25 results on '"Siveke, Jens T."'
Search Results
2. Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer – A subgroup analysis of the pivotal NAPOLI-1 trial.
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Macarulla, Teresa, Blanc, Jean-Frédéric, Wang-Gillam, Andrea, Chen, Li-Tzong, Siveke, Jens T., Mirakhur, Beloo, Chen, Jie, and de Jong, Floris A.
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Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial (NCT01494506) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [<65 versus ≥65 years], 0.89/0.88 [<70 versus ≥70 years] and 1.04/0.98 [<75 versus ≥75 years]; P >.25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% <75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions). Results suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients. [ABSTRACT FROM AUTHOR]
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- 2019
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3. Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1: Expanded analysis of a global phase 3 trial.
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Chen, Li-Tzong, Siveke, Jens T., Wang-Gillam, Andrea, Li, Chung-Pin, Bodoky, György, Dean, Andrew P., Shan, Yan-Shen, Jameson, Gayle S., Macarulla, Teresa, Lee, Kyung-Hun, Cunningham, David, Blanc, Jean-Frédéric, Chiu, Chang-Fang, Schwartsmann, Gilberto, Braiteh, Fadi S., Mamlouk, Khalid, Belanger, Bruce, de Jong, Floris A., and Hubner, Richard A.
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ANTINEOPLASTIC agents , *FLUOROURACIL , *FOLINIC acid , *IRINOTECAN , *CANCER patient psychology , *COMPARATIVE studies , *CONFIDENCE intervals , *MEDICAL protocols , *ARTIFICIAL membranes , *METASTASIS , *PANCREATIC tumors , *STATISTICS , *SURVIVAL analysis (Biometry) , *SURVIVAL , *DATA analysis , *RANDOMIZED controlled trials , *TREATMENT effectiveness , *DESCRIPTIVE statistics , *THERAPEUTICS - Abstract
Abstract Background In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population. Materials and methods The PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed. Results For PP patients, median OS was 8.9 (95% confidence interval: 6.4–10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0–7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3–5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7–3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648). Conclusion A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population. Highlights • Chemotherapy tolerance may be reduced in patients with metastatic pancreatic cancer. • Pre-planned analysis of per-protocol (PP) patients in the NAPOLI-1 phase 3 trial. • Significant survival benefit seen in PP patients with nal-IRI+5-FU/LV vs 5-FU/LV. • Safety data with nal-IRI+5-FU/LV were in line with the NAPOLI-1 primary analysis. • Signal for increased survival in non-PP patients with nal-IRI+5-FU/LV vs 5-FU/LV. [ABSTRACT FROM AUTHOR]
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- 2018
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4. Targeted mouse models for preclinical therapy trials
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Siveke, Jens T.
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- 2014
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5. The Increasing Diversity of KRAS Signaling in Pancreatic Cancer.
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Siveke, Jens T.
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- 2014
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6. Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways.
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Schlitter, Anna Melissa, Born, Diana, Bettstetter, Marcus, Specht, Katja, Kim-Fuchs, Corina, Riener, Marc-Oliver, Jeliazkova, Petia, Sipos, Bence, Siveke, Jens T, Terris, Benoit, Zen, Yoh, Schuster, Tibor, Höfler, Heinz, Perren, Aurel, Klöppel, Günter, and Esposito, Irene
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- 2014
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7. Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis.
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Dorsch, Madeleine, Kowalczyk, Manuela, Planque, Mélanie, Heilmann, Geronimo, Urban, Sebastian, Dujardin, Philip, Forster, Jan, Ueffing, Kristina, Nothdurft, Silke, Oeck, Sebastian, Paul, Annika, Liffers, Sven T., Kaschani, Farnusch, Kaiser, Markus, Schramm, Alexander, Siveke, Jens T., Winslow, Monte M., Fendt, Sarah-Maria, Nalbant, Perihan, and Grüner, Barbara M.
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Statins are among the most commonly prescribed drugs, and around every fourth person above the age of 40 is on statin medication. Therefore, it is of utmost clinical importance to understand the effect of statins on cancer cell plasticity and its consequences to not only patients with cancer but also patients who are on statins. Here, we find that statins induce a partial epithelial-to-mesenchymal transition (EMT) phenotype in cancer cells of solid tumors. Using a comprehensive STRING network analysis of transcriptome, proteome, and phosphoproteome data combined with multiple mechanistic in vitro and functional in vivo analyses, we demonstrate that statins reduce cellular plasticity by enforcing a mesenchymal-like cell state that increases metastatic seeding ability on one side but reduces the formation of (secondary) tumors on the other due to heterogeneous treatment responses. Taken together, we provide a thorough mechanistic overview of the consequences of statin use for each step of cancer development, progression, and metastasis. [Display omitted] • Statins induce a partial EMT phenotype in PDAC, lung cancer, and colon cancer • Partial EMT and reduced cellular plasticity can drive apoptosis or block MET • Cancer cells overcome statin-induced apoptosis by activating ERK • Statins increase metastatic seeding but reduce tumor formation and metastatic growth Dorsch et al. identify statins as potent modulators of cancer cell plasticity and demonstrate that cholesterol pathway inhibition induces a mesenchymal cell shift in cancer cells. They show that statin-induced EMT promotes metastatic seeding on one hand but unexpectedly counteracts tumor and metastasis formation on the other hand. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Notch Signaling Is Required for Exocrine Regeneration After Acute Pancreatitis.
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Siveke, Jens T., Lubeseder–Martellato, Clara, Lee, Marcel, Mazur, Pawel K., Nakhai, Hassan, Radtke, Freddy, and Schmid, Roland M.
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PANCREATITIS ,PANCREAS ,GENETIC transformation ,GENE transfection - Abstract
Background & Aims: The mechanisms for tissue regeneration and renewal after acute pancreatitis are not well understood but may involve activation of Notch signaling. To study the effect of Notch signaling ablation during acute experimental pancreatitis, we used a chemical and genetic approach to ablate Notch signaling in cerulein-induced pancreatitis in mice. Methods: Acute pancreatitis was induced by cerulein treatment in mice treated with the γ-secretase inhibitor dibenzazepine or in conditional Notch1 knockout mice. Mice were characterized using immunohistologic, biochemical, and molecular methods. To investigate Notch and β-catenin interaction, acinar 266-6 cells were analyzed using transfection and biochemical assays. Results: Loss of Notch signaling results in impaired regeneration after acute pancreatitis with fewer mature acinar cells in dibenzazepine-treated and Notch1-deficient mice in the regenerative phase 3 days after induction. β-catenin expression was increased and prolonged during exocrine regeneration. Crosstalk between Notch and β-catenin–mediated signaling was identified, with Notch1-IC inhibiting β-catenin–mediated transcriptional activity. This inhibition was dependent on a functional RAM domain. Conclusions: Inhibition of Notch signaling in vivo leads to impaired regeneration of the exocrine pancreas after acute pancreatitis. Our results suggest an interaction of Notch and Wnt signaling in pancreatic acinar cells, providing evidence for a role of these pathways in the regulation of the maturation process of acinar cells. [Copyright &y& Elsevier]
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- 2008
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9. Concomitant Pancreatic Activation of KrasG12D and Tgfa Results in Cystic Papillary Neoplasms Reminiscent of Human IPMN
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Siveke, Jens T., Einwächter, Henrik, Sipos, Bence, Lubeseder-Martellato, Clara, Klöppel, Günter, and Schmid, Roland M.
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TRANSFORMING growth factors , *PANCREATIC cancer , *CANCER , *GROWTH factors , *MICE - Abstract
Summary: Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant KrasG12D by crossing Elastase-Tgfa mice with p48+/Cre ;Kras+/LSL-G12D mice. We show that concomitant expression of TGFα and KrasG12D accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer. [Copyright &y& Elsevier]
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- 2007
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10. Pancreatic Cancer: Basic and Clinical Aspects.
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Schneider, Günter, Siveke, Jens T., Eckel, Florian, and Schmid, Roland M.
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- 2005
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11. Chromosomal instability in mouse metastatic pancreatic cancer—it’s Kras and Tp53 after all
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Siveke, Jens T. and Schmid, Roland M.
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PANCREATIC cancer , *ADENOCARCINOMA , *LABORATORY mice , *CANCER cells , *CHROMOSOME analysis - Abstract
A human pancreatic cancer progression model from intraepithelial neoplasia to ductal adenocarcinoma has been proposed. This process has been modeled in the mouse by activation of mutant Kras in pancreatic progenitor cells. In this issue of Cancer Cell, Hingorani et al. (2005) present a modification of their initial model by introducing a mutant Tp53. This combination of genetic alterations leads to rapid and increased frequency of neoplasia progression resulting in pancreatic cancers that manifest chromosomal instability in the presence of apparent intact telomeres. These findings introduce Tp53-mediated chromosomal instability as key event for carcinoma development in this mouse model. [Copyright &y& Elsevier]
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- 2005
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12. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors.
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Wang-Gillam, Andrea, Hubner, Richard A., Siveke, Jens T., Von Hoff, Daniel D., Belanger, Bruce, de Jong, Floris A., Mirakhur, Beloo, and Chen, Li-Tzong
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FLUOROURACIL , *FOLINIC acid , *THERAPEUTIC use of antimetabolites , *IRINOTECAN , *CANCER patients , *COMBINATION drug therapy , *CONFIDENCE intervals , *PATIENT aftercare , *METASTASIS , *NEUTROPHILS , *PANCREATIC tumors , *RANDOMIZED controlled trials , *KARNOFSKY Performance Status , *LYMPHOCYTE count , *ODDS ratio , *PROGNOSIS , *THERAPEUTICS - Abstract
Abstract Background Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial. Patients and methods Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred. Results The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57–0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected. Conclusions The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. Clinical trial registration number NCT01494506. Highlights • Final analysis of NAPOLI-1 trial of liposomal irinotecan confirmed primary analysis. • Longer overall survival in metastatic pancreatic cancer post–first line progression. • Long-term survival linked to higher performance score, younger age and lower CA19-9. • No new safety signals for liposomal irinotecan + 5-fluorouracil/leucovorin regimen. [ABSTRACT FROM AUTHOR]
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- 2019
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13. PAXgene fixation enables comprehensive metabolomic and proteomic analyses of tissue specimens by MALDI MSI.
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Urban, Christian, Buck, Achim, Siveke, Jens T., Lordick, Florian, Luber, Birgit, Walch, Axel, and Aichler, Michaela
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METABOLOMICS , *PROTEOMICS , *TISSUE fixation (Histology) , *MATRIX-assisted laser desorption-ionization , *FORMALDEHYDE - Abstract
An alcohol-based non-crosslinking tissue fixative, PAXgene Tissue System, has been proposed as alternative fixation method to formalin, providing superior and morphological preservation. To date, metabolites have not been assessed in PAXgene-fixed tissues. The study focuses on a comparison between PAXgene and standard formalin fixation for metabolomic analysis by MALDI mass spectrometry imaging. Therefore, fifty-six samples from seven mice organs were fixed with PAXgene (PFPE) or formalin (FFPE), embedded in paraffin, and processed to a tissue microarray. PAXgene was able to spatially preserve metabolites in organs achieving an overlap of common metabolites ranging from 34 to 78% with FFPE. Highly similar signal intensities and visualization of molecules demonstrated negligible differences for metabolite imaging on PFPE compared to FFPE tissues. In addition, we performed proteomic analysis of intact proteins and peptides derived from enzymatic digestion. An overlap of 33 to 58% was found between FFPE and PFPE tissue samples in peptide analysis with a higher number of PFPE-specific peaks. Analysis of intact proteins achieved an overlap in the range of 0 to 28% owing to the poor detectability of cross-linked proteins in formalin-fixed tissues. Furthermore, metabolite and peptide profiles obtained from PFPE tissues were able to correctly classify organs independent of the fixation method, whereas a distinction of organs by protein profiles was only achieved by PAXgene fixation. Finally, we applied MALDI MSI to human biopsies by sequentially analyzing metabolites and peptides within the same tissue section. Concerning prospective studies, PAXgene can be used as an alternative fixative for multi-omic tissue analysis. [ABSTRACT FROM AUTHOR]
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- 2018
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14. Direct Molecular Tissue Analysis by MALDI Imaging Mass Spectrometry in the Field of Gastrointestinal Disease.
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Balluff, Benjamin, Rauser, Sandra, Ebert, Matthias P., Siveke, Jens T., Höfler, Heinz, and Walch, Axel
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- 2012
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15. Early Requirement of Rac1 in a Mouse Model of Pancreatic Cancer.
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Heid, Irina, Lubeseder–Martellato, Clara, Sipos, Bence, Mazur, Pawel K., Lesina, Marina, Schmid, Roland M., and Siveke, Jens T.
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PANCREATIC cancer ,DUCTAL carcinoma ,CHEMOPREVENTION ,METAPLASIA ,BOTULINUM toxin ,PANCREATIC acinar cells ,CELL culture ,DEVELOPMENTAL cytology ,LABORATORY mice - Abstract
Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease without effective chemopreventive or therapeutic approaches. Although the role of oncogenic Kras in initiating development of PDAC is well established, downstream targets of aberrant Ras signaling are poorly understood. Acinar-ductal metaplasia (ADM) appears to be an important prerequisite for development of pancreatic intraepithelial neoplasia (PanIN), a common precursor to PDAC. RAS-related C3 botulinum substrate 1 (Rac1), which controls actin reorganization, can be activated by Ras, is up-regulated in several human cancers, and is required for cerulein-induced morphologic changes in acini. We investigated effects of loss of Rac1 in Kras-induced pancreatic carcinogenesis in mice. Methods: Using a Cre/lox approach, we deleted Rac1 from pancreatic progenitor cells in different mouse models of PDAC and in mice with cerulein-induced acute pancreatitis. Acinar epithelial explants of mutant mice were used to investigate the role of Rac1 in vitro. Results: Rac1 expression increased in mouse and human pancreatic tumors, particularly in the stroma. Deletion of Rac1 in Kras
G12D -induced PDAC in mice reduced formation of ADM, PanIN, and tumors and significantly prolonged survival. Pancreatic epithelial metaplasia was accompanied by apical-basolateral redistribution of F-actin, along with basal expression of Rac1. Acinar epithelial explants that lacked Rac1 or that were incubated with inhibitors of actin polymerization had a reduced ability to undergo ADM in 3-dimensional cultures. Conclusions: In mice, Rac1 is required for early metaplastic changes and neoplasia-associated actin rearrangements in development of pancreatic cancer. Rac1 might be developed as a diagnostic marker or therapeutic target for PDAC. [ABSTRACT FROM AUTHOR]- Published
- 2011
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16. Betacellulin Protects From Pancreatitis by Activating Stress-Activated Protein Kinase.
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Dahlhoff, Maik, Algül, Hana, Siveke, Jens T., Lesina, Marina, Wanke, Rüdiger, Wartmann, Thomas, Halangk, Walter, Schmid, Roland M., Wolf, Eckhard, and Schneider, Marlon R.
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EPIDERMAL growth factor ,PANCREATITIS ,PROTEIN kinases ,ENZYME activation ,PATHOLOGICAL physiology ,SERUM ,LABORATORY mice ,INFLAMMATION ,THERAPEUTICS - Abstract
Background & Aims: Acute pancreatitis (AP) is a serious, unpredictable clinical problem, the pathophysiology of which is poorly understood. Here, we evaluate whether betacellulin (BTC), a ligand of the epidermal growth factor receptor also able to activate the proapoptotic ERBB4 receptor, can protect against experimental AP. Methods: AP was induced in transgenic mice overexpressing BTC (BTC-tg), control mice, or control mice after administration of recombinant BTC. The severity of pancreatitis was assessed by measurements of serum amylase and lipase and histologic grading. The involvement of the stress-activated protein kinase (SAPK) was evaluated by treating BTC-tg mice with an SAPK inhibitor before induction of AP. Results: BTC-tg mice showed increased apoptosis and proliferation in the exocrine pancreas, indicating an increased cell turnover. There was a marked, epidermal growth factor receptor−independent decrease in pancreas weight. After induction of AP by cerulein injection, BTC-tg mice showed a significantly lower increase in serum amylase and lipase levels as well as less pronounced tissue necrosis, edema, and inflammation, as compared to nontransgenic littermates. This protective effect, also confirmed in the l-arginine AP model, was associated with increased phosphorylation of SAPK and abrogated after treatment of BTC-tg mice with a SAPK inhibitor. Finally, the protective effect of BTC against AP was confirmed by treating nontransgenic mice with recombinant BTC. Conclusions: These findings indicate a potential application of the BTC/ERBB4 pathway for modulating the course of AP. [Copyright &y& Elsevier]
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- 2010
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17. 831 Prognostic Factors and Outcome of 121 Patients with Non-Surgical Therapy of Necrotizing Pancreatitis: What Is the Impact of An Infection of the Necrosis?
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Huber, Wolfgang, Neudeck, Marion, Hauptvogel, Katja, Umgelter, Andreas, Reindl, Wolfgang, Weber, Andreas, Siveke, Jens T., Lampart, Christoph, and Schmid, Roland M.
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- 2008
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18. PET-directed combined modality therapy for gastroesophageal junction cancer: Results of the multicentre prospective MEMORI trial of the German Cancer Consortium (DKTK).
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Lorenzen, Sylvie, Quante, Michael, Rauscher, Isabel, Slotta-Huspenina, Julia, Weichert, Wilko, Feith, Marcus, Friess, Helmut, Combs, Stefanie E., Weber, Wolfgang A., Haller, Bernhard, Angele, Martin, Albertsmeier, Markus, Blankenstein, Christiane, Kasper, Stefan, Schmid, Roland M., Bassermann, Florian, Schwaiger, Markus, Liffers, Sven-Thorsten, and Siveke, Jens T.
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ADENOCARCINOMA , *STOMACH tumors , *RESEARCH , *CLINICAL trials , *CANCER chemotherapy , *CHEMORADIOTHERAPY , *TREATMENT effectiveness , *POSITRON emission tomography , *RADIOPHARMACEUTICALS , *DESCRIPTIVE statistics , *COMBINED modality therapy , *DEOXY sugars , *PROGRESSION-free survival , *ESOPHAGEAL tumors , *LONGITUDINAL method - Abstract
Positron emission tomography (PET) may differentiate responding and non-responding tumours early in the treatment of locally advanced gastroesophageal junction adenocarcinomas. Early PET non-responders (P-NR) after induction CTX might benefit from changing to chemoradiation (CRT). Patients underwent baseline 18F-FDG PET followed by 1 cycle of CTX. PET was repeated at day 14–21 and responders (P-R), defined as ≥35% decrease in SUV mean from baseline, continued with CTX. P-NR switched to CRT (CROSS). Patients underwent surgery 4–6 weeks post-CTX/CRT. The primary objective was an improvement in R0 resection rates in P-NR above a proportion of 70%. In total, 160 patients with resectable gastroesophageal junction adenocarcinomas were prospectively investigated by PET scanning. Eighty-five patients (53%) were excluded. Seventy-five eligible patients were enrolled in the study. Based on PET criteria, 50 (67.6%)/24 (32.4%) were P-R and P-NR, respectively. Resection was performed on 46 responders, including one patient who withdrew the ICF, and 22 non-responders (per-protocol population). R0 resection rates were 95.6% (43/45) for P-R and 86.4% (19/22) for P-NR. No treatment related deaths occurred. With a median follow-up time of 24.5 months, estimated 18 months DFS was 75.4%/64.2% for P-R/P-NR, respectively. The estimated 18 months OS was 95.5% for P-R and 68.2% for P-NR. The primary endpoint of the study to increase the R0 resection rate in metabolic NR was not met. PET response after induction CTX is prognostic for outcome with a prolonged OS and DFS in PET responders. NCT 2014-000860-16. • MEMORI confirms that early metabolic response is associated with favourable survival. • Radiation to neoadjuvant chemotherapy improves tumour response in metabolic non-responders. • PET/CT-guided preoperative treatment adaptation seems to be feasible and safe. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Gene expression-based prediction of pazopanib efficacy in sarcoma.
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Heilig, Christoph E., Laßmann, Andreas, Mughal, Sadaf S., Mock, Andreas, Pirmann, Sebastian, Teleanu, Veronica, Renner, Marcus, Andresen, Carolin, Köhler, Bruno C., Aybey, Bogac, Bauer, Sebastian, Siveke, Jens T., Hamacher, Rainer, Folprecht, Gunnar, Richter, Stephan, Schröck, Evelin, Brandts, Christian H., Ahrens, Marit, Hohenberger, Peter, and Egerer, Gerlinde
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THERAPEUTIC use of antineoplastic agents , *SEQUENCE analysis , *CLINICAL trials , *PHOSPHOTRANSFERASES , *GENETIC testing , *GENE expression , *SOFT tissue tumors , *TREATMENT effectiveness , *CANCER , *DESCRIPTIVE statistics , *PREDICTION models , *HISTOLOGY , *PROGRESSION-free survival , *SARCOMA - Abstract
The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug. We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers. Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3 -high, IGF1R -low and KDR -high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib. A score based on the combined expression of NTRK3 , IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic. • Reliable predictors of pazopanib efficacy in soft-tissue sarcoma are lacking. • A gene expression-based score stratifies patients with sarcoma regarding pazopanib benefit. • The score is not predictive in patients with sarcoma who received other therapies. • The pazopanib efficacy predictor warrants prospective clinical investigation. [ABSTRACT FROM AUTHOR]
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- 2022
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20. Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group 'Molecular Diagnostics and Therapy'.
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Westphalen, Benedikt C., Bokemeyer, Carsten, Büttner, Reinhard, Fröhling, Stefan, Gaidzik, Verena I., Glimm, Hanno, Hacker, Ulrich T., Heinemann, Volker, Illert, Anna L., Keilholz, Ulrich, Kindler, Thomas, Kirschner, Martin, Schilling, Bastian, Siveke, Jens T., Schroeder, Thomas, Tischler, Verena, Wagner, Sebastian, Weichert, Wilko, Zips, Daniel, and Loges, Sonja
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CANCER patient medical care , *CONCEPTUAL structures , *CONSENSUS (Social sciences) , *DELPHI method , *MOLECULAR pathology , *INDIVIDUALIZED medicine , *GENE expression profiling - Abstract
Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force ' Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality. • This consenus statement originated from collaborative efforts of all fourteen Comprehensive Cancer Centres in the German Cancer Aid network. • The consensus statement is based on all centres' consent due to implementation of a modified Delphi process. • This consensus statement will serve as a framework to establish sustainable structures for precision cancer medicine in Germany. [ABSTRACT FROM AUTHOR]
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- 2020
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21. Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin.
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Hubner, Richard A., Cubillo, Antonio, Blanc, Jean-Frédéric, Melisi, Davide, Von Hoff, Daniel D., Wang-Gillam, Andrea, Chen, Li-Tzong, Becker, Claus, Mamlouk, Khalid, Belanger, Bruce, Yang, Yoojung, de Jong, Floris A., and Siveke, Jens T.
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FLUOROURACIL , *FOLINIC acid , *IRINOTECAN , *CANCER fatigue , *ADENOCARCINOMA , *ANTIMETABOLITES , *CANCER patient psychology , *COMBINATION drug therapy , *METASTASIS , *HEALTH outcome assessment , *PANCREATIC tumors , *QUALITY of life , *QUESTIONNAIRES , *STATISTICS , *DATA analysis , *TERMINATION of treatment , *FUNCTIONAL assessment , *DIAGNOSIS , *PROGNOSIS , *THERAPEUTICS - Abstract
Abstract Background The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that also maintain the patient's health-related quality of life (HRQOL). Here, we report the HRQOL data. Methods Patients completed the European Organisation for Research and Treatment of Cancer QOL core questionnaire C30 (EORTC QLQ-C30) at baseline, every 6 weeks, and at 30 days after discontinuation of study treatment. Patient-reported outcomes (PROs) were scored according to EORTC guidelines. nal-IRI+5-FU/LV HRQOL was compared with 5-FU/LV. The PRO population comprised intent-to-treat patients who completed baseline and at least one subsequent assessment on the EORTC QLQ-C30. Data were also analysed for missingness. Results Of 236 patients in the intent-to-treat population, 128 (54.2%) comprised the PRO population (71 in the nal-IRI+5-FU/LV arm; 57 the in 5-FU/LV arm). Of the remaining 108 patients (45.8%) not included in the PRO population, most progressed rapidly, making participation difficult. Median change from baseline was ≤10 points at weeks 6 and 12 in global health status or functional and symptom scale scores, except for fatigue, which deteriorated by 11.1 points with nal-IRI+5-FU/LV but did not change vs 5-FU/LV. The proportion of patients whose HRQOL improved or deteriorated was not significantly different between the arms. Conclusion In the NAPOLI-1 study, HRQOL was maintained with nal-IRI+5-FU/LV in patients with metastatic pancreatic adenocarcinoma previously treated with a gemcitabine-based regimen, while survival was significantly extended. Highlights • Pancreatic cancer and chemotherapy can have a detrimental impact on health-related quality of life (HRQOL). • HRQOL was assessed in metastatic pancreatic ductal adenocarcinoma that had progressed on prior gemcitabine-based therapy. • In the NAPOLI-1 study, patients received liposomal irinotecan plus 5-flurouracil/leucovorin (nal-IRI+5-FU/LV) or 5-FU/LV. • HRQOL was maintained over time for nal-IRI+5-FU/LV vs 5-FU/LV alone. • Maintained patient HRQOL and survival benefit were seen with nal-IRI+5-FU/LV vs 5‑FU/LV alone in this global phase 3 study. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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22. PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer—a randomised biomarker-driven clinical phase II AIO study.
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Vogel, Arndt, Kasper, Stefan, Bitzer, Michael, Block, Andreas, Sinn, Marianne, Schulze-Bergkamen, Henning, Moehler, Markus, Pfarr, Nicole, Endris, Volker, Goeppert, Benjamin, Merx, Kirsten, Schnoy, Elisabeth, Siveke, Jens T., Michl, Patrick, Waldschmidt, Dirk, Kuhlmann, Jan, Geissler, Michael, Kahl, Christoph, Evenkamp, Ralph, and Schmidt, Torben
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THERAPEUTIC use of monoclonal antibodies , *THERAPEUTIC use of antimetabolites , *ANTIMETABOLITES , *BIOMARKERS , *CANCER chemotherapy , *COMBINATION drug therapy , *CISPLATIN , *GLOMERULAR filtration rate , *STATISTICS , *SURVIVAL , *DATA analysis , *RANDOMIZED controlled trials , *TREATMENT duration , *ODDS ratio , *PROGNOSIS ,BILE duct tumors - Abstract
Background Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer. Patients and methods Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m 2 and gemcitabine 1000 mg/m 2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end-point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), overall survival (OS), and toxicity. In addition, a post hoc assessment of genetic alterations was performed. Finally, we performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies. Results Sixty-two patients were randomised in arm A and 28 patients in arm B. Patients received 7 treatment cycles in median (1–35) with a median treatment duration of 4.7 months (141 days, 8–765). PFS rate at 6 months was 54% in patients treated with cisplatin/gemcitabine and panitumumab but was 73% in patients treated with cisplatin/gemcitabine without antibody, respectively. Secondary end-points were an ORR of 45% in treatment arm A compared with 39% receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively. In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival. In accordance with our results, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone. Conclusions Panitumumab in combination with chemotherapy does not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers. Clinical Trials Number The trial was registered with NCT01320254 . [ABSTRACT FROM AUTHOR]
- Published
- 2018
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23. Corrigendum to "Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group 'Molecular Diagnostics and Therapy'" [European Journal of Cancer 135 (2020) 1-7].
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Benedikt Westphalen, C., Bokemeyer, Carsten, Büttner, Reinhard, Fröhling, Stefan, Gaidzik, Verena I., Glimm, Hanno, Hacker, Ulrich T., Heinemann, Volker, Illert, Anna L., Keilholz, Ulrich, Kindler, Thomas, Kirschner, Martin, Schilling, Bastian, Siveke, Jens T., Schroeder, Thomas, Tischler, Verena, Wagner, Sebastian, Weichert, Wilko, Zips, Daniel, and Loges, Sonja
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INDIVIDUALIZED medicine , *CANCER patient medical care - Published
- 2022
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24. Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma – The SHELTER study.
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Bitzer, Michael, Horger, Marius, Giannini, Edoardo G., Ganten, Tom M., Wörns, Marcus A., Siveke, Jens T., Dollinger, Matthias M., Gerken, Guido, Scheulen, Max E., Wege, Henning, Zagonel, Vittorina, Cillo, Umberto, Trevisani, Franco, Santoro, Armando, Montesarchio, Vincenzo, Malek, Nisar P., Holzapfel, Julia, Herz, Thomas, Ammendola, Astrid S., and Pegoraro, Stefano
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LIVER cancer , *PHARMACOKINETICS , *SORAFENIB , *DEACETYLASES , *ZINC-finger proteins - Abstract
Background & Aims No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib. Methods Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n = 38) four dose levels ranged from daily 200 to 600 mg resminostat plus 400 to 800 mg sorafenib. The monotherapy group (n = 19) received 600 mg resminostat. Results 57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched T max of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12 weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1 months for resminostat and 6.5 and 8.0 months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival. Conclusions The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo . A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications. Lay summary No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib. Clinical trial registration The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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25. Validation of Heat Shock Protein 70 as a Tumor-Specific Biomarker for Monitoring the Outcome of Radiation Therapy in Tumor Mouse Models.
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Bayer, Christine, Liebhardt, Michael E., Schmid, Thomas E., Trajkovic-Arsic, Marija, Hube, Kathrin, Specht, Hanno M., Schilling, Daniela, Gehrmann, Mathias, Stangl, Stefan, Siveke, Jens T., Wilkens, Jan J., and Multhoff, Gabriele
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CANCER radiotherapy , *CANCER cells , *HEAT shock proteins , *TUMOR markers , *SQUAMOUS cell carcinoma , *PANCREATIC cancer , *TREATMENT effectiveness , *LABORATORY mice - Abstract
Purpose: Tumor cells, in contrast to normal cells, frequently overexpress heat shock protein 70 (Hsp70) in the cytosol, present it on their cell surface, and actively release it. Therefore, soluble Hsp70 (sHsp70) was investigated as a potential tumor biomarker for monitoring the outcome of radiation therapy. Methods and Materials: Plasma from mice bearing membrane Hsp70 (mHsp70)-positive FaDu human squamous cell carcinoma of the head and neck and spontaneous pancreatic ductal adenocarcinoma (PDAC) was investigated. A cohort of mice with FaDu tumors (0.32 cm3) was irradiated with 30 Gy, and plasma was collected 24 hours after irradiation, after the tumors had shrunk to 50% of their starting volume and after complete remission. sHsp70 levels in the plasma were quantified by enzyme-linked immunosorbent assay. Results: sHsp70 levels were significantly higher in the blood of tumor-bearing mice than that of control animals. A correlation between increasing sHsp70 plasma levels and tumor volume in the range of 0.01 cm3 to 0.66 cm3 was observed. Radiation-induced regression of the tumors was associated with significantly decreased sHsp70 levels, which returned to the level of control animals after complete remission. Conclusion: We propose sHsp70 as an innovative biomarker for detecting tumors and for monitoring the clinical outcome of radiation therapy in cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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