@article{DufnerKesslerJustetal.2022, author = {Dufner, Vera and Kessler, Almuth Friederike and Just, Larissa and Hau, Peter and Bumes, Elisabeth and Pels, Hendrik Johannes and Grauer, Oliver Martin and Wiese, Bettina and L{\"o}hr, Mario and Jordan, Karin and Strik, Herwig}, title = {The emesis trial: depressive glioma patients are more affected by chemotherapy-induced nausea and vomiting}, series = {Frontiers in Neurology}, volume = {13}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2022.773265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262859}, year = {2022}, abstract = {Purpose Glioma patients face a limited life expectancy and at the same time, they suffer from afflicting symptoms and undesired effects of tumor treatment. Apart from bone marrow suppression, standard chemotherapy with temozolomide causes nausea, emesis and loss of appetite. In this pilot study, we investigated how chemotherapy-induced nausea and vomiting (CINV) affects the patients' levels of depression and their quality of life. Methods In this prospective observational multicentre study (n = 87), nausea, emesis and loss of appetite were evaluated with an expanded MASCC questionnaire, covering 10 days during the first and the second cycle of chemotherapy. Quality of life was assessed with the EORTC QLQ-C30 and BN 20 questionnaire and levels of depression with the PHQ-9 inventory before and after the first and second cycle of chemotherapy. Results CINV affected a minor part of patients. If present, it reached its maximum at day 3 and decreased to baseline level not before day 8. Levels of depression increased significantly after the first cycle of chemotherapy, but decreased during the further course of treatment. Patients with higher levels of depression were more severely affected by CINV and showed a lower quality of life through all time-points. Conclusion We conclude that symptoms of depression should be perceived in advance and treated in order to avoid more severe side effects of tumor treatment. Additionally, in affected patients, delayed nausea was most prominent, pointing toward an activation of the NK1 receptor. We conclude that long acting antiemetics are necessary totreat temozolomide-induced nausea.}, language = {en} } @article{GaabAdolphTippeltetal.2022, author = {Gaab, Christine and Adolph, Jonas E. and Tippelt, Stephan and Mikasch, Ruth and Obrecht, Denise and Mynarek, Martin and Rutkowski, Stefan and Pfister, Stefan M. and Milde, Till and Witt, Olaf and Bison, Brigitte and Warmuth-Metz, Monika and Kortmann, Rolf-Dieter and Dietzsch, Stefan and Pietsch, Torsten and Timmermann, Beate and Str{\"a}ter, Ronald and Bode, Udo and Faldum, Andreas and Kwiecien, Robert and Fleischhack, Gudrun}, title = {Local and systemic therapy of recurrent medulloblastomas in children and adolescents: results of the P-HIT-REZ 2005 Study}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers14030471}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254809}, year = {2022}, abstract = {Recurrent medulloblastomas are associated with survival rates <10\%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9-16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7-10.0) and 18.5 months (CI: 13.6-23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7\% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8\%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients' survival.}, language = {en} } @article{KandelsPietschBisonetal.2020, author = {Kandels, Daniela and Pietsch, Torsten and Bison, Brigitte and Warmuth-Metz, Monika and Thomale, Ulrich-Wilhelm and Kortmann, Rolf-Dieter and Timmermann, Beate and Hern{\´a}iz Driever, Pablo and Witt, Olaf and Schmidt, Ren{\´e} and Gnekow, Astrid K.}, title = {Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low-grade glioma patients—Report from the German SIOP-LGG 2004 cohort}, series = {International Journal of Cancer}, volume = {147}, journal = {International Journal of Cancer}, number = {12}, doi = {10.1002/ijc.33170}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216130}, pages = {3471 -- 3489}, year = {2020}, abstract = {First-line treatment of pediatric low-grade glioma using surgery, radio- or chemotherapy fails in a relevant proportion of patients. We analyzed efficacy of subsequent surgical and nonsurgical therapies of the German cohort of the SIOP-LGG 2004 study (2004-2012, 1558 registered patients; median age at diagnosis 7.6 years, median observation time 9.2 years, overall survival 98\%/96\% at 5/10 years, 15\% neurofibromatosis type 1 [NF1]). During follow-up, 1078/1558 patients remained observed without (n = 217), with 1 (n = 707), 2 (n = 124) or 3 to 6 (n = 30) tumor volume reductions; 480/1558 had 1 (n = 332), 2 (n = 80), 3 or more (n = 68) nonsurgical treatment-lines, accompanied by up to 4 tumor-reductive surgeries in 215/480; 265/480 patients never underwent any neurosurgical tumor volume reduction (163/265 optic pathway glioma). Patients with progressing tumors after first-line adjuvant treatment were at increased risk of suffering further progressions. Risk factors were young age (<1 year) at start of treatment, tumor dissemination or progression within 18 months after start of chemotherapy. Progression-free survival rates declined with subsequent treatment-lines, yet remaining higher for patients with NF1. In non-NF1-associated tumors, vinblastine monotherapy vs platinum-based chemotherapy was noticeably less effective when used as second-line treatment. Yet, for the entire cohort, results did not favor a certain sequence of specific treatment options. Rather, all can be aligned as a portfolio of choices which need careful balancing of risks and benefits. Future molecular data may predict long-term tumor biology.}, language = {en} } @phdthesis{Laufs2019, author = {Laufs, Valeria}, title = {Evaluation von ERCC1 als pr{\"a}diktiver Biomarker bei mit platinbasierter Chemotherapie behandeltem Nebennierenrindenkarzinom}, doi = {10.25972/OPUS-18023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180230}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Platinbasierte Chemotherapie ist die effektivste Chemotherapie f{\"u}r das fortgeschrittene Nebennierenrindenkarzinom (ACC). Excision repair cross complementing group 1 (ERCC1) spielt eine entscheidende Rolle bei der Reparatur durch Platin entstandener DNA-Sch{\"a}den. Zwei Studien die die Rolle von ERCC1 per Immunhistochemie als pr{\"a}diktiver Marker f{\"u}r das Ansprechen auf platinbasierte Chemotherapie beim ACC untersuchten kamen zu sich widersprechenden Ergebnissen. Beide Studien nutzten den ERCC1-Antik{\"o}rper Klon 8F1 der sich sp{\"a}ter als nicht spezifisch herausstellte. Das Ziel der Doktorarbeit war die Evaluation von ERCC1 mit einem neuen hoch spezifischen Antik{\"o}rper in einer großen Kohorte von Patienten mit ACC. Material und Methoden: 146 Patienten mit verf{\"u}gbaren FFPE-Schnitten wurden eingeschlossen. Alle Patienten erhielten eine platinbasierte Chemotherapie im Median f{\"u}r 6 Zyklen, n{\"a}mlich Cisplatin (n=131) oder Carboplatin (n=15), in den meisten F{\"a}llen in Kombination mit Etoposid (n=144 , Doxorubicin (n=131) und Mitotane (n=131). Die Immunhistochemische F{\"a}rbung wurde mit dem neuen Antik{\"o}rper Klon 4F9 durchgef{\"u}hrt. Der Zusammenhang zwischen ERCC1-Expression und klinischen Parametern, Therapieansprechen, progressionsfreiem {\"U}berleben und Gesamt{\"u}berleben wurde analysiert. Ergebnisse: Eine hohe ERCC1-Expression wurde in 66\% der Tumorproben beobachtet. W{\"a}hrend der Chemotherapie zeigte sich bei 43 Pateinten ein Therapieansprechen (29,5\%), bei 49 Patienten eine Stabilisierung der Erkrankung (33,6\%), bei 8 Patienten ein gemischtes Ansprechen (5,5\%) und bei 46 Pateinten ein Krankheitsprogress (31,5\%), ohne Zusammenhang zur ERCC1-Expression. Auch zeigte sich kein signifikanter Zusammenhanf zwischen der ERCC1-Expression und dem progressionsfreien {\"U}berleben (Median 6.5 vs. 6 Monate, P=0.33, HR=1.23, 95\%CI=0.82-2.0) oder dem Gesamt{\"u}berleben. Zusammenfassung: Es besteht kein Zusammenhang zwischen der ERCC1-Expression und der Platinsensitivit{\"a}t beim Nebennierenrindenkarzinom. Somit werden andere Biomarker zur Therapieentscheidung ben{\"o}tigt.}, subject = {ERCC1 Chemotherapie Nebennierenrindenkarzinom}, language = {de} } @article{BartmannJanakiRamanFloeteretal.2018, author = {Bartmann, Catharina and Janaki Raman, Sudha R. and Fl{\"o}ter, Jessica and Schulze, Almut and Bahlke, Katrin and Willingstorfer, Jana and Strunz, Maria and W{\"o}ckel, Achim and Klement, Rainer J. and Kapp, Michaela and Djuzenova, Cholpon S. and Otto, Christoph and K{\"a}mmerer, Ulrike}, title = {Beta-hydroxybutyrate (3-OHB) can influence the energetic phenotype of breast cancer cells, but does not impact their proliferation and the response to chemotherapy or radiation}, series = {Cancer \& Metabolism}, volume = {6}, journal = {Cancer \& Metabolism}, number = {8}, doi = {10.1186/s40170-018-0180-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175607}, year = {2018}, abstract = {Background: Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2-6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro. Methods: Seven different human BC cell lines (BT20, BT474, HBL100, MCF-7, MDA-MB 231, MDA-MB 468, and T47D) were cultured in medium with 5 mM glucose in the presence of 3 mM 3-OHB at mild hypoxia (5\% oxygen) or normoxia (21\% oxygen). Metabolic profiling was performed by quantification of the turnover of glucose, lactate, and 3-OHB and by Seahorse metabolic flux analysis. Expression of key enzymes of ketolysis as well as the main monocarboxylic acid transporter MCT2 and the glucose-transporter GLUT1 was analyzed by RT-qPCR and Western blotting. The effect of 3-OHB on short- and long-term cell proliferation as well as chemo- and radiosensitivity were also analyzed. Results: 3-OHB significantly changed the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in BT20 cells resulting in a more oxidative energetic phenotype. MCF-7 and MDA-MB 468 cells had increased ECAR only in response to 3-OHB, while the other three cell types remained uninfluenced. All cells expressed MCT2 and GLUT1, thus being able to uptake the metabolites. The consumption of 3-OHB was not strongly linked to mRNA overexpression of key enzymes of ketolysis and did not correlate with lactate production and glucose consumption. Neither 3-OHB nor acetoacetate did interfere with proliferation. Further, 3-OHB incubation did not modify the response of the tested BC cell lines to chemotherapy or radiation. Conclusions: We found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines. However, 3-OHB failed to influence different biologic processes in these cells, e.g., cell proliferation and the response to common breast cancer chemotherapy and radiotherapy. Thus, we have no evidence that 3-OHB generally influences the biology of breast cancer cells in vitro.}, language = {en} } @article{MemmelSisarioZoelleretal.2017, author = {Memmel, Simon and Sisario, Dmitri and Z{\"o}ller, Caren and Fiedler, Vanessa and Katzer, Astrid and Heiden, Robin and Becker, Nicholas and Eing, Lorenz and Ferreira, F{\´a}bio L.R. and Zimmermann, Heiko and Sauer, Markus and Flentje, Michael and Sukhorukov, Vladimir L. and Djuzenova, Cholpon S.}, title = {Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities}, series = {Oncotarget}, volume = {8}, journal = {Oncotarget}, number = {28}, doi = {10.18632/oncotarget.16847}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170719}, pages = {45298-45310}, year = {2017}, abstract = {High invasiveness and resistance to chemo- and radiotherapy of glioblastoma multiforme (GBM) make it the most lethal brain tumor. Therefore, new treatment strategies for preventing migration and invasion of GBM cells are needed. Using two different migration assays, Western blotting, conventional and super-resolution (dSTORM) fluorescence microscopy we examine the effects of the dual PI3K/mTOR-inhibitor PI-103 alone and in combination with the Hsp90 inhibitor NVP-AUY922 and/or irradiation on the migration, expression of marker proteins, focal adhesions and F-actin cytoskeleton in two GBM cell lines (DK-MG and SNB19) markedly differing in their invasive capacity. Both lines were found to be strikingly different in morphology and migration behavior. The less invasive DK-MG cells maintained a polarized morphology and migrated in a directionally persistent manner, whereas the highly invasive SNB19 cells showed a multipolar morphology and migrated randomly. Interestingly, a single dose of 2 Gy accelerated wound closure in both cell lines without affecting their migration measured by single-cell tracking. PI-103 inhibited migration of DK-MG (p53 wt, PTEN wt) but not of SNB19 (p53 mut, PTEN mut) cells probably due to aberrant reactivation of the PI3K pathway in SNB19 cells treated with PI-103. In contrast, NVP-AUY922 exerted strong anti-migratory effects in both cell lines. Inhibition of cell migration was associated with massive morphological changes and reorganization of the actin cytoskeleton. Our results showed a cell line-specific response to PI3K/mTOR inhibition in terms of GBM cell motility. We conclude that anti-migratory agents warrant further preclinical investigation as potential therapeutics for treatment of GBM.}, language = {en} } @article{WiegeringMatthesMuehlingetal.2017, author = {Wiegering, Armin and Matthes, Niels and M{\"u}hling, Bettina and Koospal, Monika and Quenzer, Anne and Peter, Stephanie and Germer, Christoph-Thomas and Linnebacher, Michael and Otto, Christoph}, title = {Reactivating p53 and Inducing Tumor Apoptosis (RITA) Enhances the Response of RITA-Sensitive Colorectal Cancer Cells to Chemotherapeutic Agents 5-Fluorouracil and Oxaliplatin}, series = {Neoplasia}, volume = {19}, journal = {Neoplasia}, number = {4}, doi = {10.1016/j.neo.2017.01.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171067}, pages = {301-309}, year = {2017}, abstract = {Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n = 9) including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n = 5) with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC\(_{50}\)< 3.0 μmol/l) were identified within established (4/9) and primary patient-derived (2/5) CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14) that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents.}, language = {en} } @article{LichthardtKerscherDietzetal.2016, author = {Lichthardt, Sven and Kerscher, Alexander and Dietz, Ulrich A. and Jurowich, Christian and Kunzmann, Volker and von Rahden, Burkhard H. A. and Germer, Christoph-Thomas and Wiegering, Armin}, title = {Original article: role of adjuvant chemotherapy in a perioperative chemotherapy regimen for gastric cancer}, series = {BMC Cancer}, volume = {16}, journal = {BMC Cancer}, number = {650}, doi = {10.1186/s12885-016-2708-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147743}, year = {2016}, abstract = {Background Multimodal treatment strategies - perioperative chemotherapy (CTx) and radical surgery - are currently accepted as treatment standard for locally advanced gastric cancer. However, the role of adjuvant postoperative CTx (postCTx) in addition to neoadjuvant preoperative CTx (preCTx) in this setting remains controversial. Methods Between 4/2006 and 12/2013, 116 patients with locally advanced gastric cancer were treated with preCTx. 72 patients (62 \%), in whom complete tumor resection (R0, subtotal/total gastrectomy with D2-lymphadenectomy) was achieved, were divided into two groups, one of which receiving adjuvant therapy (n = 52) and one without (n = 20). These groups were analyzed with regard to survival and exclusion criteria for adjuvant therapy. Results Postoperative complications, as well as their severity grade, did not correlate with fewer postCTx cycles administered (p = n.s.). Long-term survival was shorter in patients receiving postCTx in comparison to patients without postCTx, but did not show statistical significance. In per protocol analysis by excluding two patients with perioperative death, a shorter 3-year survival rate was observed in patients receiving postCTx compared to patients without postCTx (3-year survival: 71.2 \% postCTx group vs. 90.0 \% non-postCTx group; p = 0.038). Conclusion These results appear contradicting to the anticipated outcome. While speculative, they question the value of post-CTx. Prospectively randomized studies are needed to elucidate the role of postCTx.}, language = {en} } @article{ChioreanVonHoffRenietal.2016, author = {Chiorean, E. G. and Von Hoff, D. D. and Reni, M. and Arena, F. P. and Infante, J. R. and Bathini, V. G. and Wood, T. E. and Mainwaring, P. N. and Muldoon, R. T. and Clingan, P. R. and Kunzmann, V. and Ramanathan, R. K. and Tabernero, J. and Goldstein, D. and McGovern, D. and Lu, B. and Ko, A.}, title = {CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer}, series = {Annals of Oncology}, volume = {27}, journal = {Annals of Oncology}, number = {4}, doi = {10.1093/annonc/mdw006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189659}, pages = {654-660}, year = {2016}, abstract = {Background A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. Patients and methods Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. Results Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80\%) versus those without (20\%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40\% versus 13\%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15\% versus 5\%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16\% (40/252) and 6\% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79\% and 84\% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. Conclusion This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.}, language = {en} } @article{WorkuStichDaugschiesetal.2015, author = {Worku, Netsanet and Stich, August and Daugschies, Arwid and Wenzel, Iris and Kurz, Randy and Thieme, Rene and Kurz, Susanne and Birkenmeier, Gerd}, title = {Ethyl Pyruvate Emerges as a Safe and Fast Acting Agent against Trypanosoma brucei by Targeting Pyruvate Kinase Activity}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {9}, doi = {10.1371/journal.pone.0137353}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150002}, pages = {e0137353}, year = {2015}, abstract = {Background Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease in humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100\% mortality. Currently available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to similarities in cell metabolism between cancerous tumors and trypanosoma cells, some of the current registered drugs against HAT have also been tested in cancer chemotherapy. Here we demonstrate for the first time that the simple ester, ethyl pyruvate, comprises such properties. Results The current study covers the efficacy and corresponding target evaluation of ethyl pyruvate on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, phasecontrast microscopic video imaging and ex vivo toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki = 3.0\(\pm\)0.29 mM). The potential of ethyl pyruvate as a trypanocidal compound is also strengthened by its fast acting property, killing cells within three hours post exposure. This has been demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, ethyl pyruvate produces minimal side effects in human red cells and is known to easily cross the blood-brain-barrier. This makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug-resistance tests indicate irreversible cell death and a low incidence of resistance development under experimental conditions. Conclusion Our results present ethyl pyruvate as a safe and fast acting trypanocidal compound and show that it inhibits the enzyme pyruvate kinase. Competitive inhibition of this enzyme was found to cause ATP depletion and cell death. Due to its ability to easily cross the blood-brain-barrier, ethyl pyruvate could be considered as new candidate agent to treat the hemo-lymphatic as well as neurological stages of sleeping sickness.}, language = {en} } @article{CardaniSardiLaFerlaetal.2014, author = {Cardani, Diego and Sardi, Claudia and La Ferla, Barbara and D'Orazio, Guiseppe and Sommariva, Michele and Marcucci, Fabrizio and Olivero, Daniela and Tagliabue, Elda and Koepsell, Hermann and Nicotra, Francesco and Balsari, Andrea and Rumio, Christiano}, title = {Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis}, series = {Molecular Cancer}, volume = {13}, journal = {Molecular Cancer}, number = {23}, issn = {1476-4598}, doi = {10.1186/1476-4598-13-23}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117352}, year = {2014}, abstract = {Background: Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis. Methods: Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student's t-test (paired two-tailed) and X-2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05. Results: BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR. Conclusions: BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.}, language = {en} } @article{BrehmKoziol2014, author = {Brehm, Klaus and Koziol, Uriel}, title = {On the importance of targeting parasite stem cells in anti-echinococcosis drug development}, series = {Parasite}, volume = {21}, journal = {Parasite}, issn = {1252-607X}, doi = {10.1051/parasite/2014070}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118030}, pages = {72}, year = {2014}, abstract = {The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs. Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin. However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects. Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode. Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells. Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy. Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles. In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite's stem cell population.}, language = {en} } @article{KochCappelNockeretal.2013, author = {Koch, Oliver and Cappel, Daniel and Nocker, Monika and J{\"a}ger, Timo and Floh{\´e}, Leopold and Sotriffer, Christoph A. and Selzer, Paul M.}, title = {Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {2}, doi = {10.1371/journal.pone.0056788}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131070}, pages = {e56788}, year = {2013}, abstract = {The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two \(Mg^{2+}\) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows \(N^1\)-glutathionylation of \(N^8\)-glutathionylspermidine, classifying \(N^8\)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for \(N^8\)-glutathionylspermidine was characterised as druggable.}, language = {en} } @article{SturmHessWeibeletal.2012, author = {Sturm, Julia B. and Hess, Michael and Weibel, Stephanie and Chen, Nanhei G. and Yu, Yong A. and Zhang, Quian and Donat, Ulrike and Reiss, Cora and Gambaryan, Stepan and Krohne, Georg and Stritzker, Jochen and Szalay, Aladar A.}, title = {Functional hyper-IL-6 from vaccinia virus-colonized tumors triggers platelet formation and helps to alleviate toxicity of mitomycin C enhanced virus therapy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75224}, year = {2012}, abstract = {Background: Combination of oncolytic vaccinia virus therapy with conventional chemotherapy has shown promise for tumor therapy. However, side effects of chemotherapy including thrombocytopenia, still remain problematic. Methods: Here, we describe a novel approach to optimize combination therapy of oncolytic virus and chemotherapy utilizing virus-encoding hyper-IL-6, GLV-1h90, to reduce chemotherapy-associated side effects. Results: We showed that the hyper-IL-6 cytokine was successfully produced by GLV-1h90 and was functional both in cell culture as well as in tumor-bearing animals, in which the cytokine-producing vaccinia virus strain was well tolerated. When combined with the chemotherapeutic mitomycin C, the anti-tumor effect of the oncolytic virotherapy was significantly enhanced. Moreover, hyper-IL-6 expression greatly reduced the time interval during which the mice suffered from chemotherapy-induced thrombocytopenia. Conclusion: Therefore, future clinical application would benefit from careful investigation of additional cytokine treatment to reduce chemotherapy-induced side effects.}, subject = {Biologie}, language = {en} } @article{TessmerMelikishviliFried2012, author = {Tessmer, Ingrid and Melikishvili, Manana and Fried, Michael G.}, title = {Cooperative cluster formation, DNA bending and base-flipping by O\(^6\)-alkylguanine-DNA alkyltransferase}, series = {Nucleic Acids Research}, volume = {40}, journal = {Nucleic Acids Research}, number = {17}, doi = {10.1093/nar/gks574}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133949}, pages = {8296-8308}, year = {2012}, abstract = {O\(^6\)-Alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine adducts in DNA, protecting the genome and also contributing to the resistance of tumors to chemotherapeutic alkylating agents. AGT binds DNA cooperatively, and cooperative interactions are likely to be important in lesion search and repair. We examined morphologies of complexes on long, unmodified DNAs, using analytical ultracentrifugation and atomic force microscopy. AGT formed clusters of 11 proteins. Longer clusters, predicted by the McGhee-von Hippel model, were not seen even at high [protein]. Interestingly, torsional stress due to DNA unwinding has the potential to limit cluster size to the observed range. DNA at cluster sites showed bend angles (similar to 0, similar to 30 and similar to 60 degrees) that are consistent with models in which each protein induces a bend of similar to 30 degrees. Distributions of complexes along the DNA are incompatible with sequence specificity but suggest modest preference for DNA ends. These properties tell us about environments in which AGT may function. Small cooperative clusters and the ability to accommodate a range of DNA bends allow function where DNA topology is constrained, such as near DNA-replication complexes. The low sequence specificity allows efficient and unbiased lesion search across the entire genome.}, language = {en} } @phdthesis{Wierlemann2008, author = {Wierlemann, Alexander}, title = {Entwicklung eines rechnergest{\"u}tzten Therapiemanagementsystems f{\"u}r die medizinische Onkologie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-37366}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {Durch die Einf{\"u}hrung eines neuen fallpauschalierten Abrechnungssystems (Diangnosis related groups, DRG) sowie zahlreiche neue Maßnahmen der Qualit{\"a}tssicherung w{\"a}chst der Anteil administrativer T{\"a}tigkeiten f{\"u}r die klinisch t{\"a}tigen {\"A}rztinnen und {\"A}rzte. Diese Entwicklung hat nicht zuletzt auch Auswirkungen auf die zeitlichen Ressourcen, die f{\"u}r die {\"a}rztlichen Kernaufgaben zur Verf{\"u}gung stehen. In Bereichen mit intensiver klinischer Forschung steigen dar{\"u}berhinaus auch die Anforderungen an die forschungsbegleitende Dokumentation. Eine effiziente Unterst{\"u}tzung bei der Kalkulation, Planung und Durchf{\"u}hrung von Therapien durch Informationstechnologische (IT-) Systeme kann eine sinnvolle Entlastung der {\"A}rzte darstellen. Es wurde ein einsatzf{\"a}higer Prototyp entwickelt, prgrammiert und implementiert. Anschließend wurde das Ergebnis mit potentiellen Anwendern der Software evaluiert.}, subject = {Computergest{\"u}tzte Medizin}, language = {de} } @phdthesis{Schramm2008, author = {Schramm, Stefanie}, title = {{\"U}berleben und Lebensqualit{\"a}t sprechen f{\"u}r ein konservatives Therapiekonzept bei Patienten mit Magenlymphomen : Ergebnisse einer prospektiven randomisierten Studie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-30698}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {Gastrointestinale Lymphome des MALT sind heute als eigenst{\"a}ndige Entit{\"a}t anerkannt. Sie zeichnen sich durch morphologische, molekularbiologische, {\"a}tiopathogenetische und biologische Besonderheiten aus, die sie von den nodalen Lymphomen abgrenzen lassen. Im Rahmen der W{\"u}rzburger Multicenterstudie „Gastrointestinale Lymphome II" soll die Frage gekl{\"a}rt werden, ob in den lokalisierten Stadien I und II prim{\"a}rer Magenlymphome unter Ber{\"u}cksichtigung der posttherapeutischen Lebensqualit{\"a}t der operativen oder einer prim{\"a}r konservativen Therapie (Chemo- oder Radiotherapie) Vorzug gegeben werden soll. Von 1998 bis 2002 wurden dazu 49 Patienten mit neu diagnostiziertem niedrig- (n=19) oder hochmalignen (n=30) NHL des Magens in die Studie eingeschlossen. Nach zentraler Randomisierung wurden die Patienten mit low grade NHL der Operation (n=10) oder der Radiotherapie (n=9) zugeteilt. Die Patienten mit high grade NHL erhielten Operation plus Chemotherapie (n=16) oder alleinige Chemotherapie (n=14). Das mediane follow up betrug 74 Monate. Sowohl das operative als auch das konservative Vorgehen zeigten bei beiden Lymphomhistologien {\"u}beraus hohe Remissionsraten in den Stadien EI und EII (CR um 90\%). Unterschiede zwischen den Behandlungsmethoden konnten, evtl. auch bedingt durch die kleinen Gruppengr{\"o}ßen, nicht nachgewiesen werden. Insgesamt verstarben sechs Patienten, die sich in etwa gleichm{\"a}ßig auf die Gruppen verteilten. Die Auswertung der Frageb{\"o}gen zur Lebensqualit{\"a}t ergab gem{\"a}ß SF-36 durchaus hohe Werte zur posttherapeutischen Lebensqualit{\"a}t. Eine Differenzierung der Patienten nach Behandlungsmethode oder Malignit{\"a}tsgrad (low, high grade) war nicht m{\"o}glich. Der Lebensqualit{\"a}tsindex nach Troidl ließ einen pr{\"a}-post-therapeutischen Vergleich zu: Betrachtet man die Kombination von Therapie und Malignit{\"a}tsgrad, so fallen konservativ therapierte Patienten (unabh{\"a}ngig vom Malignit{\"a}tsgrad) durch deutlich ansteigende Lebensqualit{\"a}t auf. Es l{\"a}sst sich festhalten, dass bei prim{\"a}r gastrointestinalen Lymphomen sowohl mit operativem als auch konservativem Vorgehen hohe Remissionsraten erzielt werden k{\"o}nnen. Jedoch sind im Hinblick auf Organerhalt und die h{\"o}here post-therapeutische Lebensqualit{\"a}t die prim{\"a}re Radio- und/oder Chemotherapie dem operativen Vorgehen vorzuziehen.}, subject = {Non-Hodgkin-Lymphom}, language = {de} } @phdthesis{Gelmedin2008, author = {Gelmedin, Verena Magdalena}, title = {Targeting flatworm signaling cascades for the development of novel anthelminthic drugs}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-33334}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {Echinococcus multilocularis verursacht die Alveol{\"a}re Echinokokkose (AE), eine lebendsbedrohliche Krankheit mit limitierten chemotherapeutischen M{\"o}glichkeiten. Die jetzige Anti-AE Chemotherapie basiert auf einer einzigen Wirkstoffklasse, den Benzimidazolen. Obwohl Benzimidazole in vitro parasitozid wirken, wirken sie in vivo bei AE-Behandlung lediglich parasitostatisch und rufen schwere Nebenwirkungen hervor. In F{\"a}llen operabler L{\"a}sionen erfordert die Resektion des Parasitengewebes {\"u}ber einen l{\"a}ngeren Zeitraum eine chemotherapeutische Unterst{\"u}tzung. Damit sind die jetzigen Behandlungsm{\"o}glichkeiten inad{\"a}quat und ben{\"o}tigen Alternativen. In der vorliegenden Arbeit wurden die Signalwege von Plattw{\"u}rmern analysiert, um potentielle Targets f{\"u}r neue therapeutische Ans{\"a}tze zu identifizieren. Dabei konzentrierte ich mich unter Anwendung von molekularbiologischer, biochemischer und zellbiologischer Methoden auf Faktoren, die an Entwicklung und Proliferation von E. multilocularis beteiligt sind. Darunter waren die drei MAP kinases des Parasiten EmMPK1, ein Erk1/2-Ortholog, EmMPK2, ein p38-Ortholog und EmMPK3, ein Erk7/8-Ortholog. Des Weiteren identifizierte und charakterisierte ich EmMKK2, ein MEK1/2-Ortholog des Parasiten, welches zusammen mit den bekannten Kinasen EmRaf und EmMPK1 ein Erk1/2-{\"a}hnliches MAPK Modul bildet. Ich konnte zudem verschiedene Einfl{\"u}sse von Wirtswachstumsfaktoren wie EGF (epidermal growth factor) und Insulin auf die Signalmechanismen des Parasiten und das Larvenwachstum zeigen, darunter die Phosphorylierung von Elp, ein Ezrin-Radixin-Moesin {\"a}hnliches Protein, die Aktivierung von EmMPK1 und EmMPK3 und eine gesteigerte mitotische Aktivit{\"a}t der Echinokokkenzellen. Zus{\"a}tzlich wurden verschiedene Substanzen auf ihre letale Wirkung auf den Parasiten untersucht, darunter befanden sich (1.) generelle Inhibitoren von Tyrosinkinasen (PP2, Leflunamid), (2.) gegen die Aktivit{\"a}t von Rezeptor-Tyrosin-Kinasen gerichtete Pr{\"a}parate, (3.) urspr{\"u}nglich anti-neoplastische Wirkstoffe wie Miltefosin und Perifosin, (4.) Inhibitoren von Serin/ Threonin-Kinasen, die die Erk1/2 MAPK Kaskade blockieren und (5.) Inhibitoren der p38 MAPK. In diesen Untersuchungen hat sich EmMPK2 aus den folgenden Gr{\"u}nden als vielversprechendes Target erwiesen. Aminos{\"a}uresequenz-Analysen offenbarten einige Unterschiede zu menschlichen p38 MAP Kinasen, welche sehr wahrscheinlich die beobachtete gesteigerte basale Aktivit{\"a}t des rekombinanten EmMPK2 verursachen, verglichen mit der Aktivit{\"a}t humaner p38 MAPK-\&\#945;. Zus{\"a}tzlich suggerieren die prominente Autophosphorylierungsaktivit{\"a}t von rekombinantem EmMPK2 und das Ausbleiben einer Interaktion mit den Echinococcus MKKs einen unterschiedlichen Regulierungsmechanismus im Vergleich zu den humanen Proteinen. Die Aktivit{\"a}t von EmMPK2 konnte sowohl in vitro als auch in kultivierten Metazestodenvesikeln durch die Behandlung mit SB202190 und ML3403, zwei ATP kompetitiven Pyridinylimidazolinhibitoren der p38 MAPK, in Konzentrations-abh{\"a}ngiger Weise inhibiert werden. Zudem verursachten beide Substanzen, insbesondere ML3403 die Inaktivierung von Parasitenvesikeln bei Konzentrationen, die kultivierte S{\"a}ugerzellen nicht beeintr{\"a}chtigten. Ebenso verhinderte die Anwesenheit von ML3403 die Generation von neuen Vesikeln w{\"a}hrend der Kultivierung von Echinococcus Prim{\"a}rzellen. Das Targeting von Mitgliedern des EGF-Signalwegs, insbesondere der Erk1/2-{\"a}hnlichen MAPK Kaskade mit Raf- und MEK- Inhibitoren verhinderte die Phosphorylierung von EmMPK1 in in vitro kultivierten Metazestoden. Obwohl das Parasitenwachstum unter diesen Konditionen verhindert wurde, blieb die strukturelle Integrit{\"a}t der Metazestodenvesikeln w{\"a}hrend der Langzeitkultivierung in Anwesenheit der MAPK Kaskade-Inhibitoren erhalten. {\"A}hnliche Effekte wurden beobachtet nach Behandlung mit den anderen zuvor aufgef{\"u}hrten Inhibitoren. Zusammenfassend l{\"a}sst sich festhalten, dass verschiedene Targets identifiziert werden konnten, die hoch sensibel auf die Anwesenheit der inhibitorischen Substanzen reagierten, aber nicht zum Absterben des Parasiten f{\"u}hrten, mit Ausnahme der Pyridinylimidazolen. Die vorliegenden Daten zeigen, dass EmMPK2 ein {\"U}berlebendsignal vermittelnden Faktor darstellt und dessen Inhibierung zur Behandlung der AE benutzt werden k{\"o}nnte. Dabei erwiesen sich p38 MAPK Inhibitoren der Pyridinylimidazolklasse als potentielle neue Substanzklasse gegen Echinokokken.}, subject = {Fuchsbandwurm}, language = {en} } @phdthesis{Klingelhoeffer2006, author = {Klingelh{\"o}ffer, Christoph}, title = {Untersuchung zur Lebensqualit{\"a}t nach neoadjuvanter Chemotherapie und Radiatio bei fortgeschrittenen Larynx- und Hypopharynxkarzinomen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-20134}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2006}, abstract = {Diese Studie stellt die Lebensqualit{\"a}t und den Gesundheitszustand von Patienten mit einem fortgeschrittenen Larynx- oder Hypopharynxkarzinom nach neoadjuvanter Chemotherapie und Radiatio dar. Hierbei wird auf verschiedene Teilbereiche der Auswirkungen dieser Erkrankung eingegangen, die individuell den Grad der Lebensqualit{\"a}t beeinflussen. Die Werte geben die durchschnittliche Meinung des Patientenkollektivs wieder und k{\"o}nnen somit nur gemeinsame Tendenzen hervorbringen. Die Patienten gaben an, nur eine geringe Minderung ihrer Lebensqualit{\"a}t durch die Erkrankung festzustellen. {\"U}ber 60\% des Patientenkollektivs sch{\"a}tzten ihre Lebensqualit{\"a}t bzw. ihren Gesundheitszustand als sehr gut oder nur wenig beeintr{\"a}chtigt ein. Das Patientenkollektiv best{\"a}tigt durch seinen hohen Nikotin- und Alkoholkonsumenten-anteil die Risikofaktoren f{\"u}r diese Erkrankung. Leider konnte der Großteil der Patienten nicht dazu bewegt werden, das Alkoholgenussverhalten zu {\"u}berdenken und es deutlich zu reduzieren. Die Notwendigkeit, den Nikotinkonsum einzuschr{\"a}nken, wurde eher akzeptiert. Im Hinblick auf die alternative operative Entfernung des Prim{\"a}rtumors und damit des Kehlkopfes, war die erneute Entscheidung f{\"u}r die konservative Therapie f{\"u}r die meisten Patienten eindeutig. Auch die Aufkl{\"a}rung wurde in der Regel positiv bewertet. Der hohe Stellenwert einer erhaltenen Kommunikationsf{\"a}higkeit ist f{\"u}r die Patienten der ausschlaggebende Punkt, sich wieder f{\"u}r diese Therapie zu entscheiden. Das Symptom der Xerostomie bereitet den Patienten die gr{\"o}ßten Schwierigkeiten. Die Auswirkung auf andere Bereiche wie verminderte Gleitf{\"a}higkeit der Speisen, schlechterer Prothesensitz und verst{\"a}rkte Zerkleinerung der Speisen sind hier zu ber{\"u}cksichtigen. Eine erh{\"o}hte psychische Belastung ist die Folge, die auch das Sozialleben der Patienten beeinflusst. Dies zeigte sich vor allem in der Frage nach Genuss von Essen in der Gesellschaft. 44 \% vermieden es, in der {\"O}ffentlichkeit zu essen oder schr{\"a}nkten es zumindest stark ein. H{\"a}ufiger traten Ver{\"a}nderungen der Stimme auf. Sie waren vor allem durch Heiserkeit bedingt. Die Betroffenen wurden jedoch dadurch nur im geringen Maße gest{\"o}rt. Einschr{\"a}nkungen in der Kopf- und Armbewegung stellen sich aufgrund der nichtoperativen Therapie als geringf{\"u}giges Problem dar. Dies tr{\"a}gt dazu bei, dass nur wenige Einschr{\"a}nkungen im Bereich Mobilit{\"a}t bzw. Arbeitsf{\"a}higkeit zu verzeichnen waren. Eine geringere Abh{\"a}ngigkeit von den Angeh{\"o}rigen ist die Folge, was die Selbstst{\"a}ndigkeit der Patienten erh{\"a}lt und gleichzeitig psychische Belastungen abbaut. Andere Symptome wie Schmerzen, Kieferklemme, Entz{\"u}ndungen im Mund- und Rachenraum kommen aufgrund der bereits durchschnittlich l{\"a}ngeren Genesungsphase nur selten vor.}, language = {de} } @phdthesis{Kuhn2006, author = {Kuhn, Jochen}, title = {Das Medulloblastom bei Erwachsenen : Prognostische Faktoren und histologische Besonderheiten einer seltenen Tumorentit{\"a}t : Vergleich einer adjuvanten mit einer neoadjuvanten Chemotherapie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-21060}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2006}, abstract = {In dieser retrospektiven multizentrischen Analyse wurde bei 46 Beobachtungspatienten mit Medulloblastom im Alter von 16 bis 51 Jahren bei einem Median von 20,5 Jahren die Wirksamkeit und Vertr{\"a}glichkeit einer neoadjuvanten Chemotherapie, bestehend aus Procarbacin, Ifosfamid, Etoposid, Methotrexat, Cisplatin und Cytarabin mit einer Erhaltungschemotherapie mit Vincristin, CCNU und Cisplatin verglichen. Die progressionsfreie 4-Jahres{\"u}berlebensrate war bei der Erhaltungstherapie mit 86 \% tendenziell, jedoch nicht signifikant h{\"o}her als bei der Sandwichtherapie mit 61 \%. Die 4-Jahres-Gesamt{\"u}berlebensrate aller 46 Patienten lag bei 85 \% und das 4-Jahres-PFS aller Patienten bei 72 \%. Unter Erhaltungschemotherapie kam es h{\"a}ufiger zu relevanten Nebenwirkungen, so dass die Zytostatikadosis verringert oder die Chemotherapie abgebrochen werden musste. Bei der Erhaltungstherapie war dies bei 10 von 19 Patienten der Fall, bei neoadjuvanter Therapie bei 5 von 24 Patienten. Der Allgemeinzustand beurteilt mittels Karnofsky-Index mindestens ein Jahr nach Ende der Therapie war im Erhaltungstherapiearm signifikant schlechter als im Sandwichtherapiearm (p= 0,001). Im Vergleich zum Sandwichtherapiearm waren deutlich mehr Patienten, die eine Erhaltungstherapie erhalten hatten (5 von 15 vs. 0 von 14), nach {\"u}ber einem Jahr nach Ende der Therapie immer noch arbeitsunf{\"a}hig. Bei der histologischen Untersuchung trat die desmoplastische Variante gegen{\"u}ber der klassischen h{\"a}ufiger auf und war h{\"a}ufiger lateral im Kleinhirn lokalisiert als in vergleichbaren Studien bei Kindern. Folgende Faktoren wurden untersucht: Alter, Geschlecht, histologischer Typ, mediale oder laterale Tumorlokalisation, Resektionsgrad, Metastasierungsstadium, Vorhanden-sein eines Liquorshunts, geringere Bestrahlungsdosis sowie adjuvante oder neoadjuvante Chemotherapie. Abh{\"a}ngig vom Metastasierungsstadium zeigte sich ein starker Trend zu einer schlechteren {\"U}berlebenswahrscheinlichkeit (M2/3 Stadium 45 \% 4-J-PFS vs. 78 \% bei M0/1). Aufgrund der niedrigen Fallzahlen konnte aber in den Analysen kein Signifikanzniveau erreicht werden.}, language = {de} } @phdthesis{Milnik2002, author = {Milnik, Alexander}, title = {Depressivit{\"a}t bei Patienten mit akuter Leuk{\"a}mie oder hochmalignem Non-Hodgkin-Lymphom}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-4875}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2002}, abstract = {In der vorliegenden L{\"a}ngsschnittuntersuchung wurde die depressive Symptomatik von 40 Patienten mit akuter Leuk{\"a}mie oder hochmalignem Non-Hodgkin-Lymphom innerhalb der ersten sechs Monaten nach Diagnosestellung untersucht. Alle Patienten erhielten eine Chemotherapie. Die vorliegende Untersuchung erstreckte sich {\"u}ber insgesamt f{\"u}nf Befragungen: T 1 = ein bis drei Tage nach Diagnosestellung, T 2 = in der Aplasiephase des ersten Chemotherapiezyklus, T 3 = zu Beginn des dritten Chemotherapiezyklus, T 4 = in der Aplasiephase des dritten Chemotherapiezyklus, T 5 = sechs Monate nach Diagnosestellung. Die Einsch{\"a}tzung der depressiven Symptomatik erfolgte mit Hilfe der extrahierten Subskala „Depressivit{\"a}t" aus der deutschen Version der revidierten Symptom-Checkliste 90 (SCL-90-R) von Derogatis. Des Weiteren wurden die k{\"o}rperlichen Beschwerden der Probanden mit einem eigens f{\"u}r die vorliegende Studie konzipierten Instrument zu jedem Messzeitpunkt erfasst. Zus{\"a}tzlich erfolgte zu den einzelnen Erhebungen eine Evaluation der Prognose der Erkrankung im Rahmen eines vom Arzt auszuf{\"u}llenden Fragebogens. Die Resultate unserer Studie zeigten eine hochsignifikante Zunahme der Depressivit{\"a}t vom Erstinterview (T 1) zum zweiten Erhebungszeitpunkt (T 2), im Durchschnitt 11 Tage sp{\"a}ter in der Phase der Aplasie des ersten Chemotherapiezyklus. Das Ausmaß der Depressivit{\"a}t war zu Beginn des dritten Chemotherapiezyklus (T 3), durchschnittlich drei Monate nach Erstdiagnose, gegen{\"u}ber dem zweiten Messzeitpunkt (T 2) unver{\"a}ndert. Der Auspr{\"a}gungsgrad der Depressivit{\"a}t zu T 3 unterschied sich zudem weder von dem Level der depressiven Symptomatik in der entsprechenden Isolationsphase (T 4) noch von dem Ausmaß der Depressivit{\"a}t sechs Monate nach Diagnosestellung (T 5). Auch fr{\"u}here Arbeiten beschrieben eine signifikante Zunahme der Depressivit{\"a}t nach Diagnosestellung. Die Erhebungsintervalle lagen dabei ein bis drei Monate auseinander. Im Gegensatz zu anderen Studien wurden in unserer Untersuchung mitunter sehr kurze Zeitabschnitte (ca. ein bis zwei Wochen) zwischen zwei Erhebungszeitpunkten gew{\"a}hlt. Hierdurch konnten wir erstmalig eine hochsignifikante Zunahme der Depressivit{\"a}t bereits innerhalb weniger Tage nach Diagnosestellung feststellen. Medizinische, soziodemographische und somatische Faktoren zeigten nur wenige Zusammenh{\"a}nge mit der depressiven Symptomatik unserer Patienten. Die Ergebnisse zur Ver{\"a}nderung der Depressivit{\"a}t im Verlauf k{\"o}nnen nicht auf der Basis der hier erfassten medizinischen und somatischen Faktoren oder durch rein aplasiespezifische Umst{\"a}nde erkl{\"a}rt werden. Die Ver{\"a}nderung des Ausmaßes der Depressivit{\"a}t wird eher als Folge einer Modulation des Coping- und Abwehrverhaltens w{\"a}hrend des Krankheits- und Behandlungsverlaufes mit konsekutiver {\"A}nderung des emotionalen Befindens interpretiert.}, language = {de} }