Schweinfurt, Germany
Schweinfurt, Germany

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Klement R.J.,Leopoldina Hospital
Radiotherapy and Oncology | Year: 2017

Background and purpose: The radiobiological parameters for liver and lung metastases treated with stereotactic body radiation therapy (SBRT) are poorly defined. This project aimed at estimating these parameters from published tumor control probability (TCP) data, and separately for metastases with colorectal cancer (CRC) and non-CRC histology. Materials and methods: A total of 62 studies with 89 different treatment prescriptions for a total of 3719 metastases were analyzed in a Bayesian framework using four different radiobiological models: The LQ, mLQ, LQ-L and the regrowth model which accounts for tumor regrowth after SBRT. Results: Depending on the particular model, α/. β ratios in the range 13-23. Gy for pulmonary metastases and 16-28. Gy for hepatic metastases were estimated. For CRC metastases the estimated α/. β ratio was 43.1. ±. 4.7. Gy compared to 21.6. ±. 7.8. Gy for non-CRC metastases. Typical isocenter dose prescriptions of 3. ×. 12. Gy, 3. ×. 14.5. Gy and 3. ×. 17. Gy applied within 5. days were predicted sufficient to control 90% of lung, liver and CRC metastases after 1. yr, respectively. Conclusions: α/. β ratios for liver and lung metastases are higher than the usually assumed 10. Gy. Differences between CRC and non-CRC histology were found. Future studies confirming these findings in individual patient data are needed. © 2017 Elsevier B.V.


Guckenberger M.,University Hospital of Wuerzburg | Klement R.J.,University Hospital of Wuerzburg | Klement R.J.,Leopoldina Hospital | Allgauer M.,Barmherzige Bruder | And 12 more authors.
Radiotherapy and Oncology | Year: 2013

Background and purpose To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). Materials and methods This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). Results There was strong evidence for a dose-response relationship in the total patient cohort (BFs > 20), which was lacking in single-fraction SBRT (BFs < 3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p = 0.07, BF = 2.1 and p = 0.86, BF = 0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs > 20). Conclusion Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism. © 2013 Elsevier Ireland Ltd. All rights reserved.


Maass T.,Johannes Gutenberg University Mainz | Thieringer F.R.,Johannes Gutenberg University Mainz | Mann A.,University of Leipzig | Longerich T.,University of Heidelberg | And 7 more authors.
International Journal of Cancer | Year: 2011

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. Copyright © 2010 UICC.


Thieringer F.R.,Johannes Gutenberg University Mainz | Maass T.,Johannes Gutenberg University Mainz | Anthon B.,Johannes Gutenberg University Mainz | Meyer E.,Johannes Gutenberg University Mainz | And 5 more authors.
Molecular Carcinogenesis | Year: 2012

Matrix metalloproteinase-9 (MMP-9) plays a central role in tumor invasion and development of metastases. Expression of MMP-9 had been shown in human hepatocellular carcinomas (HCCs). However, it remained unclear whether MMP-9 could influence development of HCC. In order to address this issue, we generated transgenic mice overexpressing MMP-9 in the liver. In order to avoid embryonic lethality a Cre-lox system was utilized for conditional overexpression of MMP-9 under control of an albumin enhancer and promoter. Induction of MMP-9 overexpression in transgenic mice was achieved by i.v. injection of an adenovirus coding for the Cre recombinase. Initiation of liver carcinogenesis was achieved by injection of diethylnitrosamine (DEN) followed by Phenobarbital administration in drinking water. Transgene expression was induced at the age of 6wk. Four and six months later mice were sacrificed and examined macroscopically and microscopically in a blinded manner. Alb/Cre/MMP-9-transgenic mice showed liver specific overexpression of MMP-9-mRNA and protein after induction. At the age of 6 months livers of transgenic mice showed 15.7±11.6 tumors (mean±SD) in contrast to wildtype mice with only 7.9±11.0 tumors (P<0.03). By histopathology examination of the livers HCCs were identified in 42% of the transgenic mouse livers but only 8% in wildtype animals. In summary, we established a novel MMP-9 transgenic mouse model, and report on a significantly increased susceptibility of MMP-9 transgenic mice to chemically induced carcinogenesis. This is the first in vivo proof that MMP-9 overexpression promotes liver tumor development. © 2011 Wiley Periodicals, Inc.


Fink T.,Saarland University | Glas M.,Saarland University | Wolf A.,Saarland University | Kleber A.,Saarland University | And 7 more authors.
Critical Care Medicine | Year: 2014

OBJECTIVES:: Melatonin has been demonstrated to improve survival after experimental sepsis via antioxidant effects. Yet, recent evidence suggests that this protective capacity may also rely on melatonin receptor activation. Therefore, the present study was designed to investigate whether selective melatonin receptor-agonist ramelteon may influence survival and immune response in a model of polymicrobial sepsis in rats, wild-type and melatonin receptor MT1/MT2 double knockout mice. DESIGN:: Prospective, randomized, controlled study. SETTING:: University research laboratory. SUBJECTS:: Male Sprague-Dawley rats (200-250 g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20-22 g). INTERVENTIONS:: Animals underwent cecal ligation and incision and remained anesthetized for evaluation of survival for 12 hours (rats: n = 15 per group) or 15 hours (mice: n = 10 per group). Analysis of immune response by means of enzyme-linked immunosorbent assay was performed before and 5 hours after cecal ligation and incision (rats only; n = 5 per group). After induction of sepsis, animals were treated IV with vehicle, different doses of melatonin (rats: 0.01/0.1/1.0/10 mg/kg; mice: 1.0 mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0 mg/kg). Sham controls underwent laparotomy but not cecal ligation and incision. MEASUREMENTS AND MAIN RESULTS:: Compared with vehicle, administration of ramelteon or melatonin significantly improved median survival time in rats (sepsis/melatonin [0.1 mg/kg], 554 min, [1.0 mg/kg] 570 min, [10 mg/kg] 579 min; sepsis/ramelteon, 468 min; each p < 0.001 vs sepsis/vehicle, 303 min) and wild-type mice (sepsis/melatonin, 781 min; sepsis/ramelteon, 701 min; both p < 0.001 vs sepsis/vehicle, 435 min). This effect was completely antagonized by coadministration of luzindole in all groups. Melatonin, ramelteon, or luzindole had no significant effect on survival time in knockout mice. Significantly elevated concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-10 were observed 5 hours after cecal ligation and incision in rats (p < 0.05 vs baseline and corresponding sham); neither ramelteon nor melatonin treatment significantly affected immune response. CONCLUSIONS:: Melatonin receptors mediate improvements of survival after polymicrobial sepsis in rats and mice; this effect appears to be independent from major alterations of cytokine release. © 2013 by the Society of Critical Care Medicine.


Fink T.,Saarland University | Heymann P.,Saarland University | Taha-Melitz S.,Saarland University | Taha A.,Saarland University | And 4 more authors.
Shock | Year: 2013

Dobutamine is recommended for the treatment of sepsis-related circulatory failure in international guidelines. Furthermore, dobutamine has been demonstrated to improve liver function and hepatic perfusion after experimental hemorrhagic shock. Yet, it is unknown whether dobutamine may also induce hepatoprotective effects in sepsis. This study was designed to investigate the effect of dobutamine on survival, hepatic function, and microcirculation after polymicrobial sepsis in rat. Under general anesthesia, male Sprague-Dawley rats (n = 25/group) underwent pretreatment with dobutamine (10 μg/kg per minute) in the presence or absence of β1-receptor antagonist esmolol (500 μg/kg per minute), esmolol alone, or vehicle for 6 h, before induction of sepsis (cecal ligation and incision [CLI]). Sham-operated animals were treated likewise but underwent no CLI. Five hours after CLI, either liver function was assessed by plasma disappearance rate of indocyanine green (n = 5/group), or intravital microscopy was performed (n = 5/group) for evaluation of hepatic perfusion index and hepatic integrity (as propidium iodide-stained cells per field). Alternatively, survival time after induction of CLI was monitored under general anesthesia (n = 15/group). Compared with controls, dobutamine pretreatment significantly improved plasma disappearance rate of indocyanine green (13.8% ± 4.1% vs. 20.6% ± 4.6%; P = 0.029), hepatic perfusion index (275.0 ± 126.1 vs. 703.5 ± 177.4 pL/s per mm; P < 0.001), hepatocellular injury (22.2 ± 6.7 vs. 6.4 ± 3.1 cells per field; P < 0.001), and survival time (326 ± 20 vs. 603 ± 41 min; P < 0.001). Coadministration of esmolol abolished the protective effect of dobutamine completely. Our results indicate that pretreatment with dobutamine may improve survival, liver function, and hepatic microcirculation after polymicrobial sepsis in rat via β1-adrenoceptor activation. Dobutamine could therefore play a relevant role for hepatoprotection under septic conditions. Copyright © 2013 by the Shock Society.


Kehl S.,University of Mannheim | Weigel M.,Leopoldina Hospital | Muller D.,University of Mannheim | Gentili M.,University of Mannheim | And 3 more authors.
Archives of Gynecology and Obstetrics | Year: 2011

Purpose: Serodiscordant couples with a human immunodeficiency virus type 1 (HIV-1)-infected man request assisted reproductive technology (ART) in order to achieve safe conception. Most of these men are on highly active antiretroviral therapy (HAART). HIV-1 infection and the antiretroviral drugs are blamed for semen alterations. The aim of our study was to investigate the semen parameters in HIV-1-infected patients with and without HAART and to compare their sperm characteristics with those of healthy men. Materials and methods: A prospective study of 226 men attended the university fertility center of Mannheim between May 1996 and July 2003. The patients were divided into three groups: HIV-infected men taking antiretroviral therapy, HIV-infected patients who did not take antiretroviral therapy until now and a control group with 93 men consulting our fertility center together with their wives because of tubal sterility. Semen samples were examined with regard to ejaculate volume, sperm concentration, motility, and morphology. Results: The study showed significant differences between the ejaculate of HIV-infected and non-infected men. The HIV-infected men as a whole group and the subgroup of men with HAART had a lower ejaculate volume, less slow progressive and more abnormally shaped spermatozoa compared with the control group. The HIV-infected men without an antiretroviral therapy had a significant lower ejaculate volume compared with the control group; the other parameters were not altered significantly. Differences between the subgroups with and without HAART were not significant. Conclusion: The spermiogram in HIV-1-infected men in comparison to a control group of healthy men is negatively altered. Especially in men with HAART, ejaculate volume as well as sperm morphology and motility changed significantly. © 2011 Springer-Verlag.


Klement R.J.,Leopoldina Hospital | Sweeney R.A.,Leopoldina Hospital
Clinical Nutrition ESPEN | Year: 2016

Background: We have found that a ketogenic diet (KD) during the course of radiotherapy (RT) was feasible and led to a preservation or favorable changes of body composition. Based on these observations and theoretical considerations, we initiated a study to investigate the impact of a KD or a ketogenic breakfast intervention in patients undergoing RT. Methods: All patients presenting for curative RT with age between 18 and 75, body mass index between 18 and 34 kg/m2 and a histologically confirmed cancer of the breast, colorectum or head and neck region are considered for inclusion. Exclusion criteria are Karnofsky index <70, pregnancy, metallic body parts that interfere with bioimpedance analysis (BIA), type I diabetes, known enzyme defects that contradict a KD and renal insufficiency. Randomization is achieved by all consecutive patients first entering the control group and then an intervention group 1 until both groups contain 15 breast, 15 colorectal and 5 head and neck cancer patients. Intervention group 1 will receive each radiotherapy fraction after an overnight fast and subsequently ingest a ketogenic breakfast consisting of (i) 50-250 ml of a medium-chain triglyceride drink (betaquick®, vitaflo, Bad Homburg, Germany) plus (ii) 5-15 g amino acids (MAP, dr. reinwald healthcare gmbh+co kg, Schwarzenbruck, Germany). If willing to undertake a complete KD for the duration of RT, patients are entered into intervention group 2. Intervention group 2 does not have to fast prior to RT fractions but will be supplemented with MAP analogous to intervention group 1. The control group will not receive dietary advice to follow a KD or reduce carbohydrate intake. The objective is twofold: (i) to test whether the ketogenic interventions are feasibly, as measured by the number of dropouts; (ii) to see whether intervention groups 1 and 2 attain a better preservation of BIA phase angle than the control group. Endpoints: Primary endpoints are the feasibility of the interventions (measured through dropout rates), and changes in body weight and composition (measured through BIA). Secondary endpoints are changes in quality of life (EORTC questionnaires) and blood parameters as well as the occurrence and grade of toxicities and grade of regression after surgery in case of colorectal carcinomas. Trial registration: Registered under ClinicalTrials.gov Identifier no. NCT00123456. © 2015 European Society for Clinical Nutrition and Metabolism.


Klement R.J.,Leopoldina Hospital
Trends in molecular medicine | Year: 2014

As ongoing research continues to reveal the links between metabolism, cancer, and aging it is good to see non-toxic interventions such as caloric restriction (CR) coming into focus. Recently, Meynet and Ricci provided a timely review summarizing the current state of research on the possible role of CR in cancer treatment. In discussing ways to implement clinically the beneficial effects of CR without a need for overall reduced food intake these authors focused on CR-mimicking drugs that have several limitations. I propose carbohydrate restriction as probably the best way to mimic CR in humans without the need to restrict energy intake. Copyright © 2014 Elsevier Ltd. All rights reserved.


Klement R.J.,Leopoldina Hospital
Cancer Biology and Medicine | Year: 2014

Head and neck cancers (HNCs) are aggressive tumors that typically demonstrate a high glycolytic rate, which results in resistance to cytotoxic therapy and poor prognosis. Due to their location these tumors specifically impair food intake and quality of life, so that prevention of weight loss through nutrition support becomes an important treatment goal. Dietary restriction of carbohydrates (CHOs) and their replacement with fat, mostly in form of a ketogenic diet (KD), have been suggested to accommodate for both the altered tumor cell metabolism and cancer-associated weight loss. In this review, I present three specific rationales for CHO restriction and nutritional ketosis as supportive treatment options for the HNC patient. These are (1) targeting the origin and specific aspects of tumor glycolysis; (2) protecting normal tissue from but sensitizing tumor tissue to radiation- and chemotherapy induced cell kill; (3) supporting body and muscle mass maintenance. While most of these benefits of CHO restriction apply to cancer in general, specific aspects of implementation are discussed in relation to HNC patients. While CHO restriction seems feasible in HNC patients the available evidence indicates that its role may extend beyond fighting malnutrition to fighting HNC itself. Copyright © 2014 by Cancer Biology & Medicine.

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