PubMed Health⌕ Search

Biomedical subjects

R Issels

Publications and source records attributed to R Issels.

At least 19 recordsLinked to original sources
PubMed2004

[MRI-assisted thermometry for regional hyperthermia and interstitial laser thermotherapy].

PURPOSE: To demonstrate the potential of quantitative MRI-assisted thermometry for the treatment of tumor patients with regional hyperthermia (RHT) and interstitial laser thermotherapy (ILTT). METHODS: Two patients and seven tissue samples were investigated using the T1-relaxation time and the chemical shift of the proton resonance frequency (PRF) as temperature sensitive MRI-parameters at 0.2 and 1.5 T. Thermotherapy was applied using either a dedicated MRI-hyperthermia hybrid system or a temperature controlled laser with 830 nm. RESULTS: Both patients were treated successfully showing clinical benefit. T1 and PRF are depending on the applied thermotherapy method and on the MR-system suitable for MRI-assisted thermometry. The clinical application based on phantom results is not necessarily adequate. CONCLUSION: Clinical application and phantom experiments of RHT and ILTT show the potential of MRI-assisted thermometry for further improvement of both minimal invasive thermotherapy methods. Further investigations concerning optimization of the MRI-techniques, the influence of perfusion or the determination of threshold values are necessary.

Adult↗
PubMed2003

[Leiomyosarcoma of the heart--interdisciplinary therapeutic approach of systemic chemotherapy and subsequent heart transplantation].

HISTORY AND ADMISSION FINDINGS: A 35-year-old man reported progressive exercise dyspnea, decreased exercise tolerance and weight loss of 10 kg in 2 months. Imaging tests demonstrated a tumor of maximally 7 cm diameter in the region of the left atrium. Histologically it was a poorly differentiated leiomyosarcoma G 3, which could not be completely resected (R 2 resection). SUBSEQUENT INVESTIGATION: Six weeks after surgical resection a rapidly growing tumor, maximally 7.5 cm in diameter, was visualized at the right lateral region of the left atrium. It filled it almost completely and extended via the right upper pulmonary vein to the right hilus. TREATMENT AND COURSE: As part of a multimodal therapeutic approach he was given 6 cycles of chemotherapy (doxorubicin and ifosfamide), bringing about significant reduction of the tumor size. The tumor was then completely resected, followed by an orthotopic heart transplantation with right pneumonectomy. The resected surgical specimen indicated complete remission, no vital tumor cells being demonstrated. No tumor recurrence or distal metastasis was seen during a follow-up period of 36 months. The patient died from right heart failure with advanced pulmonary hypertension 45 months after the diagnosis had first been made, 37 months after the cardiac transplantation.

Adult↗
PubMed1999

[MRI-controlled regional hyperthermia].

PURPOSE: Regional hyperthermia in combination with chemotherapy or/and radiotherapy is a promising treatment concept for locally advanced, deep-seated tumors. The purpose of the project is the optimization of the therapy using non-invasive, three-dimensional imaging of tissue changes or of the temperature distribution during regional hyperthermia. METHODS: MRI offers methods suitable in principle for tissue characterization and MR thermometry. A new MRI-hyperthermia hybrid system has been developed based on an innovative hyperthermia applicator and an open MRI system. RESULTS: After successful testing of the new MRI-hyperthermia hybrid system simultaneous MRI and regional hyperthermia in patients could be accomplished for the first time. At present the T1 relaxation time seems to be a promising parameter for MR thermometry. CONCLUSION: The first clinical application of the MRI-hyperthermia hybrid system can be regarded as an important step towards the development of regional hyperthermia. This new hybrid system and the MR thermometry methods have to be investigated prospectively in clinical studies.

Equipment Design↗
PubMed1999

Validation of MR thermometry technology: a small animal model for hyperthermic treatment of tumours.

BACKGROUND: Local hyperthermia has been shown to be an effective adjuvant therapy for cancer. However, progress in this treatment modality requires the non-invasive assessment of temperature distribution in the entire tumour to enable administration of an efficient thermal dose to all tumour areas. Magnetic resonance (MR) imaging offers a promising tool to quantify, non-invasively and three-dimensionally, temperature distribution within tumours. An animal model taking into account the complex interrelationship between pathophysiological changes within a tumour during hyperthermia and temperature-sensitive MR parameters is warranted for the development and validation of new MR thermometry technology. METHODS: An experimental set-up was implemented to allow simultaneous measurements of temperature, tumour blood flow and temperature-sensitive MR parameters under standardised conditions in vivo. Local hyperthermia was induced at 44 degrees C for 20 min under inhalation anaesthesia on seven Syrian Golden hamsters bearing an amelanotic melanoma. Fibreoptic probes were used for reference temperature measurements. Laser Doppler flowmetry served for on-line tumour blood flow determination, and MR thermometry was performed using longitudinal T1 relaxation time measurements. RESULTS: The experimental design enables multifunctional MR thermometry. T1 relaxation times of tumours were 1.44 s (1.36, 1.46) and 1.53 s (1. 48, 1.75) at 37 degrees C and during hyperthermia at 44 degrees C, respectively (median, 25% and 75% quartiles, respectively; P<0.05). At the end of 20 min of hyperthermic treatment at 44 degrees C, relative tumour blood flow was reduced to 40.5% (20.7, 43.3) compared to values before treatment (median, 25% and 75% quartiles, respectively; P<0.05). Imaging of T1 relaxation times revealed a heterogeneous distribution in temperature during hyperthermic treatment. CONCLUSION: This novel in vivo model allows standardised investigations for the development and validation of MR thermography methods.

Animals↗
PubMed1998

Differential Hsp70 plasma-membrane expression on primary human tumors and metastases in mice with severe combined immunodeficiency.

To study the role of cell-surface expression of a tumor-selective heat-shock protein 70 (Hsp70) in vivo, the colon-carcinoma cell line CX2, and the clonal sub-lines CX+ and CX-, which differ in Hsp70 cell-surface expression, but not in MHC and adhesion-molecule expression, were implanted into immunodeficient SCID/beige mice by s.c., i.p., i.v. and orthotopic (o.t.) inoculation. On day 18 after s.c. injection, all animals developed s.c. tumors, ranging in size from 2.5 to 3 cm2. Phenotypic characterization of single-cell suspensions generated from freshly isolated tumor material revealed that the pattern of cell-surface expression is identical to that of the injected tumor cells from cell culture. Comparable results were obtained following i.p. inoculation of CX+ and CX- cells. Macroscopic and microscopic evaluation of lymph nodes, lung, liver and spleen at autopsy of tumor-bearing mice showed no tumor burden except the primary tumor, following s.c. or i.p. injection. After i.v. inoculation of CX+ and of CX- cells, weak tumor growth was observed in lung and liver, the Hsp70 cell-surface-expression pattern on these tumors being identical to that of the injected cells. However, o.t. injection of colon-carcinoma cell lines CX+ and CX- into the cecum resulted in tumor growth at the injection site and in spread of distant metastases in lung, liver and spleen. Most interestingly, and in contrast to the primary colon carcinomas, metastases of CX+ and of CX- tumor cells both revealed strong Hsp70 plasma-membrane expression, although the total amount of cytoplasmic Hsp70 was comparable.

Animals↗
PubMed1998

Non-invasive temperature mapping using MRI: comparison of two methods based on chemical shift and T1-relaxation.

PURPOSE: To implement and evaluate the accuracy of non-invasive temperature mapping using MRI methods based on the chemical shift (CS) and T1 relaxation in media of various heterogeneity during focal (laser) and external thermal energy deposition. MATERIALS AND METHODS: All measurements were performed on a 1.5 T superconducting clinical scanner using the temperature dependence of the water proton chemical shift and the T1 relaxation time. Homogeneous gel and heterogeneous muscle phantoms were heated focally with a fiberoptic laser probe and externally of varying degree ex vivo by water circulating in a temperature range of 20-50 degrees C. Magnetic resonance imaging data were compared to simultaneously recorded fiberoptic temperature readings. RESULTS: Both methods provided accurate results in homogeneous media (turkey) with better accuracy for the chemical shift method (CS:+/-1.5 degrees C, T1:+/-2.0 degrees C). In gel, the accuracy with the CS method was +/-0.6 degrees C. The accuracy decreased in heterogeneous media containing fat (T1:+/-3.5 degrees C, CS: +5 degrees C). In focal heating of turkey muscle, the accuracy was within 1.5 degrees C with the T1 method. CONCLUSION: Temperature monitoring with the chemical shift provides better results in homogeneous media containing no fat. In fat tissue, the temperature calculation proved to be difficult.

Animals↗
PubMed1998

The role of heat shock proteins in the stimulation of an immune response.

Heat shock proteins (HSP) have been defined as immunodominant, although most of them are highly conserved and ubiquitously distributed. Members of the 60, 70 and 90 kDa HSP families are involved in important aspects of viral and bacterial infections, in autoimmune diseases and in cancer immunity. HSP act as immunological target structures either by themselves because of an unusual expression pattern, or they are carrier proteins for immunogenic peptides. In addition to a classical major histocompatibility complex (MHC) restricted T cell response, a major contribution in the recognition of heat shock proteins has been shown for non-MHC restricted effector cells including gamma/delta TcR positive T lymphocytes and natural killer (NK) cells.

Animals↗
PubMed1997

Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells.

Evidence is accumulating that members of the heat shock protein 70 (HSP70) family are found on the cell surface of certain tumor cells where they elicit a strong antitumor immune response. We demonstrated that HSP72, the major heat-inducible form of the HSP70 group, is located on the cell surface of approximately 60% of the human colon carcinoma cells CX2 with two different mAbs by indirect immunofluorescence, by electron microscopy, and by selective cell surface biotinylation. In an effort to analyze the role of HSP72 cell surface expression as a tumor-specific recognition structure within an "autologous" tumor system, the CX2 cells were separated into a stably HSP72 high expressing (CX+: >90%) and a stably HSP72 low expressing (CX-: <20%) subline. The expression "autologous" was written in parentheses to indicate that the colon carcinoma sublines CX+ and CX- derived from the original CX2 tumor cell line differ with respect to the cell surface expression pattern of HSP72, whereas they exhibit an identical cell surface expression pattern of MHC and cellular adhesion molecules (e.g., intercellular cellular adhesion molecule, neural cellular adhesion molecule, vascular cellular adhesion molecule). Within this "autologous" tumor cell system, we demonstrate that the sensitivity to lysis mediated by adherent non-MHC-restricted effector cells correlates (p < 0.05) with the amount of HSP72 that is expressed on the cell surface. Blocking studies using an HSP72-specific mAb revealed that HSP72 might act in an MHC-unrestricted manner as a tumor-specific recognition structure for a distinct NK cell population.

Antigens, Surface↗
PubMed1997

A comparison of the effects of ifosfamide vs. mafosfamide treatment on intracellular glutathione levels and immunological functions of immunocompetent lymphocyte subsets.

This study compares the effects of ifosfamide treatment with those of mafosfamide treatment with respect to important immunological functions and intracellular glutathione (GSH) levels of immunocompetent lymphocyte subsets such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The proliferative and cytotoxic capacity of human peripheral blood lymphocyte (PBL) subsets was measured by a standard [3H] thymidine uptake assay and a [51Cr] release assay; the intracellular glutathione levels were determined by using an established HPLC method described by Reed. Following incubation of human PBLs with the activated forms of ifosfamide (4-OH-IF) and mafosfamide (4-OH-CP), the proliferative capacity of recombinant interleukin 2 (rIL-2)-stimulated PBLs was reduced by both drugs in a dose-dependent manner. However, a three-fold higher concentration of ifosfamide compared with mafosfamide is needed to achieve a comparable inhibition rate in the proliferative capacity of theses lymphocytes. Separation of PBLs into a CD3+ CTL and a CD3- NK subpopulation revealed that proliferative activity was reduced in both subpopulations in a dose-dependent manner by ifosfamide and mafosfamide. However, growth inhibition was much more pronounced in the CD3+ CTL compared with the CD3- NK cells. The intracellular GSH level in CTL, and to a lower extent in NK cells, was reduced more substantially following an ifosfamide treatment compared with a mafosfamide treatment. With respect to our previous finding that an ifosfamide-induced reduction of intracellular GSH levels correlates with decreased cytotoxic function, in this study we compared the effects of ifosfamide treatment with those of mafosfamide treatment on the cytolytic activity of lymphocyte subpopulations. The cytotoxic activity of CD3+ CTL against allogeneic target cells (B-lymphoblastoid cells) was significantly reduced after preincubation with either activated ifosfamide or mafosfamide. In contrast, the lysis of NK-sensitive tumor target cells (K562), mediated by CD3- NK cells is only affected if the effector cells are exposed to high concentrations (100 microM) of activated ifosfamide. The cytotoxic activity of NK cells pretreated with high concentrations of activated mafosfamide (33 microM) had no significant inhibitory effect on the cytotoxic function. Taken together, our findings were as follows: 1) A three-fold higher concentration of activated ifosfamide compared with mafosfamide results in a comparable inhibition of the proliferative activity, in vitro. 2) The intracellular GSH levels of unseparated rIL-2 activated lymphocytes were reduced by ifosfamide and mafosfamide at concentrations above 16 microM. 3) Separated NK cells compared with CTLs are more resistant to treatment with ifosfamide with respect to their intracellular GSH levels. This phenomenon is even more pronounced after treatment with mafosfamide. 4) The reduction in intracellular GSH levels after treatment with ifosfamide and mafosfamide could be correlated with a reduction in the cytotoxic activity.

Antineoplastic Agents↗
PubMed1996

Effects of ifosfamide on immunocompetent effector cells.

We analyzed the effects of ifosfamide, a chemotherapeutic agent that is broadly used within anticancer therapy, on immunocompetent effector cell subpopulations. For our in vitro studies we used 4-hydroperoxyifosfamide (4-OOH-IF), which rapidly gives rise to 4-OH-IF, the activated form of ifosfamide. Activated cytotoxic T lymphocytes and natural killer (NK) cells were used because of their antitumor activity and their antiviral or antibacterial activity. Our study demonstrated three major findings. (1) The capacity of cytotoxic T cells to lyse their specific target cells was substantially reduced by 4-OH-IF treatment. This inhibition of the lytic activity could be correlated with a substantial depletion of the intracellular glutathione (GSH) levels. A rapid reconstitution of the depleted GSH levels and of the cytotoxic activity was achieved by incubation of the T cells with thiols such as mercaptoethanesulfonate (mesna). (2) In contrast to T cells the lytic activity of NK cells was not substantially affected by 4-OH-IF treatment; this increased resistance of NK cells against 4-OH-IF treatment could be explained by their higher initial GSH levels and by their higher rate of GSH synthesis. Furthermore, we demonstrated that (3) NK cells, but not T cells, have the capacity to take up cystine, the oxidized form of cysteine, from the medium. In conclusion we can state that NK cells are much more resistant to ifosfamide treatment compared to T cells with respect to intracellular GSH levels and cytotoxic activity.

Antineoplastic Agents, Alkylating↗
PubMed1996

Heat-shock protein 72 cell-surface expression on human lung carcinoma cells in associated with an increased sensitivity to lysis mediated by adherent natural killer cells.

The cell-surface expression patterns of major histocompatibility complex (MHC) class I, class II and heat-shock protein 72 (HSP72) molecules were measured on human lung (LX-1) and mammary (MX-1) carcinoma cells. No major differences were found in the MHC cell-surface expression pattern of both cell lines. However, they differ significantly in their capacity to express HSP72 on their cell surface. Under physiological conditions LX-1 cells express HSP72 molecules on more than 90% of the cells, whereas MX-1 cells exhibit no significant HSP72 cell-surface expression (less than 5%). These expression patterns remained stable in all further cell passages tested. The sensitivity to lysis mediated by an interleukin-2 (IL-2)-stimulated, adherent natural killer (NK) cell population could be correlated with the amount of cell-surface-expressed HSP72 molecules. By antibody-blocking studies, using HSP72-specific monoclonal antibody (mAb), a strong inhibition of lysis was only found with LX-1 cells but not with MX-1 cells. In contrast to the cell-surface expression, the cytoplasmic amount of HSP72 in MX-1 cells was twice as high compared to LX-1 cells under physiological conditions. After nonlethal heat-shock the rate of induction and the total cytoplasmic amounts of HSP72 were comparable in both cell lines. The clonogenic cell viability of LX-1 cells after incubation at temperatures ranging from 41 degrees C to 44 degrees C was significantly elevated compared to that of MX-1 cells. In conclusion we state the following: (i) HSP72 cell-surface expression on human carcinoma cells is independent of the cytoplasmic amount of HSP72; (ii) the cell-surface expression of HSP72 is associated with an increased sensitivity of tumor cells to lysis mediated by an IL-2-stimulated, adherent NK cell population; (iii) thermoresistance is not related to the cytoplasmic HSP72 level but might be related to the amount of HSP72 expressed on the cell surface.

Cell Adhesion↗
PubMed1995

CD3- large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat shock protein on human sarcoma cells.

Traditionally, heat shock proteins (HSPs) are believed to be located intracellularly, where they perform a variety of chaperoning functions. Recently, evidence has accumulated that some tumor cells express HSPs on the cell surface. The present study confirms this finding and correlates HSP72 cell surface expression, induced by nonlethal heat shock, with an increased sensitivity to interleukin-2-stimulated CD3-natural killer (NK) cells. After nonlethal heat shock, a monoclonal antibody directed against the major heat-inducible 72-kD HSP (HSP72) stains the cell surface of sarcoma cells (ie, Ewing's sarcoma cells or osteosarcoma cells) but not that of normal cells (ie, peripheral blood lymphocytes, fibroblasts, phytohemagglutin-stimulated blasts, B-lymphoblastoid cell lines) or of mammary carcinoma cell line MX-1 carcinoma cells. In this study, we show for the first time a correlation of HSP72 cell surface expression with an increased susceptibility to lysis by NK effector cells. This finding is supported by the following points: (1) HLA-disparate effector cells show similar, elevated lysis of HSP72+ heat-treated sarcoma cells; (2) CD(3-) NK cells, but not CD3+ cytotoxic T lymphocytes, are responsible for the recognition of heat-shocked sarcoma cells; (3) by antibody-blocking studies, an immunogenic HSP72 determinant, which is expressed selectively on the cell surface of heat-treated sarcoma cells could be correlated with NK recognition; (4) the reported phenomenon is independent of a heat-induced, transient downregulation of major histocompatibility complex (MHC) class-I expression; and (5) blocking of MHC class-I-restricted recognition, using either MHC class-I-specific monoclonal antibody W6/32 on the target cells or alpha/beta T-cell receptor monoclonal antibody WT31 on effector cells, also has no inhibitory effect on the lysis of HSP72+ tumor cells. Finally, our in vitro data might have further clinical implications with respect to HSP72 as a stress-inducible, sarcoma-specific NK recognition structure.

Antibodies, Monoclonal↗
PubMed1994

Ifosfamide induced depletion of glutathione in human peripheral blood lymphocytes and protection by mesna.

We studied the effects of ifosfamide and major metabolites on intracellular glutathione (GSH) levels in human peripheral blood lymphocytes (PBL). In vitro exposure of PBL to 4-hydroperoxyifosfamide (4-OOH-IF), acrolein or chloroacetaldehyde at 37 degrees C for 60 min led to a concentration dependent depletion of intracellular GSH. The concentration of the three metabolites to cause a 50% depletion of GSH in PBL was in the micromolar range (acrolein: 16 +/- 4 microM; 4-OOH-IF: 22 +/- 9 microM; chloroacetaldehyde: 30 +/- 7 microM). Exposure to ifosfamide, the non-activated drug, had no effects on the intracellular GSH levels. Pretreatment with 4-OOH-IF suppressed dose-dependently the interleukin-2-induced proliferation of PBL. Incubation of PBL together with 2-mercaptoethanesulfonate (mesna) and 4-OOH-IF, acrolein or chloroacetaldehyde prevented the GSH depletion. The protecting effect of mesna in combination with 4-OOH-IF was independent of GSH biosynthesis, because addition of buthionine sulfoximine had no significant influence on this effect. These findings indicate a novel protective mechanism of mesna against intracellular GSH depletion of PBL during exposure to metabolites of ifosfamide.

Acetaldehyde↗
PubMed1993

Interaction between tumor necrosis factor-alpha and HSP 70 in human leukemia cells.

We confirm here by immunoblotting that a cell line resistant to clonal inhibition from tumor necrosis factor (K562) expresses high levels of HSP 70, whereas two sensitive cell lines (HL60 blast and EM3) express low levels. When sensitive cell lines are exposed to tumor necrosis factor, HSP 70 is not generally induced; when tumor necrosis factor is removed, however, HSP 70 is transiently induced. In five bone marrow samples from patients, generally low levels of HSP 70 were detected.

Blotting, Western↗