Publications by authors named "Jozef Zustin"

111 Publications

Compound heterozygous frameshift mutations in MESD cause a lethal syndrome suggestive of osteogenesis imperfecta type XX.

J Bone Miner Res 2021 Feb 17. Epub 2021 Feb 17.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, 22529, Germany.

Multiple genes are known to be associated with osteogenesis imperfecta (OI), a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures. Recently, mutations affecting MESD, which encodes for a chaperone required for trafficking of the low-density lipoprotein receptors LRP5 and LRP6 in the endoplasmic reticulum, were described to cause autosomal-recessive OI XX in homozygous children. In the present study, whole-exome sequencing of three stillbirths in one family was performed to evaluate the presence of a hereditary disorder. To further characterize the skeletal phenotype, fetal autopsy, bone histology, and quantitative backscattered electron imaging (qBEI) were performed, and the results were compared to those from an age-matched control with regular skeletal phenotype. In each of the affected individuals, compound heterozygous mutations in MESD exon 2 and exon 3 were detected. Based on the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals. Histological evaluation of MESD specimens revealed an impaired osseous development with an altered osteocyte morphology and reduced canalicular connectivity. Moreover, analysis of bone mineral density distribution by qBEI indicated an impaired and more heterogeneous matrix mineralization in individuals with MESD mutations than in controls. In contrast to the previously reported phenotypes of individuals with OI XX, the more severe phenotype in the present study is likely explained by a mutation in exon 2, located within the chaperone domain of MESD, that leads to a complete loss of function, which indicates the relevance of MESD in early skeletal development. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jbmr.4277DOI Listing
February 2021

Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone.

Nat Commun 2020 10 27;11(1):5414. Epub 2020 Oct 27.

Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.
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http://dx.doi.org/10.1038/s41467-020-18955-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591516PMC
October 2020

Case Report: Molecular Identification of Larval Infection in the Pouch of Douglas.

Am J Trop Med Hyg 2020 12 17;103(6):2315-2317. Epub 2020 Sep 17.

National Reference Center for Tropical Pathogens, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

is a tapeworm dwelling in the intestine of mustelids and a rare zoonotic cysticercosis pathogen in its larval stage. The metacestode is morphologically very similar to more prevalent cysticercosis parasites, such as the larvae of and , and may be indistinguishable from other metacestodes on histological sections. However, the epidemiology of human . infections is different, and for prognosis, prevention, and detection of natural parasite reservoirs, the species should be identified. We here report the molecular identification of a larva located in the pouch of Douglas in a female German patient who underwent surgery for endometriosis. This case represents the fifth human infection described worldwide; all previous cases were also in European women, involving the eye, brain, and the peritoneum.
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http://dx.doi.org/10.4269/ajtmh.20-0782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695056PMC
December 2020

Lingual Mandibular Bone Depression.

In Vivo 2020 Sep-Oct;34(5):2527-2541

Department of Oral and Craniomaxillofacial Surgery, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany.

Background/aim: In the area of the jaw angle, osteolytic lesions can occur, the differential diagnosis of which can be difficult and require very different therapeutic measures. One of these lesions is lingual mandibular bone depression (LMBD). The aim of this study was to present the characteristics of the lesion in a group of LMBD patients and to differentiate it from other lesions.

Patients And Methods: Radiological images of 21 patients with LMBD were examined.

Results: The majority of LMBDs were located in the jaw angle. On cross-sectional images, the lesion could be distinguished from salivary tissue (n=2). One case of LMBD had an impact on the course of the fracture line in the mandibular trauma.

Conclusion: LMBD is a developmental disorder of the mandible and only rarely of pathological importance. Imaging the lesion with cross-sectional images is preferable to using plain X-ray projections. In some cases, surgical exploration is essential for diagnosis.
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http://dx.doi.org/10.21873/invivo.12070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652515PMC
April 2020

Ablation Precision and Thermal Effects of a Picosecond Infrared Laser (PIRL) on Roots of Human Teeth: A Pilot Study .

In Vivo 2020 Sep-Oct;34(5):2325-2336

Atomically Resolved Dynamics Division, Max Planck Research Department for Structural Dynamics, University of Hamburg, Hamburg, Germany.

Background/aim: Picosecond infrared laser (PIRL) was investigated regarding its possible therapeutic application in cutting dental roots.

Materials And Methods: Extracted human teeth were processed in the root area by laser ablations followed by histological evaluation. Dentin adjacent to the cutting surface was evaluated morphometrically.

Results: PIRL produced clearly defined cutting boundaries in dental roots. At the bottom of the cavity, the ablation surface became slightly concave. Heat development in this scantly hydrated tissue was considerable. We attributed the excess heating effects to heat accumulation due to multiple pulse overlap across a limited scan range imposed by tooth geometries.

Conclusion: Defined areas of the tooth root may be treated using the PIRL. For clinical translation, it would be necessary to improve beam delivery to facilitate beam steering for the intended oral application (e.g. by using a fiber) and identify optimal repetition rates/scan speeds combined with cooling techniques to minimize accumulated heat within ablation cavities.
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http://dx.doi.org/10.21873/invivo.12045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652512PMC
May 2020

Can necrotic bone be objectively identified in chronic fracture related infections? - First clinical experience with an intraoperative fluorescence imaging technique.

Injury 2020 Nov 1;51(11):2541-2545. Epub 2020 Aug 1.

University Medical Centre Regensburg, Department for Trauma Surgery, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.

Introduction: Adequate debridement of necrotic bone is of paramount importance for eradication of infection in chronic osteomyelitis. Currently, no tools are available to detect the exact amount of necrotic bone in order to optimize surgical resection. The aim of the present study was to evaluate the feasibility of an intraoperative illumination method (VELscope®) and the correlation between intraoperative and pathohistological findings in surgically treated chronic fracture related infection patients.

Methods: Ten consecutive patients with chronic fracture related infections of the lower extremity were included into this prospectively performed case series. All patients had to be treated surgically for fracture related infections requiring bony debridement. An intraoperative illumination method (VELscope®) was used to intraoperatively differentiate between viable and necrotic bone. Tissue samples from the identified viable and necrotic bone areas were histopathologically examined and compared to intraoperative findings.

Results: In all included patients, the intraoperative illumination was deemed helpful to differentiate between necrotic and viable bone tissues during bony debridement. The histopathological examination of the samples showed good correlation of the intraoperative illumination findings with histopathological signs of necrosis for areas deemed dead and histopathological signs of intact bone for areas deemed vital during illumination.

Conclusion: The fluorescence-assisted, intraoperative detection of necrotic and viable bone using the VELscope® is an easy-to-use procedure that can help surgeons to optimize intraoperative bone resection in chronic fracture related infections by unmasking viable from necrotic bone tissue. This may help to improve resection techniques and eventually treatment outcome in patients in the future.
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http://dx.doi.org/10.1016/j.injury.2020.07.062DOI Listing
November 2020

Radiological and Histopathological Features of Internal Tooth Resorption.

In Vivo 2020 Jul-Aug;34(4):1875-1882

Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Internal root resorption is an endodontic disease characterized by progressive resorption of dentin from the inside of the pulp chamber. It is a comparatively rare finding in the permanent dentition, and the underlying pathology is not fully understood.

Case Report: A 45-year-old patient was referred to our Department for the evaluation of the lower right canine and the upper left wisdom tooth. Pulp sensitivity tests, cone-beam tomography, and magnetic resonance imaging were used to determine the extent of lesions of the affected teeth. The teeth were subsequently extracted due the extent of the lesions. The same was the case for the upper right canine, which developed a severe internal resorption 10 months later. Micro-computed tomography of the extracted teeth revealed that all lesions had a well-defined border with no evidence of sclerosis or hypomineralization. Pulp stones were evident inside the pulp chamber. Ground sectioning of the upper right canine revealed pulp necrosis and an acute infection that had gradually moved in the apical direction. Large multi-nucleated resorbing cells were found on the dentin surface. Importantly, the apical half of the pulp exhibited comparatively normal tissue without substantial inflammatory changes. Decalcified histology of the upper left wisdom tooth demonstrated a completely different histopathological appearance characterized by chronically inflamed granulation tissue with pseudoepitheliomatous hyperplasia and massive bacterial colonization.

Conclusion: Our analyses demonstrate that internal root resorption is a multifaceted dental disease with considerable variability in the rate of the underlying inflammatory changes. Oral surgeons should take this into consideration when evaluating the need for extraction of teeth with internal root resorption.
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http://dx.doi.org/10.21873/invivo.11983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439852PMC
March 2020

Intraossäres Hibernom der Lendenwirbelsäule.

Rofo 2021 Jan 9;193(1):80-82. Epub 2020 Jun 9.

Pathologisch-Anatomisches Institut, Pathologisch-Anatomisches Institut Regensburg, Germany.

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http://dx.doi.org/10.1055/a-1172-6628DOI Listing
January 2021

Osteoidosis leads to altered differentiation and function of osteoclasts.

J Cell Mol Med 2020 05 13;24(10):5665-5674. Epub 2020 Apr 13.

Experimental Plastic Surgery, Clinic for Plastic and Hand Surgery, Technische Universität München, Munich, Germany.

In patients with osteomalacia, a defect in bone mineralization leads to changed characteristics of the bone surface. Considering that the properties of the surrounding matrix influence function and differentiation of cells, we aimed to investigate the effect of osteoidosis on differentiation and function of osteoclasts. Based on osteomalacic bone biopsies, a model for osteoidosis in vitro (OIV) was established. Peripheral blood mononuclear cells were differentiated to osteoclasts on mineralized surfaces (MS) as internal control and on OIV. We observed a significantly reduced number of osteoclasts and surface resorption on OIV. Atomic force microscopy revealed a significant effect of the altered degree of mineralization on surface mechanics and an unmasking of collagen fibres on the surface. Indeed, coating of MS with RGD peptides mimicked the resorption phenotype observed in OIV, suggesting that the altered differentiation of osteoclasts on OIV might be associated with an interaction of the cells with amino acid sequences of unmasked extracellular matrix proteins containing RGD sequences. Transcriptome analysis uncovered a strong significant up-regulation of transmembrane glycoprotein TROP2 in osteoclastic cultures on OIV. TROP2 expression on OIV was also confirmed on the protein level and found on the bone surface of patients with osteomalacia. Taken together, our results show a direct influence of the mineralization state of the extracellular matrix surface on differentiation and function of osteoclasts on this surface which may be important for the pathophysiology of osteomalacia and other bone disorders with changed ratio of osteoid to bone.
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http://dx.doi.org/10.1111/jcmm.15227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214153PMC
May 2020

Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation.

J Bone Miner Res 2020 07 19;35(7):1322-1332. Epub 2020 Mar 19.

Institut für Medizinische Genetik und Humangenetik, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34-year-old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast-rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio-based exome sequencing. The novel homozygous splice-site mutation c.261G>A in the gene LRRK1 was found and co-segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L-plastin at position Ser5 was strongly reduced in patient-derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1-related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3995DOI Listing
July 2020

Histological, epidemiological and anatomical analysis of 193 bone tumours of the scapula.

J Bone Oncol 2019 Oct 22;18:100258. Epub 2019 Aug 22.

Department of Pediatric Orthopaedic Surgery, Children's Hospital Hamburg-Altona, Bleickenallee 37, 22763 Hamburg, Germany.

Backround: This study aimed to determine the frequency and distribution of bone tumours of the scapula as well as the histological and anatomical characteristics of these rare lesions in a large case series.

Methods: The records of all lesions of the scapula collected from 1975 to 2018 in our bone tumour registry and institute of pathology were evaluated. During these 43 years, 223 cases were identified. Analysis included assessment of age, gender, side, imaging findings, tumour location, and histological evaluation with the assignment of each lesion to one of the bone tumours according to the World Health Organization (WHO) classification of bone tumours.

Results: Bone tumours of the scapula were found in 193 cases. Mean patient age was 38.4 years (2.6-82.4). Most of the lesions were of cartilage origin (47%). 59 bone tumours were benign (30.6%), 29 were intermediate (15.0%), and 105 were malignant (54.4%). The most commonly found bone tumour was Osteochondroma (23.3%), followed by Chondrosarcoma (17.6%), Bone metastases (16.6%), Ewing sarcoma (8.8%), and Osteosarcoma (7.8%). The percentage of malignant bone tumours increased with increasing age. In patients >50 years of age, 91% had a malignant lesion of the scapula.

Conclusions: Evaluation of 193 bone tumours of the scapula revealed a high incidence of malignancy in this series, while increased patient age was identified as a potential risk factor for the development of a malignant lesion of the scapula. These findings highlight the importance of early diagnosis and treatment of suspicious lesions of the scapula to improve patient outcome.
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http://dx.doi.org/10.1016/j.jbo.2019.100258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722280PMC
October 2019

Intra-articular osteoid osteoma accompanied by extensive bone marrow edema. A clinical and micro-morphological analysis.

J Bone Oncol 2019 Oct 20;18:100256. Epub 2019 Aug 20.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Osteoid osteoma (OO) is a benign bone tumor producing non-mineralized bone matrix (i.e., osteoid). While peritumoral edema is commonly found in OO, extensive bone marrow edema has been reported less frequently. Furthermore, the micro-morphological characteristics of the nidus and its central calcification remain unclear. In this study, a consecutive series of four patients suffering from extensive bone marrow edema triggered by intra-articular osteoid osteoma underwent clinical examination, magnetic resonance imaging (MRI) and computed tomography (CT) as well as dual-energy X-ray absorptiometry (DXA) and laboratory bone turnover analyses. The obtained resection specimens were processed by undecalcified histology and were subsequently analyzed by light microscopy and quantitative backscattered electron imaging (qBEI). We report an entity of intra-articular osteoid osteoma in the knee and foot, in which an extensive and persistent bone marrow edema syndrome masked the correct diagnosis. While metabolic bone diseases were excluded in all cases, the reassessment of the patients' clinical history including pain characteristics (nocturnal, aspirin sensitivity) led us to perform additional CT, where the tumor was diagnosed. The micro-morphological analysis of the OO biopsies revealed that the nidus was surrounded by hyperosteoidosis, while central mineralization was detected in all cases. This mineralized area showed a significantly higher mineralization heterogeneity than the surrounding trabecular bone and more disorganized collagen fibers detected by qBEI and polarized light microscopy, respectively. Taken together, our results indicate that osteoid osteoma should be considered when persistent and extensive, peri-articular bone marrow edema is diagnosed. The central calcification that is found inside the nidus in conventional imaging was mirrored by bone matrix with a heterogeneous mineralization pattern.
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http://dx.doi.org/10.1016/j.jbo.2019.100256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722254PMC
October 2019

Primary intraosseous meningioma: clinical, histological, and differential diagnostic aspects.

J Neurosurg 2019 Jun 21:1-10. Epub 2019 Jun 21.

5Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: Primary intraosseous meningioma (PIM) is a rare manifestation of meningioma, a benign, neoplastic lesion of the meninges. Its characteristic appearance is hyperostosis, while no or only minimal dural changes can be observed. This study aims to characterize this rare entity from both a clinical and histopathological point of view in order to improve clinical management.

Methods: In the years 2009-2017, 26 cases of PIM were diagnosed using MRI and CT scans. In 16 cases the indication for resection was given, and specimens were further examined using a multilevel approach, including histological and immunohistochemical analyses. Additionally, the local database was searched for all cases of meningiomas, as well as osteosclerotic differential diagnoses-i.e., fibrous dysplasia, Paget's disease of bone, and other benign osteosclerotic lesions.

Results: In this study, PIM represented 2.4% of all meningiomas with a predominant occurrence in females (85%). Regarding the initial manifestation, PIMs show a slightly earlier onset than meningiomas. While most PIMs are located in the sphenoid bone, associated calcifications were visible in 58% of the cases on CT scans. Most of the cases were classified as WHO grade I (93%) and meningotheliomatous meningiomas (91%). Tumor growth was associated with an increased bone resorption followed by massive osteoid deposition and consecutive sclerosis. The frequently observed frayed appearance results from multiple bony canals, which contain blood vessels for the blood supply of the highly vascularized tumor tissue.

Conclusions: PIM is a rare but important differential diagnosis for osteosclerotic lesions of the skull, especially in women. Tumor-induced, cellular-mediated bone resorption and formation may play a central role in the underlying pathogenesis.
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http://dx.doi.org/10.3171/2019.3.JNS182968DOI Listing
June 2019

Management of bone disease in cystinosis: Statement from an international conference.

J Inherit Metab Dis 2019 09 5;42(5):1019-1029. Epub 2019 Aug 5.

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.

Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016.
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http://dx.doi.org/10.1002/jimd.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379238PMC
September 2019

Bone tumours of the clavicle: Histopathological, anatomical and epidemiological analysis of 113 cases.

J Bone Oncol 2019 Jun 6;16:100229. Epub 2019 Mar 6.

Department of Pediatric Orthopaedic Surgery, Children's Hospital Hamburg-Altona, Hamburg, Germany.

Backround: This retrospective study aimed to determine the frequency of bone tumours of the clavicle and their histopathological, anatomical and epidemiological characteristics in a large case series.

Methods: The records of 327 lesions of the clavicle collected from 1976 to 2018 in our bone tumour registry and institute of pathology were reviewed. Following data were evaluated: age, gender, side, radiological assessment, tumour location within the clavicle, and histopathological findings.

Results: Bone tumours were detected in 113 patients with a mean age of 40 years. The lateral third of the clavicle was most frequently involved. Analysis revealed 22 benign, 31 intermediate, and 60 malignant tumours. Eosinophilic granuloma was the most commonly found neoplasm (18.6%), followed by bone metastases (15.0%), Plasma cell myeloma (8.8%), Ewing sarcoma (8.8%), and Osteosarcoma (8.0%). 53% of the tumours were malignant. Mean age was 51 years in the malignant tumour group and 28 years in patients with a benign/intermediate lesion ( < 0.001).

Conclusions: The high incidence of malignant bone tumours of the clavicle found in this study highlight the importance of biopsy to prevent delay in diagnosis and treatment of these lesions, especially in patients with increased age. We believe that the results of this study are of clinical importance and may aid the physician in the management of these rare lesions.
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http://dx.doi.org/10.1016/j.jbo.2019.100229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439286PMC
June 2019

Developmental Transformation and Reduction of Connective Cavities within the Subchondral Bone.

Int J Mol Sci 2019 Feb 12;20(3). Epub 2019 Feb 12.

Clinic for Trauma Surgery, Orthopaedic Surgery and Plastic Surgery, Universitätsmedizin Göttingen, 37075 Göttingen, Germany.

It is widely accepted that the subchondral bone (SCB) plays a crucial role in the physiopathology of osteoarthritis (OA), although its contribution is still debated. Much of the pre-clinical research on the role of SCB is concentrated on comparative evaluations of healthy vs. early OA or early OA vs. advanced OA cases, while neglecting how pure maturation could change the SCB's microstructure. To assess the transformations of the healthy SCB from young age to early adulthood, we examined the microstructure and material composition of the medial condyle of the femur in calves (three months) and cattle (18 months) for the calcified cartilage (CC) and the subchondral bone plate (SCBP). The entire subchondral zone (SCZ) was significantly thicker in cattle compared to calves, although the proportion of the CC and SCBP thicknesses were relatively constant. The trabecular number (Tb.N.) and the connectivity density (Conn.D) were significantly higher in the deeper region of the SCZ, while the bone volume fraction (BV/TV), and the degree of anisotropy (DA) were more affected by age rather than the region. The mineralization increased within the first 250 µm of the SCZ irrespective of sample type, and became stable thereafter. Cattle exhibited higher mineralization than calves at all depths, with a mean Ca/P ratio of 1.59 and 1.64 for calves and cattle, respectively. Collectively, these results indicate that the SCZ is highly dynamic at early age, and CC is the most dynamic layer of the SCZ.
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http://dx.doi.org/10.3390/ijms20030770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387253PMC
February 2019

Osteoid Osteoma of the Mandible - Clinical and Histological Findings.

Anticancer Res 2019 Jan;39(1):291-296

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background/aim: Osteoid osteoma (OO) is a benign tumor characterized by the excessive formation of unmineralized bone matrix. It is mostly located in the long bones of the lower extremities or the spine, but can also occur in atypical locations.

Patients And Methods: Here we report on a rare case of OO in the mandible in an 18-year-old male patient with a simultaneous finding of a pilomatrixoma in the parietal region. Initially, a biopsy had been taken due to an unclear tumor mass and non-specific pain adjacent to tooth 46.

Results: The detailed radiographic and histopathological analysis revealed the diagnosis of OO in terms of a characteristic radiolucent nidus and structurally disorganized woven bone with osteoid, respectively. The tumor was subsequently completely resected resulting in a complete recovery of symptoms.

Conclusion: As we demonstrate an infrequent finding of OO in the mandible, it is important to diagnose and treat this condition appropriately.
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http://dx.doi.org/10.21873/anticanres.13110DOI Listing
January 2019

Transcriptome and protein interaction profiling in cancer cells with mutations in histone H3.3.

Sci Data 2018 12 11;5:180283. Epub 2018 Dec 11.

Graduate School of Cancer Science and Policy, Cancer Biomedical Science, National Cancer Center, Gyeonggi-do, Republic of Korea.

Mutations of histone variant H3.3 are highly recurrent in childhood glioblastoma and in young adults with Giant Cell Tumor of the Bone (GCTB). The heterozygotic representation of the mutations in the tumors, and with potential histone H3 and H3.3 redundancy, suggest that the mutations are gain-of-function by nature. To address common H3.3 point mutations, we have generated data from GCTB patient samples with H3.3 G34W substitutions and engineered human GFP-tagged H3.3-mutated isogenic cell lines for high throughput data comparisons. First, a total of thirty-six patient samples and cell lines were used to acquire gene expression transcriptome data using microarray and RNA-sequencing. The expression data were validated with the orthogonal nCounter assay. Second, to uncover the H3.3-GFP interaction proteomes from the isogenic cell lines, immunoprecipitation of unmutated wild type, K27M, G34R, and G34W substitutions were performed. The RNA-sequencing data and the H3.3 interaction proteome enable potentially important functional insight into the tumorigenic process and should spur further detailed analysis.
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http://dx.doi.org/10.1038/sdata.2018.283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289111PMC
December 2018

Periosteal chondroma of the cuboid with secondary aneurysmal bone cyst in a setting of secondary hyperparathyroidism.

Foot Ankle Surg 2018 Feb 22;24(1):71-75. Epub 2017 Sep 22.

Department of Foot and Hand Surgery, Agaplesion Diakonieklinikum Hamburg, Hohe Weide 17, 20259 Hamburg, Germany.

We report the case of a 35-year-old woman with painful, nontender mass at the right lateral hindfoot. Computed tomography (CT) and magnetic resonance imaging (MRI) indicated the suspect of a chondroid tumour in the cuboid. The tumour was resected en bloc and histology revealed the presence of a periosteal (juxtacortical) chondroma with secondary aneurysmal bone cyst. Secondary hyperparathyroidism was detected in laboratory tests and put into context with the histopathologic findings. In conclusion, a rare case of periosteal chondroma of the cuboid with secondary aneurysmal bone cyst in a setting of secondary hyperparathyroidism due to vitamin D deficiency is presented.

Level Of Clinical Evidence: 4.
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http://dx.doi.org/10.1016/j.fas.2017.09.003DOI Listing
February 2018

Skeletal dissemination in Paget's disease of the spine.

Eur Spine J 2018 07 17;27(Suppl 3):453-457. Epub 2018 Jan 17.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestr. 59, 22529, Hamburg, Germany.

Purpose: Paget's disease of bone (PDB) is a common skeletal disorder that is associated with locally increased bone turnover, skeletal deformity and pain. We report a case of skeletal dissemination in PDB of the spine.

Methods: Case report.

Results: A 46-year-old former professional athlete suffered from disseminated PDB throughout the spine and hips after various surgical interventions including spondylodesis, bone grafting and bone morphogenetic protein (rhBMP-2) administration. Only intravenous zoledronic acid prevented the further progression of skeletal dissemination, which was expressed by a normalization of (bone-specific) alkaline phosphatase levels. The biopsy obtained from the lumbar spine confirmed the diagnosis of PDB in the absence of malignant transformation.

Conclusions: We outline skeletal dissemination as a possibly surgery-related complication in a patient with PDB in the lumbar spine. Bisphosphonates remain the treatment of first choice in PDB and surgical interventions should be considered very carefully.
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http://dx.doi.org/10.1007/s00586-018-5477-4DOI Listing
July 2018

Intra-articular osteoid osteoma as a differential diagnosis of diffuse mono-articular joint pain.

BMC Musculoskelet Disord 2016 11 4;17(1):455. Epub 2016 Nov 4.

Department of Osteology and Biomechanics, University Medical Centre Hamburg-Eppendorf, Lottestr. 59, Hamburg, 22529, Germany.

Background: The aim of this retrospective study was to investigate the frequency of intra-articular osteoid osteoma (iaOO) in a large study cohort and to demonstrate its clinical relevance as an important differential diagnosis of non-specific mono-articular joint pain.

Methods: We searched the registry for bone tumours of the University Medical Centre Hamburg-Eppendorf for osteoid osteomas in the last 42 years. Herein, we present three selected iaOO which were detected in the three major weight-bearing joints. Computed tomography (CT) or magnetic resonance imaging (MRI) scans were performed for initial diagnosis.

Results: Out of a total of 367 osteoid osteomas, 19 (5.2 %) tumours were localized intra-articularly. In all three presented tumours, a history of severe mono-articular pain was reported; however, the mean time to correct diagnosis was delayed to 20.7 months. Clearly, the nidus seen in CT and MRI images in combination with inconsistent salicylate-responsive nocturnal pain led to the diagnosis of iaOO.

Conclusions: Rarely, osteoid osteoma can occur in an intra-articular location. In cases of diffuse mono-articular pain, iaOO should be considered both in large and smaller joints to avoid delays in diagnosis and therapy of this benign bone tumour.
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http://dx.doi.org/10.1186/s12891-016-1313-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096000PMC
November 2016

The incorporation of fluoride and strontium in hydroxyapatite affects the composition, structure, and mechanical properties of human cortical bone.

J Biomed Mater Res A 2017 02 21;105(2):433-442. Epub 2016 Oct 21.

Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Lottestrasse 55A, Hamburg, 22529, Germany.

Strontium ranelate and fluoride salts are therapeutic options to reduce fracture risk in osteoporosis. Incorporation of these elements in the physiological hydroxyapatite matrix of bone is accompanied by changes in bone remodeling, composition, and structure. However, a direct comparison of the effectiveness of strontium and fluoride treatment in human cortical bone with a focus on the resulting mechanical properties remains to be established. Study groups are composed of undecalcified specimens from healthy controls, treatment-naïve osteoporosis cases, and strontium ranelate or fluoride-treated osteoporosis cases. Concentrations of both elements were determined using instrumental neutron activation analysis (INAA). Backscattered electron imaging was carried out to investigate the calcium content and the cortical microstructure. In comparison to osteoporotic patients, fluoride and strontium-treated patients have a lower cortical porosity indicating an improvement in bone microstructure. Mechanical properties were assessed via reference point indentation as a measure of bone's resistance to deformation. The strontium-incorporation led to significantly lower total indentation distance values compared to osteoporotic cases; controls have the highest resistance to indentation. In conclusion, osteoporosis treatment with strontium and fluoride showed positive effects on the microstructure and the mechanical characteristics of bone in comparison to treatment-naïve osteoporotic bone. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 433-442, 2017.
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http://dx.doi.org/10.1002/jbm.a.35917DOI Listing
February 2017

Skeletal implications and management of cystinosis: three case reports and literature review.

Bonekey Rep 2016 17;5:828. Epub 2016 Aug 17.

INSERM, Faculté de Médecine Lyon Est, site Laennec, Lyon, France; Université de Lyon, Lyon, France.

Hypophosphatemic rickets and short stature are observed in nephropathic cystinosis, an orphan autosomal recessive lysosomal storage disease due to a deficiency of cystinosin (CTNS gene). Although bone impairment is not common, it nevertheless appears to be more and more discussed by experts, even though the exact underlying pathophysiology is unclear. Four hypotheses are currently discussed to explain such impairment: copper deficiency, bone consequences of severe hypophosphatemic rickets during infancy, cysteamine toxicity and abnormal thyroid metabolism. In murine models, the invalidation of the CTNS gene is associated neither with renal phosphate wasting nor with renal failure, but causes severe osteopenia and growth retardation, thus raising the hypothesis of a specific underlying bone defect in cystinosis. Moreover, the in vitro ability of mesenchymal stromal cells isolated from bone marrow to differentiate along the osteoblastic lineage is reduced in patients with cystinosis as compared with cells obtained from healthy controls, this cellular abnormality being reverted after cysteamine treatment. From our experience of three pediatric patients with cystinosis and severe bone deformations having undergone a thorough biochemical evaluation, as well as a bone biopsy, we conclude that even though copper deficiency, high-doses cysteamine regimens and abnormal thyroid metabolism may worsen the bone picture in cystinosis patients, the exact pathophysiology of such impairment remains to be defined. The role of chronic hypoparathyroidism due to chronic phosphate wasting could also be discussed. In the future, larger and prospective studies should focus on this topic because of the potential major impact on patients' quality of life.
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http://dx.doi.org/10.1038/bonekey.2016.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988218PMC
August 2016

Recurrent multilocular mandibular giant cell granuloma in neurofibromatosis type 1: Evidence for second hit mutation of NF1 gene in the jaw lesion and treatment with curettage and bone substitute materials.

J Craniomaxillofac Surg 2016 Aug 15;44(8):1054-60. Epub 2016 May 15.

Department of Human Genetics, Catholic University Leuven/University Hospital Leuven, Leuven, Belgium.

Giant cell granuloma (GCG) of the jaw is a rare, well-known feature of neurofibromatosis type 1 (NF1), an inborn multisystem disorder. Recently, the development of GCG in NF1 was attributed to second hit mutations in the NF1 gene. The treatment of GCG is pragmatic with a preference for local curettage of lytic osseous areas. This report describes the surgical therapy of an NF1-affected female with multilocular mandibular GCG and hypodontia who additionally suffered from a brain tumour and Hashimoto's thyroiditis. Although local recurrence of GCG was noted, augmentation of the curetted cavities with a bone substitute in successive interventions successfully restored the extensive periradicular local defects and stabilised the teeth. A meticulous in vitro study of the GCG specimen revealed a second hit mutation in the NF1 gene in the GCG spindle-cells. This study contributes to the increasing knowledge of the molecular basis for GCG in the jaw of NF1 patients, indicating that it is a neoplasm.
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http://dx.doi.org/10.1016/j.jcms.2016.05.010DOI Listing
August 2016

Mucoepidermoid Carcinoma - Unknown Primary Affecting the Neck.

Anticancer Res 2016 Jun;36(6):3169-71

Institute of Pathology, University of Münster, Münster, Germany.

The present report describes therapy and follow-up of a patient who experienced a localized swelling of the neck that proved to be a mucoepidermoid carcinoma. Extensive staging revealed no primary site. Therapy was modified neck dissection followed by external application of chemotherapy combined with fractionated radiotherapy. Over a period of 43 months, the patient has remained free of local tumour growth and distant metastasis. Whereas prognosis of mucoepidermoid carcinoma in general is good, prognosis of patients affected by mucoepidermoid carcinoma with carcinoma of unknown primary is ambiguous.
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June 2016

Expression of DOG1 (Using SP31) in Poorly Differentiated Carcinoma of the Head and Neck.

Anticancer Res 2016 Jun;36(6):3117-22

Institute of Histopathology, Royal National Orthopaedic Hospital, NHS Trust Stanmore, London, U.K.

Background: The calcium-activated chloride channel protein discovered on gastrointestinal stromal tumour 1 (DOG1) is expressed in a variety of normal and neoplastic tissues. DOG1 is a specific marker for gastrointestinal stromal tumour. In the head and neck region, DOG1 is a sensitive discriminator for acinar cell carcinoma. Only a few publications have presented data concerning the expression of DOG1 in head and neck squamous cell carcinoma (HNSCC). The expression of DOG1 in HNSCC appears to be associated with a poor prognosis. The aim of this study was to analyze the expression pattern of DOG1 in poorly differentiated carcinoma of the upper aerodigestive tract.

Materials And Methods: A total of 84 specimens from 31 patients with carcinomas of the upper aerodigestive tract were immunohistochemically investigated for DOG1 expression. Inclusion criterion was poorly to undifferentiated carcinoma of the head and neck, but samples of the same resection site that exhibited moderate or well-differentiated squamous cell carcinoma were also enrolled. Immunoreactivity in carcinomas was estimated using a visual score (0: negative; 1: basally positive, 2: parabasally positive, 3: completely positive, 4: basally and parabasally positive).

Results: Fifteen out of 84 specimens were immunoreactive to antibody to DOG1 (17.8%). DOG1 immunoreactivity was restricted to eight patients (25.8%). However, DOG1 expression was considerably heterogeneous in tumours, with three (9.6%) cases showing a positive reaction in all samples. Basal and parabasal staining patterns (five specimens each) dominated.

Discussion: This study demonstrated expression of DOG1 to be restricted to some poorly differentiated carcinomas of the upper aerodigestive tract. Although the proportion of DOG1-positive carcinomas was moderate compared to results of previous studies on head and neck cancer tissues, DOG1 expression possibly indicates a subset of HNSCC. Further studies are necessary to investigate the heterogeneity and clinical relevance of DOG1 expression in HNSCC.
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June 2016

Cherubism: A Case Report with Surgical Intervention.

Anticancer Res 2016 Jun;36(6):3109-15

Institute of Pathology, Eppendorf University Hospital, University of Hamburg, Hamburg, Germany.

Cherubism is a rare benign, autosomal-dominant hereditary fibro-osseous condition predominantly affecting the jaws. Symmetrical cyst-like expansions of the jaws cause the characteristic facial swellings. The disease is often associated with severe malposition of teeth. The gene for cherubism is src homology 3 binding protein 2 (SH3BP2) located on chromosome 4p16.3. The repeated experience of this self-limiting disorder in affected individuals published in the medical literature has resulted in a wait-and-see strategy regarding therapeutic options. Indeed, cessation and regression of even large bone expansions can be expected in early adulthood. Nevertheless, severe facial disfiguring and functional impairment can make surgical intervention necessary. This report details the surgical procedures carried out in a patient with progressive and disfiguring jaw expansions at the end of adolescence, the mutation of SH3BP2 gene, and the limited effect of surgically assisted orthodontic tooth movement in a patient with disease-associated impaired tooth development and tooth eruption.
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June 2016

Expression of the Insulin-like Growth Factor-1 Receptor in Odontogenic Myxoma.

Anticancer Res 2016 Jun;36(6):3103-7

Royal National Orthopaedic Hospital NHS Trust - Histopathology, Bone Tumours and Metabolic Bone Diseases, London, U.K.

Unlabelled: Odontogenic myxoma (OM) is a rare mesenchymal tumour arising in the jaws. The origin and pathogenesis of OM is poorly understood. The aim of this study was to characterize OM by immunolocalization of certain antigens in the tumour that are relevant for cellular differentiation, migration and maintenance.

Materials And Methods: Five OMs were immunohistochemically investigated for expression of nestin, CD133, podoplanin, and insulin-like growth factor 1 receptor (IGF-1R).

Results: OM failed to react with antibodies applied in this study, with the exception of IGF-1R in tumour cells.

Discussion: OM is a poorly characterized benign, invasive tumour of the jaws. The absence of stem cell marker in OM does not exclude possible temporary expression of these antigens during certain phases of tumour development. The identification of IGF-1R in OM is shared with numerous tumours and indicates the ability of these tumour cells to respond to growth factors.
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June 2016

Cobalt deposition in mineralized bone tissue after metal-on-metal hip resurfacing: Quantitative μ-X-ray-fluorescence analysis of implant material incorporation in periprosthetic tissue.

J Biomed Mater Res B Appl Biomater 2017 10 30;105(7):1855-1862. Epub 2016 May 30.

ORTHOCLINIC Hamburg, D-22457, Hamburg, Germany.

Most resurfacing systems are manufactured from cobalt-chromium alloys with metal-on-metal (MoM) bearing couples. Because the quantity of particulate metal and corrosion products which can be released into the periprosthetic milieu is greater in MoM bearings than in metal-on-polyethylene (MoP) bearings, it is hypothesized that the quantity and distribution of debris released by the MoM components induce a compositional change in the periprosthetic bone. To determine the validity of this claim, nondestructive µ-X-ray fluorescence analysis was carried out on undecalcified histological samples from 13 femoral heads which had undergone surface replacement. These samples were extracted from the patients after gradient time points due to required revision surgery. Samples from nonintervened femoral heads as well as from a MoP resurfaced implant served as controls. Light microscopy and µ-X-ray fluorescence analyses revealed that cobalt debris was found not only in the soft tissue around the prosthesis and the bone marrow, but also in the mineralized bone tissue. Mineralized bone exposed to surface replacements showed significant increases in cobalt concentrations in comparison with control specimens without an implant. A maximum cobalt concentration in mineralized hard tissue of up to 380 ppm was detected as early as 2 years after implantation. Values of this magnitude are not found in implants with a MoP surface bearing until a lifetime of more than 20 years. This study demonstrates that hip resurfacing implants with MoM bearings present a potential long-term health risk due to rapid cobalt ion accumulation in periprosthetic hard tissue. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1855-1862, 2017.
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http://dx.doi.org/10.1002/jbm.b.33667DOI Listing
October 2017

Azzopardi phenomenon in cystic pseudotumours associated with retrieved metal-on-metal arthroplasty.

Hum Pathol 2016 May 5;51:134-7. Epub 2016 Feb 5.

Clinic of Orthopaedics, London Implant Retrieval Centre, Royal National Orthopaedic Hospital NHS Trust, HA7 4LP, Stanmore, UK.

The Azzopardi phenomenon represents a morphologically well defined lesion characterised by a deposition of basophilic material in the vessel walls associated with several malignant tumours. We report on 4 cases (3 men and 1 woman) showing the Azzopardi effect in retrieved metal-on-metal arthroplasty unrelated to malignancy. All cases were revised for groin pain and radiological findings of so-called pseudotumours. The Azzopardi phenomenon was seen in cases with cystic pseudotumours characterised by superficial necrobiosis, proliferative desquamative synovitis, finding of metal and corrosion wear particles and cellular infiltration by macrophages. The lesions, which were recognized as bluish substance in the hematoxylin and eosin staining, demonstrated a positive Feulgen reaction. We report on the Azzopardi phenomenon in non-neoplastic cystic pseudotumours from retrieved metal-on-metal arthroplasties. Although clinical relevance of this finding remains unclear, further research is necessary to investigate the possible relationship of this lesion with deliberation of metal ions from metal and corrosion wear particles and their role in a broad spectrum of adverse reactions to metal debris.
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http://dx.doi.org/10.1016/j.humpath.2016.01.009DOI Listing
May 2016