Chromosomal breakage tests in the differential diagnosis of Fanconi anemia and aplastic anemia.

BACKGROUND: FA patients are hypersensitive to preconditioning of bone marrow transplantation. OBJECTIVE: Assessment of the power of mitomycin C (MMC) test to assign FA patients. METHODS: We analysed 195 patients with hematological disorders using spontaneous and two types of chromosomal breakage tests (MMC and bleomycin). In case of presumed Ataxia telangiectasia (AT), patients' blood was irradiated in vitro to determine the radiosensitivity of the patients. RESULTS: Seven patients were diagnosed as having FA. The number of spontaneous chromosomal aberrations was significantly higher in FA patients than in aplastic anemia (AA) patients including chromatid breaks, exchanges, total aberrations, aberrant cells. MMC-induced ≥10 break/cell was 83.9 ± 11.4% in FA patients and 1.94 ± 0.41% in AA patients (p < .0001). The difference in bleomycin-induced breaks/cell was also significant: 2.01 ± 0.25 (FA) versus 1.30 ± 0.10 (AA) (p = .019). Seven patients showed increased radiation sensitivity. Both dicentric + ring, and total aberrations were significantly higher at 3 and 6 Gy compared to controls. CONCLUSIONS: MMC and Bleomycin tests together proved to be more informative than MMC test alone for the diagnostic classification of AA patients, while in vitro irradiation tests could help detect radiosensitive-as such, individuals with AT.

Relationship between spontaneous frequency of aneuploidy and cancer risk in 2145 healthy Hungarian subjects.

Numerical and structural chromosomal abnormalities are the hallmarks of cancer. Whereas the structural chromosome aberrations got more substantial attention for cancer risk assessment in a healthy population, the role of aneuploidy is much less understood in this respect. We analysed the frequency of numerical (and structural) aberrations in peripheral blood lymphocytes of 2145 healthy individuals between 1989 and 2010, taking into account different biological- and exposure-conditions. We also studied to what extent chromosome gains or losses may predict the probability of cancer. The average frequency of all aneuploid cells was 1.78±0.06% in the entire study population, which increased linearly with age. Gender and smoking did not influence the values, however, occupational exposures did. The highest frequency of aneuploidy was found in chemical industry-workers (1.89±0.05%) compared with the lowest value of medical radiation workers (1.44±0.10%), respectively. No correlation was found between numerical and structural chromosomal aberrations. Cancer incidence followed for 1-23 years after the chromosome analysis showed a 1.26-fold relative risk (confidence interval: 1.02-1.58; P = 0.04) for those with higher frequency of aneuploid cells (1.82% vs. 1.44% in controls). Hypodiploidy had higher impact on the cancer risk than hyperdiploidy (1.72% vs. 0.10%). Our findings on the frequency of numerical aberrations in a healthy cohort represent the largest cytogenetic database from one laboratory with an unchanged mechanistic scoring method during a 30-year period, and provide basic information not only for genotoxicological studies but also confirm the association between numerical aberrations and cancer risk.

Computer algorithms for three-dimensional measurement of humeral anatomy: analysis of 140 paired humeri.

BACKGROUND: In the presence of severe osteoarthritis, osteonecrosis, or proximal humeral fracture, the contralateral humerus may serve as a template for the 3-dimensional (3D) preoperative planning of reconstructive surgery. The purpose of this study was to develop algorithms for performing 3D measurements of the humeral anatomy and further to assess side-to-side (bilateral) differences in humeral head retrotorsion, humeral head inclination, humeral length, and humeral head radius and height. METHODS: The 3D models of 140 paired humeri (70 cadavers) were extracted from computed tomographic data. Geometric characteristics quantifying the humeral anatomy in 3D were determined in a semiautomatic fashion using the developed computer algorithms. The results between the sides were compared for evaluating bilateral differences. RESULTS: The mean bilateral difference of the humeral retrotorsion angle was 6.7° (standard deviation [SD], 5.7°; range, -15.1° to 24.0°; P = .063); the mean side difference of the humeral head inclination angle was 2.3° (SD, 1.8°; range, -5.1° to 8.4°; P = .12). The side difference in humeral length (mean, 2.9 mm; SD, 2.5 mm; range, -8.7 mm to 10.1 mm; P = .04) was significant. The mean side difference in the head sphere radius was 0.5 mm (SD, 0.6 mm; range, -3.2 mm to 2.2 mm; P = .76), and the mean side difference in humeral head height was 0.8 mm (SD, 0.6 mm; range, -2.4 mm to 2.4 mm; P = .44). CONCLUSIONS: The contralateral anatomy may serve as a reliable reconstruction template for humeral length, humeral head radius, and humeral head height if it is analyzed with 3D algorithms. In contrast, determining humeral head retrotorsion and humeral head inclination from the contralateral anatomy may be more prone to error.

[Frequency of spontaneous aneuploidy in the healthy Hungarian population]. / A spontán aneuploidia gyakorisága egészséges magyar populációban.

Aneuploidy plays very important role in tumor development as the consequence of either congenital or acquired mutations. In order to evaluate the adverse effects of various aneugens, the knowledge of the spontaneous frequency of numerical chromosome abnormalities in healthy population is fundamental. In our study we analyzed the spontaneous rate of numerical and structural chromosome aberrations in peripheral blood lymphocytes of 2145 healthy individuals, with special attention to the influence of biological (gender, age) and life-style factors (smoking, different occupational exposure). Correlation between aneuploidy and risk of cancer development were investigated according to National Cancer Registry data followed for 1-23 years. In the whole population the average frequency of aneuploid cells was 1.77±0.06%. This value increased by age linearly (r2=0.81) regardless of occupational exposures. Gender (biological factor) or smoking (life style factor) did not influence the values, however, the occupation of individuals modified the frequency of numerical aberrations. Individuals who worked at workplaces with radiation hazard had the lowest (1.44±0.10%), and those working in the chemical industry had the highest (1.89±0.05%) values of aneuploidy, respectively. We could not find any correlation between numerical and structural chromosome aberrations. In our population studied 97 individuals developed cancer and only those who had ≤2% aneuploidy survived more than 12 years in good health conditions. To our knowledge, this study has the highest case number investigated up to now. Our results support that aneuploidy, similarly to structural chromosomal aberrations, might be an additional cytogenetic biomarker of the genetic instability.

A review of numerical and experimental compensation techniques for skull-induced phase aberrations in transcranial focused ultrasound.

The development of phased array transducers and their integration with magnetic resonance (MR) guidance and thermal monitoring has established transcranial MR-guided focused ultrasound (tcMRgFUS) as an attractive non-invasive modality for neurosurgical interventions. The presence of the skull, however, compromises the efficiency of transcranial FUS (tcFUS) therapy, as its heterogeneous nature and acoustic characteristics induce significant phase aberrations and energy attenuation, especially at the higher acoustic frequencies employed in tcFUS thermal therapy. These aberrations may distort and shift the acoustic focus as well as induce heating at the patient's scalp and skull bone. Phased array transducers feature hundreds of elements that can be driven individually, each with its own phase and amplitude. This feature allows for compensation of skull-induced aberrations by calculation and application of appropriate phase and amplitude corrections. In this paper, we illustrate the importance of precise refocusing and provide a comprehensive review of the wide variety of numerical and experimental techniques that have been used to estimate these corrections.

No short-term cytogenetic consequences of Hungarian red mud catastrophe.

Red mud is an industrial waste produced in the process of alumina extraction from bauxite with concentrated NaOH. When the red mud-containing reservoir collapsed in Ajka Alumina Plant Hungary in October 2010, the most serious immediate effects were caused by the high alkalinity (pH ≥ 13) of the flood. Many persons suffered burn-like damage to tissues and contact with caustic desiccated ultra-fine dust with traces of toxic metals also caused irritation of upper respiratory tract and eyes. This catastrophe was unique from the point of view of genotoxic effects as well. Therefore cytogenetic examinations were carried out on inhabitants, either with burns (17 persons) or on those inhaling desiccated caustic dust (42 persons). Chromosomal aberration (CA) analysis and bleomycin (BLM)-sensitivity assays, as possible markers of effects, were studied in peripheral blood lymphocytes of persons within 4-6 weeks following the catastrophe. Controls were matched for age, sex and smoking habits, and also places of residence with different constituents of air pollution either from rural (59 persons), or from urban environments (59 persons). Neither spontaneous rate of CAs (1.47% vs. 1.69%) nor BLM-induced in vitro chromosomal breakage (0.79 vs. 0.83 break/cell) showed elevated rates when cytogenetic biomarkers of genotoxicity were compared between controls and exposed persons. Time spent in cleaning did not affect cytogenetic changes either (R(2) = 0.04). BLM-induced mutagen sensitivity was similar in exposed and control persons (27.1% vs. 30.5%). It seems that the red mud exposure does not appear to pose an immediate genotoxic hazard on residents when measured with cytogenetic methods. We recommend, however, that those involved in clean-up activities should be followed closely not only for overall health, but also for further genotoxic risk assessment, because the long-term hazards of ultra-fine fugitive dust particles with alkalinity of residual NaOH in red mud are still unknown.

Hierarchical enhanced non-rigid registration for target volume correction and propagation for adaptive external beam radiotherapy of carcinoma of the prostate.

Volumes change during fractionated radiotherapy (RT). We investigate a tool based on the Hierarchical Enhanced Registration Algorithm (HERA) to project a 3D segmentation set of the prostate into the subsequent imaging sets at any time point during RT by using intensity-based image registration techniques. Sequential CT sets during RT at 15, 30, 45, and 60 Gy of two patients were used. Five expert clinicians outlined the prostate in a blinded fashion, defining intraobserver and interobserver variability on a set of 35 and 25 scans, respectively. The observer variability and positioning for manual correction was compared to both affine and elastic image registration-based contour propagation. The overall mean error of the registration-based correction of the planning target volume was comparable to the interobserver variability of manual target volume definition. The correction by affine image fusion was inferior to the results of elastic registration. The maximal deviation for the interobserver segmentation was 15.4 mm, 10.5 mm for the affine and 8.0 mm for the elastic registration. The mean interobserver variability was 1.5 (± 1.4) mm, 2.8 (± 2.3) mm for the affine, and 2.2 (± 1.9) mm for the elastic registration. Intensity-based elastic registration of deformable anatomical structures with HERA is suitable for the assessment of changes of prostate volumes for the purpose of target propagation and adaptive radiotherapy.

Neck Node Squamous Cell Metastasis from Unknown Primary and Mutagen Sensitivity: A Case Series.

Most of the neck node metastases from cancer of unknown primary (CUP) are squamous cell carcinomas (SCCs). The majority of which are human papillomavirus (HPV)-related, frequently show cystic morphology referring to Waldeyer's ring origin. Here, we report four cases of neck node SCCs metastases from CUP. In our institute, 432 patients with head and neck (HN) SCC underwent pretreatment mutagen sensitivity (MS) assay between 1996 and 2006. Among them, 4 patients ≤50 years of age had metastatic cervical nodes from CUP. The primary treatment was cervical node dissection ± radiotherapy. All patients had elevated (>1.0 chromatid break/cell) MS. One male patient died of progressive neck metastasis within 3 years and the 3 female patients are still alive more than 15 years after initial treatment of HPV+ (two) or cystic (one) SCC. Two female patients developed second and third distant site metachronous primary cancers. HPV+ or cystic HNSCC from CUP with elevated MS indicates good outcome. Distant site metachronous cancers of different histologic origins cannot be explained by field cancerization. The clinical significance of elevated MS in neck node SCC metastasis from CUP requires further investigation.

MRI driven magnetic microswimmers.

Capsule endoscopy is a promising technique for diagnosing diseases in the digestive system. Here we design and characterize a miniature swimming mechanism that uses the magnetic fields of the MRI for both propulsion and wireless powering of the capsule. Our method uses both the static and the radio frequency (RF) magnetic fields inherently available in MRI to generate a propulsive force. Our study focuses on the evaluation of the propulsive force for different swimming tails and experimental estimation of the parameters that influence its magnitude. We have found that an approximately 20 mm long, 5 mm wide swimming tail is capable of producing 0.21 mN propulsive force in water when driven by a 20 Hz signal providing 0.85 mW power and the tail located within the homogeneous field of a 3 T MRI scanner. We also analyze the parallel operation of the swimming mechanism and the scanner imaging. We characterize the size of artifacts caused by the propulsion system. We show that while the magnetic micro swimmer is propelling the capsule endoscope, the operator can locate the capsule on the image of an interventional scene without being obscured by significant artifacts. Although this swimming method does not scale down favorably, the high magnetic field of the MRI allows self propulsion speed on the order of several millimeter per second and can propel an endoscopic capsule in the stomach.

Review on 4D models for organ motion compensation.

Minimal invasive tumor therapies are getting ever more sophisticated with novel treatment approaches and new devices allowing for improved targeting precision. Applying these effectively requires precise localization of the structures of interest. Vital processes, such as respiration and heartbeat, induce organ motion, which cannot be neglected during therapy. This review focuses on 4D organ models to compensate for respiratory motion during therapy. An overview is given on the effects of motion on the therapeutical outcome, methods required to capture and quantify respiratory motion, range of reported tumor motion, types of surrogates used when tumors are not directly observable, and methods for temporal prediction of surrogate motion. Organ motion models, which predict the location of structures of interest from surrogates measured during therapy, are discussed in detail.

Spontaneous Chromosomal Aberrations in Lymphocytes and Development of Tumor in Hospital Workers.

BACKGROUND: Cytogenetic analysis of chromosomes in blood lymphocytes can be used to reveal biomarkers of tumor risk. The frequency of chromosomal aberrations (CAs) appears to correlate with the later incidence of cancer. PATIENTS AND METHODS: In our work, a total of 515 healthy Hungarian medical workers and 725 controls were enrolled in our investigation. The CAs in peripheral blood lymphocytes were analyzed. RESULTS: The frequency of CAs was significantly higher in the groups working with ionizing radiation and with cytostatic agents compared to unexposed controls and in male smokers rather than non-smokers. The frequency of dicentric chromosomes, however, was not significantly different between control and exposed groups. Among 82 cancer cases (6.6%), the most frequent types were cancer of the breast (20.5%), colon (12.8%), lung and thyroid gland (9-9%). Our analysis showed 8.1% cancer cases in smokers compared to 5.7% in non-smokers. CONCLUSION: The potential exposure to carcinogens did not modify the effect of CAs on cancer risk but tobacco smoking did increase risk.

Prostate Cancer Survivors Present Long-Term, Residual Systemic Immune Alterations.

BACKGROUND: The development of cancer and anti-tumor therapies can lead to systemic immune alterations but little is known about how long immune dysfunction persists in cancer survivors. METHODS: We followed changes in the cellular immune parameters of prostate cancer patients with good prognostic criteria treated with low dose rate brachytherapy before and up to 3 years after the initiation of therapy. RESULTS: Patients before therapy had a reduced CD4+ T cell pool and increased regulatory T cell fraction and these alterations persisted or got amplified during the 36-month follow-up. A significant decrease in the total NK cell number and a redistribution of the circulating NK cells in favor of a less functional anergic subpopulation was seen in patients before therapy but tumor regression led to the regeneration of the NK cell pool and functional integrity. The fraction of lymphoid DCs was increased in patients both before therapy and throughout the whole follow-up. Increased PDGF-AA, BB, CCL5 and CXCL5 levels were measured in patients before treatment but protein levels rapidly normalized. CONCLUSIONS: while NK cell dysfunction recovered, long-term, residual alterations persisted in the adaptive and partly in the innate immune system.

X-ray absorption-based imaging and its limitations in the differentiation of ancient mummified tissue.

OBJECTIVES: Differentiation of ancient tissues is of key importance in the study of paleopathology and in the evolution of human diseases. Currently, the number of imaging facilities for the non-destructive discrimination of dehydrated tissue is limited, and little is known about the role that emerging imaging technologies may play in this field. Therefore, this study investigated the feasibility and quality of dual-energy computed tomography (DECT) for the discrimination of dry and brittle soft tissue. Moreover, this study explored the relationship between morphological changes and image contrast in ancient tissue by using X-ray micro-tomography (micro-CT). MATERIALS AND METHODS: An Egyptian mummy head and neck was scanned with DECT at tube voltage/current of 140 kVp/27 mAs (tube A) and 100 kVp/120 mAs (tube B). The CT attenuation was determined by regions of interest (ROI) measurements of hard and soft tissue of the mummy skull. Finally, two samples from the posterior neck were dissected to acquire micro-CT images of shrunken dehydrated tissue. RESULTS: Dual-energy CT images demonstrated the high contrast resolution of surface structures from mummy skull. Bone density changes in the posterior skull base as well as soft-tissue alterations of the eyes and tongue were assessed. Micro-CT scans allowed the identification of morphological changes and the discrimination of muscle tissue from inorganic material in samples taken from the neck. CONCLUSIONS: Significant attenuation differences (p < 0.0007) were observed within 12 of the 15 ancient tissue groups and organic materials using DECT. We detected a correlation between X-ray scattering and image contrast reduction in dehydrated tissue with micro-CT imaging.

Smoking, chromosomal aberrations, and cancer incidence in healthy subjects.

Chromosomal aberrations (CAs) in peripheral blood lymphocytes can be used as biomarkers of cancer risk. Cytogenetic tests were conducted on 2396 healthy Hungarian individuals and cancer incidence was followed up from 1989 to 2018. Venous blood samples were obtained from the subjects and metaphases from lymphocyte cultures were prepared. We compared the CA frequencies of the various smoking (1-5; 6-10; 11-19; or 20-40 cigarettes/day) and exposure (irradiation; chemical industry; chemical research laboratory) groups. Chromatid break (p = 0.0002), total aberration (p = 0.002), and aberrant cell (p = 0.001) frequencies were higher in smokers than in non-smokers. For very heavy smokers, total CAs were significantly higher than for non-smokers (<0.001) or less intensive smokers (p = 0.003-0.0006). Intensity of smoking was a predictor of chromosomal aberrations, while duration was not. During follow-up, 177 (7.3 %) cancer cases were found. A Cox-regression model showed that subjects with cell values ≥2 CAs developed cancer more frequently (hazard ratio = 1.39; 95 % CI, 1.02-1.90). The relative risks of cancer were 1.06 (95 % CI 0.53-2.06) for light smokers and 1.74 (95 % CI 1.08-2.77) for very heavy smokers. The distributions of cancer sites showed differences between smoker and non-smoker groups: in male smokers, lung cancer, in non-smokers, prostate, and in females (both groups) breast cancer were most common. Cancer incidence correlated with chromosome aberrations; smoking was not a confounder in this relationship.

[And what about doctors? Associations between spontaneous chromosomal aberrations and cancer morbidity in healthcare workers]. / És mi van az orvosokkal? Egészségügyi dolgozók spontán kromoszómaaberrációi és rákmorbiditása közti kapcsolat.

Healthcare workers may be occupationally exposed to low dose rate radiation or different chemicals during their work. There are strong associations between the increased frequency of spontaneous chromosomal aberrations in blood lymphocytes and the risk of cancer. Cytogenetic tests were conducted on 1240 healthy medical workers and cancer incidence was followed up between 1997-2018. Both structural and numerical chromosome aberrations were evaluated and the results were compared taking into account gender, age, and smoking. The frequency of aberrant cells was significantly higher in smoker males than in non-smokers (p=0.009). Within the same study period, there was no significant difference in chromosome aberrations between the potentially exposed group of workers and the control group. Among 82 cancer cases (6.6%) the most common tumors were breast (16), colon (12), lung (7) and thyroid gland cancers (7). Our analysis showed 7.3% cancer occurrence among smokers compared to 6.2% among non-smokers. These results suggest that in our cases cytogenetic effects of smoking are more deleterious than occupational exposures.

[Biological dose estimation for photons of different qualities in radiation therapy]. / Biológiai dózisbecslés a sugárterápiában alkalmazott különbözo sugárminoségu fotonnyaláboknál.

Flattening filter free mode (FFF) has been introduced in radiotherapy during the past decades, however, not much has been reported on its radiobiological effect. The purpose of our study was to compare the radiobiological effects of flattening filter and flattening filter free photon beams on chromosomal aberrations in peripheral blood lymphocytes. In our study the blood of the same healthy donor was irradiated with linear accelerator using both conventional flattening filter (FF) and FFF photon beams at dose rate of 3.57-23.08 Gy/min, using 6 or 10 MV. The dose-response calibration curves for dicentric + ring chromosomes induced by irradiation were fitted with linear-quadratic model. CABAS (Chromosomal Aberration Calculation Software) was used to prepare the curves. The coefficients and equations of the curves were calculated and compared with the results of other authors. We found significant differences in the number of aberrations at different irradiation parameters. Based on our results, FFF mode has a 10-20% higher biological effect than FF mode. These results can be used during radiotherapy or to estimate the biological doses in case of an accidental exposure to radiation.

[Mutagen sensitivity and risk of second cancer in young patients with head and neck squamous cell cancer]. / Mutagénérzékenység és második primer daganat kialakulása fiatal fej-nyaki laphámrákos betegeknél.

Head and neck cancer patients are at high risk for secondary primary cancer (SPC) development. Mutagen hypersensitivity may be associated with elevated risk of SPC. A survey was made of SPC among 124 young (≤50 years) patients with squamous cell carcinoma of the head and neck who were enrolled in a pretreatment mutagen sensitivity investigation during 1996-2006. Mutagen sensitivity was assessed by exposing lymphocytes to bleomycin in vitro and quantitating the bleomycin-induced chromatid breaks per cell (b/c). Patients were classified as hypersensitive (>1 b/c) or not hypersensitive (≤1 b/c). The mean follow-up time was 64 months (range: 5-244 months). Eighteen patients (15%) developed a SPC. The 10-year estimated rate of SPC for hypersensitive (n=65) or not hypersensitive (n=59) patients were 17% and 30%, respectively (p=0.4272). Thirty-nine percent of SPC was developed after 10-year follow-up. The 5-year cancer-specific survival was 17% following the development of SPC. According to our findings, mutagen hypersensitivity does not increase the risk of developing SPC.

Relationship between biodosimetric parameters and treatment volumes in three types of prostate radiotherapy.

Brachytherapy (BT) and external beam radiotherapy (EBRT) apply different dose rates, overall treatment times, energies and fractionation. However, the overall impact of these variables on the biological dose of blood is neglected. As the size of the irradiated volume influences the biological effect as well, we studied chromosome aberrations (CAs) as biodosimetric parameters, and explored the relationship of isodose surface volumes (ISVs: V1%, V1Gy, V10%, V10Gy, V100%, V150%) and CAs of both irradiation modalities. We performed extended dicentrics assay of lymphocytes from 102 prostate radiotherapy patients three-monthly for a year. Aberration frequency was the highest after EBRT treatment. It increased after the therapy and did not decrease significantly during the first follow-up year. We showed that various types of CAs 9 months after LDR BT, 3 months after HDR BT and in a long time-range (even up to 1 year) after EBRT positively correlated with ISVs. Regression analysis confirmed these relationships in the case of HDR BT and EBRT. The observed differences in the time points and aberration types are discussed. The ISVs irradiated by EBRT showed stronger correlation and regression relationships with CAs than the ISVs of brachytherapy.

Chromosomal Aberrations in Blood Lymphocytes as Predictors of Respiratory Function After Stereotactic Lung Irradiation.

Due to the profound difference in radiosensitivity of patients and various side effects caused by this phenomenon, a radiosensitivity marker is needed. Prediction by a marker may help personalise the treatment. In this study, we tested chromosomal aberrations (CA) of in vitro irradiated blood as predictor of pulmonary function decrease of nonsmall cell lung cancer (NSCLC) patients and also compared it with the CAs in the blood of irradiated patients. Peripheral blood samples were taken from 45 lung cancer patients before stereotactic radiotherapy (SBRT) and immediately after the last fraction and 3, 6, 9, 12, 15, 18, 21, and 24 months later. Respiratory function measurements were performed at the same time. Diffusing capacity of lung for carbon monoxide (DLCO), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1s), and FEV1s/FVC (FEV1%) were monitored. Metaphase preparations of lymphocytes were made with standard procedures, and chromosome aberrations were analysed. In our cohort, the 36-month local relapse-free survival was 97.4%, and the distant metastasis-free survival was 71.5% at 36 months. There was no change in the mean of the pulmonary function tests (PFTs) after the therapy. However, there was a considerable variability between the patients. Therefore, we subtracted the baseline and normalised the PFT values. There were significant decreases at 12-24 months in relative FEV1s and relative FEV1%. The tendentious decrease of the PFTs could be predicted by the in vitro chromosome aberration data. We also found connections between the in vitro and in vivo CA values (i.e., dicentrics plus rings after 3 Gy irradiation predicts dicentric-plus-ring value directly after the radiotherapy/V54 Gy (p = 0.001 24.2%)). We found that-after further validation-chromosome aberrations resulted from in vitro irradiation before radiotherapy can be a predictive marker of pulmonary function decrease after lung irradiation.

A mean three-dimensional atlas of the human thalamus: generation from multiple histological data.

Functional neurosurgery relies on robust localization of the subcortical target structures, which cannot be visualized directly with current clinically available in-vivo imaging techniques. Therefore, one has still to rely on an indirect approach, by transferring detailed histological maps onto the patient's individual brain images. In contrast to macroscopic MRI atlases, which often represent the average of a population, each stack of sections, which a stereotactic atlas provides, is based on a single specimen. In addition to this bias, the anatomy is displayed with a highly anisotropic resolution, leading to topological ambiguities and limiting the accuracy of geometric reconstruction. In this work we construct an unbiased, high-resolution three-dimensional atlas of the thalamic structures, representing the average of several stereotactically oriented histological maps. We resolve the topological ambiguity by combining the information provided by histological data from different stereotactic directions. Since the stacks differ not only in geometrical detail provided, but also due to inter-individual variability, we adopt an iterative approach for reconstructing the mean model. Starting with a reconstruction from a single stack of sections, we iteratively register the current reference model onto the available data and reconstruct a refined mean three-dimensional model. The results show that integration of multiple stereotactic anatomical data to produce an unbiased, mean model of the thalamic nuclei and their subdivisions is feasible and that the integration reduces problems of atlas reconstruction inherent to histological stacks to a large extent.