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7. Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008

Author

Brüggemann, M, Schrauder, A, Raff, T, Pfeifer, H, Dworzak, M, Ottmann, O G, Asnafi, V, Baruchel, A, Bassan, R, Benoit, Y, Biondi, A, Cavé, H, Dombret, H, Fielding, A K, Foà, R, Gökbuget, N, Goldstone, A H, Goulden, N, Henze, G, Hoelzer, D, Janka-Schaub, G E, Macintyre, E A, Pieters, R, Rambaldi, A, Ribera, J-M, Schmiegelow, K, Spinelli, O, Stary, J, von Stackelberg, A, Kneba, M, Schrappe, M, and van Dongen, J J M

Published
2010
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26. Irish Association for Cancer Research: Proceedings of annual scientific meeting held at Kinsale on April 15–16th, 1994

Author

Lawler, M., Locasciulli, A., Bacigalupo, A., Humphries, P., Ljungman, P., McCann, S. R., Nolan, N., McDermott, E. W., Reynolds, J. R., McCann, A., Rafferty, R., Sweeney, P., Carney, D., O’Higgins, N. J., Duffy, M. J., Gardiner, C., Reen, D. J., O’Connell, M. A., Kelleher, D., Hall, N., O’Neill, L. A. J., Long, A., McCarthy, J. V., Fernandes, R. S., Cotter, T. G., Ryan, E., Kitching, A., MacMathuna, P., Mulligan, E., Merriman, R., Dervan, P., Kelly, P., Gorey, T. F., Lennon, J. R., Crowe, J., Bennett, M. A., Kay, E. W., Curran, B., O’Donoghue, D. P., Leader, M., Croke, D. T., O’Connor, J. M., McKelvey-Martin, V. J., McKenna, P. G., O’Riordan, J. M., Tobin, A., O’Mahoney, M., Keogh, F. M., O’Riordan, J., McNamara, C., McEneaney, P., Daly, P. A., Farrell, M., Young, S., Gibbons, D., McCarthy, P., Mulcahy, H., Parfrey, N. A., Sheahan, K., Lambkin, H., Mothersill, C., Chin, D., Sheehan, K., Kelehan, P., Parfrey, N., Morrin, M., Khan, F., Delaney, P., Rowan, D. M., Orminston, W. J., Donnellan, P. P., Khalid, A., Kerin, M., O’Hanlon, D. M., Kent, P., Given, H. F., Kennedy, S. M., McGeoch, G., Spurr, N. K., Barrett, J., O’Sullivan, G., Collins, J. K., Willcocks, T., Kennedy, S., Dolan, J., Gallagher, W., McDermott, E., O’Higgins, N., Hagan, R., McManus, R., Ormiston, W., Daly, P., Sheils, O., McDermott, M., O’Briain, D. S., Maher, D., Costello, P., Flanagan, F., Stack, J., Ennis, J., Grimes, H., Yanni, A., Harrison, M., Lowry, W. S., Russell, S. E. H., Atkinson, R. J., White, P., Hickey, I., Bell, D. W., Biggart, D., Doyle, J., Staunton, M. J., Gaffney, E. F., Dervan, P. A., McCabe, M. M., Fennelly, J. J., Carney, D. N., O’Reilly, M., McMahon, J. N., Moriarty, M., Hurson, B., O’Neill, A. J., Magee, H., O’Loughlin, J., Dervan, P. A., Cremin, P., Orminston, W., McCarthy, J., Redmond, P., Duggan, S., Rea, S., Bouchier-Hayes, D., O’Donnell, J., Duggan, C., Crown, J., Bermingham, D., Nugent, A., Fleming, C., Crosby, P., Wolff, S., McCarthy, D., Walsh, C. Barry, Cassidy, M., Husain, S., Kay, E., Thornhilll, M., Whelan, D., Barry, D., Turner, M., Prenderville, W., Murphy, F., Prendiville, W., Gibson, G., O’Grady, T., Carmody, M., Donohoe, J., Walshe, J., Murphy, G. M., O’Donoghue, J., Kerin, K., Ahern, S., Molloy, K., Goulden, N., Pamphilon, D. H., O’Connell, M., Power, C., Leroux, A., Perricaudet, M., Walls, D., Britton, F., Brennan, L., Barnett, Y. A., Madden, B., Wakelin, L. P. G., Loughrey, H. C., Corley, P., Redmond, H. P., Watson, R. W. G., Keogh, I., O’Hanlon, D., Walsh, S., Callaghan, J., McNamara, M., Benedict-Smith, A., Barnes, C., Neylon, D., Fenton, M., Searcey, M., Topham, C. M., Wakelin, L. G., Howarth, N. M., Purohit, A., Reed, M. J., Potter, B. V. L., Hatton, W. J., McKerr, G., Harvey, D., Carson, J., Hannigan, B. M., McCarthy, P. J., McClean, S., Hill, B. T., Costelloe, C., Denny, W. A., Fingleton, B., McDonnell, S., Butler, M., Corbally, N., Dervan, P. A., Stephens, J. F., Martin, G., McGirl, A., Lawlor, E., Gardiner, N., Lynch, S., Arce, M. de, O’Brien, F., Duggan, A., O’Herlihy, S., Shanahan, F., O’Keeffe, G., McCann, S., Sweeney, K., Neill, A. O., Pamphilon, D., Sheridan, M., Reid, I., Seymour, C. B., Walshe, T., Hennessy, T. P., O’Mahony, A., O’Connell’, J., Lawlor, C., Nolan, S., Morrisey, D., Pedlow, P. J., Walsh, M., Lowry, S. W., McAleer, J. J. A., McKeown, S. R., Afrasiabi, M., Lappin, T. R. J., Joiner, B., Hirst, K. V., Hirst, D. G., Sweeney, E., VanderSpek, J., Murphy, J., and Foss, F.

Published
1995
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27. National scientific medical meeting 1995 abstracts: Oral presentations

Author

Norris, S., Collins, C., Hegarty, J., O’Farrelly, C., Carton, J., Madrigal, L., O’Donoghue, D. P., O’Farrelly, C., Holloway, H., Fielding, J. F., Mullins, W., Hone, S. W., Donnelly, M., Powell, F., Blayney, A. W., Cahill, E. A., Daly, S. F., Turner, M. J., Sullivan, P. A., McLoughlin, M., Skelly, M. M., Mulcahy, H. E., Connell, T., O’Donoghue, D. P., Duggan, C., Duffy, M. J., Troy, A., Sheahan, K., Whelan, A., Herra, C. M., Keane, C. T., Johnson, H., Lee, B., Doherty, E., McDonnell, T., Mulherin, D., FitzGerald, O., Bresnihan, B., Hassett, H. M., Boyce, A., Greig, V., O’Herlihy, C., Smyth, P. P. A., Roche, E. F., McCormack, I., Tempany, E., Cullen, M. J., Smith, D. F., Smyth, P. P. A., McBrinn, Y., Murray, B., Freaney, R., Keating, D., McKenna, M. J., O’Hare, J. A., Alam, H., Raza, Q., Geoghegan, M., Killalea, S., Hall, M., Feely, J., Kyne, L., O’Hara, B., Cullen, M., Rea, I. M., Donnelly, J. P., Stout, R. W., Lacey, P., Donnelly, M. J., McGrath, J., Hennessy, T. P., Timon, C. V. I., Hyde, D., Xia, H. X., Keane, C. T., Buckley, M., O’Morain, C., Buckley, M., Keating, S., Xia, H., Hyde, D., O’Morain, C., McGrath, J. P., Stuart, R. C., Lawlor, P., Byrne, P. J., Walsh, T. N., Hennessy, T. P. J., Skelly, M. M., Mulcahy, H. E., Connell, T., O’Donoghue, D. P., Duggan, C., Duffy, M., Troy, A., Sheahan, K., Norris, S., Tubridy, M., Redmond, J., Hegarty, J., Holloway, H., Fielding, J. F., Mullins, W., Monahan, K., Murphy, R. P., Headon, D. R., O’Gorman, T., O’Reilly, F. M., Darby, C., Fielding, J. F., Murphy, G. M., Murphy, A., Codd, M., Powell, F., Dervan, P., Lawlor, D., Loughlin, S. O., Flanagan, N., Watson, R., Barnes, L., Flanagan, N., Watson, R., Kilgallen, C., Sweeney, E., Mynes, A., Mooney, D., Donoghue, I., Browne, O., Kirrane, J. A., Murphy, G. M., McKenna, D., Young, M., McKenna, D., Young, M., O’Toole, E., Young, M., O’Briain, S., Srinivasan, U., Feighery, C., Leonard, N., Jones, E., O’Farrelly, C., Moloney, M. A., O’Farrelly, C., Weir, D. G., Lawler, M., O’Neill, A., Gowing, H., Pamphilon, D., McCann, S. R., O’Toole, G., Orren, A., Seifer, C. M., Crowley, D. C., Sheehan, G. J., Deignan, T., Kelly, J., O’Farrelly, C., Tormey, V. J., Faul, J., Leonard, C., Burke, C. M., Poulter, L. W., Collins, C., Lynch, S., Madrigal, L., Norris, S., McEntee, G., Traynor, O., Hegarty, J., O’Farrelly, C., Barry, E., Collins, C., Costello, P., Keavney, A., O’Donoghue, D. P., O’Farrelly, C., Willoughby, R., Feighery, C., O’Donnell, C., Cahill, M., Earley, A., Eustace, P., Osborne, R., Cahill, M., Saidlear, C., Holmes, B., Early, A., Eustace, P., Moran, A. P., Neisser, A., Polt, R. J., Bernheimer, H., Kainz, M., Schwerer, B., Gallagher, L., Cahill, M., Saidlear, C., Early, A., Firth, R., Eustace, P., Kennedy, N., McGilloway, E., Redmond, J., McGilloway, E., Kennedy, N., Tubridy, N., Shields, K., Cullen, W. K., Rowan, M. J., Moore, A. R., Rowan, M., Feely, J., Coakley, D., Lawlor, B., Swanwick, G., Al-Naeemi, R., Redmond, J., Murphy, R., Feely, J., Codd, N. M., Goggins, M., Kennedy, N. P., Mallon, B. L., Kennedy, N. P., Mulherin, D., FitzGerald, O., Bresnihan, B., Mulcahy, H., Skelly, M., Donoghue, D. O., McCarthy, D., Saunders, A., Mulherin, D., Bresnihan, B., FitzGerald, O., Veale, D. J., Belch, J. J. F., Mulherin, D., Bresnihan, B., FitzGerald, O., Veale, D. J., Belch, J. J. F., Mulherin, D., FitzGerald, O., Bresnihan, B., Costello, P., Breathnach, D., Murphy, E., Mulherin, D., FitzGerald, O., Bresnihan, B., Breathnach, D., Costello, P., Mulherin, D., Bresnihan, B., FitzGerald, O., Breathnach, D., Mulherin, D., Costello, P., Bresnihan, B., FitzGerald, O., Kernohan, G., Gibson, K., Wilson, A. G., Duff, G. W., de Vries, N., van de Putte, L. B. A., Donoghue, J., O’Kelly, F., Johnson, Z., Maher, T., Kyne, L., Moran, A., Keane, C., O’Neill, D., Horgan, N., Barragry, J. M., O’Neill, D., O’Herlihy, C., Campbell, D. M., Behan, M., O’Connell, P. R., Donnelly, V. S., Crowley, D., Geary, M., Boylan, P., Geary, M., Fanagan, M., Boylan, P., Hickey, K., Teoh, T., Doyle, M., Harrison, R., Hickey, K., Lyons, D., Shenouda, Y., Coughlan, M., McKenna, P., Hickey, K., Shenouda, Y., Lyons, D., McKenna, P., Coughlan, M., Lenehan, P., Foley, M., Kelehan, P., Ravichandran, P., Kelly, M., Conroy, A., Fitzpatrick, C., Egan, D., Regan, C. L., McAdam, B. V., McParland, P., Boylan, P., FitzGerald, G. A., Fitzgerald, D. J., Sharma, S. C., Foran, K., Barry-Kinsella, C., Harrison, R. F., Gillespie, F. J., O’Mahony, P., Boyle, M., White, M. J., Donohoe, F., Birrane, Y., Naughton, M., Tempany, E., Fitzsimons, R. B., Piracha, M., McConkey, S., Griffin, E., Hayes, E., Clarke, T., Parfrey, N., Butler, K., Fitzpatrick, C., Malone, A. J., Kearney, P. J., Duggan, P. F., Lane, A., Keville, R., Turner, M., Barry, S., Sloan, D., Gallagher, S., Darby, M., Galligan, P., Stack, J., Walsh, N., O’Sullivan, M., Fitzgerald, M., O’Sullivan, M., Meagher, D., Sloan, D., Browne, S., Meagher, D., Larkin, C., Lane, A., Casey, P., O’Callaghan, E., Walsh, N., Rooney, S., Walsh, E., Morris, M., Lane, A., Burke, T., Larkin, C., O’Callaghan, E., Browne, S., Roe, M., Lane, A., Larkin, C., O’Callaghan, E., Maher, C., Wrigley, M., Gill, M., Burgess, M., Corcoran, E., Walsh, D., Gilmer, B., Johnson, H., Hayes, C. B., Thornton, L., Fogarty, J., Lyons, R., O’Connor, M., Delaney, V., Buckley, K., Johnson, Z., Johnson, Z., Lillis, D., Delany, V., Hayes, C., Dack, P., Igoe, D., Gilmer, B., O’Neill, H. J., Johnson, H., Igoe, D., Delaney, V., Johnson, Z., Kelly, P., McKeown, D., Clancy, L., Varghese, G., Hennessy, S., Codd, M., Gilmartin, J. J., Birthistle, K., Carrington, D., Maguire, H., Atkinson, P., Foley-Nolan, C., Lynch, M., Cryan, B., Whyte, D., Cryan, B., Conlon, C., Foley-Nolan, C., Johnson, Z., Hayes, C., Delany, V., Kucinskas, V., Usinskiene, U., Sakalyte, I., Johnson, Z., Hayes, C., Delaney, V., Dack, P., Gill, M., Dawson, E., Molloy, K., Goulden, N., Lawler, M., McCann, S. R., Doyle, J., Lawlor, E., Lawler, M., Harrington, M. G., El-Nageh, N., Nolan, M. -L., El-Nageh, N., Nolan, M. -L., Harrington, M. G., Lawlor, E., O’Riordan, J., McCann, S. R., Judge, G., Crotty, G., Finch, T., Borton, M., Barnes, T., Gilligan, O., Lee, G., Limmer, R., Madden, M., Whyte, D., Cryan, B., Bergin, C., O’Leary, A., Keating, S., Mulcahy, F., Wallis, F., Glennon, M., Cormican, M., NiRiain, U., Heiginbothom, M., Gannon, F., Smith, T., O’Sullivan, C., Hone, R., Orren, A., Caugant, D. A., Fijen, C. A. P., Van Schalkwyk, E. J., Coetzee, G. J., Lynch, M., Cryan, B., Riain, U. Ni, Cormican, M. G., Park, L., Flynn, J., Glennon, M., O’Connor, M., Regazzoli, V., O’Connor, M., Hayes, M., Nicholson, G., Higgins, P., NiRiain, U., Flynn, N., Corbett-Feeney, G., Conway, D. J., Sheahan, K., O’Higgins, N. J., Smyth, P. P. A., Rajendiran, S., Byrne, J., Kilfeather, E., Dingle, P., Hunter, M., Kelehan, P., Al-Ghazal, S. K., Stanley, P., Palmer, J., Hong, A., Al-Ghazal, S. K., Saxby, P., Al-Ghazal, S. K., Saxby, P., McConkey, S., Sheehan, D., Regan, I., O’Mullane, J., Chaoimh, M. Ni, Leahy, M., Heffron, J. J., Lehane, M., Keohane, C., O’Leary, N., Sheehan, M., Renny-Walsh, E., Whelton, M. J., Doyle, C. T., Webster, J., Benjamin, N., Lyons, D., FitzGerald, S., Chadha, J. S., FitzGerald, M. G., FitzGerald, G. R., Hemeryck, L., McGettigan, P., Feely, J., McGettigan, P., Feely, J., McGettigan, P., Golden, J., Feely, J., Arthur, N., Wen, S. Y., Killalea, S., Deegan, P., McGettigan, P., Feely, J., Cooke, T., Adebayo, G. I., Feely, J., Gaffney, P., Sinnot, M., O’Riordan, D., Hayes, T., O’Connor, C. M., FitzGerald, M. X., Costello, C., Finlay, G., Hayes, J., O’Connor, C., FitzGerald, M. X., McMahon, K., O’Farrelly, C., O’Connor, C., FitzGerald, M. X., Donnelly, M. J., Hone, S., Robertson, J., Coakley, R., O’Neill, S., Walsh, M., McCarthy, J., Lannon, D., Wood, A. E., Sharkey, R., Mulloy, E., Long, M., Kilgallen, I., O’Neill, S., Faul, J., Tormey, V., Leonard, C., Burke, C. M., Poulter, L. W., Horne, S., Tormey, V. J., Faul, J., Leonard, C., Burke, C. M., Feeney, T., Muiré, Ó. Ó, Gilmartin, J. J., Griffin, M. J., Hughes, D., Knaggs, A., Magee, D., Donnelly, M., McCrory, C., March, B., Hone, R., Phelan, D., White, M., Fabry, J., Lynch, M., Buggy, D., Cooney, C., Hughes, D., McCrory, C., Aziz, E., O’Herlihy, C., Kelly, J., O’Keefe, D., McShane, A. J., Boylan, J., Tobin, E., Smith, T., Motherway, C., Colreavy, F., Denish, N., Dwyer, R., Bergin, A., O’Brien, K., MacSullivan, R., Carson, K. D., Blunnie, W. P., Moriarty, D. C., Carson, K. D., Blunnie, W. P., Moriarty, D. C., Kinirons, B., Lyons, B., Cregg, N., Casey, W., Moore, K. P., Colbert, S. A., Ecoffey, C., O’Gorman, D., Fitzgerald, J., Phelan, D., Diamond, P., Codd, M. B., Sugrue, D. D., Kellett, J., Tighe, M., McKenna, C. J., Galvin, J., McCann, H. A., Sugrue, D. D., McKenna, C. J., Codd, M. B., McCann, H. A., Sugrue, D. D., Scallon, A., Buckley, M., Fraser, A., Norton, M., Tomkin, G., Graham, I., Byrne, A., Maher, M., Moran, N., Fitzgerald, D., O’Callaghan, D., Coyle, D., Nugent, A. G., McGurk, C., Johnston, G. D., McGurk, C., Nugent, A., Silke, B., Nugent, A. G., Johnston, G. D., Murphy, N., Jennings, L., Pratico, D., Doyle, C., Fitzgerald, D., Hennessy, T., McCann, H., Sugrue, D., Hennessy, T., Codd, M., Donnelly, S., Hennessy, A., Hartigan, C., McCann, H., Sugrue, D., Hennessy, T., Codd, M., Donnelly, S., Hennessy, A., Hartigan, C., McCann, H., Sugrue, D., Hennessy, T., MacDonald, D., Blake, S., McCann, H., Sugrue, D., Hennessy, T., Sugrue, D., McCann, H., Hennessy, T., McCann, H., Sugrue, D., Hennessy, T., McDonald, D., Blake, S., Dominque, D., Sugrue, D., McMechan, S. R., MacKenzie, G., Allen, J., Wright, G. T., Dempsey, G. J., Crawley, M., Anderson, J., Adgey, A. A. J., Harbinson, M. T., Campbell, N. P. S., Wilson, C. M., Ellis, P. K., McIlrath, E. M., Freaney, R., McShane, A., Keaveny, T. V., McKenna, M. J., Rabenstein, K., Scheller, F., Pfeiffer, D., Urban, C., Moser, I., Jobst, G., Manz, A., Verpoorte, S., Dempsey, F., Diamond, D., Smyth, M., Rabenstein, K., Dempsey, E., McShane, A., Keaveny, T. V., McKenna, M. J., Freaney, R., Hamilton, V., Dwyer, R., Twomey, J., Crowley, R., Fenelon, L., Walsh, F., McCann, J., McDonagh, P., White, M., McGovern, E., Luke, D., Phelan, D., McCrory, C., Crowley, K., Lyons, B., Mannion, D., Wood, A. E., Casey, W., Murphy, D., Clarkson, K., Carton, E., Higgins, P., Leonard, I., O’Toole, D., Staunton, M., Phelan, D., Srinivasan, U., Leonard, N., Jones, E., Moloney, M. A., Weir, D. G., O’Farrelly, C., Feighery, C., Griffin, M., Owens, D., Collins, P., Johnson, A., Tomkin, G. H., Herity, N. A., Allen, J. D., Silke, B., Adgey, A. A. J., O’Reilly, F. M., Darby, C., O’Moore, R., Fielding, J. F., Murphy, G. M., Crotty, G. M., Judge, G., McCann, S. R., DeArce, M., Nugent, A. G., McGurk, C., Johnston, G. D., Nikookam, K., Keenan, P., Cregan, D., Firth, R., O’Meara, N., Forman, S., Cusack, D. A., and Farrell, B.

Published
1995
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35. Lessons learnt from a discontinued randomised controlled trial:adalimumab injection compared with placebo for patients receiving physiotherapy treatment for sciatica (Subcutaneous Injection of Adalimumab Trial compared with Control: SCIATiC)

Author

Williams, N. H. (Nefyn H.), Jenkins, A. (Alison), Goulden, N. (Nia), Hoare, Z. (Zoe), Hughes, D. A. (Dyfrig A.), Wood, E. (Eifiona), Foster, N. E. (Nadine E.), Walsh, D. (David), Carnes, D. (Dawn), Sparkes, V. (Valerie), Hay, E. M. (Elaine M.), Isaacs, J. (John), Konstantinou, K. (Kika), Morrissey, D. (Dylan), Karppinen, J. (Jaro), Genevay, S. (Stephane), and Wilkinson, C. (Clare)

Subjects
Randomised controlled trial, Biological agents, Sciatica, Anti-TNF-α, Adalimumab, Feasibility, Economic evaluation
Abstract

Background: Adalimumab, a biological treatment targeting tumour necrosis factor α, might be useful in sciatica. This paper describes the challenges faced when developing a new treatment pathway for a randomised controlled trial of adalimumab for people with sciatica, as well as the reasons why the trial discussed was stopped early. Methods: A pragmatic, parallel group, randomised controlled trial with blinded (masked) participants, clinicians, outcome assessment and statistical analysis was conducted in six UK sites. Participants were identified and recruited from general practices, musculoskeletal services and outpatient physiotherapy clinics. They were adults with persistent symptoms of sciatica of 1 to 6 months’ duration with moderate to high level of disability. Eligibility was assessed by research physiotherapists according to clinical criteria, and participants were randomised to receive two doses of adalimumab (80 mg then 40 mg 2 weeks later) or saline placebo subcutaneous injections in the posterior lateral thigh. Both groups were referred for a course of physiotherapy. Outcomes were measured at baseline, 6-week, 6-month and 12-month follow-up. The main outcome measure was disability measured using the Oswestry Disability Index. The planned sample size was 332, with the first 50 in an internal pilot phase. Results: The internal pilot phase was discontinued after 10 months from opening owing to low recruitment (two of the six sites active, eight participants recruited). There were several challenges: contractual delays; one site did not complete contract negotiations, and two sites signed contracts shortly before trial closure; site withdrawal owing to patient safety concerns; difficulties obtaining excess treatment costs; and in the two sites that did recruit, recruitment was slower than planned because of operational issues and low uptake by potential participants. Conclusions: Improved patient care requires robust clinical research within contexts in which treatments can realistically be provided. Step changes in treatment, such as the introduction of biologic treatments for severe sciatica, raise complex issues that can delay trial initiation and retard recruitment. Additional preparatory work might be required before testing novel treatments. A randomised controlled trial of tumour necrosis factor-α blockade is still needed to determine its cost-effectiveness in severe sciatica.

Published
2018

39. Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial

Author

Jenkinson, S, Kirkwood, A A, Goulden, N, Vora, A, Linch, D C, and Gale, R E

Subjects
Adult, Male, F-Box-WD Repeat-Containing Protein 7, Adolescent, F-Box Proteins, Ubiquitin-Protein Ligases, Gene Dosage, PTEN Phosphohydrolase, Infant, Cell Cycle Proteins, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Polymorphism, Single Nucleotide, Genes, ras, Child, Preschool, Mutation, Humans, Original Article, Female, Receptor, Notch1, Child
Abstract

PTEN gene inactivation by mutation or deletion is common in pediatric T-cell acute lymphoblastic leukemia (T-ALL), but the impact on outcome is unclear, particularly in patients with NOTCH1/FBXW7 mutations. We screened samples from 145 patients treated on the MRC UKALL2003 trial for PTEN mutations using heteroduplex analysis and gene deletions using single nucleotide polymorphism arrays, and related genotype to response to therapy and long-term outcome. PTEN loss-of-function mutations/gene deletions were detected in 22% (PTEN(ABN)). Quantification of mutant level indicated that 67% of mutated cases harbored more than one mutant, with up to four mutants detected, consistent with the presence of multiple leukemic sub-clones. Overall, 41% of PTEN(ABN) cases were considered to have biallelic abnormalities (mutation and/or deletion) with complete loss of PTEN in a proportion of cells. In addition, 9% of cases had N- or K-RAS mutations. Neither PTEN nor RAS genotype significantly impacted on response to therapy or long-term outcome, irrespective of mutant level, and there was no evidence that they changed the highly favorable outcome of patients with double NOTCH1/FBXW7 mutations. These results indicate that, for pediatric patients treated according to current protocols, routine screening for PTEN or RAS abnormalities at diagnosis is not warranted to further refine risk stratification.

Published
2015

43. Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study

Author

Eiser, C., Stride, C.B., Vora, A., Goulden, N., Mitchell, C., Buck, G., Adams, M., and Jenney, M.

Subjects
humanities
Abstract

Background: Health-related quality of life (HRQoL) from diagnosis until end of treatment for children\ud with Acute Lymphoblastic Leukaemia (ALL) was investigated, examining effects of age, gender, risk\ud stratified treatment regimen (A,B,C) and therapy intensity (1 vs 2 ‘delayed intensifications’: DI).\ud \ud Method: \ud In a multi-centre prospective study, parents reported their child’s generic and disease specific\ud HRQoL and their own care-giving burden at five time-points. From 1428 eligible patients, 874\ud parents completed questionnaires at least once during treatment.\ud \ud Results:\ud At each time-point, generic HRQoL was significantly lower than equivalent norm scores for healthy\ud children. HRQoL decreased significantly at the start of treatment, before recovering gradually (but\ud remained below pre-treatment levels). Parents reported that older children worried more about side effects and their appearance but showed less procedural anxiety than younger children. Concern for appearance was greater among girls than boys. Compared to regimen B (i.e.additional doxorubicin\ud during induction and additional cyclophosphamide and cytarabine during consolidation\ud chemotherapy), patients receiving regimen A had fewer problems with pain and nausea. There were\ud no statistically significant differences in HRQoL by number of DI blocks received.\ud \ud Interpretation: HRQoL is compromised at all stages of treatment, and is partly dependent on age.\ud The findings increase understanding of the impact of therapy on children’s HRQoL and parental caregiving burden, and will contribute to the design of future trials.

Published
2017

45. Human CD8+ CTL recognition and in vitro lysis of herpes simplex virus-infected cells by a non-MHC restricted mechanism

Author

Garland, R. J., Al-Shanti, Nasser, West, N. A., Hancock, J. P., Goulden, N. J., Steward, C. G., and Rowbottom, A. W.

Subjects
chemical and pharmacologic phenomena
Abstract

Cytotoxic T lymphocytes (CTL) are important for the recognition and lysis of virally infected cells, but their effectiveness can be limited by viral immune evasion mechanisms. We investigated the immunophenotype and function of human CD8+ T cells raised in response to herpes simplex virus (HSV). The expanded population contained cells of an activated and mature phenotype, as determined by the expressions of CD25, CD45RO, CD57, CD95 and HLA-DR. Cultured cells also expressed CD45RA. These cells lysed autologous and allogeneic HSV-infected lymphoblastoid cell line (LCL) targets via a non-major histocompatibility complex (MHC) restricted recognition pathway. Inhibition assays showed the mechanism of cytotoxicity to be calcium-dependent, granule exocytosis pathway, rather than the internal disintegration pathway. Cold target competition assays indicated that a common CTL population contributed to the recognition of autologous and allogeneic-infected targets. These effectors showed recognition of infected targets which was distinct from that of K562 cells. Non-MHC restricted lysis-associated molecule 2B4 (CD244) was upregulated on culturing and made a significant contribution to lysis of FcγR-bearing targets in a redirected killing assay. These findings suggest that CTL can recognize virally infected cells through a combination of non-MHC restricted mechanisms and may result in more efficient lysis than classical CD8+ T cells.

Published
2002

47. Human CD8+ CTL Recognition and In vitro Lysis of Herpes Simplex Virus-Infected Cells by a Non-MHC Restricted Mechanism.

Author

Garland, R, El-Shanti, N, West, S, Hancock, J, Goulden, N, Steward, C, and Rowbottom, A

Subjects
HERPES simplex virus, T cells, MAJOR histocompatibility complex
Abstract

Cytotoxic T lymphocytes (CTL) are important for the recognition and lysis of virally infected cells, but their effectiveness can be limited by viral immune evasion mechanisms. We investigated the immunophenotype and function of human CD8+ T cells raised in response to herpes simplex virus (HSV). The expanded population contained cells of an activated and mature phenotype, as determined by the expressions of CD25, CD45RO, CD57, CD95 and HLA-DR. Cultured cells also expressed CD45RA. These cells lysed autologous and allogeneic HSV-infected lymphoblastoid cell line (LCL) targets via a non-major histocompatibility complex (MHC) restricted recognition pathway. Inhibition assays showed the mechanism of cytotoxicity to be calcium-dependent, granule exocytosis pathway, rather than the internal disintegration pathway. Cold target competition assays indicated that a common CTL population contributed to the recognition of autologous and allogeneic-infected targets. These effectors showed recognition of infected targets which was distinct from that of K562 cells. Non-MHC restricted lysis-associated molecule 2B4 (CD244) was upregulated on culturing and made a significant contribution to lysis of FcγR-bearing targets in a redirected killing assay. These findings suggest that CTL can recognize virally infected cells through a combination of non-MHC restricted mechanisms and may result in more efficient lysis than classical CD8+ T cells. [ABSTRACT FROM AUTHOR]

Published
2002
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48. An optimised biphasic culture system for the generation of functional dendritic cells from patients with acute lymphoblastic leukaemia at presentation and in clinical remission.

Author

Blair, A, Rowbottom, A W, Browne, S J, Goulden, N J, Steward, C G, Oakhill, A, and Pamphilon, D H

Subjects
LYMPHOBLASTIC leukemia treatment, IMMUNOTHERAPY
Abstract

We have tested the hypothesis that functional dendritic cells (DC) may be generated from patients with acute lymphoblastic leukaemia (ALL). We evaluated the production of DC from blast cells taken at presentation from nine children with ALL. Blast cells were expanded in serum-free medium supplemented with Flt3L, G-CSF, GM-CSF, IL-3, IL-6 and SCF for 7 days and subsequently stimulated with Flt3L, GM-CSF and TGF-beta for a further 14 days, with the addition of TNF-alpha for the final 48 h of culture. Cultured cells had the morphological appearance of DC and expressed the DC-associated antigens CD1A (range 2-87%) and CD83 (15-44%). Expression of the co-stimulatory molecules CD80 and CD86 was increased and the majority of these cells retained their expression of CD34 (73+/-4%) and HLA-DR (79+/-5%). Seven of the nine ALL had a leukaemia-specific abnormality and DC generated from five of these seven cases were derived from the leukaemic clone. Leukaemic DC derived from four HLA-A*02-positive ALL pulsed with CMV-associated peptides could induce significant proliferation of peptide-specific CD8+ T cells. This specificity was verified using tetrameric complexes of HLA class l/antigenic peptide. DC could also be generated from cells taken at times of complete remission of ALL and from normal controls using these culture conditions. These findings show that functional DC can be generated both from ALL blasts and from patients in remission; these might be utilised in future for immunotherapeutic strategies in the treatment of ALL. [ABSTRACT FROM AUTHOR]

Published
2001
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49. Functional analysis of the CD8+CD57+ cell population in normal healthy individuals and matched unrelated T-cell-depleted bone marrow transplant recipients.

Author

Rowbottom, A. W., Garland, R. J., Lepper, M. W., Kaneria, S. S., Goulden, N. J., Oakhill, A., and Steward, C. G.

Subjects
BONE marrow transplantation, CYTOMEGALOVIRUS diseases, INTERLEUKIN-2
Abstract

The biological activities of CD8+ that co-express CD57 remain poorly defined. It is unclear whether all CD8+ cells have the potential to become CD57+ or whether they represent a unique subset with distinct functions. Several studies have reported the association between elevated numbers of CD8+CD57+ and a wide range of clinical disorders such as viral reactivation of human cytomegalovirus (HCMV). In this study, we have investigated the relationship between viral reactivation and the effect of diminished interleukin (IL)-2 production. Using CD8+ cells isolated from patients at various times after allogeneic transplants and in vitro models of HCMV infection, we determined their combined effect on CD8+CD57+. Our results show that high numbers of CD8+CD57+ correlated with diminished killing of HCMV-infected targets. In addition, we showed a synergistic effect between IL-2 and HCMV in the expansion of CD8+CD57+ cells. Furthermore, these cells after anti-CD3 stimulation did not produce tumour necrosis factor (TNF)-α or interferon (IFN)-γ. Interestingly, IL-10 production was elevated in several patients which appeared to be associated with the time from transplant. [ABSTRACT FROM AUTHOR]

Published
2000
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