A new approach for modeling patient overall radiosensitivity and predicting multiple toxicity endpoints for breast cancer patients.

INTRODUCTION: Evaluation of patient characteristics inducing toxicity in breast radiotherapy, using simultaneous modeling of multiple endpoints. METHODS AND MATERIALS: In 269 early-stage breast cancer patients treated with whole-breast irradiation (WBI) after breast-conserving surgery, toxicity was scored, based on five dichotomized endpoints. Five logistic regression models were fitted, one for each endpoint and the effect sizes of all variables were estimated using maximum likelihood (MLE). The MLEs are improved with James-Stein estimates (JSEs). The method combines all the MLEs, obtained for the same variable but from different endpoints. Misclassification errors were computed using MLE- and JSE-based prediction models. For associations, p-values from the sum of squares of MLEs were compared with p-values from the Standardized Total Average Toxicity (STAT) Score. RESULTS: With JSEs, 19 highest ranked variables were predictive of the five different endpoints. Important variables increasing radiation-induced toxicity were chemotherapy, age, SATB2 rs2881208 SNP and nodal irradiation. Treatment position (prone position) was most protective and ranked eighth. Overall, the misclassification errors were 45% and 34% for the MLE- and JSE-based models, respectively. p-Values from the sum of squares of MLEs and p-values from STAT score led to very similar conclusions, except for the variables nodal irradiation and treatment position, for which STAT p-values suggested an association with radiosensitivity, whereas p-values from the sum of squares indicated no association. Breast volume was ranked as the most significant variable in both strategies. DISCUSSION: The James-Stein estimator was used for selecting variables that are predictive for multiple toxicity endpoints. With this estimator, 19 variables were predictive for all toxicities of which four were significantly associated with overall radiosensitivity. JSEs led to almost 25% reduction in the misclassification error rate compared to conventional MLEs. Finally, patient characteristics that are associated with radiosensitivity were identified without explicitly quantifying radiosensitivity.

Screen-detected versus interval cancers: Effect of imaging modality and breast density in the Flemish Breast Cancer Screening Programme.

OBJECTIVES: To investigate if direct radiography (DR) performs better than screen-film mammography (SF) and computed radiography (CR) in dense breasts in a decentralized organised Breast Cancer Screening Programme. To this end, screen-detected versus interval cancers were studied in different BI-RADS density classes for these imaging modalities. METHODS: The study cohort consisted of 351,532 women who participated in the Flemish Breast Cancer Screening Programme in 2009 and 2010. Information on screen-detected and interval cancers, breast density scores of radiologist second readers, and imaging modality was obtained by linkage of the databases of the Centre of Cancer Detection and the Belgian Cancer Registry. RESULTS: Overall, 67% of occurring breast cancers are screen detected and 33% are interval cancers, with DR performing better than SF and CR. The interval cancer rate increases gradually with breast density, regardless of modality. In the high-density class, the interval cancer rate exceeds the cancer detection rate for SF and CR, but not for DR. CONCLUSIONS: DR is superior to SF and CR with respect to cancer detection rates for high-density breasts. To reduce the high interval cancer rate in dense breasts, use of an additional imaging technique in screening can be taken into consideration. KEY POINTS: • Interval cancer rate increases gradually with breast density, regardless of modality. • Cancer detection rate in high-density breasts is superior in DR. • IC rate exceeds CDR for SF and CR in high-density breasts. • DR performs better in high-density breasts for third readings and false-positives.

The role of Size-Specific Dose Estimate (SSDE) in patient-specific organ dose and cancer risk estimation in paediatric chest and abdominopelvic CT examinations.

OBJECTIVES: To develop a clinically applicable method to estimate patient-specific organ and blood doses and lifetime attributable risks (LAR) from paediatric torso CT examinations. METHODS: Individualized voxel models were created from full-body CT data of 10 paediatric patients (2-18 years). Patient-specific dose distributions of chest and abdominopelvic CT scans were simulated using Monte Carlo methods. Blood dose was calculated as a weighted sum of simulated organ doses. LAR of cancer incidence and mortality were estimated, according to BEIR-VII. A second simulation and blood dose calculation was performed using only the thoracic and abdominopelvic region of the original voxel models. For each simulation, the size-specific dose estimate (SSDE) was calculated. RESULTS: SSDE showed a significant strong linear correlation with organ dose (r > 0.8) and blood dose (r > 0.9) and LAR (r > 0.9). No significant differences were found between blood dose calculations with the full-body voxel models and the thoracic or abdominopelvic models. CONCLUSION: Even though clinical CT images mostly do not cover the whole body of the patient, they can be used as a voxel model for blood dose calculation. In addition, SSDE can estimate patient-specific organ and blood doses and LAR in paediatric torso CT examinations. KEY POINTS: • Blood dose can be simulated using the patient's clinical CT images. • SSDE estimates patient-specific organ/blood dose and LAR in paediatric CAP CT-examinations. • SSDE makes on-the-spot dose and LAR estimations possible in routine clinical practice.

Novel X-ray imaging technology enables significant patient dose reduction in interventional cardiology while maintaining diagnostic image quality.

OBJECTIVES: The purpose of this study was to quantify the reduction in patient radiation dose during coronary angiography (CA) by a new X-ray technology, and to assess its impact on diagnostic image quality. BACKGROUND: Recently, a novel X-ray imaging technology has become available for interventional cardiology, using advanced image processing and an optimized acquisition chain for radiation dose reduction. METHODS: 70 adult patients were randomly assigned to a reference X-ray system or the novel X-ray system. Patient demographics were registered and exposure parameters were recorded for each radiation event. Clinical image quality was assessed for both patient groups. RESULTS: With the same angiographic technique and a comparable patient population, the new imaging technology was associated with a 75% reduction in total kerma-area product (KAP) value (decrease from 47 Gycm2 to 12 Gycm2, P<0.001). Clinical image quality showed an equivalent detail and contrast for both imaging systems. On the other hand, the subjective appreciation of noise was more apparent in images of the new image processing system, acquired at lower doses, compared to the reference system. However, the higher noise content did not affect the overall image quality score, which was adequate for diagnosis in both systems. CONCLUSIONS: For the first time, we present a new X-ray imaging technology, combining advanced noise reduction algorithms and an optimized acquisition chain, which reduces patient radiation dose in CA drastically (75%), while maintaining diagnostic image quality. Use of this technology may further improve the radiation safety of cardiac angiography and interventions.

Analysis of metal artifact reduction tools for dental hardware in CT scans of the oral cavity: kVp, iterative reconstruction, dual-energy CT, metal artifact reduction software: does it make a difference?

INTRODUCTION: Metal artifacts may negatively affect radiologic assessment in the oral cavity. The aim of this study was to evaluate different metal artifact reduction techniques for metal artifacts induced by dental hardware in CT scans of the oral cavity. METHODS: Clinical image quality was assessed using a Thiel-embalmed cadaver. A Catphan phantom and a polymethylmethacrylate (PMMA) phantom were used to evaluate physical-technical image quality parameters such as artifact area, artifact index (AI), and contrast detail (IQFinv). Metal cylinders were inserted in each phantom to create metal artifacts. CT images of both phantoms and the Thiel-embalmed cadaver were acquired on a multislice CT scanner using 80, 100, 120, and 140 kVp; model-based iterative reconstruction (Veo); and synthesized monochromatic keV images with and without metal artifact reduction software (MARs). Four radiologists assessed the clinical image quality, using an image criteria score (ICS). RESULTS: Significant influence of increasing kVp and the use of Veo was found on clinical image quality (p = 0.007 and p = 0.014, respectively). Application of MARs resulted in a smaller artifact area (p < 0.05). However, MARs reconstructed images resulted in lower ICS. CONCLUSION: Of all investigated techniques, Veo shows to be most promising, with a significant improvement of both the clinical and physical-technical image quality without adversely affecting contrast detail. MARs reconstruction in CT images of the oral cavity to reduce dental hardware metallic artifacts is not sufficient and may even adversely influence the image quality.

Organ Doses and Radiation Risk of Computed Tomographic Coronary Angiography in a Clinical Patient Population: How Do Low-Dose Acquisition Modes Compare?

OBJECTIVE: To compare the organ doses and lifetime-attributable risk of cancer for electrocardiogram-triggered sequential and high-pitch helical scanning in a clinical patient population. METHODS: Phantom thermoluminiscence dosimeter measurements were used as a model for the organ dose assessment of 314 individual patients who underwent coronary computed tomographic angiography. Patient-specific lifetime-attributable cancer risks were calculated. RESULTS: Phantom measurements showed that heart rate had a significant influence on the delivered radiation exposure in sequential mode, and calcium scoring and contrast bolus tracking scans make a nonnegligible contribution to patients' dose. Therefore, they should be taken into account for patients' organ dose estimations. Median cancer induction risks are low, with 0.008% (0.0016%) and 0.022% (0.056%) for high-pitch and sequential scanning for men (women), respectively. CONCLUSIONS: The use of high-pitch helical scanning leads to 65% and 72% lower lifetime-attributable risk values for men and women, respectively, compared with sequential scanning.

Correlation of clinical and physical-technical image quality in chest CT: a human cadaver study applied on iterative reconstruction.

BACKGROUND: The first aim of this study was to evaluate the correlation between clinical and physical-technical image quality applied to different strengths of iterative reconstruction in chest CT images using Thiel cadaver acquisitions and Catphan images. The second aim was to determine the potential dose reduction of iterative reconstruction compared to conventional filtered back projection based on different clinical and physical-technical image quality parameters. METHODS: Clinical image quality was assessed using three Thiel embalmed human cadavers. A Catphan phantom was used to assess physical-technical image quality parameters such as noise, contrast-detail and contrast-to-noise ratio (CNR). Both Catphan and chest Thiel CT images were acquired on a multislice CT scanner at 120 kVp and 0.9 pitch. Six different refmAs settings were applied (12, 30, 60, 90, 120 and 150refmAs) and each scan was reconstructed using filtered back projection (FBP) and iterative reconstruction (SAFIRE) algorithms (1,3 and 5 strengths) using a sharp kernel, resulting in 24 image series. Four radiologists assessed the clinical image quality, using a visual grading analysis (VGA) technique based on the European Quality Criteria for Chest CT. RESULTS: Correlation coefficients between clinical and physical-technical image quality varied from 0.88 to 0.92, depending on the selected physical-technical parameter. Depending on the strength of SAFIRE, the potential dose reduction based on noise, CNR and the inverse image quality figure (IQF(inv)) varied from 14.0 to 67.8%, 16.0 to 71.5% and 22.7 to 50.6% respectively. Potential dose reduction based on clinical image quality varied from 27 to 37.4%, depending on the strength of SAFIRE. CONCLUSION: Our results demonstrate that noise assessments in a uniform phantom overestimate the potential dose reduction for the SAFIRE IR algorithm. Since the IQF(inv) based dose reduction is quite consistent with the clinical based dose reduction, an optimised contrast-detail phantom could improve the use of contrast-detail analysis for image quality assessment in chest CT imaging. In conclusion, one should be cautious to evaluate the performance of CT equipment taking into account only physical-technical parameters as noise and CNR, as this might give an incomplete representation of the actual clinical image quality performance.

Factors modifying the risk for developing acute skin toxicity after whole-breast intensity modulated radiotherapy.

BACKGROUND: After breast-conserving radiation therapy most patients experience acute skin toxicity to some degree. This may impair patients' quality of life, cause pain and discomfort. In this study, we investigated treatment and patient-related factors, including genetic polymorphisms, that can modify the risk for severe radiation-induced skin toxicity in breast cancer patients. METHODS: We studied 377 patients treated at Ghent University Hospital and at ST.-Elisabeth Clinic and Maternity in Namur, with adjuvant intensity modulated radiotherapy (IMRT) after breast-conserving surgery for breast cancer. Women were treated in a prone or supine position with normofractionated (25 × 2 Gy) or hypofractionated (15 × 2.67 Gy) IMRT alone or in combination with other adjuvant therapies. Patient- and treatment-related factors and genetic markers in regulatory regions of radioresponsive genes and in LIG3, MLH1 and XRCC3 genes were considered as variables. Acute dermatitis was scored using the CTCAEv3.0 scoring system. Desquamation was scored separately on a 3-point scale (0-none, 1-dry, 2-moist). RESULTS: Two-hundred and twenty patients (58%) developed G2+ dermatitis whereas moist desquamation occurred in 56 patients (15%). Normofractionation (both p < 0.001), high body mass index (BMI) (p = 0.003 and p < 0.001), bra cup size ≥ D (p = 0.001 and p = 0.043) and concurrent hormone therapy (p = 0.001 and p = 0.037) were significantly associated with occurrence of acute dermatitis and moist desquamation, respectively. Additional factors associated with an increased risk of acute dermatitis were the genetic variation in MLH1 rs1800734 (p=0.008), smoking during RT (p = 0.010) and supine IMRT (p = 0.004). Patients receiving trastuzumab showed decreased risk of acute dermatitis (p < 0.001). CONCLUSIONS: The normofractionation schedule, supine IMRT, concomitant hormone treatment and patient related factors (high BMI, large breast, smoking during treatment and the genetic variation in MLH1 rs1800734) were associated with increased acute skin toxicity in patients receiving radiation therapy after breast-conserving surgery. Trastuzumab seemed to be protective.

Impact of the digitalisation of mammography on performance parameters and breast dose in the Flemish Breast Cancer Screening Programme.

OBJECTIVES: To investigate the impact of digitalisation on performance parameters and breast dose of the Flemish Breast Cancer Screening Programme. Both computed (CR) and direct radiography (DR) are compared with screen-film mammography (SFM). METHODS: Data from 975,673 mammographic examinations were collected from units which underwent digitalisation from SFM to CR (41 units) or DR (72 units) in the period 2005-2011. Performance indicators were obtained by consulting the Screening Programme database. Phantom and patient dosimetry data were acquired from the physical technical quality assurance of the programme. RESULTS: Digitalisation induced no significant change in cancer detection rate (CDR), percentage of ductal carcinomas in situ and percentage of breast cancers smaller than 1 cm. A decrease in false-positive results and third readings was observed, which was a time-related observation. After digitalisation, positive predictive value (PPV) increased and recall rates decreased. Compared with SFM, an increase of 30% in mean glandular dose (MGD) was found for CR, while a similar change in the opposite direction was found for DR. CONCLUSIONS: No major differences in performance parameters after digitalisation were found. Transition of SFM to CR resulted in a higher MGD and associated lower detection-over-induction ratio (DIR), while the change to DR induced an improvement of DIR. KEY POINTS: • Performance parameters showed no major differences after digitalisation to CR or DR. • Transition from SFM to CR results in a higher mean glandular dose. • Transition from SFM to DR results in a lower mean glandular dose.

Three-dimensional rotational X-ray acquisition technique is reducing patients' cancer risk in coronary angiography.

OBJECTIVES: The purpose of this study was to assess patient-specific organ doses and cancer risk with 3D-rotational acquisitions versus the current standard of multiple single-plane coronary angiography (CA). BACKGROUND: Catheter-based CA remains one of the most commonly performed diagnostic invasive procedures delivering a relatively high radiation dose to the patient. With the introduction of flat-panel technology, three-dimensional rotational angiography became an alternative for the conventional two-dimensional angiography. However, limited information is available on the difference in patient radiation exposure with both acquisition techniques. METHODS: Eighty adult patients (45 males, age 38-93 years) were randomly assigned to the rotational or standard angiography group. Exposure parameters were registered and skin dose distribution was measured during the procedure. Patient-specific organ doses and related cancer risks were assessed with dedicated software. RESULTS: Rotational angiograms were associated with 33% lower KAP-values (decrease from 49.99 Gycm(2) to 33.37 Gycm(2), P < 0.001). A significant (P < 0.001) lower peak skin dose was measured with rotational acquisitions (80 mGy, median) versus planar imaging (172 mGy, median). Moreover, the skin dose was smoothed over the whole chest of the patient. Contrast medium consumption decreased from 104 mL to 73 mL (P < 0.001) with the use of 3D-imaging. The reduction in radiation exposure resulted in a corresponding decrease of organ doses. The latter contributed to an overall cancer risk reduction of 21% for males and 50% for females. CONCLUSIONS: The current study demonstrates that in CA radiation risk reduction is feasible by using a rotational acquisition technique.

Technical and clinical breast cancer screening performance indicators for computed radiography versus direct digital radiography.

OBJECTIVES: To compare technical and clinical screening performance parameters between computed radiography (CR) and direct digital radiography (DR) systems. METHODS: The number of women screened with CR was 73,008 and with DR 116,945. Technical and patient dose survey data of 25 CR and 37 DR systems were available. Technical performance was expressed by threshold thickness values at the mean glandular dose (MGD) level of routine practice. Clinical indicators included recall rate (RR), cancer detection rate (CDR), percentage of ductal carcinoma in situ (DCIS), percentage of cancers with T-scores smaller than 1 cm and positive predictive value (PPV). RESULTS: Contrast threshold values for the 0.1-mm gold disk were 1.44 µm (SD 0.13 µm) for CR and 1.20 µm (SD 0.13 µm for DR). MGD was 2.16 mGy (SD 0.36 mGy) and 1.35 mGy (SD 0.32 mGy) for CR and DR respectively. We obtained for CR, respectively DR, the following results: RR in the first round of 5.48 % versus 5.61 %; RR in subsequent rounds of 2.52 % versus 2.65 %; CDR of 0.52 % versus 0.53 %; DCIS of 0.08 % versus 0.11 %; a rate of cancers with T-scores smaller than 1 cm of 0.11 % versus 0.11 %; PPV of 18.45 % versus 18.64 %; none of them was significantly different. CONCLUSION: Our screening indicators are reassuring for the use of CR and DR, with CR operating at 60 % higher MGD. KEY POINTS: • Breast cancer screening can employ both computed (CR) and direct digital radiography (DR). • Screening performance parameters for CR and DR technology are not significantly different. • Screening parameters are in accordance with European Guidelines. • Radiation doses employed for CR are generally 60 % greater than for DR.

Manual versus automated γ-H2AX foci analysis across five European laboratories: can this assay be used for rapid biodosimetry in a large scale radiation accident?

The identification of severely exposed individuals and reassurance of the 'worried well' are of prime importance for initial triage following a large scale radiation accident. We aim to develop the γ-H2AX foci assay into a rapid biomarker tool for use in accidents. Here, five laboratories established a standard operating procedure and analysed 100 ex vivo γ-irradiated, 4 or 24h incubated and overnight-shipped lymphocyte samples from four donors to generate γ-H2AX reference data, using manual and/or automated foci scoring strategies. In addition to acute, homogeneous exposures to 0, 1, 2 and 4Gy, acute simulated partial body (4Gy to 50% of cells) and protracted exposures (4Gy over 24h) were analysed. Data from all laboratories could be satisfactorily fitted with linear dose response functions. Average yields observed at 4h post exposure were 2-4 times higher than at 24h and varied considerably between laboratories. Automated scoring caused larger uncertainties than manual scoring and was unable to identify partial exposures, which were detectable in manually scored samples due to their overdispersed foci distributions. Protracted exposures were detectable but doses could not be accurately estimated with the γ-H2AX assay. We conclude that the γ-H2AX assay may be useful for rapid triage following a recent acute radiation exposure. The potentially higher speed and convenience of automated relative to manual foci scoring needs to be balanced against its compromised accuracy and inability to detect partial body exposures. Regular re-calibration or inclusion of reference samples may be necessary to ensure consistent results between laboratories or over long time periods.

An optimized growth factor cocktail for ovine mesenchymal stem cells.

Growth factors that regulate proliferation, migration, and invasion of ovine mesenchymal stem cells (oMSCs) are not well defined. In this study, we have evaluated five growth factors for their ability to initiate and support in vitro proliferation, migration, and invasion of oMSCs. oMSCs were exposed to different doses and combinations of the growth factors: basic fibroblast growth factor (bFGF), transforming growth factor-ß (TGF-ß), epidermal growth factor (EGF), insulin growth factor-I (IGF-I), connective tissue growth factor, and platelet-derived growth factor-AB (PDGF-AB). Cellular proliferation, motility, and invasiveness were assayed. The most proliferative stimulating growth factors are PDGF-AB+TGF-ß and PDGF-AB+IGF-I. Combinations EGF+bFGF and EGF+bFGF+PDGF-AB demonstrated the greatest ability to stimulate migration. Moreover, the triple cocktail EGF+bFGF+TGF-ß has the most significant effect on invasion. Different growth factor cocktails are required to enhance proliferation, migration, and invasion. These results may be useful for the development of a tissue-engineered heart valve by stimulating cellular repopulation.

Correlation of contrast-detail analysis and clinical image quality assessment in chest radiography with a human cadaver study.

PURPOSE: To determine the correlation between the clinical and physical image quality of chest images by using cadavers embalmed with the Thiel technique and a contrast-detail phantom. MATERIALS AND METHODS: The use of human cadavers fulfilled the requirements of the institutional ethics committee. Clinical image quality was assessed by using three human cadavers embalmed with the Thiel technique, which results in excellent preservation of the flexibility and plasticity of organs and tissues. As a result, lungs can be inflated during image acquisition to simulate the pulmonary anatomy seen on a chest radiograph. Both contrast-detail phantom images and chest images of the Thiel-embalmed bodies were acquired with an amorphous silicon flat-panel detector. Tube voltage (70, 81, 90, 100, 113, 125 kVp), copper filtration (0.1, 0.2, 0.3 mm Cu), and exposure settings (200, 280, 400, 560, 800 speed class) were altered to simulate different quality levels. Four experienced radiologists assessed the image quality by using a visual grading analysis (VGA) technique based on European Quality Criteria for Chest Radiology. The phantom images were scored manually and automatically with use of dedicated software, both resulting in an inverse image quality figure (IQF). Spearman rank correlations between inverse IQFs and VGA scores were calculated. RESULTS: A statistically significant correlation (r = 0.80, P < .01) was observed between the VGA scores and the manually obtained inverse IQFs. Comparison of the VGA scores and the automated evaluated phantom images showed an even better correlation (r = 0.92, P < .001). CONCLUSION: The results support the value of contrast-detail phantom analysis for evaluating clinical image quality in chest radiography.

Bioactive porcine matrices in heart valve tissue engineering.

BACKGROUND AND AIM OF THE STUDY: Platelet gel (PG), a storage vehicle of growth factors, can be considered for the application of growth factors in combination with mesenchymal stem cells (MSCs) to accelerate tissue regeneration. Moreover, the addition of bioactive factors to porcine aortic valves could result in a more rapid repopulation. The study aim was to load acellular porcine aortic valve matrices with the PG-rich growth factors and to evaluate the effect on MSC repopulation. METHODS: Ovine mesenchymal stem cells (oMSCs) were isolated from sheep bone marrow. Acellular porcine heart valve matrices (n = 3) were preloaded with heparin and incubated with the PG for 2 h. A quantitative sandwich enzyme immunoassay was used to examine the release of basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-beta) from the matrices, oMSC repopulation was stimulated by static and dynamic culture. RESULTS: The immunoassays revealed that heparin-preloaded PG-incubated matrices showed a sustained release of 56.28 pg/ml bFGF and 30.66 ng/ml TGF-beta1 after 24 h. Dynamic culture induced oMSC invasion in growth factor-loaded matrices. Cell density results showed that dynamic culture significantly enhanced the repopulation of growth factor-loaded matrices (75 +/- 21 cells/mm2) when compared to static culture (26 +/- 10 cells/mm2). CONCLUSION: The incubation of a porcine aortic valve matrix with a PG concentrate creates a bioactive matrix. However, further fine-tuning of the PG concentration is necessary to take full advantage of platelet growth factor interaction between cells and the extracellular matrix in order to optimize cellular repopulation.

Decellularization of heart valve matrices: search for the ideal balance.

OBJECTIVE: Currently used decellularization procedures have negative effects on extracellular matrix (ECM) integrity. The objective of this study is to evaluate four decellularization methods and their effect on the collagen ultrastructure, mechanical behavior and antigenicity of porcine aortic valves. METHODS: Aortic valves were placed in a trypsin, osmotic, trypsin-osmotic or detergent-osmotic solution. Leaflets were processed for histology and mechanical testing. Matrices were implanted subdermally in rats to evaluate immune reaction and calcification. RESULTS: Trypsin-osmotic methodology effected near-complete decellularization. Trypsin treatment resulted in cell removal only in the spongiosa layer. Osmotic and detergent-osmotic treatments did not remove any cells from the cusps. Mechanical strength was significantly inferior in the trypsin (p50,03) and trypsin-osmotic treated group (p50,04). Trypsin and trypsin-osmotic decellularized matrices evoked a strong CD31 inflammatory cell infiltration. CONCLUSION: Enzymatic-osmotic decellularization appears to be the only effective method to remove cellular components. However, the near cell free scaffolds still evokes a strong CD31 T-cell inflammatory reaction.

Tumour characteristics of screen-detected and interval cancers in the Flemish Breast Cancer Screening Programme: A mammographic breast density study.

OBJECTIVE: The objective is to investigate tumour prognostic factors versus breast density in screen-detected cancers and interval cancers. The results may highlight the need for more personalised screening protocols based on breast density in organized screening programmes. STUDY DESIGN: A retrospective study was performed of tumour characteristics of screen-detected cancers (n=468) and interval cancers (n=515) of 983 women who participated in the Flemish Breast Cancer Screening Programme in 2009-2010. Breast density was obtained from the screening programme data. Information on nodal invasion and histological grading was taken from the Belgian Cancer Registry. Tumour size and proliferation and receptor expression status were retrieved from pathology reports. The differences in tumour characteristics between screen-detected and interval cancers as well as the variation in these variables with breast density in both groups were studied by logistic regression. RESULTS: A comparison of tumour characteristics between screen-detected cancers and interval cancers systematically showed features of more aggressive tumours in interval cancers: larger tumour size, nodal invasion, grade 3 tumours, and hormone receptor negative phenotype (p<0.05). The analysis of tumour characteristics versus breast density in screen-detected cancers showed higher numbers of aggressive grade 3 tumours in low-density breasts and of the luminal A subtype with good prognosis in high-density breasts (p<0.05). This analysis for interval cancers highlights a high proportion of the difficult-to-treat triple-negative subtype in low-density breasts compared with high-density breasts. In conclusion, the study data support arguments against changes in breast cancer screening programmes with prolongation of screening intervals in low-density breasts.

The micronucleus assay as a biological dosimeter of in vivo ionising radiation exposure.

Biological dosimetry, based on the analysis of micronuclei (MN) in the cytokinesis-block micronucleus (CBMN) assay can be used as an alternative method for scoring dicentric chromosomes in the field of radiation protection. Biological dosimetry or Biodosimetry, is mainly performed, in addition to physical dosimetry, with the aim of individual dose assessment. Many studies have shown that the number of radiation-induced MN is strongly correlated with dose and quality of radiation. The CBMN assay has become, in the last years, a thoroughly validated and standardised technique to evaluate in vivo radiation exposure of occupational, medical and accidentally exposed individuals. Compared to the gold standard, the dicentric assay, the CBMN assay has the important advantage of allowing economical, easy and quick analysis. The main disadvantage of the CBMN assay is related to the variable micronucleus (MN) background frequency, by which only in vivo exposures in excess of 0.2-0.3 Gy X-rays can be detected. In the last years, several improvements have been achieved, with the ultimate goals (i) of further increasing the sensitivity of the CBMN assay for low-dose detection by combining the assay with a fluorescence in situ hybridisation centromere staining technique, (ii) of increasing the specificity of the test for radiation by scoring nucleoplasmic bridges in binucleated cells and (iii) of making the assay optimally suitable for rapid automated analysis of a large number of samples, viz. in case of a large-scale radiation accident. The development of a combined automated MN-centromere scoring procedure remains a challenge for the future, as it will allow systematic biomonitoring of radiation workers exposed to low-dose radiation.

gamma-H2AX foci as a biomarker for patient X-ray exposure in pediatric cardiac catheterization: are we underestimating radiation risks?

BACKGROUND: A better knowledge of patient x-ray dose and the associated radiation risk in pediatric interventional cardiology is warranted in view of the extensive use of x-rays and the higher radiosensitivity of children. In the present study, gamma-H2AX foci were used as a biomarker for radiation-induced effects. Patient-specific dose was assessed and radiation risks were estimated according to the linear-no-threshold model, commonly used in radiation protection, and the gamma-H2AX foci data. METHODS AND RESULTS: In 49 pediatric patients (median age, 0.75 years) with congenital heart disease who underwent cardiac catheterization procedures, blood samples were taken before and shortly after the procedure. gamma-H2AX foci were determined in peripheral blood T lymphocytes. In each patient, a net increase in gamma-H2AX foci, representing DNA double-strand breaks induced by interventional x-rays, was observed. In addition, a patient-specific Monte Carlo simulation of the procedure was performed, resulting in individual blood, organ, and tissue doses. Plotting of gamma-H2AX foci versus blood dose indicated a low-dose hypersensitivity. Median effective doses calculated according to the International Commission on Radiological Protection 60 and 103 publications are 5.6 and 6.4 mSv, respectively. The lifetime-attributable risk of cancer mortality was calculated from the linear-no-threshold model and the gamma-H2AX foci data. This resulted in lifetime-attributable risk values of 1% and 4%, respectively, for the patient population under study. CONCLUSIONS: gamma-H2AX foci as a biomarker for DNA damage indicate that radiation risk estimates according to the linear-no-threshold hypothesis are possibly underestimates. Great care should be taken to minimize and optimize patient radiation exposure.

Polymorphisms in nonhomologous end-joining genes associated with breast cancer risk and chromosomal radiosensitivity.

As enhanced chromosomal radiosensitivity (CRS) results from non- or misrepaired double strand breaks (DSBs) and is a hallmark for breast cancer and single nucleotide polymorphisms (SNPs) in DSB repair genes, such as non homologous end-joining (NHEJ) genes, could be involved in CRS and genetic predisposition to breast cancer. In this study, we investigated the association of five SNPs in three different NHEJ genes with breast cancer in a population-based case-control setting. The total patient population composed of a selected group of patients with a family history of the disease and an unselected group, consisting mainly of sporadic cases. SNP analysis showed that the c.2099-2408G>A SNP (XRCC5Ku80) [corrected] has a significant, positive odds ratio (OR) of 2.81 (95% confidence interval (CI): 1.30-6.05) for the heterozygous (He) and homozygous variant (HV) genotypes in the selected patient group. For the c.-1310 C>G SNP (XRCC6Ku70)[corrected] a significant OR of 1.85 (95%CI: 1.01-3.41) was found for the He genotype in the unselected patient group. On the contrary, the HV genotype of c.1781G>T (XRCC6Ku70) [corrected] displays a significant, negative OR of 0.43 (95%CI: 0.18-0.99) in the total patient population. The He+HV genotypes of the c.2099-2408G>A SNP (XRCC5Ku80) [corrected] also showed high and significant ORs in the group of "radiosensitive," familial breast cancer patients. In conclusion, our results provide preliminary evidence that the variant allele of c.-1310C>G (XRCC6Ku70) [corrected]and c.2099-2408G>A (XRCC5Ku80) [corrected] are risk alleles for breast cancer as well as CRS. The HV genotype of c.1781G>T (XRCC6Ku70) [corrected] on the contrary, seems to protect against breast cancer and ionizing radiation induced micronuclei.