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.

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.

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.

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.

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.

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.

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.

Quantifying biological effects of radiation from high-energy linear accelerators on lymphocytes.

The aim of this study was to investigate the radiobiological effects of flattening filter (FF) and flattening filter-free (FFF) modes of linear electron accelerators and to understand whether there is any difference between the effects of these modes. We evaluated the number of chromosome aberrations following irradiation of lymphocytes from healthy volunteers with X-ray photons at two energy levels, 6 and 10 MV; the dose rate ranged between 5.50 and 23.08 Gy/min and absorbed doses ranged between 0.5 and 8 Gy. A 60Co curve was employed for comparison. Metaphases from the lymphocyte cultures were prepared using standard cytogenetic techniques and chromosome analysis was performed. Our results allow the performance of biodosimetry at higher energies and doses than the currently used reference dosimetry. We observed significant differences in aberration frequencies when different irradiation techniques were used. FFF mode has a higher radiobiological effect than the FF mode. Linear-quadratic dose response calibration curves were constructed and relative biological effectiveness (RBE) values were calculated. Average RBE values using 6 MV (5.50 Gy/min) as a reference radiation were 1.28 for 60Co γ irradiation, 1.11 for 6 FFF and 0.79-0.92 for 10 FFF. Since there are compelling differences between radiation modalities in cases of hypofractionation, these results may be even more important in a therapeutic situation. In case of an accidental overdose of a patient, use of the appropriate calibration curves for biodosimetry are also essential for quantifying the overdose.

Y-chromosomal connection between Hungarians and geographically distant populations of the Ural Mountain region and West Siberia.

Hungarians who live in Central Europe today are one of the westernmost Uralic speakers. Despite of the proposed Volga-Ural/West Siberian roots of the Hungarian language, the present-day Hungarian gene pool is highly similar to that of the surrounding Indo-European speaking populations. However, a limited portion of specific Y-chromosomal lineages from haplogroup N, sometimes associated with the spread of Uralic languages, link modern Hungarians with populations living close to the Ural Mountain range on the border of Europe and Asia. Here we investigate the paternal genetic connection between these spatially separated populations. We reconstruct the phylogeny of N3a4-Z1936 clade by using 33 high-coverage Y-chromosomal sequences and estimate the coalescent times of its sub-clades. We genotype close to 5000 samples from 46 Eurasian populations to show the presence of N3a4-B539 lineages among Hungarians and in the populations from Ural Mountain region, including Ob-Ugric-speakers from West Siberia who are geographically distant but linguistically closest to Hungarians. This sub-clade splits from its sister-branch N3a4-B535, frequent today among Northeast European Uralic speakers, 4000-5000 ya, which is in the time-frame of the proposed divergence of Ugric languages.

Modeling Point Spread Function in Fluorescence Microscopy With a Sparse Gaussian Mixture: Tradeoff Between Accuracy and Efficiency.

Deblurring is a fundamental inverse problem in bioimaging. It requires modeling the point spread function (PSF), which captures the optical distortions entailed by the image formation process. The PSF limits the spatial resolution attainable for a given microscope. However, recent applications require a higher resolution and have prompted the development of super-resolution techniques to achieve sub-pixel accuracy. This requirement restricts the class of suitable PSF models to analog ones. In addition, deblurring is computationally intensive, hence further requiring computationally efficient models. A custom candidate fitting both the requirements is the Gaussian model. However, this model cannot capture the rich tail structures found in both the theoretical and empirical PSFs. In this paper, we aim at improving the reconstruction accuracy beyond the Gaussian model, while preserving its computational efficiency. We introduce a new class of analog PSF models based on the Gaussian mixtures. The number of Gaussian kernels controls both the modeling accuracy and the computational efficiency of the model: the lower the number of kernels, the lower the accuracy and the higher the efficiency. To explore the accuracy-efficiency tradeoff, we propose a variational formulation of the PSF calibration problem, where a convex sparsity-inducing penalty on the number of Gaussian kernels allows trading accuracy for efficiency. We derive an efficient algorithm based on a fully split formulation of alternating split Bregman. We assess our framework on synthetic and real data, and demonstrate a better reconstruction accuracy in both geometry and photometry in point source localization-a fundamental inverse problem in fluorescence microscopy.

Progressive breast fibrosis caused by extreme radiosensitivity: Oncocytogenetic diagnosis and treatment by reconstructive flap surgery.

BACKGROUND: Fibrosis, a proliferative response of fibrocytes after tissue injury, is a common sequela of external radiotherapy and can vary greatly among patients even in the absence of DNA repair syndromes, due to their different intrinsic radiosensitivity. Fibrosis is also a serious cosmetic problem for patients, and in some cases it can also imply pain. CASE: Here, we report a case of a severe fibrosis 2 years after breast conserving surgery and postoperative 3D conformal breast irradiation. Furthermore, our patient had the suspicion of tumour recurrence. Our examinations were aimed at diagnosing recurrence or the lack of recurrence and investigating whether the symptoms occurred due to overdosing or extreme intrinsic radiosensitivity. Therefore, examining the patients' radiosensitivity, a cytogenetic test was performed, which revealed the patient's increased susceptibility to ionizing radiation, and therefore we rejected the prospect of overdosage. As a solution for the fibrosis, mastectomy was effectuated, and a latissimus dorsi musculocutaneous flap was used for reconstruction. CONCLUSIONS: We suggest a multi-disciplinary approach to manage fibrosis and propose cytogenetic markers to be used as predictors to identify patients who most likely benefit from a certain therapeutic regimen in terms of reduction of therapy-related side effects.

A Bayesian framework for the analog reconstruction of kymographs from fluorescence microscopy data.

Kymographs are widely used to represent and analyse spatio-temporal dynamics of fluorescence markers along curvilinear biological compartments. These objects have a singular geometry, thus kymograph reconstruction is inherently an analog image processing task. However, the existing approaches are essentially digital: the kymograph photometry is sampled directly from the time-lapse images. As a result, such kymographs rely on raw image data that suffer from the degradations entailed by the image formation process and the spatio-temporal resolution of the imaging setup. In this work, we address these limitations and introduce a well-grounded Bayesian framework for the analog reconstruction of kymographs. To handle the movement of the object, we introduce an intrinsic description of kymographs using differential geometry: a kymograph is a photometry defined on a parameter space that is embedded in physical space by a time-varying map that follows the object geometry. We model the kymograph photometry as a Lévy innovation process, a flexible class of non-parametric signal priors. We account for the image formation process using the virtual microscope framework. We formulate a computationally tractable representation of the associated maximum a posteriori problem and solve it using a class of efficient and modular algorithms based on the alternating split Bregman. We assess the performance of our Bayesian framework on synthetic data and apply it to reconstruct the fluorescence dynamics along microtubules in vivo in the budding yeast S. cerevisiae. We demonstrate that our framework allows revealing patterns from single time-lapse data that are invisible on standard digital kymographs.

A Novel Method for the Approximation of Humeral Head Retrotorsion Based on Three-Dimensional Registration of the Bicipital Groove.

BACKGROUND: The accurate restoration of premorbid anatomy is key for the success of reconstructive surgeries of the proximal part of the humerus. The bicipital groove has been proposed as a landmark for the prediction of humeral head retrotorsion. We hypothesized that a novel method based on bilateral registration of the bicipital groove yields an accurate approximation of the premorbid anatomy of the proximal part of the humerus. METHODS: Three-dimensional (3D) triangular surface models were created from computed tomographic data of 100 paired humeri (50 cadavers). Segments of the distal part of the humerus and the humeral shaft of prespecified lengths were defined. A surface registration algorithm was applied to superimpose the models onto the mirrored contralateral humeral model based on the defined segments. We evaluated the 3D proximal humeral contralateral registration (p-HCR) errors, defined as the difference in 3D rotation of the humeral head between the models when superimposed. For comparison, we quantified the landmark-based retrotorsion (LBR) error, defined as the intra-individual difference in retrotorsion, measured with a landmark-based 3D method. RESULTS: The mean 3D p-HCR error using the most proximal humeral shaft (bicipital groove) segment for the registration was 2.8° (standard deviation [SD], 1.5°; range, 0.6° to 7.4°). The mean LBR error of the reference method was 6.4° (SD, 5.9°; range, 0.5° to 24.0°). CONCLUSIONS: Bilateral 3D registration of the bicipital groove is a reliable method for approximating the premorbid anatomy of the proximal part of the humerus. CLINICAL RELEVANCE: The accurate approximation of the premorbid anatomy is a key for the successful restoration of the premorbid anatomy of the proximal part of the humerus.

Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy.

Sinusoidal endothelial cells and mesenchymal CXCL12-abundant reticular cells are principal bone marrow stromal components, which critically modulate haematopoiesis at various levels, including haematopoietic stem cell maintenance. These stromal subsets are thought to be scarce and function via highly specific interactions in anatomically confined niches. Yet, knowledge on their abundance, global distribution and spatial associations remains limited. Using three-dimensional quantitative microscopy we show that sinusoidal endothelial and mesenchymal reticular subsets are remarkably more abundant than estimated by conventional flow cytometry. Moreover, both cell types assemble in topologically complex networks, associate to extracellular matrix and pervade marrow tissues. Through spatial statistical methods we challenge previous models and demonstrate that even in the absence of major specific interaction forces, virtually all tissue-resident cells are invariably in physical contact with, or close proximity to, mesenchymal reticular and sinusoidal endothelial cells. We further show that basic structural features of these stromal components are preserved during ageing.

Restoration of the Patient-Specific Anatomy of the Proximal and Distal Parts of the Humerus: Statistical Shape Modeling Versus Contralateral Registration Method.

BACKGROUND: In computer-assisted reconstructive surgeries, the contralateral anatomy is established as the best available reconstruction template. However, existing intra-individual bilateral differences or a pathological, contralateral humerus may limit the applicability of the method. The aim of the study was to evaluate whether a statistical shape model (SSM) has the potential to predict accurately the pretraumatic anatomy of the humerus from the posttraumatic condition. METHODS: Three-dimensional (3D) triangular surface models were extracted from the computed tomographic data of 100 paired cadaveric humeri without a pathological condition. An SSM was constructed, encoding the characteristic shape variations among the individuals. To predict the patient-specific anatomy of the proximal (or distal) part of the humerus with the SSM, we generated segments of the humerus of predefined length excluding the part to predict. The proximal and distal humeral prediction (p-HP and d-HP) errors, defined as the deviation of the predicted (bone) model from the original (bone) model, were evaluated. For comparison with the state-of-the-art technique, i.e., the contralateral registration method, we used the same segments of the humerus to evaluate whether the SSM or the contralateral anatomy yields a more accurate reconstruction template. RESULTS: The p-HP error (mean and standard deviation, 3.8° ± 1.9°) using 85% of the distal end of the humerus to predict the proximal humeral anatomy was significantly smaller (p = 0.001) compared with the contralateral registration method. The difference between the d-HP error (mean, 5.5° ± 2.9°), using 85% of the proximal part of the humerus to predict the distal humeral anatomy, and the contralateral registration method was not significant (p = 0.61). The restoration of the humeral length was not significantly different between the SSM and the contralateral registration method. CONCLUSIONS: SSMs accurately predict the patient-specific anatomy of the proximal and distal aspects of the humerus. The prediction errors of the SSM depend on the size of the healthy part of the humerus. CLINICAL RELEVANCE: The prediction of the patient-specific anatomy of the humerus is of fundamental importance for computer-assisted reconstructive surgeries.

A scale-space curvature matching algorithm for the reconstruction of complex proximal humeral fractures.

The optimal surgical treatment of complex fractures of the proximal humerus is controversial. It is proven that best results are obtained if an anatomical reduction of the fragments is achieved and, therefore, computer-assisted methods have been proposed for the reconstruction of the fractures. However, complex fractures of the proximal humerus are commonly accompanied with a relevant displacement of the fragments and, therefore, algorithms relying on the initial position of the fragments might fail. The state-of-the-art algorithm for complex fractures of the proximal humerus requires the acquisition of a CT scan of the (healthy) contralateral anatomy as a reconstruction template to address the displacement of the fragments. Pose-invariant fracture line based reconstruction algorithms have been applied successful for reassembling broken vessels in archaeology. Nevertheless, the extraction of the fracture lines and the necessary computation of their curvature are susceptible to noise and make the application of previous approaches difficult or even impossible for bone fractures close to the joints, where the cortical layer is thin. We present a novel scale-space representation of the curvature, permitting to calculate the correct alignment between bone fragments solely based on corresponding regions of the fracture lines. The fractures of the proximal humerus are automatically reconstructed based on iterative pairwise reduction of the fragments. The validation of the presented method was performed on twelve clinical cases, surgically treated after complex proximal humeral fracture, and by cadaver experiments. The accuracy of our approach was compared to the state-of-the-art algorithm for complex fractures of the proximal humerus. All reconstructions of the clinical cases resulted in an accurate approximation of the pre-traumatic anatomy. The accuracy of the reconstructed cadaver cases outperformed the current state-of-the-art algorithm.

A Novel Registration-Based Approach for 3D Assessment of Posttraumatic Distal Humeral Deformities.

BACKGROUND: With current 3-dimensional (3D) computer-based methods for the assessment of deformities, a surface registration method is applied to superimpose a computer model of the pathological bone onto a mirrored computer model of the contralateral side. However, because of bilateral differences, especially in humeral torsion, such template-based approaches may introduce bias in the assessment of a distal humeral deformity. We hypothesized that a novel registration approach might prove superior to the current approach in reducing such bias, thus yielding improved accuracy of 3D assessment of distal humeral deformities. METHODS: Three-dimensional triangular surface models were generated from computed tomographic (CT) data of 100 paired humeri without a pathological condition. Humeral segments of varying, predetermined lengths, excluding the distal part of the humerus, were defined. A surface registration algorithm was applied to superimpose the humeral models of both sides based on each selected segment. Humeral contralateral registration (HCR) errors, defined as the residual differences in apparent 3D orientation between the distal parts, were evaluated. RESULTS: The mean HCR error (and standard deviation) using the distal-most humeral shaft segment to assess the angular orientation was 2.3° ± 1.1 (range, 0.5° to 5.8°). Including the humeral head in the surface registration algorithm, however, as is done currently, resulted in a higher HCR error (p < 0.001). The HCR error using the proximal-most segment was >10° in 20% of the cases and between 5° and 10° in an additional 50% of the cases. By comparison, using the proposed distal-most humeral shaft segment, the HCR error was between 5° and 10° in only 2% of cases, and was never >10°. The proximal segments are nevertheless used in the proposed method for registering humeral length. CONCLUSIONS: The proposed new approach yields a deformity assessment that is less prone to bias arising from inherent bilateral differences and therefore is more accurate than current surface registration approaches. CLINICAL RELEVANCE: Accurate 3D assessment is of fundamental importance if computer-based methods are applied in the correction of posttraumatic deformities.