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1. Simulation of a radiobiology facility for the Centre for the Clinical Application of Particles

Author

Kurup, A., Pasternak, J., Taylor, R., Murgatroyd, L., Ettlinger, O., Shields, W., Nevay, L., Gruber, S., Pozimski, J., Lau, H. T., Long, K., Blackmore, V., Barber, G., Najmudin, Z., and Yarnold, J.

Subjects
Physics - Accelerator Physics, Physics - Medical Physics
Abstract

The Centre for the Clinical Application of Particles' Laser-hybrid Accelerator for Radiobiological Applications (LhARA) facility is being studied and requires simulation of novel accelerator components (such as the Gabor lens capture system), detector simulation and simulation of the ion beam interaction with cells. The first stage of LhARA will provide protons up to 15 MeV for in vitro studies. The second stage of LhARA will use a fixed-field accelerator to increase the energy of the particles to allow in vivo studies with protons and in vitro studies with heavier ions. BDSIM, a Geant4 based accelerator simulation tool, has been used to perform particle tracking simulations to verify the beam optics design done by BeamOptics and these show good agreement. Design parameters were defined based on an EPOCH simulation of the laser source and a series of mono-energetic input beams were generated from this by BDSIM. The tracking results show the large angular spread of the input beam (0.2 rad) can be transported with a transmission of almost 100% whilst keeping divergence at the end station very low (<0.1 mrad). The legacy of LhARA will be the demonstration of technologies that could drive a step-change in the provision of proton and light ion therapy (i.e. a laser source coupled to a Gabor lens capture and a fixed-field accelerator), and a system capable of delivering a comprehensive set of experimental data that can be used to enhance the clinical application of proton and light ion therapy.

Published
2019

3. Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)

Author

Gourgou-Bourgade, S., Cameron, D., Poortmans, P., Asselain, B., Azria, D., Cardoso, F., A'Hern, R., Bliss, J., Bogaerts, J., Bonnefoi, H., Brain, E., Cardoso, M.J., Chibaudel, B., Coleman, R., Cufer, T., Dal Lago, L., Dalenc, F., De Azambuja, E., Debled, M., Delaloge, S., Filleron, T., Gligorov, J., Gutowski, M., Jacot, W., Kirkove, C., MacGrogan, G., Michiels, S., Negreiros, I., Offersen, B.V., Penault Llorca, F., Pruneri, G., Roche, H., Russell, N.S., Schmitt, F., Servent, V., Thürlimann, B., Untch, M., van der Hage, J.A., van Tienhoven, G., Wildiers, H., Yarnold, J., Bonnetain, F., Mathoulin-Pélissier, S., Bellera, C., and Dabakuyo-Yonli, T.S.

Published
2015
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8. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1

Author

Offersen, B.V., Boersma, L.J., Kirkove, C., Hol, S., Aznar, M.C., Sola, A.B., Kirova, Y.M., Pignol, J.P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., Poortmans, P., Offersen, B.V., Boersma, L.J., Kirkove, C., Hol, S., Aznar, M.C., Sola, A.B., Kirova, Y.M., Pignol, J.P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., and Poortmans, P.

Abstract

Item does not contain fulltext

Published
2016

9. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.

Author

Offersen, B. V., Boersma, L. J., Kirkove, C., Hol, S., Aznar, M. C., Sola, A. B., Kirova, Y. M., Pignol, J.-P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., Poortmans, P., Offersen, B. V., Boersma, L. J., Kirkove, C., Hol, S., Aznar, M. C., Sola, A. B., Kirova, Y. M., Pignol, J.-P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., and Poortmans, P.

Published
2016

10. ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

Author

Pinhel, I, Hills, M, Drury, S, Salter, J, Sumo, G, A'Hern, R, Bliss, JM, Sestak, I, Cuzick, J, Barrett-Lee, P, Harris, A, Dowsett, M, Bliss, M, Johnson, L, Lawrence, D, Price, D, Peto, J, Yarnold, J, Brunt, AM, Dodwell, D, Earl, H, Fernando, I, Foster, L, George, WD, Harnett, AM, Perren, T, Poole, C, Raina, V, and Robinson, A

Subjects
skin and connective tissue diseases, neoplasms
Abstract

Introduction: Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas.Methods: ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm. Relations at the RNA level were assessed in 1,139 TransATAC tumors.Results: ER and HER2 RNA levels were negatively correlated as expected in HER2+ve (IHC 3+ and/or FISH-amplified) tumors (r = -0.45; P = 0.0028). However, in HER2-ve tumors (ER+ve and ER-ve combined), a significant positive correlation was found (r = 0.43; P < 0.0001), HER2 RNA levels being 1.74-fold higher in ER+ve versus ER-ve tumors. This correlation was maintained in the ER+veHER2-ve subgroup (r = 0.24; P = 0.0023) and confirmed in this subgroup in 1,139 TransATAC tumours (r = 0.25; P < 0.0001). The positive relation extended to IHC-detected ER in ABC: mean ± 95% confidence interval (CI) H-scores were 90 ± 19 and 134 ± 19 for 0 and 1+ HER2 IHC categories, respectively (P = 0.0013). A trend toward lower relapse-free survival (RFS) was observed in patients with the lowest levels of ER and HER2 RNA levels within the ER+veHER2-ve subgroup both for ABC and TransATAC cohorts.Conclusions: ER and HER2 expression is positively correlated in HER2-ve tumors. The distinction between HER2+ve and HER2-ve is greater in ER-ve than in ER+ve tumors. These findings are important to consider in clinical trials of anti-HER2 and anti-endocrine therapy in HER2-ve disease. Trial Registration: Clinical trial identifier: ISRCTN31514446.

Published
2012

11. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer

Author

Offersen, B.V., Boersma, L.J., Kirkove, C., Hol, S., Aznar, M.C., Sola, A. Biete, Kirova, Y.M., Pignol, J.P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., Poortmans, P.M.P., Offersen, B.V., Boersma, L.J., Kirkove, C., Hol, S., Aznar, M.C., Sola, A. Biete, Kirova, Y.M., Pignol, J.P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., and Poortmans, P.M.P.

Abstract

Item does not contain fulltext, BACKGROUND AND PURPOSE: Delineation of clinical target volumes (CTVs) is a weak link in radiation therapy (RT), and large inter-observer variation is seen in breast cancer patients. Several guidelines have been proposed, but most result in larger CTVs than based on conventional simulator-based RT. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS: During ESTRO teaching courses on breast cancer, teachers sought consensus on delineation of CTV through dialogue based on cases. One teacher delineated CTV on CT scans of 2 patients, followed by discussion and adaptation of the delineation. The consensus established between teachers was sent to other teams working in the same field, both locally and on a national level, for their input. This was followed by developing a broad consensus based on discussions. RESULTS: Borders of the CTV encompassing a 5mm margin around the large veins, running through the regional lymph node levels were agreed, and for the breast/thoracic wall other vessels were pointed out to guide delineation, with comments on margins for patients with advanced breast cancer. CONCLUSION: The ESTRO consensus on CTV for elective RT of breast cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency.

Published
2015

12. Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†

Author

UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service de radiothérapie oncologique, Gourgou-Bourgade, S, Cameron, D, Poortmans, P, Asselain, B, Azria, D, Cardoso, F, A'Hern, R, Bliss, J, Bogaerts, J, Bonnefoi, H, Brain, E, Cardoso, M J, Chibaudel, B, Coleman, R, Cufer, T, Dal Lago, L, Dalenc, F, De Azambuja, E, Debled, M, Delaloge, S, Filleron, T, Gligorov, J, Gutowski, M, Jacot, W, Kirkove, Carine, MacGrogan, G, Michiels, S, Negreiros, I, Offersen, B V, Penault Llorca, F, Pruneri, G, Roche, H, Russell, N S, Schmitt, F, Servent, V, Thürlimann, B, Untch, M, van der Hage, J A, van Tienhoven, G, Wildiers, H, Yarnold, J, Bonnetain, F, Mathoulin-Pélissier, S, Bellera, C, Dabakuyo-Yonli, T S, Definition for the Assessment of Time-to-event Endpoints in Cancer Trials Initiative, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Service de radiothérapie oncologique, Gourgou-Bourgade, S, Cameron, D, Poortmans, P, Asselain, B, Azria, D, Cardoso, F, A'Hern, R, Bliss, J, Bogaerts, J, Bonnefoi, H, Brain, E, Cardoso, M J, Chibaudel, B, Coleman, R, Cufer, T, Dal Lago, L, Dalenc, F, De Azambuja, E, Debled, M, Delaloge, S, Filleron, T, Gligorov, J, Gutowski, M, Jacot, W, Kirkove, Carine, MacGrogan, G, Michiels, S, Negreiros, I, Offersen, B V, Penault Llorca, F, Pruneri, G, Roche, H, Russell, N S, Schmitt, F, Servent, V, Thürlimann, B, Untch, M, van der Hage, J A, van Tienhoven, G, Wildiers, H, Yarnold, J, Bonnetain, F, Mathoulin-Pélissier, S, Bellera, C, Dabakuyo-Yonli, T S, and Definition for the Assessment of Time-to-event Endpoints in Cancer Trials Initiative

Abstract

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.

Published
2015

13. ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.

Author

Offersen, B. V., Boersma, L. J., Kirkove, C., Hol, S., Aznar, M. C., Biete Sola, A., Kirova, Y. M., Pignol, J. P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., Poortmans, P., Offersen, B. V., Boersma, L. J., Kirkove, C., Hol, S., Aznar, M. C., Biete Sola, A., Kirova, Y. M., Pignol, J. P., Remouchamps, V., Verhoeven, K., Weltens, C., Arenas, M., Gabrys, D., Kopek, N., Krause, M., Lundstedt, D., Marinko, T., Montero, A., Yarnold, J., and Poortmans, P.

Abstract

BACKGROUND AND PURPOSE: Delineation of clinical target volumes (CTVs) is a weak link in radiation therapy (RT), and large inter-observer variation is seen in breast cancer patients. Several guidelines have been proposed, but most result in larger CTVs than based on conventional simulator-based RT. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS: During ESTRO teaching courses on breast cancer, teachers sought consensus on delineation of CTV through dialogue based on cases. One teacher delineated CTV on CT scans of 2 patients, followed by discussion and adaptation of the delineation. The consensus established between teachers was sent to other teams working in the same field, both locally and on a national level, for their input. This was followed by developing a broad consensus based on discussions. RESULTS: Borders of the CTV encompassing a 5mm margin around the large veins, running through the regional lymph node levels were agreed, and for the breast/thoracic wall other vessels were pointed out to guide delineation, with comments on margins for patients with advanced breast cancer. CONCLUSION: The ESTRO consensus on CTV for elective RT of breast cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency.

Published
2015

17. Radiotherapy for breast cancer, the TARGIT-A trial

Author

Yarnold, J., Offersen, B.V., Olivotto, I., Poortmans, P.M.P., Sarin, R., Yarnold, J., Offersen, B.V., Olivotto, I., Poortmans, P.M.P., and Sarin, R.

Abstract

Item does not contain fulltext

Published
2014

18. Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage

Author

Risselada, R. (Roelof), Roozenbeek, B. (Bob), Molyneux, A.J. (Andrew), Kerr, R.S.C., Yarnold, J. (Julia), Sneade, M. (Mary), Steyerberg, E.W. (Ewout), Sturkenboom, M.C.J.M. (Miriam), Risselada, R. (Roelof), Roozenbeek, B. (Bob), Molyneux, A.J. (Andrew), Kerr, R.S.C., Yarnold, J. (Julia), Sneade, M. (Mary), Steyerberg, E.W. (Ewout), and Sturkenboom, M.C.J.M. (Miriam)

Abstract

Background. Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. Methods. We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients. Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. Results. The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). Conclusion. We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. A

Published
2010
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19. Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT)

Author

Risselada, R. (Roelof), Lingsma, H.F. (Hester), Bauer-Mehren, A. (Anna), Friedrich, C.M. (Christoph), Molyneux, A.J. (Andrew), Kerr, R.S.C., Yarnold, J. (Julia), Sneade, M. (Mary), Steyerberg, E.W. (Ewout), Sturkenboom, M.C.J.M. (Miriam), Risselada, R. (Roelof), Lingsma, H.F. (Hester), Bauer-Mehren, A. (Anna), Friedrich, C.M. (Christoph), Molyneux, A.J. (Andrew), Kerr, R.S.C., Yarnold, J. (Julia), Sneade, M. (Mary), Steyerberg, E.W. (Ewout), and Sturkenboom, M.C.J.M. (Miriam)

Abstract

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making.

Published
2010
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20. Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage

Author

Risselada, Roelof, Lingsma, Hester, Molyneux, AJ, Kerr, RSC, Yarnold, J, Sneade, M, Steyerberg, Ewout, Sturkenboom, MCJM, Risselada, Roelof, Lingsma, Hester, Molyneux, AJ, Kerr, RSC, Yarnold, J, Sneade, M, Steyerberg, Ewout, and Sturkenboom, MCJM

Abstract

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. Methods: We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients. Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. Results: The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). Conclusion: We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. Although generalizability of the model is limited due to the selected population in which it was developed, this model could eventually be used to support clinical decision making after external validation.

Published
2010

21. Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT)

Author

Risselada, Roelof, Lingsma, Hester, Bauer-Mehren, A, Friedrich, CM, Molyneux, AJ, Kerr, RSC, Yarnold, J, Sneade, M, Steyerberg, Ewout, Sturkenboom, MCJM, Risselada, Roelof, Lingsma, Hester, Bauer-Mehren, A, Friedrich, CM, Molyneux, AJ, Kerr, RSC, Yarnold, J, Sneade, M, Steyerberg, Ewout, and Sturkenboom, MCJM

Abstract

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making.

Published
2010

23. Abstract P1-13-03: Mature analysis of UK Taxotere as Adjuvant Chemotherapy (TACT) trial (CRUK 01/001); effects of treatment and characterisation of patterns of breast cancer relapse.

Author

Bliss, JM, primary, Ellis, P, additional, Kilburn, L, additional, Bartlett, J, additional, Bloomfield, D, additional, Cameron, D, additional, Canney, P, additional, Coleman, RE, additional, Dowsett, M, additional, Earl, H, additional, Verril, M, additional, Wardley, A, additional, Yarnold, J, additional, Ahern, R, additional, Atkins, N, additional, Fletcher, M, additional, McLinden, M, additional, and Barrett-Lee, P, additional

Published
2012
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24. A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy

Author

Talbot, C J, primary, Tanteles, G A, additional, Barnett, G C, additional, Burnet, N G, additional, Chang-Claude, J, additional, Coles, C E, additional, Davidson, S, additional, Dunning, A M, additional, Mills, J, additional, Murray, R J S, additional, Popanda, O, additional, Seibold, P, additional, West, C M L, additional, Yarnold, J R, additional, and Symonds, R P, additional

Published
2012
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28. Modelling the cost-effectiveness of first, second and third generation polychemotherapy regimens in women with early breast cancer who have differing prognoses.

Author

Campbell, H, primary, Epstein, D, additional, Griffin, S, additional, Sculpher, M, additional, Manca, A, additional, Bloomfield, D, additional, Yarnold, J, additional, Bliss, J, additional, Johnson, L, additional, Earl, H, additional, Poole, C, additional, Hiller, L, additional, Dunn, J, additional, Rea, D, additional, Hopwood, P, additional, Barrett-Lee, P, additional, and Ellis, P, additional

Published
2009
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31. PALLIATION AND LIFE QUALITY IN LUNG-CANCER - HOW GOOD ARE CLINICIAN AT JUDGING TREATMENT OUTCOME

Author

Regan, J, Yarnold, J, Jones, PW, and Cooke, NT

Abstract

A recent trial by the MRC Lung Cancer Working Party used physician assessments to compare two palliative schedules of radiotherapy in lung cancer. A prospective study has been undertaken on a subset of these trial patients to see how physician assessments of symptomatic relief and general condition correlate with patient perception of therapeutic response. In 40 patients followed up monthly from presentation until close to death, good agreement was found between doctors and patients on change in specific physical symptoms and overall physical condition. Doctors were poor judges of life quality at presentation but appeared able to identify relative improvement or deterioration in overall quality of life. In conclusion, physician assessments may constitute valid end-points for radiotherapy trials comparing palliative schedules in lung cancer

Published
1991

38. Management of breast cancer Refer women to multidisciplinary breast clinics

Author

Yarnold, J R, primary, Bliss, J M, additional, Brunt, M, additional, Earl, H, additional, Kaye, S, additional, Mason, M, additional, Mossman, J, additional, Perren, T, additional, Richards, M, additional, Clamp, S E, additional, Kunkler, I H, additional, Chetty, U, additional, Rodger, A, additional, Rothwell, I, additional, Morrison, L, additional, Statham, H, additional, Green, J, additional, and Murton, F, additional

Published
1994
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39. Increased collagen production in fibroblasts cultured from irradiated skin and effect of TGF β1– clinical study.

Author

Illsley, M C, Peacock, J H, McAnulty, R J, and Yarnold, J R

Subjects
FIBROBLASTS, COLLAGEN, TRANSFORMING growth factors-beta, RADIOTHERAPY
Abstract

Fibrosis in normal tissues is a common and dose-limiting late complication of radiotherapy at many cancer sites, but its pathogenesis is poorly understood. We undertook a controlled study of the effect of irradiation on the collagen production of fibroblasts cultured from skin biopsies taken from patients undergoing radiotherapy treatment. Eight weeks after a single 8 Gy fraction using 300 kV X-rays, five patients treated at the Royal Marsden Hospital underwent biopsy of the irradiated site and of the contralateral, unirradiated body site. Fibroblasts from irradiated and control, unirradiated sites were cultured in vitro, and collagen production rates were measured during a 48-hour incubation under standardized conditions and in the presence and absence of transforming growth factor β[SUB1] (TGF β[SUB1]), 1 ng/ml, using HPLC. Collagen production was elevated in cells cultured from irradiated skin; median collagen production rates 61.16 pmoles hydroxyproline/10[SUP5] cells/hour in irradiated cells, 39.78 pmoles hydroxyproline/10[SUP5] cells/hour in unirradiated cells, P = 0.016 (Mann-Whitney U-test). In fibroblasts from unirradiated sites, collagen production rates were increased by the addition of TGF β[SUB1]; however, in three of the cell lines cultured from irradiated sites this effect of TGF β[SUB1] on collagen production was not observed. [ABSTRACT FROM AUTHOR]

Published
2000
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42. Dr Yarnold replies

Author

Yarnold, J R

Subjects
Letters to the Editor
Published
1986

43. Management of radiation injuries to the bowel associated with treatment of uterine carcinoma by radiotherapy: preliminary communication.

Author

Cochrane, J. P. S. and Yarnold, J. R.

Subjects
MEDICAL radiology, MEDICAL electronics, HOSPITAL radiological services, CANCER patients, RADIOTHERAPY, CERVICAL cancer, ENDOMETRIAL cancer
Abstract

The article discusses the use of intracavitary radiation through Catheron as treatment for carcinoma of the cervix or endometrium in Great Britain. According to the author, carcinoma patients are required to take a high-dose external radiotherapy with the intracavitary Catheron treatment. Details regarding the study conducted on thirteen patients with the said disease is illustrated.

Published
1979
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46. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials

Author

Abe, O., Abe, R., Enomoto, K., Kikuchi, K., Koyama, H., Masuda, H., Nomura, Y., Sakai, K., Sugimachi, K., Tominaga, T., Uchino, J., Yoshida, M., Haybittle, J. L., Davies, C., Harvey, V. J., Holdaway, T. M., Kay, R. G., Mason, B. H., Forbes, J. F., Wilcken, N., Gnant, M., Jakesz, R., Ploner, M., Yosef, H. M. A., Focan, C., Lobelle, J. P., Peek, U., Oates, G. D., Powell, J., Durand, M., Mauriac, L., Di Leo, A., Dolci, S., Piccart, M. J., Masood, M. B., Parker, D., Price, J. J., Hupperets, P. S. G. J., Jackson, S., Ragaz, J., Berry, D., Broadwater, G., Cirrincione, C., Muss, H., Norton, L., Weiss, R. B., Abu-Zahra, H. T., Portnoj, S. M., Baum, M., Cuzick, J., Houghton, J., Riley, D., Mansel, R. E., Gordon, N. H., Davis, H. L., Beatrice, A., Mihura, J., Naja, A., Lehingue, Y., Romestaing, P., Dubois, J. B., Delozier, T., Mace Lesec'h, J., Rambert, P., Petruzelka, L., Pribylova, O., Owen, J. R., Harbeck, N., Jänicke, F., Meisner, C., Meier, P., Howell, A., Ribeiro, G. C., Swindell, R., Burrett, J., Clarke, M., Collins, R., Darby, S., Elphinstone, P., Evans, V., Godwin, J., Gray, R., Harwood, C., Hicks, C., Jackson, D., James, S., Mackinnon, E., Mcgale, P., Mchugh, T., Mead, G., Morris, P., Oulds, J., Peto, R., Taylor, C., Wang, Y., Albano, J., De Oliveira, C. F., Gervásio, H., Gordilho, J., Johansen, H., Mouridsen, H. T., Gelman, R. S., Harris, J. R., Henderson, I. C., Shapiro, C. L., Christiansen, P., Ejlertsen, B., Møller, S., Overgaard, M., Carstensen, B., Palshof, T., Trampisch, H. J., Dalesio, O., De Vries, E. G. E., Rodenhuis, S., Van Tinteren, H., Comis, R. L., Davidson, N. E., Robert, N., Sledge, G., Tormey, D. C., Wood, W., Cameron, D., Chetty, U., Forrest, P., Jack, W., Rossbach, J., Klijn, J. G. M., Treurniet-Donker, A. D., Van Putten, W. L. J., Costa, A., Veronesi, U., Bartelink, H., Duchateau, L., Legrand, C., Sylvester, R., Van Der Hage, J. A., Van De Velde, C. J. H., Cunningham, M. P., Catalano, R., Creech, R. H., Bonneterre, J., Fargeot, P., Fumoleau, P., Kerbrat, P., Namer, M., Jonat, W., Kaufmann, M., Schumacher, M., Von Minckwitz, G., Bastert, G., Rauschecker, H., Sauer, R., Sauerbrei, W., Schauer, A., De Schryver, A., Vakaet, L., Belfiglio, M., Nicolucci, A., Pellegrini, F., Sacco, M., Valentini, M., Mcardle, C. S., Smith, D. C., Galligioni, E., Boccardo, F., Rubagotti, A., Dent, D. M., Gudgeon, C. A., Hacking, A., Erazo, A., Medina, J. Y., Izuo, M., Morishita, Y., Takei, H., Fentiman, I. S., Hayward, J. L., Rubens, R. D., Skilton, D., Scheurlen, H., Von Fournier, D., Dafni, U., Fountzilas, G., Klefstrom, P., Blomqvist, C., Saarto, T., Margreiter, R., Asselain, B., Salmon, R. J., Vilcoq, J. R., Arriagada, R., Hill, C., Laplanche, A., M. G., Lê, Spielmann, M., Bruzzi, P., Montanaro, E., Rosso, R., Sertoli, M. R., Venturini, M., Amadori, D., Benraadt, J., Kooi, M., Van De Velde, A. O., Van Dongen, J. A., Vermorken, J. B., Castiglione, M., Cavalli, F., Coates, A., Collins, J., Forbes, J., Gelber, R. D., Goldhirsch, A., Lindtner, J., Price, K. N., Rudenstam, C. M., Senn, H. J., Bliss, J. M., Chilvers, C. E. D., Coombes, R. C., Hall, E., Marty, M., Borovik, R., Brufman, G., Hayat, H., Robinson, E., Wigler, N., Bonadonna, G., Camerini, T., De Palo, G., Del Vecchio, M., Formelli, F., Valagussa, P., Martoni, A., Pannuti, F., Cocconi, G., Colozza, A., Camisa, R., Aogi, K., Takashima, S., Ikeda, T., Inokuchi, K., Sawa, K., Sonoo, H., Korzeniowski, S., Skolyszewski, J., Ogawa, M., Yamashita, J., Bonte, J., Christiaens, R., Paridaens, R., Van Den Bogaert, W., Martin, P., Geniez, ROMAIN SYLVAIN JEAN, Hakes, T., Hudis, C. A., Wittes, R., Giokas, G., Kondylis, D., Lissaios, B., De La Huerta, R., Sainz, M. G., Altemus, R., Cowan, K., Danforth, D., Lichter, A., Lippman, M., O'Shaughnessy, J., Pierce, L. J., Steinberg, S., Venzon, D., Zujewski, J. A., Paradiso, A., De Lena, M., Schittulli, F., Myles, J. D., Pater, J. L., Pritchard, K. I., Whelan, T., Anderson, S., Bass, G., Brown, A., Bryant, J., Costantino, J., Dignam, J., Fisher, B., Redmond, C., Wieand, S., Wolmark, N., Jackson, I. M., Palmer, M. K., Ingle, J. N., Suman, V. J., Bengtsson, N. O., Jonsson, H., Larsson, L. G., Lythgoe, J. P., Kissin, M., Erikstein, B., Hannisdal, E., Jacobsen, A. B., Varhaug, J. E., Gundersen, S., Hauer-Jensen, M., Høst, H., Nissen-Meyer, R., Blamey, R. W., Mitchell, A. K., Morgan, D. A. L., Robertson, J. F. R., Di Palma, M., Mathé, G., Misset, J. L., Clark, R. M., Levine, M., Morimoto, K., Takatsuka, Y., Crossley, E., Harris, A., Talbot, D., Taylor, M., Di Blasio, B., Ivanov, V., Semiglazov, V., Brockschmidt, J., Cooper, M. R., Ueo, H., Falkson, C. I., A'Hern, R., Ashley, S., Powles, T. J., Smith, I. E., Yarnold, J. R., Gazet, J. C., Corcoran, N., Deshpande, N., Di Martino, L., Douglas, P., Lindtner, A., Notter, G., Bryant, A. J. S., Ewing, G. H., Firth, L. A., Krushen-Kosloski, J. L., Foster, L., George, W. D., Stewart, H. J., Stroner, P., Malmström, P., Möller, T. R., Rydén, S., Tengrup, I., Tennvall-Nittby, L., Carstenssen, J., Dufmats, M., Hatschek, T., Nordenskjöld, B., Söderberg, M., Carpenter, J. T., Albain, K., Crowley, J., Green, S., Martino, S., Osborne, C. K., Ravdin, P. M., Glas, U., Johansson, U., Rutqvist, L. E., Singnomklao, T., Wallgren, A., Maibach, R., Thürlimann, B., Brenner, H., Hercbergs, A., Yoshimoto, M., Deboer, G., Paterson, A. H. G., Meakin, J. W., Panzarella, T., Shan, Y., Shao, Y. F., Wang, X., Zhao, D. B., Chen, Z. M., Pan, H. C., Bahi, J., Reid, M., Spittle, M., Deutsch, G. P., Senanayake, F., Kwong, D. L. W., Bianco, A. R., Carlomagno, C., De Laurentiis, M., De Placido, S., Buzdar, A. U., Smith, T., Bergh, J., Holmberg, L., Liljegren, G., Nilsson, J., Seifert, M., Sevelda, P., Zielinsky, C. C., Buchanan, R. B., Cross, M., Royle, G. T., Dunn, J. A., Hills, R. K., Lee, M., Morrison, J. M., Spooner, D., Litton, A., Chlebowski, R. T., Caffier, H., Clarke, M, Collins, R, Darby, S, Davies, C, Elphinstone, P, Evans, E, Godwin, J, Gray, R, Hicks, C, James, S, MacKinnon, E, McGale, P, McHugh, T, Peto, R, Taylor, C, and Wang, Y

Subjects
medicine.medical_specialty, Time Factors, medicine.medical_treatment, Breast Neoplasms, Rate ratio, Breast Conservation Treatment, Disease-Free Survival, Breast cancer, Cause of Death, Breast-conserving surgery, Medicine, Humans, Lung cancer, Aged, Probability, Randomized Controlled Trials as Topic, business.industry, Female, Middle Aged, Neoplasm Recurrence, Local, Medicine (all), General Medicine, medicine.disease, Surgery, Radiation therapy, Unilateral Breast Neoplasms, Neoplasm Recurrence, Local, business, Mastectomy
Abstract

Background In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995. Methods Information was available on 42 000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23 500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (10%, 25 000 women). Findings About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44·6% versus 49·5% (absolute reduction 5·0%, SE 0·8, 2p These 25 000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30·5% versus 35·9% (reduction 5·4%, SE 1·7, 2p=0·0002; overall mortality reduction 5·3%, SE 1·8, 2p=0·005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54·7% versus 60·1% (reduction 5·4%, SE 1·3, 2p=0·0002; overall mortality reduction 4·4%, SE 1·2, 2p=0·0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1·18, SE 0·06, 2p=0·002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1·12, SE 0·04, 2p=0·001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1·27, SE 0·07, 2p=0·0001) and lung cancer (rate ratio 1·78, SE 0·22, 2p=0·0004). Interpretation In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.

47. Investigation of the effects of hydrogen peroxide in combination with ionising radiation in cancer

Author

Nimalasena, Samantha and Yarnold, J.

Abstract

Introduction: In the early 2000s, Japanese colleagues reported sensitisation of normal and tumour cell lines to cytotoxic doses of ionising radiation (IR) by low concentrations of hydrogen peroxide (H2O2), research that prompted clinical studies testing intratumoural (IT) injections of 0.5% H2O2 in 1% sodium hyaluronate gel during radiotherapy in patients with inoperable breast cancer. Five-year local control rates were substantially higher than expected from the radiotherapy dose intensities used, with no additional late adverse effects. Methods: Using the radioresistant cell lines HCT116 and HN5, the effect of H2O2 + IR was investigated in 2D clonogenic survival and 3D spheroid growth assays. A dual hypoxia marker technique was used to capture the effect of IT H2O2 in murine xenografts. In paralleL, a phase I clinical trial of IT H2O2 + radiotherapy was conducted in 12 patients with breast cancer to evaluate safety and cute toxicity. Results: 2D clonogenic assays did not confirm sensitisation of HCT116 or HN5 under normoxic conditions. Growth inhibition was demonstrated in HCT116 spheroids treated with H2O2 + IR, compared with H2O2/IR alone. Xenograft tumours injected with H2O2 + sodium hyaluronate exhibited a reduction in hypoxia staining compared to baseline. A significant difference in pimonidazole versus CCI-103F staining was demonstrated in H2O2-injected tumours (p0=02), with no significant difference in the control groups. The phase I clinical trial confirmed safety with no additional toxicity compared to RT alone. Conclusion: 3D spheroid results are in keeping with clinical reports of enhancement of radiation effect by H2O2. Reoxygenation by IT H2O2 may be an important mechanism by which tumour response is enhanced for therapeutic gain, and which has implications for scheduling of H2O2 relative to radiotherapy in the clinical setting. If this method of increasing oxygen delivery to tumours is confirmed to be successful, it has potential to be utilised in several other tumour types.

Published
2022

48. Gene expression profiling of human dermal fibroblasts exposed to bleomycin sulphate does not differentiate between radiation sensitive and control patients

Author

Borresen-Dale Anne-Lise, Sahlberg Kristine, Westbury Charlotte B, Isacke Clare M, and Yarnold John R

Subjects
Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Gene expression profiling of the transcriptional response of human dermal fibroblasts to in vitro radiation has shown promise as a predictive test of radiosensitivity. This study tested if treatment with the radiomimetic drug bleomycin sulphate could be used to differentiate radiation sensitive patients and controls in patients who had previously received radiotherapy for early breast cancer. Findings Eight patients who developed marked late radiation change assessed by photographic breast appearance and 8 matched patients without any change were selected from women entered in a prospective randomised trial of breast radiotherapy fractionation. Gene expression profiling of primary skin fibroblasts exposed in vitro to bleomycin sulphate and mock treated fibroblast controls was performed. 973 genes were up-regulated and 923 down-reguated in bleomycin sulphate treated compared to mock treated control fibroblasts. Gene ontology analysis revealed enriched groups were cellular localisation, apoptosis, cell cycle and DNA damage response for the deregulated genes. No transcriptional differences were identified between fibroblasts from radiation sensitive cases and control patients; subgroup analysis using cases exhibiting severe radiation sensitivity or with high risk alleles present in TGF β1 also showed no difference. Conclusions The transcriptional response of human dermal fibroblasts to bleomycin sulphate has been characterised. No differences between clinically radiation sensitive and control patients were detected using this approach.

Published
2011
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49. Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage

Author

Sneade Mary, Yarnold Julia, Kerr Richard SC, Molyneux Andrew J, Lingsma Hester F, Risselada Roelof, Steyerberg Ewout W, and Sturkenboom Miriam CJM

Subjects
Medicine (General), R5-920
Abstract

Abstract Background Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. Methods We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients. Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. Results The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). Conclusion We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. Although generalizability of the model is limited due to the selected population in which it was developed, this model could eventually be used to support clinical decision making after external validation. Trial Registration International Standard Randomised Controlled Trial, Number ISRCTN49866681

Published
2010
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50. Investigating the molecular mechanisms of fraction size sensitivity in irradiated cells

Author

McBay, David and Yarnold, J.

Subjects
Radiation Oncology, Radiotherapy--Methods
Abstract

Fractionated radiotherapy is used clinically when it spares healthy tissue relative to the cancer; the healthy tissue is described as more fraction size sensitive. However, a molecular understanding of the mechanisms that determine this sensitivity are limited. The recently demonstrated response of breast and prostate cancers to hypofractionation highlights the need to understand the mechanisms of fraction size sensitivity in order to improve dose regimens. We must also develop biomarkers and drugs that leverage this sensitivity to individualise and improve radiotherapy outcomes. DNA double-strand breaks (DSB) are the most deleterious form of damage caused by irradiation due to their potential for misrepair. The cell cycle stage influences the availability of DSB repair pathways. There is a tight inverse association between fraction size sensitivity and proliferation rate. We hypothesise that the enhanced fidelity of Homologous Recombination (HR) repair in S/G2 phase decreases fraction size sensitivity through a reduction of misrepair. Using a non-cancerous repair-proficient fibroblast model, we show that fraction size sensitivity is comparable across all cell cycle phases by clonogenic survival. Chromosome aberration analyses are consistent with survival and suggest that mis-repair events in G1 and G2 phase cells are spared by fractionation. We conclude that the availability of HR in G2 does not impact fraction size sensitivity. Using y-H2AX foci as a surrogate for DSBs we show that induction and kinetics of repair do not alter between fractions, however after complete repair persistent foci are shown to increase with dose and are spared with fractionation, suggesting a role for unrepaired DSBs. The chromatin environment can impact repair pathway choice, we demonstrate through global changes to chromatin state with histone deacetylase inhibition (HDAC) and CRISPR-Cas9 guided BRG1 mutations that these changes do not impact fraction size sensitivity. Finally, a single cell sequencing approach begins to establish a mutational signature for irradiation.

Published
2020

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