Sources of variation in patient response to radiation treatment

Crompton, N. E. A.; Shi, Yu; Emery, Gillian C; Wisser, Lothar; Blattmann, H.; Maier, Andreas; Li, Ling; Schindler, Dorothee; Özşahin, Hülya; Ozşahin, Mahmut

doi:10.1016/s0360-3016(00)01477-2

Cited by 53 publications

(35 citation statements)

References 37 publications

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“…2-3 months) method for use as a diagnostic assay in routine practice (23,24). Lymphocyte assays are rapid and reproducible between donors (9) and between healthy donors and cancer patients (11,31). The nonapoptotic methods require more time whereas results of micronucleus assay in peripheral blood lymphocytes are available within 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

CD4 and CD8 T-Lymphocyte Apoptosis Can Predict Radiation-Induced Late Toxicity: A Prospective Study in 399 Patients

Ozşahin

Crompton

Gourgou

et al. 2005

Clinical Cancer Research

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192

122

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Purpose: Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment. Experimental Design: In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence. Results: No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiationinducedT-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Gray's test, P < 0.0001). CD8 (area under the curve = 0.83) was more sensitive and specific than CD4. No grade 3 late toxicity was observed for patients with CD4 and CD8 values greater than 15% and 24%, respectively. The 2-year cumulative incidence for grade 2 or 3 late toxicity was 70%, 32%, and 12% for patients with absolute change in CD8 T-lymphocyte apoptosis of V16, 16 to 24, and >24, respectively.Conclusions: Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.

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Section: Discussionmentioning

confidence: 99%

CD4 and CD8 T-Lymphocyte Apoptosis Can Predict Radiation-Induced Late Toxicity: A Prospective Study in 399 Patients

Ozşahin

Crompton

Gourgou

et al. 2005

Clinical Cancer Research

Self Cite

192

122

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“…29 There are no similar studies about NBS in the literature, but a clear reduction in the levels of radiation-induced apoptosis has been observed both in AT and NBS cells. It has been demonstrated that in normal subjects, the level of induced apoptosis depends on the age of the donors 30 and that the frequency of chromosome alterations in peripheral blood lymphocytes increases with age. 27,28 A decrement with the age in the ability of programmed death for cells with chromosome abnormalities could explain both the high frequency of chromosome rearrangements present in healthy donors over 60 and the higher risk to develop a cancer with increasing age.…”

Section: Discussionmentioning

confidence: 99%

Chromosome instability and nibrin protein variants in NBS heterozygotes

et al. 2003

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The frequency of spontaneous chromosome abnormalities in peripheral blood lymphocytes and the X-ray G2 sensitivity in lymphoblastoid cell lines (LCL) have been evaluated in heterozygous subjects from three unrelated Nijmegen Breakage Syndrome (NBS) families, characterised by different mutations in the NBS1 gene. In all the 13 NBS heterozygotes analysed, we found spontaneous chromosome instability consisting in chromosome and chromatid breakages and rearrangements, while radiosensitivity was similar to that of control LCLs in seven out of eight tested NBS heterozygotes. The densitometric analysis of nibrin by immunoblotting indicated only a slight reduction in some of the LCLs from NBS carriers, whereas the immunoprecipitation assay appears a more reliable tool to detect NBS carriers. By means of immunoprecipitation, we investigated two homozygous and four heterozygous subjects. In the cells of the NBS patient 668, with the mutation 900del25, an alternative form of nibrin with a molecular weight of approximately 55 kDa has been detected. This variant protein, together with the normal p95, was also found in the LCL 34 established from a carrier of the same family. Signals of nibrin with a molecular weight lower than 95 kDa, but higher than that observed in LCLs 668 and 34, were detected also in three carriers from the family with mutation 835del4.

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“…Assays such as the leukocyte apoptosis assay or tunel assay have therefore been used to try to establish a link between apoptotic response and cancer susceptibility or radiosensitivity. A decreased apoptotic response to radiation has been observed in AT patients and in RT patients displaying toxicity in comparison with normal donors [99,100]. This correlation between apoptosis and toxicity has also been identified in gene sets [73].…”

Section: Radiosensitivitymentioning

confidence: 69%

“…The Tlymphocyte apoptosis assay used by Ozsahin et al [101] can predict Grade 2 or Grade 3 late-stage toxicity with a 70% level of accuracy. Sources of variation using the leukocyte apoptosis assay include hereditary factors, cell type and age [100]. Most importantly, for this assay from a clinical point of view, it can produce results in 48 h. Despite these promising results, no large-scale study has yet confirmed a technique capable of identifying radiosensitive patients in a clinical setting.…”

Section: Radiosensitivitymentioning

confidence: 99%

Deoxyribonucleic acid damage-associated biomarkers of ionising radiation: current status and future relevance for radiology and radiotherapy

Manning

Rothkamm²

2013

BJR

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Diagnostic and therapeutic radiation technology has developed dramatically in recent years, and its use has increased significantly, bringing clinical benefit. The use of diagnostic radiology has become widespread in modern society, particularly in paediatrics where the clinical benefit needs to be balanced with the risk of leukaemia and brain cancer increasing after exposure to low doses of radiation. With improving long-term survival rates of radiotherapy patients and the ever-increasing use of diagnostic and interventional radiology procedures, concern has risen over the long-term risks and side effects from such treatments. Biomarker development in radiology and radiotherapy has progressed significantly in recent years to investigate the effects of such use and optimise treatment. Recent biomarker development has focused on improving the limitations of established techniques by the use of automation, increasing sensitivity and developing novel biomarkers capable of quicker results. The effect of low-dose exposure (0-100 mGy) used in radiology, which is increasingly linked to cancer incidences, is being investigated, as some recent research challenges the linear-no-threshold model. Radiotherapy biomarkers are focused on identifying radiosensitive patients, determining the treatment-associated risk and allowing for a tailored and more successful treatment of cancer patients. For biomarkers in any of these areas to be successfully developed, stringent criteria must be applied in techniques and analysis of data to reduce variation among reports and allow data sets to be accurately compared. Newly developed biomarkers can then be used in combination with the established techniques to better understand and quantify the individual biological response to exposures associated with radiology tests and to personalise treatment plans for patients.

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Sources of variation in patient response to radiation treatment

Cited by 53 publications

References 37 publications

CD4 and CD8 T-Lymphocyte Apoptosis Can Predict Radiation-Induced Late Toxicity: A Prospective Study in 399 Patients

CD4 and CD8 T-Lymphocyte Apoptosis Can Predict Radiation-Induced Late Toxicity: A Prospective Study in 399 Patients

Chromosome instability and nibrin protein variants in NBS heterozygotes

Deoxyribonucleic acid damage-associated biomarkers of ionising radiation: current status and future relevance for radiology and radiotherapy

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