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Esgueva R.,New York Medical College | Perner S.,University Hospital of Tuebingen | J Lafargue C.,New York Medical College | Scheble V.,University Hospital of Tuebingen | And 6 more authors.
Modern Pathology | Year: 2010

The majority of prostate cancers harbor recurrent gene fusions between the hormone-regulated TMPRSS2 and members of the ETS family of transcription factors, most commonly ERG. Prostate cancer with ERG rearrangements represent a distinct sub-class of tumor based on studies reporting associations with histomorphologic features, characteristic somatic copy number alterations, and gene expression signatures. This study describes the frequency of ERG rearrangement prostate cancer and three 5 prime (5′) gene fusion partners (ie, TMPRSS2, SLC45A3, and NDRG1) in a large prostatectomy cohort. ERG gene rearrangements and mechanism of rearrangement, as well as rearrangements of TMPRSS2, SLC45A3, and NDRG1, were assessed using fluorescence in situ hybridization (FISH) on prostate cancer samples from 614 patients treated using radical prostatectomy. ERG rearrangement occurred in 53% of the 540 assessable cases. TMPRSS2 and SLC45A3 were the only 5′ partner in 78% and 6% of these ERG rearranged cases, respectively. Interestingly, 11% of the ERG rearranged cases showed concurrent TMPRSS2 and SLC45A3 rearrangements. TMPRSS2 or SLC45A3 rearrangements could not be identified for 5% of the ERG rearranged cases. From these remaining cases we identified one case with NDRG1 rearrangement. We did not observe any associations with pathologic parameters or clinical outcome. This is the first study to describe the frequency of SLC45A3-ERG fusions in a large clinical cohort. Most studies have assumed that all ERG rearranged prostate cancers harbor TMPRSS2-ERG fusions. This is also the first study to report concurrent TMPRSS2 and SLC45A3 rearrangements in the same tumor focus, suggesting additional complexity that had not been previously appreciated. This study has important clinical implications for the development of diagnostic assays to detect ETS rearranged prostate cancer. Incorporation of these less common ERG rearranged prostate cancer fusion assays could further increase the sensitivity of the current PCR-based approaches. © 2010 USCAP, Inc. All rights reserved.


Vinzon S.E.,German Cancer Research Center | Braspenning-Wesch I.,German Cancer Research Center | Muller M.,German Cancer Research Center | Geissler E.K.,University of Regensburg | And 4 more authors.
PLoS Pathogens | Year: 2014

Certain cutaneous human papillomaviruses (HPVs), which are ubiquitous and acquired early during childhood, can cause a variety of skin tumors and are likely involved in the development of non-melanoma skin cancer, especially in immunosuppressed patients. Hence, the burden of these clinical manifestations demands for a prophylactic approach. To evaluate whether protective efficacy of a vaccine is potentially translatable to patients, we used the rodent Mastomys coucha that is naturally infected with Mastomys natalensis papillomavirus (MnPV). This skin type papillomavirus induces not only benign skin tumours, such as papillomas and keratoacanthomas, but also squamous cell carcinomas, thereby allowing a straightforward read-out for successful vaccination in a small immunocompetent laboratory animal. Here, we examined the efficacy of a virus-like particle (VLP)-based vaccine on either previously or newly established infections. VLPs raise a strong and long-lasting neutralizing antibody response that confers protection even under systemic long-term cyclosporine A treatment. Remarkably, the vaccine completely prevents the appearance of benign as well as malignant skin tumors. Protection involves the maintenance of a low viral load in the skin by an antibody-dependent prevention of virus spread. Our results provide first evidence that VLPs elicit an effective immune response in the skin under immunocompetent and immunosuppressed conditions in an outbred animal model, irrespective of the infection status at the time of vaccination. These findings provide the basis for the clinical development of potent vaccination strategies against cutaneous HPV infections and HPV-induced tumors, especially in patients awaiting organ transplantation. © 2014 Vinzón et al.


Schneider I.,University Hospital of Berlin | Lehmann M.D.,University Hospital of Berlin | Kogosov V.,German Cancer Research Center | Stockfleth E.,University Hospital of Berlin | And 3 more authors.
BMC Infectious Diseases | Year: 2013

Background: Cutaneous human papillomavirus (HPV) infections seem to be associated with the onset of actinic keratosis (AK). This study compares the presence of cutaneous HPV types in eyebrow hairs to those in tissues of normal skin and skin lesions of 75 immunocompetent AK patients.Methods: Biopsies from AK lesions, normal skin and plucked eyebrow hairs were collected from each patient. DNA from these specimens was tested for the presence of 28 cutaneous HPV (betaPV and gammaPV) by a PCR based method.Results: The highest number of HPV prevalence was detected in 84% of the eyebrow hairs (63/75, median 6 types) compared to 47% of AK lesions (35/75, median 3 types) (p< 0.001) and 37% of normal skin (28/75, median 4 types) (p< 0.001), respectively. A total of 228 HPV infections were found in eyebrow hairs compared to only 92 HPV infections in AK and 69 in normal skin. In all three specimens HPV20, HPV23 and/or HPV37 were the most prevalent types. The highest number of multiple types of HPV positive specimens was found in 76% of the eyebrow hairs compared to 60% in AK and 57% in normal skin. The concordance of at least one HPV type in virus positive specimens was 81% (three specimens) and 88-93% of all three combinations with two specimens.Conclusions: Thus, eyebrow hairs revealed the highest number of cutaneous HPV infections, are easy to collect and are an appropriate screening tool in order to identify a possible association of HPV and AK. © 2013 Schneider et al.; licensee BioMed Central Ltd.


Antonsson A.,Queensland Institute of Medical Research | Pawlita M.,German Cancer Research Center | Feltkamp M.C.,Leiden University | Bouwes Bavinck J.N.,Leiden University | And 7 more authors.
Journal of Medical Virology | Year: 2013

The human polyomaviruses BKV and JCV cause mostly subclinical infections in childhood. Systemical immunosuppression after organ transplantation can lead to reactivation of persistent polyomavirus infections which may cause rejection of the transplanted organ. BKV and JCV seroprevalence and serostability was measured in 441 European solid organ transplanted recipients. Baseline samples were collected on average 24 days post-transplantation and sera were then collected over an 18 months follow-up period on up to six different time points. The overall seroprevalence at baseline for BKV was 97% with very little change over time. Prevalence for JCV was 76% at baseline and increased to 80% at the end of follow-up. BKV seroprevalence was highest in the youngest age group (100%) and decreased with increasing age (92% in the oldest age group; P<0.0001), while JCV increased with age (69% vs. 81%; P=0.020). Antibody reactivities for both BKV and JCV increased significantly with time (P=0.0002 and P<0.0001, respectively). Among the 406 patients with several samples, 94% were stably seropositive for BKV and 1% remained seronegative during the follow-up. JCV antibody stability was somewhat lower: 67% remained stably seropositive and 13% seronegative. While seroprevalence of BKV and JCV decrease and increase with age, respectively, both polyomaviruses showed significant increasing antibody reactivity over time in organ transplanted recipients at the onset of immunosuppression. J. Med. Virol. 85:327-335, 2013. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.


Muschik D.,German Cancer Research Center | Braspenning-Wesch I.,German Cancer Research Center | Stockfleth E.,University Hospital of Berlin | Rosl F.,German Cancer Research Center | And 3 more authors.
PLoS ONE | Year: 2011

Ultraviolet irradiation (UV) is the major risk factor for the development of skin cancer. Moreover, increasing evidence suggests cutaneotropic human papillomaviruses (HPV) from the beta genus to play a causal role as a co-factor in the development of cutaneous squamous cell carcinoma. Homeodomain-interacting protein kinase 2 (HIPK2) operates as a potential suppressor in skin tumorigenesis and is stabilized by UV-damage. HIPK2 is an important regulator of apoptosis, which forms a complex with the tumor suppressor p53, mediating p53 phosphorylation at Ser 46 and thus promoting pro-apoptotic gene expression. In our study, we demonstrate that cutaneous HPV23 E6 protein directly targets HIPK2 function. Accordingly, HPV23 E6 interacts with HIPK2 both in vitro and in vivo. Furthermore, upon massive UVB-damage HPV23 E6 co-localizes with endogenous HIPK2 at nuclear bodies. Functionally, we demonstrate that HPV23 E6 inhibits HIPK2-mediated p53 Ser 46 phosphorylation through enforcing dissociation of the HIPK2/p53 complex. In addition, HPV23 E6 co-accumulates with endogenous HIPK2 upon UV damage suggesting a mechanism by which HPV23 E6 keeps HIPK2 in check after UV damage. Thus, cutaneous HPV23 E6 prevents HIPK2-mediated p53 Ser 46 phosphorylation, which may favour survival of UV-damaged keratinocytes and skin carcinogenesis by apoptosis evasion. © 2011 Muschik et al.


PubMed | Ludwig Maximilians University of Munich, University Hospital of Goettingen, University of Cologne and University Hospital of Berlin
Type: Journal Article | Journal: Journal of vascular and interventional neurology | Year: 2016

The pipeline embolization device (PED) is a treatment option for wide-neck intracranial aneurysms. The individual number of implants needed to securely exclude an aneurysm is unknown. Our primary objective was to compare midterm occlusion and complication rates in aneurysms treated with a single versus multiple PEDs without adjunctive coiling in a single procedure.Fifty-five patients harboring 58 intracranial aneurysms were treated with 121 PEDs between March 2011 and December 2013. About 38 aneurysms in 37 patients were treated exclusively with PED without adjunctive coiling in a single procedure. All pretreated (recurrent) aneurysms were excluded from analysis. Occlusion results were rated using the OKM-scale. Periprocedural complications were recorded.Immediate angiographic results showed favorable obliteration (OKM C1-3+D) in 5/20 (25%) single-PED cases versus 8/18 (44%) in multiple-PED cases (The nonstaged use of multiple PEDs may result in a higher rate of favorable occlusions at midterm in wide-neck aneurysms treated without adjunctive coiling without significantly increasing the rate of procedural complications.


Liu H.,University Hospital of Berlin | Scholz C.,University Hospital of Berlin | Zang C.,University Hospital of Berlin | Schefe J.H.,University Hospital of Berlin | And 5 more authors.
Anticancer Research | Year: 2012

Aim: Metformin appears to interfere directly with cell proliferation and apoptosis in cancer cells in a non-insulin-mediated manner. One of the key mechanisms of metformin's action is the activation of adenosine monophosphate activated protein kinase (AMPK). AMPK is linked with the phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) pathway and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) cascades - all known for being frequently dysregulated in breast cancer. Therefore, simultaneously targeting AMPK through metformin and the PI3K/AKT/mTOR pathway by an mTOR inhibitor could become a therapeutic approach. The aim of this study was to evaluate the anticancer effect of metformin alone and in combination with chemotherapeutic drugs and the mTOR inhibitor RAD001. Materials and Methods: The proliferation of breast cancer cells was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay; and the cell apoptosis with enzyme-linked immunosorbent assay (ELISA). Gene expression at the protein level was determined by western blot. Results: We tested metformin alone and in combination with RAD001 and/or chemotherapeutic agents (carboplatin, paclitaxel and doxorubicin, respectively) on several human breast cancer cell lines with respect to cell proliferation, apoptosis and autophagy. Metformin alone inhibited cell proliferation and induced apoptosis in different breast cancer cell lines (ERα-positive, HER2-positive, and triple-negative). The cytotoxic effect of metformin was more remarkable in triple-negative breast cancer cell lines than in other cell lines. The cell apoptosis induced by metformin is, at least partly, caspase-dependent and apoptosis inducing factor (AIF)-dependent. Interestingly, we demonstrated that metformin induced cell autophagy. Inhibiting autophagy with chloroquine, enhanced the treatment efficacy of metformin, indicating that autophagy induced by metformin may protect breast cancer cells from apoptosis. We further demonstrated that co-administration of metformin with chemotherapeutic agents and RAD001 intensified the inhibition of cell proliferation. The analysis of cell cycle-regulating proteins cyclin D, cyclin E and p27 by western blot indicated that the synergistic inhibition of G1 phase of the cell cycle by the combination treatment of metformin, chemotherapeutic drugs and/or RAD001 contributed to the synergistic inhibition of cell proliferation. Conclusion: Our investigation provides a rationale for the clinical application of metformin within treatment regimens for breast cancer.


Kavvadias T.,Cantonal Hospital of Lucerne | Baessler K.,University Hospital of Berlin | Schuessler B.,Cantonal Hospital of Lucerne
International Urogynecology Journal and Pelvic Floor Dysfunction | Year: 2012

Therapeutic options for chronic pelvic pain in women offer only a limited symptom relief. Especially in the patient with lower urinary tract symptoms (LUTS), where overlap of pain, storage and voiding symptoms is common, data on the efficacy of treatment of pain are limited. We conducted a literature review to detect articles which pertained to female patients with LUTS and pelvic pain and we included articles which evaluated the efficacy of the treatment of pelvic pain. Forty-one articles were detected, which included nerve stimulation (sacral and pudendal), intravesical instillations and injections, oral pharmacological treatments, periurethral injections as well as physical and manual therapy as treatment options. Only five controlled trials were found, which did not show superiority of the active treatment versus placebo. Although some treatment options show promising results in the treatment of pelvic pain in patients with LUTS, more randomised controlled trials are needed to confirm these results. © The International Urogynecological Association 2012.


Badakhshi H.,University Hospital of Berlin | Wust P.,University Hospital of Berlin | Budach V.,University Hospital of Berlin | Graf R.,University Hospital of Berlin
Anticancer Research | Year: 2013

Background/Aim: To assess intrafractional prostate and patient movement using intra-prostatic fiducials and stereoscopic kilovoltage (kV) X-ray imaging in a 6-dimensional (6D) position correction protocol. To evaluate potential gains of intra-treatment repositioning with respect to treatment margins. Patients and Methods: In intensity-modulated radiotherapy of prostate cancer patients were positioned according to internal fiducials in six dimensions by the use of ExacTrac/Novalis Body™ (ET/NB) System and a robotic couch. Intrafractional displacement of both, prostate and patient were analyzed in 427 treatment fractions of 13 patients. Systematic and random components were specified and used for intra-treatment margin calculation. The potential reduction of treatment margins, and intrafractional repositioning by use of the ET Snap Verification presumed, was simulated. Results: The mean treatment duration was 14.2±2.6 min. Standard deviations (SDs) of the effective intrafractional target displacement in superior-inferior (SI) and anterior-posterior (AP) axes were 2.4 mm and 2.1 mm, respectively. Systematic errors for patient were 1.8 and 1.7 mm, and for prostate movement were 2.1 and 2.0 mm in SI and AP, respectively. The SDs of intrafractional rotation errors of the prostate around SI and left right (LR) were on average 2.2 and 3.6 degrees, respectively. Margins covering intrafractional motion were 4.5 and 4.3 mm in SI and AP without intrafractional correction and were estimated to 2.9 mm and 2.8 mm in SI and AP, respectively for simulated intra-treatment intervention. Conclusion: After positioning according to fiducials, intrafractional motion is significant for treatment margins. Despite correcting rotational deviations by couch angulation, the systematic error for the component of prostate motion was somewhat larger than that of patient displacement. Intrafractional correction could be useful in reducing treatment margins.


Badakhshi H.,University Hospital of Berlin | Muellner S.,University Hospital of Berlin | Wiener E.,University Hospital of Berlin | Budach V.,University Hospital of Berlin
Strahlentherapie und Onkologie | Year: 2014

Introduction: Local tumor control and functional outcome after linac-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for vestibular schwannoma (VS) were assessed. Methods: In all, 250 patients with VS were treated: 190 patients with tumors <∈2 cm diameter underwent SRS and 60 patients with tumors >2 to 3.5 cm underwent FSRT. Dose prescription for all cases with SRS (n∈=∈190, 76∈%) was 13.5 Gy. For FSRT, mainly two hypofractionated schedules (n∈=∈60, 24∈%) with either 7 fractions of 5 Gy (total dose: 35 Gy; n∈=∈35) or 11 fractions of 3.8 Gy (total dose: 41.8 Gy; n∈=∈16) were used. The primary endpoint was local tumor control. Secondary endpoints were symptomatic control and morbidity. Results: The median follow-up was 33.8 months. The 3-year local tumor control was 88.9∈%. Local control for SRS and FSRT was 88 and 92∈%, respectively. For FSRT with 35 and 41.8 Gy, local control was 90 and 100∈%, respectively. There were no acute reactions exceeding grade I. In 61 cases (24.4∈% of the entire cohort), trigeminal neuralgia was reported prior to treatment. At last follow-up, 16.3∈% (10/61) of those patients reported relief of pain. Regarding facial nerve dysfunction, 45 patients (18∈%) presented with symptoms prior to RT. At the last follow-up, 13.3% (6/45) of those patients reported a relief of dysesthesia. Conclusion: Using SRS to treat small VS results in good local control rates. FSRT for larger lesions also seems effective. Severe treatment-related complications are not frequent. Therefore, image-guided stereotactic radiotherapy is an appropriate alternative to microsurgery for patients with VS. © 2014 Springer-Verlag Berlin Heidelberg.

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