Torsten Hansen

Actinomycosis of the jaws—histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis

Actinomycosis of the jaws is a rare disease, which has been recently described in patients with infected osteoradionecrosis (IORN) and bisphosphonate-associated osteonecrosis (BON). We investigated our archive material for Actinomycosis of the jaws with special regard to underlying disease. Out of a total number of 45 patients with Actinomycosis, 43 (93.5%) suffered from BON (58.7%) or IORN (35.6%), while there were only 3 patients (6.7%) without anti-tumor treatment. In all cases, we found direct association of Actinomyces colonies with bone; in the surrounding medullary space, mixed inflammatory infiltrates with variable amounts of osteoclasts were a typical finding. Pseudoepitheliomatous hyperplasia occurred in 60.9% of patients. Cell-rich vessel obliteration was seen in less than 25.9% of BON patients, while hyalinized vessel obliteration was obtained in 37.5% of IORN patients. Additionally performed polymerase chain reaction (PCR) on paraffin-embedded and ethylene diamine tetracetic acid (EDTA)-decalcified tissue specimens confirmed the presence of Actinomyces israelii in seven of seven cases analyzed. We conclude that Actinomycosis of the jaws is a particular complication in patients with BON and/or IORN. Patients with Actinomycosis of the jaws during or after these forms of anti-cancer therapy are suggested to represent a distinct patient cohort with a relevant impairment of their general condition.

Interferon-β: A Therapeutic for Autoimmune Lupus in MRL-Faslpr Mice

Type I interferons are associated with lupus. Genes that are regulated by IFN-alpha are upregulated in pediatric lupus patients. Gene deletion of the IFN-alpha/beta receptor in experimental lupus-like NZB mice results in reduced disease activity. Conversely, IFN-beta is a well-established treatment in multiple sclerosis, another autoimmune disease. For determining whether IFN-beta treatment is harmful or beneficial in lupus, MRL-Fas(lpr) mice were injected with this type I IFN. Treatment was initiated in MRL-Fas(lpr) mice with mild and advanced disease. IFN-beta was highly effective in prolonging survival and ameliorating the clinical (renal function, proteinuria, splenomegaly, and skin lesions), serologic (autoantibodies and cytokines), and histologic parameters of the lupus-like disease in mice that had mild and advanced disease. Several underlying mechanisms of IFN-beta therapy involving cellular (decreased T cell proliferation and infiltration of leukocytes into the kidney) and humoral (decrease in IgG3 isotypes) immune responses and a reduction in nephrogenic cytokines were identified. In conclusion, IFN-beta treatment of lupus nephritis in MRL-Fas(lpr) mice is remarkably beneficial and suggests that IFN-beta may be an appealing therapeutic candidate for subtypes of human lupus.

Expression of fibronectin splice variants and oncofetal glycosylated fibronectin in the synovial membranes of patients with rheumatoid arthritis and osteoarthritis

ObjectiveThe aim of this study was to define and compare the expression of fibronectin (Fn) isoforms in synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA).MethodsUsing monoclonal antibodies specific for total Fn, extra domain (ED)-A Fn, ED-B Fn, and oncofetal glycosylated Fn, we studied the expression of the Fn isoforms in synovium. Furthermore, in situ hybridization for the detection of ED-B Fn mRNA including a double labeling technique for the detection of cell type was applied.ResultsStrong expression of total Fn, ED-A Fn, oncofetal glycosylated Fn and, to a lesser extent, ED-B Fn could be demonstrated in the synovial lining layer in both RA and OA. Stromal and vessel expression of Fn isoforms was more prominent in RA tissue. Pannus tissue showed strong labeling with ED-B Fn.ConclusionThe expression of alternatively spliced isoforms of Fn is associated with tissue remodeling and, as a partial process of this phenomenon, with neovascularization rather than underlying disease, X-ray status, or parameters of acute inflammation. In the lining layer, Fn expression correlates with hyperplasia associated with cell recruitment but not with proliferative status. Most remarkably, the expression of ED-B Fn in pannus tissue seems to be associated with the invasive phenotype described in RA tissue.

Biological tolerance of different materials in bulk and nanoparticulate form in a rat model: sarcoma development by nanoparticles

In order to study the pathobiological impact of the nanometre-scale of materials, we evaluated the effects of five different materials as nanoparticulate biomaterials in comparison with bulk samples in contact with living tissues. Five groups out of 10 rats were implanted bilaterally for up to 12 months with materials of the same type, namely TiO2, SiO2, Ni, Co and polyvinyl chloride (PVC), subcutaneously with bulk material on one side of the vertebral column and intramuscularly with nanoparticulate material on the contralateral side. At the end of each implantation time, the site was macroscopically examined, followed by histological processing according to standard techniques. Malignant mesenchymal tumours (pleomorphic sarcomas) were obtained in five out of six cases of implanted Co nanoparticle sites, while a preneoplastic lesion was observed in an animal implanted with Co in bulk form. In the Ni group, all animals rapidly developed visible nodules at the implanted sites between 4 and 6 months, which were diagnosed as rhabdomyosarcomas. Since the ratio of surface area to volume did not show significant differences between the Ni/Co group and the TiO2/SiO2/PVC group, we suggested that the induction of neoplasia was not mediated by physical effects, but was mediated by the well-known carcinogenic impact of Ni and Co. The data from the Co group show that the physical properties (particulate versus bulk form) could have a significant influence on the acceleration of the neoplastic process.

New aspects in the histological examination of polyethylene wear particles in failed total joint replacements

The most important long-term complication in total joint replacements is aseptic osteolysis. Wear particles such as polyethylene (PE) debris are considered to be one of the causes that play a central role. Several studies indicated that PE can be visualised in paraffin-embedded tissue sections not only by polarised light, but also after oil red staining. To determine whether oil red staining enables sensitive detection of PE, we examined staining of mechanically-produced PE particles by oil red. Furthermore, we studied oil red staining of paraffin-embedded tissue specimens of patients with failed uncemented and cemented total knee and hip prostheses. We applied double labelling of sections by immunohistochemistry using the macrophage marker anti-CD68 and oil red staining. We found that oil red stains both isolated PE particles and PE particles in paraffin-embedded tissue sections. Polymethylmethacrylate particles in failed cemented arthroplasties did not stain in paraffin sections. Double labelling showed strong colocalisation of CD68 and PE. We suggest that oil red staining is a sensitive method to detect PE particles. Oil red staining is particularly helpful in these cases which show a characteristic histological feature of aseptic prosthesis loosening without particles being detectable with routine microscopy and polarised light. We also established that immunohistochemical methods can be applied together with the oil red staining method.

Trends in epidemiology, treatment, and survival of hepatocellular carcinoma patients between 1998 and 2009: an analysis of 1066 cases of a German HCC Registry.

Goals: The aim of this study was to analyze clinical presentation, course of disease, and management of patients with hepatocellular carcinoma (HCC) in a German referral center between 1998 and 2009. Background: HCC is a rare tumor in Germany, but its incidence has increased over the last 30 years. New therapies such as chemoembolization with drug-eluting beads, selective internal radiotherapy, and sorafenib were introduced recently; however, the impact on clinical management and overall survival (OS) is unclear. Study: In this retrospective analysis, 1066 patients with HCC, separated into two 6-year periods (n=385; 1998 to 2003 and n=681; 2004 to 2009) were evaluated. Results: The number of patients presenting each year (64 vs. 114 per year), with an age over 80 years or with nonalcoholic steatohepatitis increased significantly between periods. The main risk factors were alcoholic liver disease in 51.7%, chronic hepatitis C virus in 28.2%, and chronic hepatitis B virus in 13.4% of patients with liver cirrhosis and HCC. Patients presented with more advanced tumor stages and with worse liver function in period 2. The majority (61.6%) of patients received local treatment over a spectrum of Barcelona Clinic Liver-Cancer (BCLC) stages, whereas systemic therapy was offered to a minority (8.8%) and limited to BCLC stage C patients only. OS decreased in BCLC stage A and D and improved in BCLC stage B and C and decreased for all patients from 16.5 to 15.3 months between periods. Conclusions: No improvement of OS was observed when comparing time periods, partly because of the more advanced stage of HCC and because of the increasing age in the second time period. Improved and new therapeutic options and the intensification of surveillance programs are likely to increase survival of HCC patients in the future.

Liver specific overexpression of platelet‐derived growth factor‐B accelerates liver cancer development in chemically induced liver carcinogenesis

A genetic basis of hepatocellular carcinoma (HCC) has been well‐established and major signaling pathways, such as p53, Wnt‐signaling, transforming growth factor‐β (TGF‐β) and Ras pathways, have been identified to be essential to HCC development. Lately, the family of platelet‐derived growth factors (PDGFs) has shifted to the center of interest. We have reported on spontaneously developing liver fibrosis in PDGF‐B transgenic mice. Since HCC rarely occurs in healthy liver, but dramatically increases at the cirrhosis stage of which liver fibrosis is a preliminary stage, we investigated liver cancer development in chemically induced liver carcinogenesis in these mice. HCC induction was performed by treatment of the mice with diethylnitrosamine and phenobarbital. At an age of 6 months, the tumor development of these animals was analyzed. Not only the development of dysplastic lesions in PDGF‐B transgenic mice was significantly increased but also their malignant transformation to HCC. Furthermore, we were able to establish a key role of PDGF‐B signaling at diverse stages of liver cancer development. Here, we show that development of liver fibrosis is likely through upregulation of TGF‐β receptors by PDGF‐B. Additionally, overexpression of PDGF‐B also leads to an increased expression of β‐catenin as well as vascular endothelial growth factor and platelet endothelial cell adhesion molecule‐1 (PECAM‐1/CD31), all factors with established roles in carcinogenesis. We were able to extend the understanding of key genetic regulators in HCC development by PDGF‐B and decode essential downstream signals.

Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn's disease and ulcerative colitis

Background:Increased cell shedding with gap formation and local barrier dysfunction can be identified endomicroscopically in the terminal ileum of patients with inflammatory bowel disease. We aim to evaluate whether these changes are also present in the duodenum of patients with inflammatory bowel disease. Methods:Fifteen patients with Crohns disease (CD), 10 patients with ulcerative colitis (UC), and 10 controls underwent fluorescein-aided confocal laser endomicroscopy (CLE). CLE was performed on macroscopically normal antral and duodenal (D1, D2, D3, D4) mucosa. Representative CLE images were prospectively analyzed. Images were scored for the number of epithelial gaps, cell shedding, and the degree of fluorescein leakage into the intestinal lumen. Results:Both CD and UC patients had significantly more epithelial gaps, epithelial cell shedding, and leakage of fluorescein into the duodenal lumen than controls. The degree of cell shedding and epithelial gap formation was similar in CD and UC patients. In all cases, macroscopic endoscopic appearances of the duodenum were normal, and conventional histological analysis showed a mild nonspecific duodenitis in 7 of 15 patients with CD. Patients with UC had a histologically normal duodenum. Gap formation, cell shedding, and fluorescein leakage was similar in CD with active compared with inactive disease, except for D2 shedding. Conclusions:CLE can detect epithelial damage and barrier loss in the duodenum of CD and UC patients that is not apparent on conventional endoscopy or histology.

Susceptibility to collagen-induced arthritis is modulated by TGFβ responsiveness of T cells

The objective of our study was to determine the regulatory effects that endogenous transforming growth factor β (TGFβ) exerts on T cells in the pathogenesis of collagen-induced arthritis (CIA). CIA was induced in transgenic mice expressing a dominant negative TGFβ type II receptor in T cells under the control of the human CD2 promoter. Clinical and histological arthritis scores were determined and experiments on disease induction and the healing phase of disease were performed. The proliferation and cytokine production of draining lymph node cells in vitro were analyzed. Transgenic mice were more susceptible to induction of CIA. The overall incidence was higher in transgenic mice than in wild-type mice (57% vs 35%, P < 0.05). Affected transgenic animals displayed a significantly higher clinical (4.5 ± 0.6 vs 1.67 ± 0.19, P = 0.001) and histological arthritis score (8.01 ± 0.9 vs 4.06 ± 1.1, P < 0.05). Draining lymph node cells of transgenic mice secreted more tumor necrosis factor α and IFNγ and proliferated more vigorously in response to collagen type II and upon CD3/CD28 costimulation in vitro. Therefore, the regulation of T cells by endogenous TGFβ is important for the maintenance of joint integrity after arthritis induction. Defects in TGFβ-signalling as a susceptibility factor for rheumatoid arthritis may warrant further investigation.

Rectal Cancer: Mucinous Carcinoma on Magnetic Resonance Imaging Indicates Poor Response to Neoadjuvant Chemoradiation

PURPOSE To assess response of locally advanced rectal carcinoma to chemoradiation with regard to mucinous status and local tumor invasion found at pretherapeutic magnetic resonance imaging (MRI). METHODS AND MATERIALS A total of 88 patients were included in this prospective study of patients with advanced mrT3 and mrT4 carcinomas. Carcinomas were categorized by MRI as mucinous (mucin proportion >50% within the tumor volume), and as nonmucinous. Patients received neoadjuvant chemoradiation consisting of 50.4 Gy (1.8 Gy/fraction) and 5-fluorouracil on Days 1 to 5 and Days 29 to 33. Therapy response was assessed by comparing pretherapeutic MRI with histopathology of surgical specimens (minimum distance between outer tumor edge and circumferential resection margin = CRM, T, and N category). RESULTS A mucinous carcinoma was found in 21 of 88 patients. Pretherapeutic mrCRM was 0 mm (median) in the mucinous and nonmucinous group. Of the 88 patients, 83 underwent surgery with tumor resection. The ypCRM (mm) at histopathology was significantly lower in mucinous carcinomas than in nonmucinous carcinomas (p ≤ 0.001). Positive resection margins (ypCRM ≤ 1 mm) were found more frequently in mucinous carcinomas than in nonmucinous ones (p ≤ 0.001). Treatment had less effect on local tumor stage in mucinous carcinomas than in nonmucinous carcinomas (for T downsizing, p = 0.012; for N downstaging, p = 0.007). Disease progression was observed only in patients with mucinous carcinomas (n = 5). CONCLUSION Mucinous status at pretherapeutic MRI was associated with a noticeably worse response to chemoradiation and should be assessed by MRI in addition to local tumor staging to estimate response to treatment before it is initiated.