[Robotics and intraoperative navigation]. / Robotik und intraoperative Navigation.

Urology has always been closely linked to technological progress. In the last few decades, we have witnessed increasing implementation of various technologies and innovations in subdisciplines of urology. While conventional laparoscopy is increasingly being replaced by robot-assisted procedures and the introduction of new robotic systems from various manufactures will continue for years, the field of endourolgy is still not dominated by robotic systems. However, new systems (e.g., autonomous, robot-controlled aquablation of the prostate) are becoming increasingly popular and numerous development projects will also probably change clinical care in coming years. In addition, further advancements in the combination of robotics with intraoperative navigation through the integration of imaging and augmented-reality (AR) and virtual reality (VR) technology can be expected. This combination of navigation and robotic technology is already being used successfully in prostate biopsy.

[Surgery 4.0-are we ready?] / Wie weit ist Chirugie 4.0?

The increasing networking of data systems in medicine is not only leading to modern interdisciplinarity in the sense of cooperation between different medical departments, but also poses new challenges regarding the building and room infrastructure. The surgical operating room of the future expands or augments its reality, away from the pure building characteristics, towards an intelligent and communicative space platform. The building infrastructure (operating theatre) serves as sensor and actuator. Thus, it is possible to inform about missing diagnostics as well as to register them directly in the contextualization of the planned surgical intervention or to integrate them into the processes. Integrated operating theatres represent a comprehensive computer platform based on a corresponding system architecture with software-based protocols. An underlying modular system consisting of various modules for image acquisition and analysis, interaction and visualization supports the integration and merging of heterogeneous data that are generated in a hospital operation. Integral building data (e.g., air conditioning, lighting control, device registration) are merged with patient-related data (age, type of illness, concomitant diseases, existing diagnostic CT and MRI images). New systems coming onto the market, as well as already existing systems will have to be measured by the extent to which they will be able to guarantee this integration of information-similar to the development from mobile phone to smartphone. Cost reduction should not be the only legitimizing argument for the market launch, but the vision of a new quality of surgical perception and action.

Strong CD8+ lymphocyte infiltration in combination with expression of HLA class I is associated with better tumor control in breast cancer patients treated with neoadjuvant chemotherapy.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) are associated with pathological complete response (pCR) and survival after neoadjuvant chemotherapy (NAC) in patients with early breast cancer. We investigated the prognostic and predictive role of TILs, macrophages, and HLA class 1 expression after NAC with or without the potentially immune modulating compound zoledronic acid (ZA). METHODS: Baseline tumor biopsies from 196 patients in the NEOZOTAC trial were analyzed for CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), CD68 (macrophages), and HLA class I (HCA2/HC10) expression by immunohistochemistry and subsequently related to pCR and disease-free survival (DFS). RESULTS: A strong intratumoral CD8+ infiltration or expression of HLA class 1 by cancer cells was associated with a higher pCR rate (p < 0.05). Clinical benefit of high CD8+ T-cell infiltration was found when cancer cells expressed HLA class 1 (pCR: 21.8% vs. 6.7%, p = 0.04) but not when HLA class 1 expression was lost or downregulated (pCR: 5.9% vs. 0%, p = 0.38). Interaction analyses revealed survival benefit between HLA class 1 expression and strong CD8+ T-cell infiltration, whereas in the absence or downregulation of HLA class 1 expression, high levels of CD8+ T-cells were associated with survival disadvantage (p for interaction 0.01; hazard ratio 0.41, 95% CI 0.15-1.10, p = 0.08 and hazard ratio 7.67, 95% CI 0.88-66.4, p = 0.07, respectively). Baseline immune markers were not related to ZA treatment. CONCLUSIONS: Strong baseline tumor infiltration with CD8+ T-cells in the presence of tumoral HLA class 1 expression in patients with HER2-negative breast cancer is related to a higher pCR rate and a better DFS after NAC.

Prognostic value of tumor-stroma ratio combined with the immune status of tumors in invasive breast carcinoma.

PURPOSE: Complex interactions occur between cancer cells and cells in the tumor microenvironment. In this study, the prognostic value of the interplay between tumor-stroma ratio (TSR) and the immune status of tumors in breast cancer patients was evaluated. METHODS: A cohort of 574 breast cancer patients was analyzed. The percentage of tumor stroma was visually estimated on Hematoxylin and Eosin (H&E) stained histological tumor tissue sections. Immunohistochemical staining was performed for classical human leukocyte antigen (HLA) class I, HLA-E, HLA-G, markers for regulatory T (Treg) cells, natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs). RESULTS: TSR (P < .001) and immune status of tumors (P < .001) were both statistically significant for recurrence free period (RFP) and both independent prognosticators (P < .001) in which tumors with a high stromal content behave more aggressively as well as tumors with a low immune status. Ten years RFP for patients with a stroma-low tumor and high immune status profile was 87% compared to 17% of patients with a stroma-high tumor combined with low immune status profile (P < .001). Classical HLA class I is the most prominent immune marker in the immune status profiles. CONCLUSIONS: Determination of TSR is a simple, fast and cheap method. The effect on RFP of TSR when combined with immune status of tumors or expression of classical HLA class I is even stronger. Both are promising for further prediction and achievement of tailored treatment for breast cancer patients.

Validity of the online PREDICT tool in older patients with breast cancer: a population-based study.

BACKGROUND: Predicting breast cancer outcome in older patients is challenging, as it has been shown that the available tools are not accurate in older patients. The PREDICT tool may serve as an alternative tool, as it was developed in a cohort that included almost 1800 women aged 65 years or over. The aim of this study was to assess the validity of the online PREDICT tool in a population-based cohort of unselected older patients with breast cancer. METHODS: Patients were included from the population-based FOCUS-cohort. Observed 5- and 10-year overall survival were estimated using the Kaplan-Meier method, and compared with predicted outcomes. Calibration was tested by composing calibration plots and Poisson Regression. Discriminatory accuracy was assessed by composing receiver-operator-curves and corresponding c-indices. RESULTS: In all 2012 included patients, observed and predicted overall survival differed by 1.7%, 95% confidence interval (CI)=-0.3-3.7, for 5-year overall survival, and 4.5%, 95% CI=2.3-6.6, for 10-year overall survival. Poisson regression showed that 5-year overall survival did not significantly differ from the ideal line (standardised mortality ratio (SMR)=1.07, 95% CI=0.98-1.16, P=0.133), but 10-year overall survival was significantly different from the perfect calibration (SMR=1.12, 95% CI=1.05-1.20, P=0.0004). The c-index for 5-year overall survival was 0.73, 95% CI=0.70-0.75, and 0.74, 95% CI=0.72-0.76, for 10-year overall survival. CONCLUSIONS: PREDICT can accurately predict 5-year overall survival in older patients with breast cancer. Ten-year predicted overall survival was, however, slightly overestimated.

Alternatively spliced tissue factor synergizes with the estrogen receptor pathway in promoting breast cancer progression.

BACKGROUND: Procoagulant full-length tissue factor (flTF) and its minimally coagulant alternatively spliced isoform (asTF), promote breast cancer (BrCa) progression via different mechanisms. We previously showed that flTF and asTF are expressed by BrCa cells, resulting in autoregulation in a cancer milieu. BrCa cells often express hormone receptors such as the estrogen receptor (ER), leading to the formation of hormone-regulated cell populations. OBJECTIVE: To investigate whether TF isoform-specific and ER-dependent pathways interact in BrCa. METHODS: Tissue factor isoform-regulated gene sets were assessed using ingenuity pathway analysis. Tissues from a cohort of BrCa patients were divided into ER-positive and ER-negative groups. Associations between TF isoform levels and tumor characteristics were analyzed in these groups. BrCa cells expressing TF isoforms were assessed for proliferation, migration and in vivo growth in the presence or absence of estradiol. RESULTS: Ingenuity pathway analysis pointed to similarities between ER- and TF-induced gene expression profiles. In BrCa tissue specimens, asTF expression was associated with grade and stage in ER-positive but not in ER-negative tumors. flTF was only associated with grade in ER-positive tumors. In MCF-7 cells, asTF accelerated proliferation in the presence of estradiol in a ß1 integrin-dependent manner. No synergy between asTF and the ER pathway was observed in a migration assay. Estradiol accelerated the growth of asTF-expressing tumors but not control tumors in vivo in an orthotopic setting. CONCLUSION: Tissue factor isoform and estrogen signaling share downstream targets in BrCa; the concomitant presence of asTF and estrogen signaling is required to promote BrCa cell proliferation.

Contralateral breast cancer risk in relation to tumor morphology and age-in which patients is preoperative MRI justified?

Identification of patients who are at increased risk for contralateral breast cancer is essential to determine which patients should be routinely screened for contralateral breast cancer using MRI. The aim of this study was to assess the association of age and tumor morphology with contralateral breast cancer incidence in a large, nationwide population-based study in the Netherlands. All patients with breast cancer stage I-III, diagnosed between 1989 and 2009, were selected from the Netherlands Cancer Registry. The association between contralateral breast cancer risk with tumor morphology and age was assessed using competing-risk regression according to Fine & Gray. Overall, 194,898 patients were included. In multivariable analyses, lobular tumors were significantly associated with an increased risk of contralateral breast cancer within 6 months (cumulative incidence 1.9 %, subdistribution hazard ratio (SHR) 1.17, 95 % confidence interval (CI) 1.06-1.30 compared with 1.3 % in ductal tumors, p = 0.002). Age was also associated with an increased risk of contralateral breast cancer within 6 months (SHR 2.34, 95 % CI 2.08-2.62, p < 0.002 for patients over the age of 75 as compared to patients younger than 50 years). The absolute risk of contralateral breast cancer within 6 months is only slightly increased in patients with a lobular tumor and older patients. In our view, this small increased risk does not justify standard use of preoperative MRI based on tumor morphology or age alone. We propose a more personalized strategy in which additional risk factors (family history, prognosis of primary tumor, and others) may play a role.

The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis.

Evidence exists for an immunomodulatory effect of endocrine therapy in hormone receptor-positive (HR+ve) breast cancer (BC). Therefore, the aim of this study was to define the prognostic and predictive value of tumor immune markers and the tumor immune profile in HR+ve BC, treated with different endocrine treatment regimens. 2,596 Dutch TEAM patients were treated with 5 years of adjuvant hormonal treatment, randomly assigned to different regimens: 5 years of exemestane or sequential treatment (2.5 years of tamoxifen-2.5 years of exemestane). Immunohistochemistry was performed for HLA class I, HLA-E, HLA-G, and FoxP3. Tumor immune subtypes (IS) (low, intermediate & high immune susceptible) were determined by the effect size of mono-immune markers on relapse rate. Patients on sequential treatment with high level of tumor-infiltrating FoxP3+ cells had significant (p = 0.019, HR 0.729, 95% CI 0.560-0.949) better OS. Significant interaction for endocrine treatment and FoxP3+ presence was seen (OS p < 0.001). Tumor IS were only of prognostic value for the sequentially endocrine-treated patients (RFP: p = 0.035, HR intermediate IS 1.420, 95% CI 0.878-2.297; HR low IS 1.657, 95% CI 1.131-2.428; BCSS: p = 0.002, HR intermediate IS 2.486, 95% CI 1.375-4.495; HR low IS 2.422, 95% CI 1.439-4.076; and OS: p = 0.005, HR intermediate IS 1.509, 95% CI 0.950-2.395; HR low IS 1.848, 95% CI 1.277-2.675). Tregs and the tumor IS presented in this study harbor prognostic value for sequentially endocrine-treated HR+ve postmenopausal BC patients, but not for solely exemestane-treated patients. Therefore, these markers could be used as a clinical risk stratification tool to guide adjuvant treatment in this BC population.

Immunological subtypes in breast cancer are prognostic for invasive ductal but not for invasive lobular breast carcinoma.

BACKGROUND: Classical patient and tumour characteristics are the benchmark of personalised breast cancer (BC) management. Recent evidence has demonstrated that immune and molecular profiling of BC may also play an important role. Despite evidence of differences between invasive ductal (IDC) and lobular (ILC) BC, they are infrequently accounted for when making treatment decisions for individual patients. The purpose of this study was to investigate the relevance of the tumour immune response in the major histological subtypes of BC. We also assessed the relationship between immune responses and molecular subtypes and their prognostic potential. METHODS: Immunostains were done for HLA-I, HLA-E, HLA-G, Tregs, NK cells and CTLs for the composition of the immune profiles and Ki67, EGFR, CK5/6, ER, PR and HER2 for molecular profiles in 714 breast cancer patients who underwent primary surgery. RESULTS: No significant association was found between IDC (90.6%) and ILC (9.4%) and tumour immune subtypes (P=0.4) and molecular subtypes (P=0.4). However, for the relapse-free period (RFP) tumour immune subtyping was prognostic (P=0.002) in IDC, but not ILC. Contrary to ILC, IDC patients frequently expressed higher cleaved caspase-3 and Ki67, which was prognostic. Intermediate immune-susceptible IDC expressing high cleaved caspase-3 or Ki67 showed worse RFP than those with low expression (caspase-3: P=0.004; Ki67: P=0.002); this was not seen for ILC or in high or low immune-susceptible tumour types for either IDC or ILC. CONCLUSIONS: Tumour immune characteristics and host immune responses are prognostic in IDC, but not ILC. In addition, tumour immune profiles are only prognostic in Luminal A tumours.

Survival of neural progenitors allografted into the CNS of immunocompetent recipients is highly dependent on transplantation site.

Allografts continue to be used in clinical neurotransplantation studies; hence, it is crucial to understand the mechanisms that govern allograft tolerance. We investigated the impact of transplantation site within the brain on graft survival. Mouse [Friend leukemia virus, strain B (FVB)] glial precursors, transfected with luciferase, were injected (3 × 10(5)) into the forceps minor (FM) or striatum (STR). Immunodeficient rag2(-/-) and immunocompetent BALB/c mice were used as recipients. Magnetic resonance imaging (MRI) confirmed that cells were precisely deposited at the selected coordinates. The graft viability was assessed noninvasively with bioluminescent imaging (BLI) for a period of 16 days. Regardless of implantation site, all grafts (n = 10) deposited in immunodeficient animals revealed excellent survival. In contrast, immunocompetent animals only accepted grafts at the STR site (n = 10), whereas all the FM grafts were rejected (n = 10). To investigate the factors that led to rejection of FM grafts, with acceptance of STR grafts, another group of animals (n = 19) was sacrificed during the prerejection period, on day 5. Near-infrared fluorescence imaging with IRDye 800CW-polyethylene glycol probe displayed similar blood-brain barrier disruption at both graft locations. The morphological distribution of FM grafts was cylindrical, parallel to the needle track, whereas cells transplanted into the STR accumulated along the border between the STR and the corpus callosum. There was significantly less infiltration by both innate and adaptive immune cells in the STR grafts, especially along the calloso-striatal border. With allograft survival being dependent on the transplantation site, the anatomical coordinates of the graft target should always be taken into account as it may determine the success or failure of therapy.

Diabetes in relation to breast cancer relapse and all-cause mortality in elderly breast cancer patients: a FOCUS study analysis.

BACKGROUND: In developed countries, 40% of breast cancer patients are >65 years of age at diagnosis, of whom 16% additionally suffer from diabetes. The aim of this study was to assess the impact of diabetes on relapse-free period (RFP) and overall mortality in elderly breast cancer patients. PATIENTS AND METHODS: Patients were selected from the retrospective FOCUS cohort, which contains detailed information of elderly breast cancer patients. RFP was calculated using Fine and Gray competing risk regression models for patients with diabetes versus patients without diabetes. Overall survival was calculated by Cox regression models, in which patients were divided into four groups: no comorbidity, diabetes only, diabetes and other comorbidity or other comorbidity without diabetes. RESULTS: Overall, 3124 patients with non-metastasized breast cancer were included. RFP was better for patients with diabetes compared with patients without diabetes (multivariable HR 0.77, 95% CI 0.59-1.01), irrespective of other comorbidity and most evident in patients aged ≥75 years (HR 0.67, 95% CI 0.45-0.98). The overall survival was similar for patients with diabetes only compared with patients without comorbidity (HR 0.86, 95% CI 0.45-0.98), while patients with diabetes and additional comorbidity had the worst overall survival (HR 1.70, 95% CI 1.44-2.01). CONCLUSION: When taking competing mortality into account, RFP was better in elderly breast cancer patients with diabetes compared with patients without diabetes. Moreover, patients with diabetes without other comorbidity had a similar overall survival as patients without any comorbidity. Possibly, unfavourable effects of (complications of) diabetes on overall survival are counterbalanced by beneficial effects of metformin on the occurrence of breast cancer recurrences.

Visualizing TGF-ß and BMP signaling in human atherosclerosis: a histological evaluation based on Smad activation.

BACKGROUND: The TGF-ß superfamily members transforming growth factor-ß (TGF-ß/Activin) and bone morphogenetic proteins (BMP) have been implicated in the pathogenesis of atherosclerosis. However, their role in human disease remains controversial. In this study we used Smad phosphorylation as a read out for TGF-ß and BMP signaling during the initiation, progression and (de)stabilization of human atherosclerotic disease. MATERIAL AND METHODS: A systematic analysis was performed in 114 peri-renal aortic patches (stained with Movat Pentachrome, H&E, pSmad2, pSmad1,5,8 and PAI-1) covering the entire atherosclerotic spectrum (van Dijk, 2010). Immunostaining against T-cells (CD3) and monocytes and macrophages (CD68) was used to explore a putative association between TGF-ß and BMP signaling and vascular inflammation. RESULTS: Smad phosphorylation was present within the normal arterial wall in approximately 10% of the endothelial cells and intimal smooth muscle cells. A significant increase in pSmad2 and pSmad1,5,8 positivity was found in non-progressive lesions (>50% positivity). No further increase or decrease was found in the progressive atherosclerotic lesions, vulnerable and stabilized lesions. No association was found between TGF-ß and BMP signaling and CD3 and CD68 expression, nor cap thickness. CONCLUSION: Activation of the TGF-ß and BMP pathways is an early event in atherosclerotic lesion formation. No significant relationships were found between Smad phosphorylation and vessel wall inflammation or plaque vulnerability.

Plant diversity effects on soil microorganisms support the singular hypothesis.

The global decline in biodiversity has generated concern over the consequences for ecosystem functioning and services. Although ecosystem functions driven by soil microorganisms such as plant productivity, decomposition, and nutrient cycling are of particular importance, interrelationships between plant diversity and soil microorganisms are poorly understood. We analyzed the response of soil microorganisms to variations in plant species richness (1-60) and plant functional group richness (1-4) in an experimental grassland system over a period of six years. Major abiotic and biotic factors were considered for exploring the mechanisms responsible for diversity effects. Further, microbial growth characteristics were assessed following the addition of macronutrients. Effects of plant diversity on soil microorganisms were most pronounced in the most diverse plant communities though differences only became established after a time lag of four years. Differences in microbial growth characteristics indicate successional changes from a disturbed (zymogeneous) to an established (autochthonous) microbial community four years after establishment of the experiment. Supporting the singular hypothesis for plant diversity, the results suggest that plant species are unique, each contributing to the functioning of the belowground system. The results reinforce the need for long-term biodiversity experiments to fully appreciate consequences of current biodiversity loss for ecosystem functioning.

Responses to iron limitation in Hordeum vulgare L. as affected by the atmospheric CO2 concentration.

Elevated atmospheric CO2 treatments stimulated biomass production in Fe-sufficient and Fe-deficient barley plants, both in hydroponics and in soil culture. Root/shoot biomass ratio was increased in severely Fe-deficient plants grown in hydroponics but not under moderate Fe limitation in soil culture. Significantly increased biomass production in high CO2 treatments, even under severe Fe deficiency in hydroponic culture, indicates an improved internal Fe utilization. Iron deficiency-induced secretion of PS in 0.5 to 2.5 cm sub-apical root zones was increased by 74% in response to elevated CO2 treatments of barley plants in hydroponics but no PS were detectable in root exudates collected from soil-grown plants. This may be attributed to suppression of PS release by internal Fe concentrations above the critical level for Fe deficiency, determined at final harvest for soil-grown barley plants, even without additional Fe supply. However, extremely low concentrations of easily plant-available Fe in the investigated soil and low Fe seed reserves suggest a contribution of PS-mediated Fe mobilization from sparingly soluble Fe sources to Fe acquisition of the soil-grown barley plants during the preceding culture period. Higher Fe contents in shoots (+52%) of plants grown in soil culture without Fe supply under elevated atmospheric CO2 concentrations may indicate an increased efficiency for Fe acquisition. No significant influence on diversity and function of rhizosphere-bacterial communities was detectable in the outer rhizosphere soil (0-3 mm distance from the root surface) by DGGE of 16S rRNA gene fragments and analysis of marker enzyme activities for C-, N-, and P-cycles.

[Histogenesis of giant cell tumors]. / Aktuelles zur Histogenese des Riesenzelltumors.

The giant cell tumor of bone (GCT) is a local osteolytic tumor with variable degrees of aggressiveness. In rare cases pulmonary metastases can be observed. The lesion most frequently occurs in the epiphysis of long tubular bones of the knee region, predominantly affecting young adults after closure of the growth plate. The characteristic histological appearance of GCT displays a high number of osteoclast-like multinucleated giant cells, which resulted in the classification "osteoclastoma" or "giant cell tumor". Apart from the multinucleated giant cells, there are two mononuclear cell types in the GCT. The first one has a round morphology and resembles a monocyte. The second cell type is the spindle-shaped, fibroblast-like stromal cell. Cell culture experiments with GCT cells revealed the stromal cell to be the proliferating component of the GCT. The other two cell types, the monocyte and the multinucleated giant cell, were lost after a few cell culture passages. Furthermore, latest results from GCT reveal that the stromal cells secrete a variety of cytokines and differentiation factors, including MCP1, ODF and M-CSF. These molecules are monocyte chemoattractants and are essential for osteoclast differentiation, suggesting that the stromal cell stimulates blood monocyte immigration into tumor tissue and enhances their fusion into osteoclast-like, multinucleated giant cells. The multinucleated giant cell itself demonstrates properties of a normal osteoclast that is able to resorb bone leading to extended osteolysis. This new model of GCT genesis supports the hypothesis that the stromal cell is the neoplastic component whilst the monocytes and the multinucleated giant cells are just a reactive component of this tumor. Taking this into consideration, the nomenclature of the "giant cell tumor" needs to be reconsidered.

[Fibrous dysplasia]. / Fibröse Dysplasie.

The observations in 222 cases of fibrous dysplasia of the Hamburg Bone Tumor Registry will be presented. This benign lesion is based on the appearance of postzygotic point mutations in a gene encoding the Gsa protein. It occurs as a mono- and a polyostotic variant and may affect every bone of the skeleton. Most often affected are the proximal femur, the skull and the ribs. Polyostotic lesions tend to occur on one side of the body. The monostotic form is 7.6 times more frequent, but both variants show no predilection for gender. Most cases are diagnosed during adulthood. On x-rays the lesion has a ground-glass appearance and is located intramedullary with a sharply defined edge. The cortical bone is arroded and the bone is expanded. Histologically typical signs are slender curved fibrous trabeculae with a C and Y shape embedded in a morphologically bland and moderately cellular fibrous stroma. Diagnostically important are collagen fibres emerging perpendicular from the surface of the trabeculae. Cartilage is present in 8% of the cases. Therapeutically, thorough clinical controls are indicated and operative procedures are rarely needed to prevent progressive deformities and fractures. The formerly applied radiotherapy is now obsolete because of the increased occurrence of malignant transformations.

Gsalpha gene mutations in monostotic fibrous dysplasia of bone and fibrous dysplasia-like low-grade central osteosarcoma.

A series of nine cases with monostotic fibrous dysplasia (FD) and five cases of fibrous dysplasia-like low-grade central osteosarcoma (fd-like lgcOSA) were applied in a mutational analysis. Restriction digestion analysis, single-stranded conformational polymorphism (SSCP) analysis, and repeated sequencing demonstrated a R201H mutation in six cases and a R201C mutation in three cases of patients with monostotic FD. These results demonstrate that the presence of Gsalpha gene mutations is a constant finding in monostotic FD. To our knowledge, this is the first report in the literature investigating Gsalpha gene mutations in lgcOSA, which is one of the most important differential diagnoses of FD because of its low-grade malignant behavior. In four of five cases of fd-like lgcOSA, no mutation has been detected. In one case of this tumor, a R201C mutation could be demonstrated. Because our results demonstrate a low prevalence of Gsalpha gene mutations in this tumor in contrast to monostotic FD, mutational analysis may be an additional helpful parameter in individual cases for the differential diagnosis of FD and fd-like lgcOSA.

The nature of giant cell tumor of bone.

Giant cell tumor of bone (GCT) is a locally osteolytic tumor with variable aggressiveness. In rare cases, pulmonary metastasis can be observed. The lesion most frequently occurs in the epiphysis of long tubular bones of the knee region, predominantly affecting young adults after closure of the growth plate. The characteristic histological appearance of GCT displays a high number of osteoclast-like multinucleated giant cells, which resulted in the classification "osteoclastoma" or "giant cell tumor". Apart from the multinucleated giant cells, there are two mononuclear cell types in GCT. The first one has a round morphology and resembles monocytes. The second cell type is the spindle-shaped, fibroblast-like stromal cell. Cell culture experiments with GCT cells revealed the stromal cell to be the proliferating component of the GCT. The other two cell types, the monocyte and the multinucleated giant cell, were lost after a few cell culture passages. Furthermore, latest results from GCT reveal that the stromal cells secrete a variety of cytokines and differentiation factors, including MCP1, ODF, and M-CSF. These molecules are monocyte chemoattractants and are essential for osteoclast differentiation, suggesting that the stromal cell stimulates blood monocyte immigration into tumor tissue and enhances their fusion into osteoclast-like, multinucleated giant cells. The multinucleated giant cell itself resembles a normal osteoclast that is able to resorb bone leading to extended osteolysis. This new model of GCT genesis supports the hypothesis that the stromal cell is the neoplastic component whilst the monocytes and the multinucleated giant cells are just reactive components of this tumor. Taking this into consideration, the nomenclature of the "giant cell tumor" needs to be reconsidered.