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W E Fleig - One of the best experts on this subject based on the ideXlab platform.
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Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma a phase iii clinical trial
BMC Cancer, 2010Co-Authors: M M Dollinger, Christine Lautenschlaeger, Joachim Lesske, Andrea Tannapfel, Annadorothea Wagner, K Schoppmeyer, Oliver Nehls, Martinwalter Welker, Reiner Wiest, W E FleigAbstract:Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of Thymostimulin in a phase III trial. The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky ≥60%/Child-Pugh ≤ 12) were randomised to receive Thymostimulin 75 mg s.c. 5×/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol. Twelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on Thymostimulin suffered from accumulating ascites and renal failure. In our phase III trial, we found no evidence of any benefit to Thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of Thymostimulin on hepato-renal function requires further confirmation. Current Controlled Trials ISRCTN64487365.
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Thymostimulin versus placebo for treatment of advanced hepatocellular carcinoma a randomised controlled double blind multicenter study
Journal of Clinical Oncology, 2008Co-Authors: M M Dollinger, Joachim Lesske, C Lautenschlager, W E FleigAbstract:4519 Background: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independ...
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Thymostimulin in advanced hepatocellular carcinoma a phase ii trial
BMC Cancer, 2008Co-Authors: M M Dollinger, Joachim Lesske, W E Fleig, Christa M Behrens, Susanne Behl, Curd BehrmannAbstract:Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. 44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received Thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. Median survival was 11.5 months (95% CI 7.9–15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than Thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to Thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8–12). Grade 1 local reactions following injection were the only side effects. Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition to response to Thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept. Current Controlled Trials ISRCTN29319366.
M M Dollinger - One of the best experts on this subject based on the ideXlab platform.
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Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma a phase iii clinical trial
BMC Cancer, 2010Co-Authors: M M Dollinger, Christine Lautenschlaeger, Joachim Lesske, Andrea Tannapfel, Annadorothea Wagner, K Schoppmeyer, Oliver Nehls, Martinwalter Welker, Reiner Wiest, W E FleigAbstract:Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of Thymostimulin in a phase III trial. The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky ≥60%/Child-Pugh ≤ 12) were randomised to receive Thymostimulin 75 mg s.c. 5×/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol. Twelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on Thymostimulin suffered from accumulating ascites and renal failure. In our phase III trial, we found no evidence of any benefit to Thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of Thymostimulin on hepato-renal function requires further confirmation. Current Controlled Trials ISRCTN64487365.
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Thymostimulin versus placebo for treatment of advanced hepatocellular carcinoma a randomised controlled double blind multicenter study
Journal of Clinical Oncology, 2008Co-Authors: M M Dollinger, Joachim Lesske, C Lautenschlager, W E FleigAbstract:4519 Background: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independ...
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Thymostimulin in advanced hepatocellular carcinoma a phase ii trial
BMC Cancer, 2008Co-Authors: M M Dollinger, Joachim Lesske, W E Fleig, Christa M Behrens, Susanne Behl, Curd BehrmannAbstract:Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. 44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received Thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. Median survival was 11.5 months (95% CI 7.9–15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than Thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to Thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8–12). Grade 1 local reactions following injection were the only side effects. Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition to response to Thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept. Current Controlled Trials ISRCTN29319366.
Joachim Lesske - One of the best experts on this subject based on the ideXlab platform.
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Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma a phase iii clinical trial
BMC Cancer, 2010Co-Authors: M M Dollinger, Christine Lautenschlaeger, Joachim Lesske, Andrea Tannapfel, Annadorothea Wagner, K Schoppmeyer, Oliver Nehls, Martinwalter Welker, Reiner Wiest, W E FleigAbstract:Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of Thymostimulin in a phase III trial. The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky ≥60%/Child-Pugh ≤ 12) were randomised to receive Thymostimulin 75 mg s.c. 5×/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol. Twelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on Thymostimulin suffered from accumulating ascites and renal failure. In our phase III trial, we found no evidence of any benefit to Thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of Thymostimulin on hepato-renal function requires further confirmation. Current Controlled Trials ISRCTN64487365.
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Thymostimulin versus placebo for treatment of advanced hepatocellular carcinoma a randomised controlled double blind multicenter study
Journal of Clinical Oncology, 2008Co-Authors: M M Dollinger, Joachim Lesske, C Lautenschlager, W E FleigAbstract:4519 Background: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independ...
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Thymostimulin in advanced hepatocellular carcinoma a phase ii trial
BMC Cancer, 2008Co-Authors: M M Dollinger, Joachim Lesske, W E Fleig, Christa M Behrens, Susanne Behl, Curd BehrmannAbstract:Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. 44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received Thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. Median survival was 11.5 months (95% CI 7.9–15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than Thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to Thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8–12). Grade 1 local reactions following injection were the only side effects. Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition to response to Thymostimulin, while an invasive HCC phenotype had no influence in the multivariate analysis. Thymostimulin could therefore be considered a safe and promising candidate for palliative treatment in a selected target population with advanced hepatocellular carcinoma, in particular as component of a multimodal therapy concept. Current Controlled Trials ISRCTN29319366.
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BMC Cancer BioMed Central
2008Co-Authors: Matthias M Dollinger, Joachim Lesske, Christa M Behrens, Susanne Behl, Curd Behrmann, Wolfgang E Fleig, Open AccessAbstract:Research article Thymostimulin in advanced hepatocellular carcinoma: A phase II tria
H A Drexhage - One of the best experts on this subject based on the ideXlab platform.
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the effects of Thymostimulin on immunological function in patients with head and neck cancer
Clinical Otolaryngology, 1996Co-Authors: Jeroen D F Kerrebijn, Peter J Simons, M Tas, P Knegt, M W M Van De Brekel, Pierre Delaere, I B Tan, H A Drexhage, A J M BalmAbstract:Patients with head and neck carcinoma show deficits of cellular immunity, probably due to low molecular mass factors (LMMFs) released by the tumour. Thymostimulin (TP1) restores the defective monocyte chemotaxis and dendritic cell clustering capability in the presence of the tumour when administered pre-operatively. In the present study we investigated these immune parameters in 39 patients treated with TP1 for 10 days pre- and 6 months post-operatively and in 22 patients who were not treated with TP1 for 6 months after operation. Removal of the tumour in non-TP1-treated patients also resulted in a restoration of monocyte and dendritic cell functions, while TP1 treatment gave no additional effect. LMMF levels in the blood of both TP1-treated and non-TP1-treated patients remained elevated even after removal of the tumour, and it is therefore concluded that it is unlikely that depression of cellular immunity is a direct effect of these LMMFS.
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Thymostimulin enhancement of t cell infiltration into head and neck squamous cell carcinoma
Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 1996Co-Authors: Jeroen D F Kerrebijn, Peter J Simons, M Tas, P Knegt, I B Tan, H A Drexhage, A J M Balm, N De VriesAbstract:Background Head and neck squamous cell carcinoma (HNSCC) produces immunosuppressive low-molecular-mass factors (LMMFs) responsible for defects in the cell-mediated immune system. These defects include impaired monocyte chemotaxis and an impaired capability of dendritic cells (DC) to form cellular clusters. It has been shown previously that the immunomodulating drug Thymostimulin (TP1) restores these defects in vitro. Methods An immunohistochemical study was performed on tumors of 18 patients with HNSCC who had preoperatively been treated with TP1 in one of three dosages (0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg body weight). Additionally, tumors of 4 patients who had been treated with a placebo and 12 patients who had not received any preoperative treatment were studied. A relative surface area of infiltration, meaning the percentage of stromal or epithelial tissue covered by infiltrating cells in histologic sections, was calculated using an image analysis system (VIDAS RT) for CD3+ T-cells, CD14+/CD68+ monocytes/macrophages and L25+/CD1a+ dendritic cells for each tumor. Results A highly significant, denser T-cell infiltration into the stromal tissue area of tumors of patients who had been treated with TP1 when compared with tumors of non-TP1-treated patients was observed for all three dosages. None of the other tumor-infiltrating cell types was affected by TP1. In addition, a correlation was found between the tumor T-cell infiltration and capability of DCs in the peripheral blood to form clusters with T-cells. No correlation existed between CD3+ T-cell numbers in peripheral blood and T-cell infiltration into the tumor; nor were monocyte chemotactic functions in peripheral blood correlated with tumor infiltration by monocytes or monocyte-derived macrophages and DCs. Conclusions Preoperative treatment of HNSCC patients with TP1 appears to strongly enhance tumor-T-cell infiltration. The number of tumor-infiltrating DCs was not affected by TP1, but a positive correlation between tumor-T-cell infiltration and DC clustering capability suggests that the functional status of DCs is important in improved cell-mediated immunity. HEAD & NECK 1996;18:335–342 © 1996 John Wiley & Sons, Inc.
Melchor Alvarezmon - One of the best experts on this subject based on the ideXlab platform.
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Thymostimulin increases natural cytotoxic activity in patients with breast cancer
International Journal of Immunopharmacology, 1997Co-Authors: G Meneses, M A Delgado, M A Perezmachado, Alfredo Prieto, R Alonso, Flavio Carrion, E Lanzos, Melchor AlvarezmonAbstract:The effect of Thymostimulin on the Natural Killer (NK) cytotoxic activity of peripheral blood mononuclear cells (PBMC) was investigated in 15 patients with breast cancer after finishing or during chemotherapy (CAF) and in 10 healthy controls. PBMC from these subjects were incubated in the presence of Thymostimulin for varying periods of time (18 h or 5 days), and then used as effector cells against 51Cr-radiolabeled NK-sensitive (K-562) and NK-resistant (JY) target cells in cytotoxicity assays. No significant differences were observed between the NK-activity from breast cancer patients and healthy controls. Thymostimulin induced a dose- and time-dependent cytotoxic enhancing effect on the cytotoxic activity of PBMC from these patients against NK-sensitive K562 target cells. The Thymostimulin (1000 ng/ml) significantly enhanced cytotoxic activity in PBMC from breast cancer patients who had previously received chemotherapy (p = 0.0277) against NK-sensitive cells. This increase was not statistically significant neither in PBMC from patients receiving chemotherapy nor in healthy controls (p > 0.05 in both cases). The incubation of PBMC from patients with breast cancer was not associated to a significant enhancement of the cytotoxic activity against NK-resistant target cells (p > 0.05). We also found that Thymostimulin could synergize with interleukin-2 in inducing NK cytotoxic activity in PBMC after 18 h of culture (p = 0.0277). In conclusion, we have demonstrated that Thymostimulin enhances the natural killer cytotoxic activity of PBMC from patients with breast cancer who have previously received chemotherapy.
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Thymostimulin enhances the natural cytotoxic activity of patients with transitional cell carcinoma of the bladder
International Journal of Immunopharmacology, 1993Co-Authors: L Molto, J Carballido, Luis Manzano, Carlos Olivier, Maria Lapuerta, Melchor AlvarezmonAbstract:We have investigated the effect of Thymostimulin on the major histocompatibility (MHC) unrestricted cytotoxic activity of peripheral blood mononuclear cells (PBMNC) from patients with superficial transitional cell carcinoma (TCC) of the bladder. PBMNC from patients and healthy controls were incubated in the presence of Thymostimulin for varying periods of time (2 or 18 h or 5 days), and were used as effectors against 51Cr-radiolabeled natural killer (NK)-sensitive (K-562) and NK-resistant (JY) target cells in cytotoxic assays. In 6 out of 14 patients analyzed, Thymostimulin enhanced the cytotoxic activity of PBMNC against NK-sensitive target cells in a dose-dependent manner. This cytotoxic inducer effect of Thymostimulin was maximal after 18 h of culture. Thymostimulin failed to induce lytic activity in PBMNC from TCC patients against NK-resistant target cells. We also found that Thymostimulin could synergize with interleukin-2 in inducing non-MHC restricted cytotoxic activity in PBMNC from TCC patients. In conclusion, we have demonstrated that Thymostimulin can enhance the natural killer cytotoxic activity of PBMNC from patients with TCC of the bladder.