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3. Diel and seasonal patterns of tropical forest CO2 exchange

Author

Goulden, N. L., Miller, S. D., da Rocha, H. R., Menton, M. C., de Freitas, H. C., Figueria, A. M. E. S., and de Sousa, C. A. D.

Subjects
Amazonia, biosphere-atmosphere exchange, canopy photosynthesis, CO2 exchange, eddy covariance, LBA, phenology, tropical forest
Abstract

We used eddy covariance to measure the net exchange of CO2between theatmosphere and an old-growth tropical forest in Para ́, Brazil from 1 July 2000 to 1 July2001. The mean air temperature and daily temperature range varied little year-round; therainy season lasted from late December to around July. Daytime CO2uptake under highirradiance averaged 16–19mmol·m22·s21. Light was the main controller of CO2exchange,accounting for 48% of the half-hour-to-half-hour variance. The rate of canopy photosyn-thesis at a given irradiance was lower in the afternoon than the morning. This photosyntheticinhibition was probably caused by high evaporative demand, high temperature, an intrinsiccircadian rhythm, or a combination of the three. Wood increment increased from Januaryto May, suggesting greater rates of carbon sequestration during the wet season. However,the daily net CO2exchange measured by eddy covariance revealed the opposite trend, withgreater carbon accumulation during the dry season. A reduction in respiration during thedry season was an important cause of this seasonal pattern. The surface litter was desiccatedin the dry season, and the seasonal pattern of respiration appears to be a direct result ofreduced forest floor decomposition during drought. In contrast, canopy photosynthesis wasnot directly reduced by the dry season, probably because deep rooting allows the forest toavoid drought stress

Published
2004

9. 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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28. 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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29. 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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37. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation

Author

van der Sluis, I, Vrooman, L, Pieters, R, Baruchel, A, Escherich, G, Goulden, N, Mondelaers, V, de Toledo, J, Rizzari, C, Silverman, L, Whitlock, J, van der Sluis I. M., Vrooman L. M., Pieters R., Baruchel A., Escherich G., Goulden N., Mondelaers V., de Toledo J. S., Rizzari C., Silverman L. B., Whitlock J. A., van der Sluis, I, Vrooman, L, Pieters, R, Baruchel, A, Escherich, G, Goulden, N, Mondelaers, V, de Toledo, J, Rizzari, C, Silverman, L, Whitlock, J, van der Sluis I. M., Vrooman L. M., Pieters R., Baruchel A., Escherich G., Goulden N., Mondelaers V., de Toledo J. S., Rizzari C., Silverman L. B., and Whitlock J. A.

Abstract

L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of hypersensitivity reactions, can limit its use in individual patients. Of considerable concern in the setting of clinical allergy is the development of neutralizing antibodies and associated asparaginase inactivity. Also problematic in the use of asparaginase is the potential for the development of silent inactivation, with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. Here we present guidelines for the identification and management of clinical hypersensitivity and silent inactivation with Escherichia coli- and Erwinia chrysanthemi- derived asparaginase preparations. These guidelines were developed by a consensus panel of experts following a review of the available published data. We provide a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation.

Published
2016

38. 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. Genotype-specific MRD interpretation improves stratification in paediatric acute lymphoblastic leukaemia

Author

O'Connor, D, Enshaei, A, Bartram, J, Hancock, J, Harrison, CJ, Hough, R, Samarasinghe, S, Schwab, C, Vora, A, Wade, R, Moppett, J, Moorman, AV, and Goulden, N

Subjects
body regions, hemic and lymphatic diseases
Abstract

Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse.

Published
2017

43. 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

47. 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

48. Prospective evaluation of quality of life in children treated in UKALL 2003 for Acute Lymphoblastic Leukaemia (ALL): A cohort study

Author

Eiser, C, Stride, C, 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 with Acute Lymphoblastic Leukaemia (ALL) was investigated, examining effects of age, gender, risk stratified treatment regimen (A,B,C) and therapy intensity (1 vs 2 ‘delayed intensifications’: DI). Method: In a multi-centre prospective study, parents reported their child’s generic and disease specific HRQoL and their own care-giving burden at five time-points. From 1428 eligible patients, 874 parents completed questionnaires at least once during treatment. Results: At each time-point, generic HRQoL was significantly lower than equivalent norm scores for healthy children. HRQoL decreased significantly at the start of treatment, before recovering gradually (but 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 during induction and additional cyclophosphamide and cytarabine during consolidation chemotherapy), patients receiving regimen A had fewer problems with pain and nausea. There were no statistically significant differences in HRQoL by number of DI blocks received. Interpretation: HRQoL is compromised at all stages of treatment, and is partly dependent on age. The findings increase understanding of the impact of therapy on children’s HRQoL and parental care-giving burden, and will contribute to the design of future trials.

Published
2017

49. Targeting acute myeloid leukemia by drug-induced c-MYB degradation

Author

Walf-Vorderwülbecke, V, primary, Pearce, K, additional, Brooks, T, additional, Hubank, M, additional, van den Heuvel-Eibrink, M M, additional, Zwaan, C M, additional, Adams, S, additional, Edwards, D, additional, Bartram, J, additional, Samarasinghe, S, additional, Ancliff, P, additional, Khwaja, A, additional, Goulden, N, additional, Williams, G, additional, de Boer, J, additional, and Williams, O, additional

Published
2017
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50. Subcutaneous injection of adalimumab trial compared with control (SCIATiC):a randomised controlled trial of adalimumab injection compared with placebo for patients receiving physiotherapy treatment for sciatica

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. A. (David A), 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), Wilkinson, C. (Clare), 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. A. (David A), 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)

Abstract

Background: Biological treatments such as adalimumab (Humira®; AbbVie Ltd, Maidenhead, UK) are antibodies targeting tumour necrosis factor alpha, released from ruptured intervertebral discs, which might be useful in sciatica. Recent systematic reviews concluded that they might be effective, but that a definitive randomised controlled trial was needed. Usual care in the NHS typically includes a physiotherapy intervention. Objectives: To test whether or not injections of adalimumab plus physiotherapy are more clinically effective and cost-effective than injections of saline plus physiotherapy for patients with sciatica. Design: Pragmatic, parallel-group, randomised controlled trial with blinded participants and clinicians, and an outcome assessment and statistical analysis with concurrent economic evaluation and internal pilot. Setting: Participants were referred from primary care and musculoskeletal services to outpatient physiotherapy clinics. Participants: Adults with persistent symptoms of sciatica of 1–6 months’ duration and with moderate to high levels of disability. Eligibility was assessed by research physiotherapists according to clinical criteria for diagnosing sciatica. Interventions: After a second eligibility check, trial participants were randomised to receive two doses of adalimumab (80 mg and then 40 mg 2 weeks later) or saline injections. Both groups were referred for a course of physiotherapy. Main outcome measures: Outcomes were measured at the start, and after 6 weeks’ and 6 months’ follow-up. The main outcome measure was the Oswestry Disability Index (ODI). Other outcomes: leg pain version of the Roland–Morris Disability Questionnaire, Sciatica Bothersomeness Index, EuroQol-5 Dimensions, 5-level version, Hospital Anxiety and Depression Scale, resource use, risk of persistent disabling pain, pain trajectory based on a single question, Pain Self-Efficacy Questionnaire, Tampa Scale of Kinesiophobia and adverse effects. Sample size: To detect

Published
2017

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