Dresden, Germany


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Reinmuth N.,Member of the German Center for Lung Research | Meyer A.,Kliniken Maria Hilf | Hartwigsen D.,Malteser Krankenhaus St. Franziskus | Schaeper C.,Universitaetsklinikum | And 6 more authors.
Lung Cancer | Year: 2014

Objectives: Adding nitroglycerin to the combination of vinorelbine plus cisplatin has been reported to improve the overall survival (OS) of Asian patients with stage IIIB/IV non-small cell lung cancer (NSCLC) probably due to better drug delivery based on changed vascular tonus. The main objective of our study was to evaluate the effect of adding nitroglycerin to vinorelbine and cisplatin in a Caucasian population. Methods: 66 chemonaïve patients with stage IIIB/IV NSCLC received oral vinorelbine (first cycle 60mg/m2, subsequent cycles: 80mg/m2 in the absence of any hematological toxicity ≥grade 3 in cycle 1) once daily on days 1 and 8 of each cycle and cisplatin (80mg/m2 i.v.) on day 1 of each cycle (q3w). Nitroglycerin (arm A, n=34) or placebo patches (arm B, n=32) were administered once daily from day -3 to day 2 of each cycle and were removed about 12h after administration. One nitroglycerin patch contained 25mg nitroglycerin. Results: Median age was 62.5 (33-82) years. In the overall population (n= 66), the objective response rate (ORR) was 27.3% (all PR; 95%CI: 17.0-39.6), with a disease control rate (DCR) of 57.6% (95%CI: 44.8-69.7), a median time to progression (TTP) of 4.8 months (n= 58; 95%CI: 3.4-5.9) and a median overall survival (OS) of 11.5 months (95%CI: 7.9-13.6). ORR and DCR were numerically higher in arm A than in arm B (35.3% vs. 18.8% and 61.8% vs. 53.1%, respectively), whereas TTP and OS were comparable. The main hematological and non-hematological toxicities grade ≥3 were moderate with no significant differences between the two treatment arms. Conclusions: Overall, oral vinorelbine plus cisplatin showed a high level of efficacy and adequate tolerability in first line treatment of NSCLC. Despite the low sample size per group the results seem to confirm the previous results reported in Asian patients. © 2014 Elsevier Ireland Ltd.

Huang L.,Genetics and Molecular Pathology | Huang L.,Central South University | Jolly L.A.,Genetics and Molecular Pathology | Willis-Owen S.,Genetics and Molecular Pathology | And 20 more authors.
American Journal of Human Genetics | Year: 2012

The discovery of mutations causing human disease has so far been biased toward protein-coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel resequencing of the nonrepetitive genomic linkage interval at Xq28 of family MRX3. We identified in the binding site of transcription factor YY1 a regulatory mutation that leads to overexpression of the chromatin-associated transcriptional regulator HCFC1. When tested on embryonic murine neural stem cells and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and a considerable reduction in neurite growth. Two other nonsynonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function. © 2012 The American Society of Human Genetics.

PubMed | Hannover Medical School, Zentrum fuer Diagnostik GmbH MVZ, Max Planck Institute for Molecular Genetics, Universitaetsklinikum and 4 more.
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

The clinical diagnosis of Lujan-Fryns syndrome (LFS) comprises X-linked intellectual disability (XLID) with marfanoid habitus, distinct combination of minor facial anomalies and nasal speech. However the definition of syndrome was significantly broadened since the original report and implies ID with marfanoid habitus. Mutations of three genes (MED12, UPF3B, and ZDHHC9) have been reported in broadly defined LFS. We examined these genes in 28 individuals with a tentative clinical diagnosis of LFS but we did not identify any causative mutation. By molecular karyotyping we detected other disorders, i.e., Phelan-McDermid syndrome and 16p11.2 microduplication, each in one patient. One affected individual was carrier of a different recurrent duplication on 16p11.2 that has been reported several times to the DECIPHER and ISCA databases in individuals with autism, intellectual disability (ID), and developmental delay. It may represent a new duplication syndrome. We also identified previously unreported de novo duplication on chromosome 12p13.31 which we considered to be disease-causing. X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each. While LFS is defined as a form of XLID, there seem to be various conditions that have rather similar phenotypes. Therefore, the combination of ID and marfanoid habitus in a male patient is not sufficient for the diagnosis of LFS. We suggest that the diagnosis of LFS in patients with ID and marfanoid habitus should be made only in presence of specific facial features, nasal speech and obvious X-linked segregation of the disorder or an unambiguously pathogenic mutation in the MED12.

Craddock C.,Queen Elizabeth Hospital | Labopin M.,EBMT ALWP Office | Pillai S.,Queen Elizabeth Hospital | Finke J.,Albert Ludwigs University of Freiburg | And 15 more authors.
Leukemia | Year: 2011

Treatment options for adults with primary refractory acute myeloid leukaemia (PREF AML) are extremely limited. Although sibling allogeneic stem cell transplantation can result in long-term survival, most patients lack a matched family donor and are destined to die of refractory disease. Greater availability of unrelated donors and improvements in supportive care have increased the proportion of patients with PREF AML in whom allografting is technically feasible, but the outcome of unrelated donor transplantation in this population has not been studied. We therefore analysed overall survival in 168 patients with PREF AML, who underwent unrelated donor transplantation between 1994 and 2006. The 5-year overall survival for the whole group was 22%. In multivariate analysis, fewer than three courses of induction chemotherapy, a lower percentage of bone marrow blasts at transplant and patient cytomegalovirus seropositivity were associated with improved survival. This allowed the development of a scoring system that identified four groups with survival rates between 4411% and 0%. This study demonstrates an important role for unrelated donor transplantation in the management of selected patients with PREF AML and confirms the importance of initiating an urgent unrelated donor search in patients with no matched sibling donor, who fail to respond to induction chemotherapy. © 2011 Macmillan Publishers Limited All rights reserved.

PubMed | University of Manchester, University of Tartu, Grazyna Pulka Specjalistyczny Osrodek ALL MED ul.Sw. Marka 31 IU, Universitaetsklinikum and 4 more.
Type: | Journal: The British journal of dermatology | Year: 2016

GP2015 is a proposed etanercept biosimilar.To demonstrate equivalent efficacy, and comparable safety and immunogenicity of GP2015 and etanercept originator (ETN, Enbrel531 eligible patients were randomised 1:1 to self-administer GP2015 or ETN twice-weekly subcutaneously. Patients with a 50% improvement in psoriasis area and severity index (PASI 50) at week 12 were re-randomised to continue the same treatment on a once-weekly dosing schedule or to undergo a sequence of 3 treatment switches between GP2015 and ETN until week 30. Thereafter, patients continued treatment with the product they had been assigned to last, up to week 52.The difference in PASI 75 (75% improvement from baseline PASI score) response rates at week 12 between GP2015 and ETN (primary endpoint) was -2.3%. The 95% confidence interval (-9.85, 5.30) was well contained within the pre-specified margin range of (-18, 18). Incidence of treatment-emergent adverse events up to week 52 was comparable between continued GP2015 (59.8%) and ETN (57.3%); switching treatments revealed comparable safety profiles. Anti-drug antibodies, all non-neutralising, were limited to 5 patients on ETN during treatment period 1, and 1 patient in the switched ETN group, who had been treated with GP2015 for 12 weeks at time of the finding.The EGALITY study demonstrated equivalent efficacy and comparable safety and immunogenicity of GP2015 and ETN. The study results provided the final clinical confirmation of biosimilarity and contributed to the totality-of-the-evidence proposing that GP2015 is an etanercept biosimilar. This article is protected by copyright. All rights reserved.

Dartell M.,Danish Cancer Society | Rasch V.,University of Southern Denmark | Munk C.,Danish Cancer Society | Kahesa C.,Ocean Road Cancer Institute | And 4 more authors.
Sexually Transmitted Diseases | Year: 2013

BACKGROUND: Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. The prevalence is dependent on several known factors notably sexual behavior and age, and factors still under scrutiny. OBJECTIVE: This study aimed to examine risk factors for high-risk (HR) HPV infection among HIV-positive and HIV-negative women from the general population of Tanzania and to assess whether specific risk factors could contribute to the high prevalence of HR HPV infection in older age found in some populations including Tanzanian women. METHODS: A cross-sectional study of 3699 women from Tanzania was conducted. We obtained information on sociodemographic and lifestyle factors through personal interview. Cervical swabs were collected for detection of HR HPV (Hybrid Capture 2; Qiagen, Hildesheim, Germany) and genotyping (LiPaExtra; Innogenetics, Gent, Belgium). Finally, we obtained a blood sample for HIV testing. RESULTS: HIV positivity was the strongest risk factor for HR HPV (odds ratio, 4.1; 95% confidence interval, 3.3-5.3). Young age, shorter duration of present relationship, and increasing number of sex partners were also associated with higher risk for HR HPV. Among women 20 to 29 years old, especially number of partners (P = 0.005) and HIV positivity (P < 0.0001) determined the risk. In underweight women 50 years or older (P = 0.004) and HIV positivity (P = 0.0009) increased the risk, whereas increasing number of partners was not related to the risk of HR HPV (P = 0.46). CONCLUSIONS: Human papillomavirus risk factors among HIV-positive and HIV-negative women were similar, but the strength of association was greater among HIV-positive women, notably for lifetime number of sex partners, time in present relationship, genital warts, and body mass index. We were not able to identify a clear explanation for the high HPV prevalence among older women. However, in the age-stratified analysis, potential indicators of decreased immunity increased the risk for HPV infection among older women, whereas in younger women, risk was particularly associated with sexual activity. Copyright © 2013 American Sexually Transmitted Diseases Association. All rights reserved.

Olesen T.B.,Danish Cancer Society | Iftner T.,Universitaetsklinikum | Mwaiselage J.,Ocean Road Cancer Institute | Kahesa C.,Ocean Road Cancer Institute | And 5 more authors.
Sexually Transmitted Diseases | Year: 2013

Background: Infection with high-risk (HR) human papillomavirus (HPV) is associated with penile cancer in men, cervical cancer in women, and anal cancer and certain types of head and neck cancers in both sexes. Few studies have assessed the prevalence and type distribution of HPV among men in sub-Saharan Africa, where the rates of HIVand penile and cervical cancer are high. Material and Methods: We used data from a cross-sectional study among 1813 men in Tanzania. Penile samples were tested using Hybrid Capture 2, and genotyping was done by the INNO-LiPA HPVGenotyping Extra test. Blood samples were tested for HIV. The overall and type-specific prevalence and 95% confidence interval of HPV was estimated in relation to age and HIV status. Results: The overall prevalence of HPV was 20.5% (95% confidence interval, 18.7-22.4), the most prevalent HR HPV types being HPV52, HPV51, HPV16, HPV18, HPV35, and HPV66. The HR HPV prevalence was significantly higher in HIV-positive men (25.7%) than in HIVnegative men (15.8%; P = 0.0027). The prevalence of HPV16, HPV18 and multiple HR HPVs tended to be higher among HIV-positive men (statistically nonsignificant), whereas no differences were observed for the other HPV types. Conclusions: We found a high prevalence of HPV types 52, 51, 16, 18, 35, and 66. This information is of relevance in the understanding of HPV type distributions across populations. Although the prevalence of HPV16 and HPV18 was slightly higher among HIV-positive men, our results indicate that HIV status does not strongly influence the distribution of HPV types. Therefore, the currently available HPV vaccines could prevent HPV infection independently of HIV status. Copyright © 2013 by the American Sexually Transmitted Diseases Association.

PubMed | Universitaetsklinikum, Danish Cancer Society, Ocean Road Cancer Institute and University of Southern Denmark
Type: Journal Article | Journal: Journal of medical virology | Year: 2016

The objective of the study was to assess risk factors for Human Papillomavirus (HPV) among men in Tanzania, both overall and in relation to HIV status. In a cross-sectional study conducted among 1,813 men in Tanzania, penile swabs were tested for HPV using Hybrid Capture 2 (HC2). Study participants were offered HIV testing. Risk factors for HPV (HC2 high-risk and/or low-risk positivity) were assessed using logistic regression with adjustment for age, lifetime number of sexual partners, and HIV status. Altogether, 372 men (20.5%) were HPV-positive. Among men tested for HIV (n=1,483), the HIV prevalence was 9.4%. The odds ratio (OR) of HPV increased with increasing age. HIV-positivity was associated with an increased odds ratio of HPV (OR=1.91; 95%CI: 1.30-2.82), whereas the odds of HPV tended to be lower in circumcised men than in uncircumcised men (OR=0.77; 95%CI: 0.54-1.09). When stratifying by HIV status, we found lower odds of HPV in overweight HIV-positive men (BMI>25) than in normal weight HIV-positive men (OR=0.25; 95%CI: 0.08-0.78). This did not apply to HIV-negative men. Circumcision tended to decrease the odds of HPV both in HIV-positive men and in HIV-negative men, although not being statistically significant. In conclusion, HIV is a strong risk factor for HPV among men in Tanzania. Additionally, in HIV-positive men a high BMI seems to be associated with a lower risk of HPV. Finally, we observed a tendency toward a lower risk of HPV both among HIV-positive and HIV-negative circumcised men compared to their uncircumcised counterparts. J. Med. Virol. 89:345-351, 2017. 2016 Wiley Periodicals, Inc.

Fraccarollo D.,Klinik fuer Kardiologie und Angiologie | Fraccarollo D.,Universitatsklinikum | Berger S.,German Cancer Research Center | Galuppo P.,Klinik fuer Kardiologie und Angiologie | And 7 more authors.
Circulation | Year: 2011

Background- Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR) that were generated with a conditional MR allele (MR) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. Methods and Results- Control (MR, MR) and MR mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR mice. Chronically infarcted MR mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O2 production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction. Conclusion- Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression. Copyright © 2011 American Heart Association. All rights reserved.

Iftner T.,Universitaetsklinikum | Eberle S.,Glaxosmithkline | Iftner A.,Universitaetsklinikum | Holz B.,Universitaetsklinikum | And 3 more authors.
Journal of Medical Virology | Year: 2010

Human papillomavirus (HPV) infection is frequent in young women and persistent infection may lead to cervical cancer. Therefore, vaccination against HPV is recommended for young women in the age group from 12-17 years in Germany. However, epidemiological data on the prevalence of HPV types and risk factors for infection for younger women in Germany is scarce. To address this, an observational study was performed in Germany including 1,692 women aged 10-30 years. After a routine Pap smear, cervical swabs were tested for high-risk and low-risk HPV, respectively, using the Hybrid Capture 2 (HC2) test, and genotyped using the PCR-based tests SPF10/LiPA25 and PapilloCheck®. In addition, the women were interviewed regarding their medical history and lifestyle factors. Three hundred seventy-seven (22.28%) women had positive HC2 results. The proportion of HPV positive women was highest in the 20-22 age group with 28.3%. Predominant HPV types were HPV 16, 42, 51 and HPV 16, 51, 31 as defined by PapilloCheck® and SPF10/LiPA25, respectively. 95.8% of women did not show signs of any cervical lesion. Adjusted analysis identified number of sexual partners (OR:1.105; 95% CI:[1.069-1.142]), smoking (OR:1.508; [1.155-1.968]), and vaccination against HPV (OR:0.589; [0.398-0.872]) rather than increasing age as risk associated with HPV infection. Comparison of the genotyping assays showed that they correspond well regarding the high-risk HPV types but less well for low-risk HPV types. This epidemiological study shows that high-risk HPV infection is common in young women in Germany. According to our data, vaccination of young women could have a potential impact on the prevention of HPV infection and cervical disease. J. Med. Virol. 82:1928-1939, 2010. © 2010 Wiley-Liss, Inc.

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