Biomedical subjects

Rolf D Issels

Publications and source records attributed to Rolf D Issels.

9 recordsLinked to original sources

PubMed2006

High-risk soft tissue sarcoma: clinical trial and hyperthermia combined chemotherapy.

For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window.

Adult↗

PubMed2005

Ferrite-enhanced MRI monitoring in hyperthermia.

In an MRI hyperthermia hybrid system, T1 changes are investigated for monitoring thermal therapy at 0.2 T. The water bolus, which is needed for power transmission and cooling of the skin, limits MR image quality by signal compression and artifacts. Superparamagnetic ferrofluid in different concentration was investigated with MR relaxometry and MRI methods. We found that using ferrofluid in a low concentration of 70-90 ppm magnetite the water signal can be suppressed without susceptibility artifacts. With our method of signal suppression, a significant improvement of spatial and temporal resolution is possible. The ferrofluid is stable and allows RF heating at 100 MHz. This method of signal extinction may also be useful for other experimental setups where suppression of water is necessary.

Artifacts↗

PubMed2004

Novel temperature-sensitive liposomes with prolonged circulation time.

Hyperthermia increases the efficiency of various chemotherapeutic drugs and is administered as an adjunct to chemotherapy for the treatment of cancer patients. The temperature-dependent effect can be strongly increased by the use of temperature-sensitive liposomes in combination with regional hyperthermia, which specifically releases the entrapped drug in the heated tumor tissue. The novel lipid 1.2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG), which is closely related to the naturally occurring 1.2-dipalmitoyl-sn-glycero-3-phosphoglycerol, in combination with 1.2-dipalmitoyl-sn-glycero-3-phosphocholine and 1.2-distearoyl-sn-glycero-3-phosphocholine provides long-circulating temperature-sensitive liposomes with favorable properties under mildly hyperthermic conditions (41-42 degrees C). DPPGOG facilitates temperature-triggered drug release from these liposomes (diameter, 175 nm) and leads to a substantially prolonged plasma half-life for the encapsulated drug with t(1/2) = 9.6 h in hamsters and t(1/2) = 5.0 h in rats. Quantitative fluorescence microscopy of amelanotic melanoma grown in the transparent dorsal skin fold chamber of hamsters demonstrated a favorable drug accumulation in heated tissue after i.v. application of these liposomes (42 degrees C for 1 h). The mean area under the curve for tissue drug concentration was increased by more than sixfold by application of the new liposomes compared with nonliposomal drug delivery. In summary, we present a new DPPGOG-based liposomal formulation enabling long circulation time combined with fast and efficient drug release under mild hyperthermia. This adds positively to the results with lipid-grafted polyethylenglycol used thus far in temperature sensitive liposomes and widens the possibilities for clinical applications.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2004

Emerging treatments for soft tissue sarcoma of adults.

Soft tissue sarcomas are a heterogeneous group of malignancies arising from mesenchymal tissues. Patients can present with a localised tumour (primary or local recurrence) at different sites (e.g., extremity, abdomen) or metastatic disease, which may require different treatment strategies. Is the surgical resection of a localised sarcoma enough or is it better to give an additional treatment like adjuvant and/or preoperative radiotherapy and/or chemotherapy? Which chemotherapy should be selected in the first or second line situation? Do new treatment options exist, such as targeted therapies? This review provides answers to some of these questions. To decide on consecutive treatment steps, it is important to know as many relevant factors as possible at first presentation. Therefore, the first part of this review discusses the specific characteristics and prognostic factors of importance for treatment planning. A short summary of current therapy strategies and existing standards is then given. The main body of the review summarises information on new and emerging clinical compounds for patients with soft tissue sarcoma of adults, including recent developments of targeted therapy.

Adult↗

PubMed2003

Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion.

Ifosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon-gamma (IFN-gamma) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-gamma. The decrease in allostimulatory capacity and in IFN-gamma and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function.

Antigen Presentation↗

PubMed2002

Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells.

Our study demonstrates that tumor-derived heat shock protein (HSP)70 chaperones a tyrosinase peptide and mediates its transfer to human immature dendritic cells (DCs) by receptor-dependent uptake. Human tumor-derived HSP70 peptide complexes (HSP70-PC) thus have the immunogenic potential to instruct DCs to cross-present endogenously expressed, nonmutated, and tumor antigenic peptides that are shared among tumors of the melanocytic lineage for T cell recognition. T cell stimulation by HSP70-instructed DCs is dependent on the Ag bound to HSP70 in that only DCs incubated with HSP70-PC purified from tyrosinase-positive (HSP70-PC/tyr(+)) but not from tyrosinase-negative (HSP70-PC/tyr(-)) melanoma cells resulted in the specific activation of the HLA-A*0201-restricted tyrosinase peptide-specific cytotoxic T cell clone. HSP70-PC-mediated T cell stimulation is very efficient, delivering the tyrosinase peptide at concentrations as low as 30 ng/ml of HSP70-PC for T cell recognition. Receptor-dependent binding of HSP70-PC and active cell metabolism are prerequisites for MHC class I-restricted cross-presentation and T cell stimulation. T cell stimulation does not require external DC maturation signals (e.g., exogenously added TNF-alpha), suggesting that signaling DC maturation is an intrinsic property of the HSP70-PC itself and related to receptor-mediated binding. The cross-presentation of a shared human tumor Ag together with the exquisite efficacy are important new aspects for HSP70-based immunotherapy in clinical anti-cancer vaccination strategies, and suggest a potential extension of HSP70-based vaccination protocols from a patient-individual treatment modality to its use in an allogeneic setting.

Antigen Presentation↗

PubMed2002

Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts long-term survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas.

PURPOSE: To determine the efficacy of neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for local tumor control and overall survival (OS) in adult patients with retroperitoneal or visceral (RP/V) high-risk soft tissue sarcomas (HR-STS). PATIENTS AND METHODS: From 1991 to 1997, 58 patients with HR-STS at RP/V sites were prospectively treated with four cycles of etoposide, ifosfamide, and doxorubicin combined with RHT followed by surgery, adjuvant chemotherapy, and radiation. RESULTS: Objective response rate assessable in 40 patients was 13% (five partial responses). Including minor responses (n = 8), the radiographic response rate was 33%. The pathologic response rate assessable in 26 patients after surgical resection was 42%. Median OS was 31 months. At a median observation time of 74 months, 5-year probability of local failure-free survival (LFFS), distant metastasis-free survival, event-free survival, and OS were 25%, 51%, 20%, and 32%, respectively. Averaged minimum temperatures (T(min)) and time-averaged temperatures achieved in 50% (T(50)) and 90% (T(90)) of all measured tumor sites differed significantly between responders and nonresponders (T(min), 39.3 degrees C v 38.0 degrees C; P =.002; T(50), 40.9 degrees C v 40.3 degrees C; P =.038; T(90), 40.1 degrees C v 39.3 degrees C; P =.017). At 5-year follow-up, probability of LFFS (59% v 0%; P <.001) and OS (60% v 10%; P <.001) was significantly in favor of patients responding to neoadjuvant thermochemotherapy. CONCLUSION: Response to neoadjuvant chemotherapy combined with RHT is predictive for an improved local tumor control resulting in a long-term survival benefit for patients with HR-STS at unfavorable RP/V sites; however, the impact of RHT has to be defined in a randomized phase III trial.

Adult↗

PubMed2002

HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway.

Human heat-shock protein (HSP)70 activates innate immune cells and hence requires no additional adjuvants to render bound peptides immunogenic. Here we tested the assumption that endogenous HSP70 activates the Toll/IL-1 receptor signal pathway similar to HSP60 and pathogen-derived molecular patterns. We show that HSP70 induces interleukin-12 (IL-12) and endothelial cell-leukocyte adhesion molecule-1 (ELAM-1) promoters in macrophages and that this is controlled by MyD88 and TRAF6. Furthermore, HSP70 causes MyD88 relocalization and MyD88-deficient dendritic cells do not respond to HSP70 with proinflammatory cytokine production. Using the system of genetic complementation with Toll-like receptors (TLR) we found that TLR2 and TLR4 confer responsiveness to HSP70 in 293T fibroblasts. The expanding list of endogenous ligands able to activate the ancient Toll/IL-1 receptor signal pathway is in line with the "danger hypothesis" proposing that the innate immune system senses danger signals even if they originate from self.

Animals↗

PubMed2002

T1 relaxation time at 0.2 Tesla for monitoring regional hyperthermia: feasibility study in muscle and adipose tissue.

The purpose of this study was to characterize T(1), particularly in the hyperthermia temperature range (ca. 37-44 degrees C), in order to control regional hyperthermia with MR monitoring using 0.2 Tesla, and to improve T(1) mapping. A single-slice and a new multislice "T One by Multiple Read-Out Pulses" (TOMROP) pulse sequence were used for fast T(1) mapping in a clinical MRI hyperthermia hybrid system. Temporal stability, temperature sensitivity, and reversibility of T(1) were investigated in a polyamidacryl gel phantom and in samples of muscle and adipose tissues from turkey and pig, and verified in patients. In the gel phantom a high linear correlation between T(1) and temperature (R(2) = 0.97) was observed. In muscle and adipose tissue, T(1) and temperature had a linear relationship below a breakpoint of 43 degrees C. Above this breakpoint muscle tissue showed irreversible tissue changes; these effects were not visible in adipose tissue. The ex vivo results were confirmed in vivo under clinical conditions. T(1) mapping allows the characterization of hyperthermia-related tissue response in healthy tissue. T(1), in combination with fast mapping, is suitable for controlling regional hyperthermia at 0.2 T within the hybrid system.

Adipose Tissue↗