatment with traditional disease modifying anti-rheumatic drugs—results of the British Rheumatoid Outcome Study Group randomized controlled clinical trial

Author

Symmons, D., primary, Tricker, K., additional, Harrison, M., additional, Roberts, C., additional, Davis, M., additional, Dawes, P., additional, Hassell, A., additional, Knight, S., additional, Mulherin, D., additional, and Scott, D. L., additional

Published
2005
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28. Research Governance: What is reasonable protection?

Author

Katherine Payne, Ea, Fargher, Tricker, K., William Newman, Ff, Qasim, Kay Poulton, Andrews, J., Brian Houston, Rachel Ann Elliott, Elles, R., David Ray, Jl, Shaffer, Christopher Griffiths, Ian Bruce, Roberts, Stephen A., and William Ollier

29. An enzyme-linked immunosorbent assay using Schistosoma mansonipurified egg antigen for the diagnosis of schistosomiasis in Saudi Arabia

Author

Ghandour, A.M., Tricker, K., Doenhoff, M.J., Al-Robai, A.A., and Banaja, A.A.

Abstract

The enzyme-linked immunosorbent assay (elisa) using purified Schistosoma mansoniegg antigen (CEF6) was compared with standard parasitological diagnostic tests (potassium hydroxide digestion of faeces and urine filtration) for diagnosis of schistosomiasis in humans in Saudi Arabia. Faecal, urine and finger-prick blood samples were collected from 2 groups of individuals of both sexes, aged 1–50 years, in 2 areas in the western region of Saudi Arabia: 983 in a schistosomiasis endemic area (Al-Hijaz highlands) and 192 in a non-endemic area (Jeddah). In the non-endemic area, almost 90% of the blood samples gave optical density readings at 492 nm (OD) <0·25. The mean OD in the schistosome endemic area (0·31) was much higher than in the non-endemic area (0·14). The prevalence of S. mansoniinfection by faecal examination in the endemic area was 10·2% and the specificity and sensitivity of the elisausing a cut-off OD of 0·25 were 55% and 90%, respectively. In the endemic area, there was a positive correlation between egg intensity and OD value. No S. haematobiumwas detected. In the non-endemic area, the specificity was 90%. The main reasons for false positive results may have been inapparent or cured S. mansoniinfection.

Published
1997
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30. Early development of infants with neurofibromatosis type 1: a case series

Author

Kolesnik, Anna May, Jones, Emily Jane Harrison, Garg, Shruti, Green, Jonathan, Charman, Tony, Johnson, Mark Henry, Baron-Cohen, Simon, Begum-Ali, Jannath, Bolton, Patrick, Cheung, Celeste, Dafner, Leila, Davies, Kim, Elsabbagh, Mayada, Fernandes, Janice, Fish, Laurel, Gammer, Isobel, Greensmith, Marian, Gliga, Teodora, Kalwarowsky, Sarah, Liew, Michelle, Pasco, Greg, Pickles, Andrew, Ribeiro, Helena, Salomone, Erica, Taylor, Chloe, Tucker, Leslie, Wass, Sam, Burkitt-Wright, Emma, Evans, D. Gareth, Vassallo, Grace, Eelloo, Judith, West, Siobhan, Howard, Elizabeth, Hupton, Eileen, Huson, Sue, Lewis, Lauren, Tricker, Karen, Dobbie, Angus, Drimer, Ruth, Sharif, Saghira Malik, Baralle, Diane, Redman, Carolyn, Sharif, Saba, Symth, Carolyn, Lam, Wayne, Bradbury, Alyson, Harrower, Neil, Quarrell, Oliver, Bethell, Helen, Jones, Rachel, Musson, Susan, Prem, Catherine, Splitt, Miranda, Horridge, Karen, Steiger, Christine, Jim, Carly, Kolesnik, A, Jones, E, Garg, S, Green, J, Charman, T, Johnson, M, Baron-Cohen, S, Begum-Ali, J, Bolton, P, Cheung, C, Dafner, L, Davies, K, Elsabbagh, M, Fernandes, J, Fish, L, Gammer, I, Greensmith, M, Gliga, T, Kalwarowsky, S, Liew, M, Pasco, G, Pickles, A, Ribeiro, H, Salomone, E, Taylor, C, Tucker, L, Wass, S, Burkitt-Wright, E, Evans, D, Vassallo, G, Eelloo, J, West, S, Howard, E, Hupton, E, Huson, S, Lewis, L, Tricker, K, Dobbie, A, Drimer, R, Sharif, S, Baralle, D, Redman, C, Symth, C, Lam, W, Bradbury, A, Harrower, N, Quarrell, O, Bethell, H, Jones, R, Musson, S, Prem, C, Splitt, M, Horridge, K, Steiger, C, Jim, C, Johnson, Mark [0000-0003-4229-2585], and Apollo - University of Cambridge Repository

Subjects
Male, Pediatrics, Autism Spectrum Disorder, Adaptive functioning, Autism, Prospective longitudinal, Developmental cognitive neuroscience, Language Development Disorder, lcsh:RC346-429, psyc, 0302 clinical medicine, Cognition, Development, Infant, NF1, Sensory processing, Social engagement, Translational neurodevelopment, Activities of Daily Living, Communication, Female, Humans, Language Development Disorders, Motor Activity, Neurofibromatosis 1, Prospective Studies, Risk, Temperament, Molecular Biology, Developmental Neuroscience, Developmental Biology, Psychiatry and Mental Health, Prospective cohort study, media_common, 05 social sciences, Neuropsychology, Autism spectrum disorder, Cohort, Psychology, 050104 developmental & child psychology, Human, medicine.medical_specialty, media_common.quotation_subject, behavioral disciplines and activities, 03 medical and health sciences, mental disorders, medicine, 0501 psychology and cognitive sciences, Neurofibromatosis, lcsh:Neurology. Diseases of the nervous system, Research, medicine.disease, Prospective Studie, 030217 neurology & neurosurgery
Abstract

Background Prospective studies of infants at familial risk for autism spectrum disorder (ASD) have yielded insights into the earliest signs of the disorder but represent heterogeneous samples of unclear aetiology. Complementing this approach by studying cohorts of infants with monogenic syndromes associated with high rates of ASD offers the opportunity to elucidate the factors that lead to ASD. Methods We present the first report from a prospective study of ten 10-month-old infants with neurofibromatosis type 1 (NF1), a monogenic disorder with high prevalence of ASD or ASD symptomatology. We compared data from infants with NF1 to a large cohort of infants at familial risk for ASD, separated by outcome at age 3 of ASD (n = 34), atypical development (n = 44), or typical development (n = 89), and low-risk controls (n = 75). Domains assessed at 10 months by parent report and examiner observation include cognitive and adaptive function, sensory processing, social engagement, and temperament. Results Infants with NF1 showed striking impairments in motor functioning relative to low-risk infants; this pattern was seen in infants with later ASD from the familial cohort (HR-ASD). Both infants with NF1 and the HR-ASD group showed communication delays relative to low-risk infants. Conclusions Ten-month-old infants with NF1 show a range of developmental difficulties that were particularly striking in motor and communication domains. As with HR-ASD infants, social skills at this age were not notably impaired. This is some of the first information on early neurodevelopment in NF1. Strong inferences are limited by the sample size, but the findings suggest implications for early comparative developmental science and highlight motor functioning as an important domain to inform the development of relevant animal models. The findings have clinical implications in indicating an important focus for early surveillance and remediation in this early diagnosed genetic disorder. Electronic supplementary material The online version of this article (10.1186/s13229-017-0178-0) contains supplementary material, which is available to authorized users.

Published
2017
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31. Exploring NICU nurses' views of a novel genetic point-of-care test identifying neonates at risk of antibiotic-induced ototoxicity: A qualitative study.

Author

Brown G, Warrington N, Ulph F, Booth N, Harvey K, James R, Tricker K, Wilson P, Newman W, Mcdermott JH, Stoddard D, Mahaveer A, Turner M, Corry R, Garlick J, Miele G, Ainsworth S, Kemp L, Bruce I, Body R, Roberts P, and Macleod R

Subjects
Humans, Infant, Newborn, Female, Male, Ototoxicity, Attitude of Health Personnel, Nursing Staff, Hospital, Adult, Point-of-Care Systems, Genetic Testing, Anti-Bacterial Agents adverse effects, Qualitative Research, Intensive Care Units, Neonatal, Point-of-Care Testing
Abstract

Aim: To explore the views of neonatal intensive care nursing staff on the deliverability of a novel genetic point-of-care test detecting a genetic variant associated with antibiotic-induced ototoxicity., Design: An interpretive, descriptive, qualitative interview study., Methods: Data were collected using semi-structured interviews undertaken between January and November 2020. Participants were neonatal intensive care nursing staff taking part in the Pharmacogenetics to Avoid Loss of Hearing trial., Results: Thematic analysis resulted in four themes: perceived clinical utility; the golden hour; point-of-care device; training and support. Recommendations were made to streamline the protocol and ongoing training and support were considered key to incorporating the test into routine care., Conclusion: Exploring the views of nurses involved in the delivery of the point-of-care test was essential in its implementation. By the study endpoint, all participants could see the value of routine clinical introduction of the point-of care test., Implications for the Profession And/or Patient Care: Nurses are in a key position to support the delivery of point-of-care genetic testing into mainstream settings. This study has implications for the successful integration of other genetic point-of-care tests in acute healthcare settings., Impact: The study will help to tailor the training and support required for routine deployment of the genetic point-of-care test. The study has relevance for nurses involved in the development and delivery of genetic point-of-care tests in other acute hospital settings., Reporting Method: This qualitative study adheres to the Standards for Reporting Qualitative Research EQUATOR guidelines and utilizes COREQ and SRQR checklists., Patient or Public Contribution: All staff working on the participating neonatal intensive care units were trained to use the genetic point-of-care test. All inpatients on the participating units were eligible to have testing via the point-of-care test. The Pharmacogenetics to Avoid Loss of Hearing Patient and Public Involvement and Engagement group provided valuable feedback., Trial and Protocol Registration: Registered within the University of Manchester. Ethics approval reference numbers: IRAS: 253102 REC reference: 19/NW/0400. Also registered with the ISRCTN ref: ISRCTN13704894., (© 2024 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

Published
2024
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32. Hereditary renal cancer patient and public involvement group: A collaborative, consensus decision process to develop a communication tool for patient use.

Author

Colvin E, Ng S, Hepworth J, Hepworth J, Hartley T, Godfrey N, Tricker K, Rothwell J, Beaman G, and Woodward ER

Abstract

Patient and public involvement (PPI) must be more frequently embedded within clinical research to ensure translational outcomes are patient-led and meet patient needs. Active partnerships with patients and public groups are an important opportunity to hear patient voices, understand patient needs, and inform future research avenues. A hereditary renal cancer (HRC) PPI group was developed with the efforts of patient participants ( n = 9), pooled from recruits within the early detection for HRC pilot study, working in collaboration with researchers and healthcare professionals ( n = 8). Patient participants had HRC conditions including Von Hippel-Lindau ( n = 3) and Hereditary Leiomyomatosis and Renal Cell Carcinoma ( n = 5), and public participants included two patient Trustees ( n = 2) from VHL UK & Ireland Charity. Discussions among the enthusiastic participants guided the development of a novel patient information sheet for HRC patients. This communication tool was designed to aid patients when informing family members about their diagnoses and the wider implications for relatives, a gap identified by participants within group discussions. While this partnership was tailored for a specific HRC patient and public group, the process implemented can be employed for other hereditary cancer groups and could be transferable within other healthcare settings., Competing Interests: The authors and members of the ACED ELECTRIC study involved in the development of this PPI group and the PIS declare no conflicts of interest with respect to the development of the PPI group, PIS nor the preparation and writing of the manuscript., (© The Author(s) 2023.)

Published
2023
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33. Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care.

Author

McDermott JH, Mahaveer A, James RA, Booth N, Turner M, Harvey KE, Miele G, Beaman GM, Stoddard DC, Tricker K, Corry RJ, Garlick J, Ainsworth S, Beevers T, Bruce IA, Body R, Ulph F, MacLeod R, Roberts PL, Wilson PM, and Newman WG

Subjects
Anti-Bacterial Agents adverse effects, Genotype, Humans, Infant, Infant, Newborn, Intensive Care, Neonatal, Point-of-Care Systems, Prospective Studies, Aminoglycosides adverse effects, Ototoxicity
Abstract

Importance: Aminoglycosides are commonly prescribed antibiotics used for the treatment of neonatal sepsis. The MT-RNR1 m.1555A>G variant predisposes to profound aminoglycoside-induced ototoxicity (AIO). Current genotyping approaches take several days, which is unfeasible in acute settings., Objective: To develop a rapid point-of-care test (POCT) for the m.1555A>G variant before implementation of this technology in the acute neonatal setting to guide antibiotic prescribing and avoid AIO., Design, Setting, and Participants: This pragmatic prospective implementation trial recruited neonates admitted to 2 large neonatal intensive care units between January 6, 2020, and November 30, 2020, in the UK., Interventions: Neonates were tested for the m.1555A>G variant via the rapid POCT on admission to the neonatal intensive care unit., Main Outcomes and Measures: The primary outcome assessed the proportion of neonates successfully tested for the variant of all infants prescribed antibiotics. Secondary outcomes measured whether implementation was negatively associated with routine clinical practice and the performance of the system. The study was statistically powered to detect a significant difference between time to antibiotic administration before and after implementation of the MT-RNR1 POCT., Results: A total of 751 neonates were recruited and had a median (range) age of 2.5 (0-198) days. The MT-RNR1 POCT was able to genotype the m.1555A>G variant in 26 minutes. Preclinical validation demonstrated a 100% sensitivity (95% CI, 93.9%-100.0%) and specificity (95% CI, 98.5%-100.0%). Three participants with the m.1555A>G variant were identified, all of whom avoided aminoglycoside antibiotics. Overall, 424 infants (80.6%) receiving antibiotics were successfully tested for the variant, and the mean time to antibiotics was equivalent to previous practice., Conclusions and Relevance: The MT-RNR1 POCT was integrated without disrupting normal clinical practice, and genotype was used to guide antibiotic prescription and avoid AIO. This approach identified the m.1555A>G variant in a practice-changing time frame, and wide adoption could significantly reduce the burden of AIO.

Published
2022
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34. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Author

Page EC, Bancroft EK, Brook MN, Assel M, Hassan Al Battat M, Thomas S, Taylor N, Chamberlain A, Pope J, Raghallaigh HN, Evans DG, Rothwell J, Maehle L, Grindedal EM, James P, Mascarenhas L, McKinley J, Side L, Thomas T, van Asperen C, Vasen H, Kiemeney LA, Ringelberg J, Jensen TD, Osther PJS, Helfand BT, Genova E, Oldenburg RA, Cybulski C, Wokolorczyk D, Ong KR, Huber C, Lam J, Taylor L, Salinas M, Feliubadaló L, Oosterwijk JC, van Zelst-Stams W, Cook J, Rosario DJ, Domchek S, Powers J, Buys S, O'Toole K, Ausems MGEM, Schmutzler RK, Rhiem K, Izatt L, Tripathi V, Teixeira MR, Cardoso M, Foulkes WD, Aprikian A, van Randeraad H, Davidson R, Longmuir M, Ruijs MWG, Helderman van den Enden ATJM, Adank M, Williams R, Andrews L, Murphy DG, Halliday D, Walker L, Liljegren A, Carlsson S, Azzabi A, Jobson I, Morton C, Shackleton K, Snape K, Hanson H, Harris M, Tischkowitz M, Taylor A, Kirk J, Susman R, Chen-Shtoyerman R, Spigelman A, Pachter N, Ahmed M, Ramon Y Cajal T, Zgajnar J, Brewer C, Gadea N, Brady AF, van Os T, Gallagher D, Johannsson O, Donaldson A, Barwell J, Nicolai N, Friedman E, Obeid E, Greenhalgh L, Murthy V, Copakova L, Saya S, McGrath J, Cooke P, Rønlund K, Richardson K, Henderson A, Teo SH, Arun B, Kast K, Dias A, Aaronson NK, Ardern-Jones A, Bangma CH, Castro E, Dearnaley D, Eccles DM, Tricker K, Eyfjord J, Falconer A, Foster C, Gronberg H, Hamdy FC, Stefansdottir V, Khoo V, Lindeman GJ, Lubinski J, Axcrona K, Mikropoulos C, Mitra A, Moynihan C, Rennert G, Suri M, Wilson P, Dudderidge T, Offman J, Kote-Jarai Z, Vickers A, Lilja H, and Eeles RA

Subjects
Adult, Aged, Humans, Kallikreins blood, Male, Middle Aged, Prospective Studies, Prostate-Specific Antigen blood, Prostatic Neoplasms blood, Early Detection of Cancer methods, Genes, BRCA1, Genes, BRCA2, Genetic Carrier Screening methods, Germ-Line Mutation, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics
Abstract

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations., Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status., Design, Setting, and Participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy., Outcome Measurements and Statistical Analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians., Results and Limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65)., Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers., Patient Summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2019
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35. Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Author

Mikropoulos C, Hutten Selkirk CG, Saya S, Bancroft E, Vertosick E, Dadaev T, Brendler C, Page E, Dias A, Evans DG, Rothwell J, Maehle L, Axcrona K, Richardson K, Eccles D, Jensen T, Osther PJ, van Asperen CJ, Vasen H, Kiemeney LA, Ringelberg J, Cybulski C, Wokolorczyk D, Hart R, Glover W, Lam J, Taylor L, Salinas M, Feliubadaló L, Oldenburg R, Cremers R, Verhaegh G, van Zelst-Stams WA, Oosterwijk JC, Cook J, Rosario DJ, Buys SS, Conner T, Domchek S, Powers J, Ausems MGEM, Teixeira MR, Maia S, Izatt L, Schmutzler R, Rhiem K, Foulkes WD, Boshari T, Davidson R, Ruijs M, Helderman-van den Enden ATJM, Andrews L, Walker L, Snape K, Henderson A, Jobson I, Lindeman GJ, Liljegren A, Harris M, Adank MA, Kirk J, Taylor A, Susman R, Chen-Shtoyerman R, Pachter N, Spigelman A, Side L, Zgajnar J, Mora J, Brewer C, Gadea N, Brady AF, Gallagher D, van Os T, Donaldson A, Stefansdottir V, Barwell J, James PA, Murphy D, Friedman E, Nicolai N, Greenhalgh L, Obeid E, Murthy V, Copakova L, McGrath J, Teo SH, Strom S, Kast K, Leongamornlert DA, Chamberlain A, Pope J, Newlin AC, Aaronson N, Ardern-Jones A, Bangma C, Castro E, Dearnaley D, Eyfjord J, Falconer A, Foster CS, Gronberg H, Hamdy FC, Johannsson O, Khoo V, Lubinski J, Grindedal EM, McKinley J, Shackleton K, Mitra AV, Moynihan C, Rennert G, Suri M, Tricker K, Moss S, Kote-Jarai Z, Vickers A, Lilja H, Helfand BT, and Eeles RA

Abstract

This corrects the article DOI: 10.1038/bjc.2017.429.

Published
2018
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36. The cost-effectiveness of a pharmacogenetic test: a trial-based evaluation of TPMT genotyping for azathioprine.

Author

Thompson AJ, Newman WG, Elliott RA, Roberts SA, Tricker K, and Payne K

Subjects
Cost-Benefit Analysis, Drug Costs, Female, Genotype, Humans, Male, Models, Economic, Prospective Studies, Quality-Adjusted Life Years, Randomized Controlled Trials as Topic, Surveys and Questionnaires, United Kingdom, Autoimmune Diseases drug therapy, Azathioprine economics, Azathioprine pharmacology, Immunosuppressive Agents economics, Immunosuppressive Agents pharmacology, Pharmacogenetics economics, Pharmacogenetics methods
Abstract

Background: Thiopurine-methyl transferase (TPMT) testing prior to the prescription of azathioprine in autoimmune diseases is one of the few examples of a pharmacogenetic test that has made the transition from research into clinical practice. TPMT testing could lead to improved prescribing of azathioprine resulting in a reduction in adverse drug reactions as well as an improvement in effectiveness. When allocating scarce resources robust evidence on cost-effectiveness is required., Objective: This study aimed to evaluate the cost-effectiveness of a TPMT genotyping test to inform azathioprine prescribing in autoimmune diseases. The secondary aim of this study was to demonstrate the complexity of undertaking a trial-based evaluation of a pharmacogenetic test., Methods: A prospective economic evaluation was conducted alongside the TARGET (TPMT: Azathioprine Response to Genotype and Enzyme Testing) study, a pragmatic controlled trial that randomized (1:1) patients to undergo TPMT genotyping before azathioprine (n = 167) or current practice (n = 166). Assuming the UK health service perspective and a time horizon of 4 months, resource-use and health status data were collected prospectively for all recruited patients., Results: The mean incremental cost for TPMT genotyping and subsequent care pathways compared with current practice for the 4-month follow-up was -£421.06 (95% confidence interval -£925.15 to £89.75). Mean incremental quality-adjusted life-years were close to zero but negative: -0.008 (95% confidence interval -0.017 to 0.0002). Assuming a threshold of £20,000 per quality-adjusted life-year, the expected incremental net benefit of introducing the test is £256.89 (95% CI -£425.94 to £932.86)., Conclusions: TPMT genotyping potentially offers a less expensive alternative than current practice, but it may also have a small but negative effect on health status. These findings are associated with significant uncertainty, and the causal effect of TPMT genotyping on changes in health status and health care resource use remains uncertain. The results from this study therefore pose a difficult challenge to decision makers., (© 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Published by International Society for Pharmacoeconomics and Outcomes Research (ISPOR) All rights reserved.)

Published
2014
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37. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study.

Author

Newman WG, Payne K, Tricker K, Roberts SA, Fargher E, Pushpakom S, Alder JE, Sidgwick GP, Payne D, Elliott RA, Heise M, Elles R, Ramsden SC, Andrews J, Houston JB, Qasim F, Shaffer J, Griffiths CE, Ray DW, Bruce I, and Ollier WE

Subjects
Adult, Drug-Related Side Effects and Adverse Reactions genetics, Drug-Related Side Effects and Adverse Reactions prevention & control, Genetic Predisposition to Disease, Genetic Variation, Genotype, Heterozygote, Homozygote, Humans, Inflammation drug therapy, Inflammation enzymology, Inflammation genetics, Neutropenia genetics, Phenotype, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Azathioprine administration & dosage, Azathioprine adverse effects, Methyltransferases genetics
Abstract

Aim: To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs)., Methods: A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping., Results: There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia., Conclusion: Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine.

Published
2011
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38. Valuing pharmacogenetic testing services: a comparison of patients' and health care professionals' preferences.

Author

Payne K, Fargher EA, Roberts SA, Tricker K, Elliott RA, Ratcliffe J, and Newman WG

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Azathioprine adverse effects, Female, Health Care Surveys, Humans, Immunosuppressive Agents adverse effects, Male, Middle Aged, Neutropenia genetics, Neutropenia prevention & control, Patient Education as Topic, Regression Analysis, United Kingdom, Attitude of Health Personnel, Genetic Services, Patient Preference, Pharmacogenetics
Abstract

Objective: The study compared the preferences of patients and health-care professionals for the key attributes of a pharmacogenetic testing service to identify a patient's risk of developing a side effect (neutropenia) from the immunosuppressant, azathioprine., Methods: A discrete choice experiment was posted to a sample of patients (n=309) and health-care professionals (HCPs) (n=410), as part of the TARGET study. Five attributes, with four levels each, described the service as follows: level of information given; predictive ability of the test; how the sample is collected; turnaround time for a result; who explains the test result. Data from each sample were first analyzed separately and responses were compared by 1) identifying the impact of the scale parameter, and 2) estimating marginal rates of substitution., Results: The final analysis included 159 patients and 138 HCPs (50% & 34% response rates). Estimated attribute coefficients from the patient and HCP sample differed in size, after taking into account the impact of the scale parameter. Patients and HCPs had similar preferences for predictive accuracy of the test and were willing to wait 2 days for a 1% improvement in test accuracy. Patients preferred to obtain more information and were willing to wait 19 days compared to 8 days for HCPs for providing higher levels of information., Conclusions: Patients demanded accurate and timely information from health-care professionals about why it was necessary to have a pharmacogenetic test and what the test results mean. In contrast, health-care professionals appear to focus more exclusively or entirely upon the predictive accuracy and waiting time for a test result., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Published
2011
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39. Patients' and healthcare professionals' views on pharmacogenetic testing and its future delivery in the NHS.

Author

Fargher EA, Eddy C, Newman W, Qasim F, Tricker K, Elliott RA, and Payne K

Subjects
Adult, Aged, Attitude of Health Personnel, Female, Health Knowledge, Attitudes, Practice, Humans, Male, Middle Aged, Patient Satisfaction, Professional-Patient Relations, Qualitative Research, Quality of Health Care, Surveys and Questionnaires, United Kingdom, Delivery of Health Care standards, Delivery of Health Care trends, National Health Programs standards, National Health Programs trends, Patient Education as Topic standards, Pharmacogenetics education, Pharmacogenetics standards, Pharmacogenetics trends
Abstract

Introduction: There is limited empirical evidence on patients' and healthcare professionals' views on the provision of pharmacogenetic testing services. These opinions may be used to shape the development of emerging pharmacogenetic services and inform healthcare professionals' future educational requirements., Objectives: To explore patients' and healthcare professionals' views about pharmacogenetic testing services and their future development., Methods: Semi-structured interviews were conducted with patients who had been prescribed azathioprine for autoimmune conditions and prevention of acute rejection in renal transplantation. Focus groups were conducted with a range of healthcare professionals. Interviews and focus groups were recorded and transcribed verbatim. Data were analyzed using the constant comparative method., Results: The views of 42 individuals - 25 patients and 17 healthcare professionals - were explored in depth. Key themes emerging from the data were: patients' and healthcare professionals' knowledge and experience of pharmacogenetics; expectations about how such a testing service could be used; and characteristics of service delivery. Knowledge and experience of pharmacogenetics varied. Pharmacogenetics was perceived to be of benefit by both groups. Patients gave opinions about pharmacogenetic services based on their experiences of illness, taking medicines and using healthcare services. Healthcare professionals based their opinions on how existing services are provided and access to limited healthcare resources. Patients had strong feelings about how this service should be delivered and expected high standards of explanation about potential pharmacogenetic tests. None of the healthcare professionals questioned expected to have responsibility for the future delivery of pharmacogenetic testing services., Conclusion: There is no clear model of how pharmacogenetic tests will be delivered in clinical practice. Patients expect to receive pharmacogenetic services from healthcare professionals who are able to explain the test, and interpret the implications for prescribing, with confidence. The gap between patients' high expectations for information and healthcare professionals' current knowledge and reluctance to deliver pharmacogenetic services highlights the urgent need for better education and training of healthcare professionals in pharmacogenetics.

Published
2007
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40. Is shared care with annual hospital review better value for money than predominantly hospital-based care in patients with established stable rheumatoid arthritis?

Author

Davies LM, Fargher EA, Tricker K, Dawes P, Scott DL, and Symmons D

Subjects
Adult, Antirheumatic Agents economics, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid economics, Cost-Benefit Analysis, Delivery of Health Care economics, Delivery of Health Care methods, Family Practice economics, Humans, Quality-Adjusted Life Years, Treatment Outcome, United Kingdom, Arthritis, Rheumatoid therapy, Family Practice methods, Health Care Costs, Hospitalization economics
Abstract

Objective: To assess the cost effectiveness and cost effectiveness acceptability of symptom control delivered by shared care (SCSC) and aggressive treatment delivered in hospital (ATH) for established rheumatoid arthritis (RA)., Methods: Economic data were collected within the British Rheumatoid Outcome Study Group randomised controlled trial of SCSC and ATH. A broad perspective was used (UK National Health Service, social support services and patients). Cost per quality adjusted life year (QALY) gained, net benefit statistics and cost effectiveness acceptability curves were estimated. Costs and outcomes were discounted at 3.5%. Sensitivity analysis tested the robustness of the results to analytical assumptions., Results: The mean (SD) cost per person was 4540 pounds (4700) in the SCSC group and 4440 pounds (4900) in the ATH group. The mean (SD) QALYs per person for 3 years were 1.67 (0.56) in the SCSC group and 1.60 (0.60) in the ATH group. If decision makers are prepared to pay > or = 2000 pounds to gain 1 QALY, SCSC is likely to be cost effective in 60-90% of cases., Conclusions: The primary economic analysis and sensitivity analyses indicate that SCSC is likely to be more cost effective than ATH in 60-90% of cases. This result seems to be robust to assumptions required by the analysis. This study is one of a limited number of randomised controlled trials to collect detailed resource use and health status data and estimate the costs and QALYs of treatment for established RA. This trial is one of the largest RA studies to use the EuroQol.

Published
2007
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41. The detection of antibodies against Schistosoma mansoni soluble egg antigens (SEA) and CEF6 in ELISA, before and after chemotherapy.

Author

Doenhoff MJ, Wheeler JG, Tricker K, Hamilton JV, Sturrock RF, Butterworth AE, Ouma JH, Mbugua GG, Kariuki C, and Koech D

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Child, Enzyme-Linked Immunosorbent Assay methods, Female, Humans, Male, Middle Aged, Ovum immunology, Parasite Egg Count, Schistosomiasis mansoni drug therapy, Schistosomiasis mansoni parasitology, Sensitivity and Specificity, Treatment Outcome, Antibodies, Helminth blood, Antigens, Helminth immunology, Immunoglobulin G blood, Schistosomiasis mansoni immunology
Abstract

Circulating IgG antibody reactivity and excreted egg counts were investigated in 489 Kenyans given chemotherapy for schistosomiasis mansoni. Antibody reactivity was measured in ELISA, using either unfractionated aqueous soluble constituents of Schistosoma mansoni eggs (SEA) or CEF6 (a soluble fraction of S. mansoni eggs containing two cationic antigens) as the antigen source. Antibody reactivity for each antigen source was strongly associated with egg counts, both pre- and post-treatment. Approximately 6 months after chemotherapy, egg counts were zero in 84% of the subjects. The mean optical densities (OD) measured in the post-treatment ELISA were 60% (CEF6) or 45% (SEA) lower than the pre-treatment values, the reduction in the OD with CEF6 as antigen source being significantly greater than that observed with SEA (P <0.001). The usefulness of an assay for antibody reactivity in monitoring the effects of the treatment of schistosomiasis is discussed.

Published
2003
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42. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.

Author

Birch JM, Blair V, Kelsey AM, Evans DG, Harris M, Tricker KJ, and Varley JM

Subjects
Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Chi-Square Distribution, Child, Child, Preschool, Cohort Studies, DNA Mutational Analysis, Family Health, Female, Genotype, Germ-Line Mutation genetics, Humans, Infant, Infant, Newborn, Male, Middle Aged, Pedigree, Phenotype, Family, Li-Fraumeni Syndrome genetics, Neoplasms genetics, Tumor Suppressor Protein p53 genetics
Abstract

The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.

Published
1998
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43. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families.

Author

Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF, Kelsey AM, Tricker KJ, Evans DG, and Birch JM

Subjects
Female, Genetic Linkage, Humans, Male, Mutation, Promoter Regions, Genetic genetics, Genes, p53 genetics, Germ-Line Mutation genetics, Li-Fraumeni Syndrome genetics
Abstract

We have previously reported on the analysis of TP53 coding mutations in 12 classic Li-Fraumeni syndrome (LFS) families plus 9 families that were Li-Fraumeni-like (LFL) families (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994). Mutations were found in 6 of 12 LFS families and in 1 of 9 LFL families. We have now extended these studies to include an additional nine LFS and nine LFL families, and TP53 mutations have been detected in eight of nine LFS families and in three of nine LFL families. Six of the new mutations described here are the same as those previously identified in other Li-Fraumeni families and are missense mutations at codons 245, 248, and 273 (in two families); a nonsense mutation at codon 209; and a mutation at the splice donor site in exon 4. The other five mutations are novel germ-line mutations and include missense mutations at codons 136 and 344, a 2-bp deletion within codon 191, a splice acceptor mutation in intron 3, and a 167-bp deletion of part of exon 1 and intron 1. In addition, we have detected a codon 175 mutation in a family previously reported as TP53 negative. To summarize all of the data from the families we have studied in this and our previous report (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994), mutations have been detected in 15 of 21 LFS families (71%) and in 4 of 18 LFL families (22%). These figures are somewhat higher than those previously reported by us and others for the frequency of TP53 mutations in LFS and LFL families. This could reflect our analysis of all 11 exons of TP53, including noncoding regions, as well as the use of direct sequencing rather than other less-sensitive mutation detection methods.

Published
1997

44. Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53.

Author

Birch JM, Heighway J, Teare MD, Kelsey AM, Hartley AL, Tricker KJ, Crowther D, Lane DP, and Santibáñez-Koref MF

Subjects
Base Sequence, DNA Primers chemistry, Female, Genetic Linkage, Genetic Markers, Humans, Male, Molecular Sequence Data, Pedigree, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53 genetics, Genes, p53, Li-Fraumeni Syndrome genetics, Nuclear Proteins, Tumor Suppressor Protein p53 metabolism
Abstract

We report a family with the Li-Fraumeni syndrome (LFS) in whom we have been unable to detect a mutation in the coding sequence of the p53 gene. Analysis of linkage to three polymorphic markers within p53 enabled direct involvement of p53 to be excluded. This is the first example of a LFS family in whom exclusion of p53 has been possible. Four affected members of the family with sarcoma or premenopausal breast cancer showed increased expression of p53 protein in their normal tissues as detected by immunohistochemistry. It therefore appears that the LFS phenotype has been conferred by an aberrant gene, showing a dominant pattern of inheritance, which may be acting to compromise normal p53 function rather than by a mutation in p53 itself. In order to try to determine the chromosomal location of this putative gene, we have carried out studies of linkage to candidate loci. By these means we have excluded involvement of Rb1 and BRCA1 on chromosomes 13q and 17q respectively. The MDM2 oncogene on chromosome 12q was considered to be the prime candidate as MDM2 is amplified in sarcomas and the MDM2 product binds to p53. Furthermore, p53 mutation and amplification of MDM2 have been shown to be mutually exclusive events in tumour development. Linkage analysis to two polymorphic markers within MDM2 yielded a three-point LOD score of -5.4 at a recombination fraction theta equal to zero. Therefore MDM2 could be excluded. It is possible that the gene which is responsible for cancer susceptibility in this family, possibly via interaction with p53, will be important in the histogenesis of breast cancer in general. We are now carrying out further studies to locate and identify this gene.

Published
1994
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45. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.

Author

Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, Harris M, Jones PH, Binchy A, and Crowther D

Subjects
Base Sequence, Child, Codon genetics, Exons genetics, Family Health, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Pedigree, Prevalence, Genes, p53 genetics, Li-Fraumeni Syndrome genetics, Mutation genetics
Abstract

The entire coding sequence of the p53 gene was analysed for the presence of mutations in 12 families conforming to a restricted definition of Li-Fraumeni syndrome (classic LFS) and nine families with features of LFS conforming to a broader definition. Mutations were detected in seven families. Six were point mutations with one each affecting codons 175, 180, and 220 and three affecting codon 248. The seventh was a deletion/insertion mutation in exon 4. Germline mutations in p53 were a feature of families which included children with rhabdomyosarcoma and/or adrenal cortical carcinoma. Germline p53 mutations were detected in six of the nine families with such tumors. An analysis of these 7 mutations, together with 34 published examples, showed that more than one-half were transitions at CpG dinucleotides, suggesting that the majority of germline p53 mutations may arise as a result of spontaneous events. The most common cancers occurring in the 41 families with germline p53 mutations, in common with classic LFS, were bone and soft tissue sarcoma, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma, although less than one-half of the probands with germline p53 mutations came from classic LFS families. More than one-half of the cancers overall and nearly one-third of the breast cancers were diagnosed before 30 years of age. These observations have important implications for asymptomatic carriers of germline p53 mutations, and there is a need for international collaboration in the development of protocols for the management of such families.

Published
1994

46. Wilms' tumor in the Li-Fraumeni cancer family syndrome.

Author

Hartley AL, Birch JM, Tricker K, Wallace SA, Kelsey AM, Harris M, and Jones PH

Subjects
Adolescent, Child, Child, Preschool, Humans, Infant, Pedigree, Syndrome, Wilms Tumor genetics
Abstract

Scrutiny of the family pedigrees of a population-based series of 176 children diagnosed with Wilms' tumor between 1954 and 1990, along with a review of the literature on the Li-Fraumeni cancer family syndrome, indicate that Wilms' tumor may be an uncommon component of the syndrome and that a small proportion of children with Wilms' tumor may be members of Li-Fraumeni syndrome (LFS) families.

Published
1993
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