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Biomedical subjects

R Osieka

Publications and source records attributed to R Osieka.

At least 37 records · Page 2Linked to original sources
PubMed1998

Positron emission tomography with 18F-FDG to detect residual disease after therapy for malignant lymphoma.

We retrospectively evaluated the use of 18F-FDG PET for assessment of residual disease in 27 patients after therapy for malignant lymphoma. The images were evaluated qualitatively and quantitatively using standardized uptake values (SUV). All findings were validated either by biopsy or by clinical follow-up and compared with corresponding CT findings. The impact of blood glucose concentration, body weight, body surface area, lesion diameter and the time between injection and imaging on the SUVs were analysed. All 15 patients with biopsy-proven residual disease or relapse during follow-up and 11 of 12 patients who remained relapse-free were correctly identified by qualitative interpretation of the PET images. A case of pneumonitis after radiotherapy/chemotherapy accounted for the only false-positive finding. Compared with CT imaging, PET had a significantly higher specificity (P < 0.01), accuracy (P < 0.05) and positive predictive value (P < 0.05). The mean and maximum SUV of the tumour lesions were positively correlated to lesion diameter (P < 0.01) and imaging time post-injection (P < 0.01). Standardized uptake values corrected for the partial volume effect and normalized to a standardized imaging time (SUVBPT) were significantly higher (P < 0.05) in high-grade than in low-grade non-Hodgkin's lymphoma. In conclusion, 18F-FDG PET may help in the identification of patients who need additional treatment after the completion of conventional therapy. Qualitative image interpretation appears sufficient for this purpose.

Adolescent↗
PubMed1998

[Palliative chemotherapy].

Recent data on cancer mortality call for a reallocation of resources from searching for new treatments of advanced disease to preventive strategies. Vaccination against HBV or other infectious agents predisposing to cancer has been more successful than non-specific prevention e.g. with supplementary vitamin intake. The effectiveness of systemic chemotherapy decreases with the number of tumour cells present and with inherent drug resistance thus limiting palliative chemotherapy. stringent criteria for duration or intensity of palliative treatment are often missing. In contrast oncologic emergencies require immediate diagnostic work-up and therapeutic intervention. Salvage chemotherapy is useful if lack of host tolerance, non-compliance, and insufficient dose intensity have been excluded as causes of previous treatment failure in addition to analgesics, antibiotics, transfusions, and haematopoetic growth factors psychological support is needed along with palliative chemotherapy. The loss of treatment efficacy with increasing number of tumour cells probably also holds true for new treatments now still in their infancy such as differentiation, immune attack or gene transfer. Despite the obvious need for a shift from palliative treatment to prevention the establishment of quality standards for palliative chemotherapy remains a major goal.

Antineoplastic Agents↗
PubMed1997

Apoptosis and resistance to daunorubicin in human leukemic cells.

We compared test methods based on specific mechanisms of daunorubicin (DNR) resistance to more global procedures. Assessment of P-glycoprotein (P-gp) expression and function by means of immunocytochemistry, DNR accumulation, and modulation of resistance and accumulation by the P-gp inhibitor cyclosporin A (CsA) were selected as parameters for multidrug resistance (MDR). On the other hand, we used the MTT assay and measured apoptosis and proliferative activity (S- and G2M-phases of the cell cycle) by flow cytometry. Validation of test methods was achieved for four leukemic cell lines (HL-60, KG-1a, K562/WT, K562/ADM). This battery of tests was then applied to mononuclear cells (MNC) from 18 leukemic patients. Low proficiency of MNC to undergo apoptosis and low proliferative activity rather than P-gp-mediated MDR correlated with DNR resistance as measured by the MTT assay. Bell-shaped dose-response curves for apoptosis, however, which reflect a switch from the apoptotic to the necrotic death mode with increasing cellular damage tend to limit practicability in clinical testing, because appropriate dose range and time points need to be explored. Thus, measurement of apoptosis by flow cytometry may be less convenient than the MTT assay for determination of chemosensitivity, if clinical samples with unknown patterns of responsiveness are to be tested. Spontaneous apoptosis in untreated MNC following 24 h incubation in vitro correlated significantly with DNR sensitivity in the MTT assay. A lack of essential viability factors (eg growth factors or cytokines) in vitro which are known to prevent apoptosis may contribute to DNR sensitivity.

Antibiotics, Antineoplastic↗
PubMed1997

[Comparison of findings with 18-FDG PET and CT in pretherapeutic staging of malignant lymphoma].

AIM: Comparison of diagnostic efficiency of FDG-PET and CT regarding localisation, histology, size and FDG-uptake of a lesion. METHODS: CT- and FDG-PET studies of 27 patients with histologically confirmed malignant lymphoma as primary disease or relapse were evaluated retrospectively. In CT lesions with a diameter (DCT) > 15 mm were regarded as positive. Focal accumulations of FDG, not explained by physiological metabolism, found by visual interpretation in iterative reconstructed PET-scans, were quantified for diameter (DPET) and corrected standardized uptake value (SUV), corrected for partial-volume-effect. Lesions were classified depending on histology and lesion quality (lymph nodes, bulks, extranodal lesions). RESULTS: CT detected 78 lesions in 26 patients, all confirmed by FDG-PET. PET localized 18 additional lesions (+23%); in high grade NHL +25%. Both methods were equally efficient in cervical lymph nodes and lung lesions, in all other regions of lymphatic nodules and in case of liver and spleen lesions PET localized more lesions. SUV was significantly higher in high-grade NHL (19.0) than in low-grade NHL and Hodgkin's disease (10.6 resp. 11.1). DCT and DPET correlated significantly (r = 0.75). CONCLUSION: Diagnostic efficiency of FDG-PET is equivalent or superior to CT in staging of malignant lymphoma before therapy. Qualitative interpretation seems sufficient for staging, quantitative analysis may add information about malignancy grade in NHL.

Fluorodeoxyglucose F18↗
PubMed1997

[Oncology].

The historic change in medicine from a holistic approach to methods based on natural sciences still reverberates in current practice as well as in the social and political framework of cancer treatment. Only recently has the perception of patients as suffering humans rather than carriers of disease to be eradicated lead to the introduction of palliative care. Advances in general pharmacotherapy have much relied on the concept of specific interaction between drug and target molecule first authored by Paul Ehrlich using the romantic term of a magic bullet. This theme of specificity was explored and described in detail as drug protein interaction during the next century. Specific cellular target proteins are ionic channels, enzymes, transporter proteins and receptors. While these may be targeted by antineoplastic agents they occur not exclusively in tumour cells but also in normal stem cells. Nonetheless, small differences in cellular behaviour after sustaining injuries have been exploited in such way that curative treatment regimens are now available for several tumour entities even in advanced state. Drug screening and development as well as principles of cancer treatment derived by empirical rationalism have been cornerstones in this process lasting for about five decades. Molecular biology has helped to elucidate several mechanisms of drug resistance, and finally gave insight how genes govern the checkpoints leading to either differentiation, proliferation or cell death. The internal control of cellular fate may be influenced via signal transduction at the level of receptors or kinases and other enzymes. Ultimately the immense specificity of nucleic acid hybridisation opens new horizons for specific drug target interaction. Immunotherapy has originally been the most successful approach in systemic therapy and is now being developed to an impressive range of passive or active treatments including vaccination.

Animals↗
PubMed1996

Anti-Fas/Apo-1 monoclonal antibody CH-11 depletes glutathione and kills multidrug-resistant human leukemic cells.

Apoptosis is a common pathway by which cells respond to noxious insults or growth regulatory factors. Since cellular glutathione (GSH) content has long been known to govern response to antineoplastic treatment we have compared induction of apoptosis in drug sensitive (HL-60 and K562/WT) and drug resistant (KG-1a and K562/ADM) human leukemic cell lines by the monoclonal antibody CH-11 (anti-Fas/Apo-1). Fraction of apoptotic cells and cellular GSH were determined by flow cytometry. All cell lines were induced to undergo apoptosis by exposure to mAb CH-11 independent of resistance to conventional antineoplastic treatment. In conjunction with exposure to daunorubicin, vincristine, carboplatin, cytosine arabinoside, dexamethasone, or ionizing irradiation the effect of mAb CH-11 on induction of apoptosis was no more than additive. In contrast, preincubation with IFN-gamma markedly enhanced the induction of apoptosis by mAb CH-11 due to an increase of Fas-receptor expression. In each instance, GSH content decreased with increasing fraction of apoptotic cells indicating a crucial role of GSH in the apoptotic pathway.

Antibodies, Monoclonal↗
PubMed1996

Gemcitabine: a phase II study in patients with advanced renal cancer.

Gemcitabine is a fluorine-substituted cytarabine analog with broad experimental antitumor activity. It's activity was explored in chemotherapy-naive patients with advanced progressive renal-cell carcinoma. A total of 39 patients were included in the study, of whom 37 were fully evaluable. In five patients the primary tumor remained in situ. Gemcitabine at 800 mg/m2 was given as a weekly 30-min infusion for 3 consecutive weeks followed by 1 week of rest. One complete response and two partial responses were observed giving a response rate of 8.1% [95% confidence interval (CI), 2-22%]. The duration of the responses is currently 32, 15, and 19 months, respectively. The median survival for all patients was 12.3 months. Gemacitabine was generally well tolerated, with nausea and vomiting (20.5% grade III) and neutropenia (5.3% grade III) being the most significant side effects. Gemcitabine given at this dose level and on this schedule has only limited activity in advanced renal-cell carcinoma.

Adult↗
PubMed1996

Detection of apoptosis in KG-1a leukemic cells treated with investigational drugs.

Four investigational drugs, p-benzoquinone, primine, miconidine acetate, and artesunate (dihydroqinghaosusuccinate), with growth inhibitory activity against flagellatae (e.g. trypanosoma, leptomonas, plasmodium) were investigated for their capability to induce programmed cell death (apoptosis) in human KG-1a leukemic cells. The results were compared with those of three well established cytostatic agents (cisplatin, daunorubicin, cytosine-arabinoside) and ionizing radiation. The antitumor activity of the drugs was validated by a cellular growth inhibition assay. The depletion of glutathione by these four investigational drugs favours the hypothesis that formation of free radicals and subsequent DNA strand breaks may be critical mechanisms of action and that the glutathione redox cycle is involved in detoxification of these reactive molecules.

Antineoplastic Agents↗
PubMed1995

Increased induction of apoptosis in mononuclear cells of a glucose-6-phosphate dehydrogenase deficient patient.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency belongs to the most common human disorders of metabolism. In affected patients generation of free radicals causes life-threatening hemolytic crises, for example, after consumption of certain drugs and foods or after infections. Rather than erythrocytes we analyzed mononuclear white blood cells of a patient suffering from G6PD deficiency with respect to their ability to enter apoptosis after treatment with daunorubicin, ionizing radiation, or dexamethasone. The induction of apoptosis was increased in G6PD-deficient cells compared to cells from eight normal donors. In parallel, the glutathione content of mononuclear cells from the G6PD-deficient patient was significantly decreased. While in affected patients decreased life span of erythrocytes damaged by oxidative stress has long been recognized as the mechanism underlying hemolysis, peripheral leukocytes have not received similar attention. Induction of apoptosis is a relatively complex process that has been linked to cellular glutathione content. This is the first report investigating G6PD deficiency and apoptosis.

Adult↗
PubMed1995

Sister chromatid exchange-inducing DNA lesions and depression of activation markers on the surface of cultured peripheral blood mononuclear cells after the addition of streptococcal pyrogenic exotoxins A and C.

Cultivation of peripheral blood mononuclear cells (PBMC) in the presence of streptococcal pyrogenic exotoxins (SPE) A and C resulted in a significant induction of sister chromatid exchange (SCE)-inducing DNA lesions. Concomitantly, the expression of interleukin-2 receptor alpha chain (IL-2R alpha chain), transferrin receptor (TfR), and major histocompatibility complex class II molecule HLA-DR on the surface of phytohemagglutinin-activated T cells from whole blood culture cells (WBCC) significantly decreased within 72 h, that is at least two cell cycles, whereas unstimulated T cells from WBCC did not express these markers but had lost their CD3 molecules, an effect reported to precede apoptosis as part of a T cell inactivation pathway. However, no apoptotic cells were observed within a cultivation period of 120 h. We observed clearcut differences in the responses towards SPE A in WBCC and isolated lymphocytes, since SPE A-treated lymphocytes showed an increase in the [3H]thymidine incorporation and did express IL-2R alpha chain and TfR on their cell surface. Regardless of the precise underlying mechanism, T cells from WBCC seem to be in a state of functional incompetence. The data presented here are the first to provide strong evidence that streptococcal toxins produce SCE-inducing DNA lesions in PBMC, an effect that might contribute to the process of immune cell lethality in streptococcal toxic shock-like syndrome and could be of pivotal importance in the pathogenesis of severe streptococcal disease.

Adult↗
PubMed1995

Expression of apoptosis-related oncoproteins and modulation of apoptosis by caffeine in human leukemic cells.

We investigated the modulation of radio- and chemoresistance by caffeine and mechanisms of resistance in human leukemic cell lines and mononuclear cells from 18 leukemic patients. Caffeine synergistically potentiated cytotoxicity and apoptosis induced by ionizing radiation or carboplatin (CPt), but attenuated induction of apoptosis by daunorubicin (DNR) in KG-1a cells. Since caffeine released irradiated as well as DNR-treated KG-1a cells from G2M cell cycle arrest and CPt-treated cells from S-phase arrest, this release does not fully explain the different effects of caffeine. Caffeine synergistically reduced the level of the apoptosis inhibitor glutathione after irradiation or CPt treatment. In contrast, treatment with DNR plus caffeine diminished glutathione levels to a lesser extent than DNR alone. We conclude that the effect of caffeine on glutathione depletion represents a mechanism of action by which caffeine can modulate apoptosis. Caffeine increased CPt cytotoxicity in K562 cells and its doxorubicin-resistant subline (K562/ADM), but little effect was seen in HL-60 cells or mononuclear cells from leukemic patients. Multivariate cluster analysis revealed an association of CPt resistance with the expression of c-Fos, c-N-Ras, and p53 oncoproteins and with proliferative activity (S-phase of cell cycle), but not with Bcl-2 expression.

Apoptosis↗
PubMed1993

Somatostatin receptor scintigraphy in malignant lymphoma: first results and comparison with glucose metabolism measured by positron-emission tomography.

Somatostatin receptor scintigraphy with 111In-labeled octreotide was performed in 22 patients with suspected or known malignant lymphoma. The majority of extra-abdominal lesions (21/24 = 87.5%) were correctly localized, however, only one of nine intraabdominal lymphomas could be detected. No significant correlation was found between scintigraphic results and histological type of lymphoma. Metabolic imaging by positron-emission tomography with 18F-labeled deoxyglucose yielded a higher rate of detection of lymphoma manifestations (92% vs 64%) and better tumor contrast. Further prospective studies are needed to establish the clinical relevance of somatostatin receptor scintigraphy in malignant lymphoma.

Adult↗
PubMed1990

[DL-1,2-bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II), a new compound for the therapy of ovarian cancer.

The synthesis of diastereoisomeric [1,2-bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes, DL-3-PtCl2 and meso-3-PtCl2, and their evaluation on the hormone-independent, human MDA-MB231 breast cancer cell line, on the cisplatin-sensitive and -resistant L1210 leukemia cell line, on the cisplatin-resistant human NIH:OVCAR 3 ovarian cancer cell line, on the P-388 leukemia of the mouse and on the cisplatin-sensitive and -resistant Ehrlich ascites tumor of the mouse are described. On all tumor models DL-3-PtCl2 produces a marked inhibitory effect. The diastereoisomer meso-3-PtCl2 is less active and more toxic. It is striking that DL-3-PtCl2 leads to a pronounced inhibition of all cisplatin-resistant tumors. At non-toxic concentrations DL-3-PtCl2 produces cytocidal effects on the NIH:OV-CAR 3 cell line. Therefore DL-3-PtCl2 is of interest for further evaluation for the therapy of ovarian cancer.

Animals↗
PubMed1989

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-compl exe s, Part I: Synthesis.

The synthesis of the stereoisomeric 1,2-bis(3-hydroxyphenyl)ethylenediamines (1-4) from meso-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3-methoxybenzaldehyde by a diaza-Cope-rearrangement and subsequent ether cleavage with BBr3 and their conversion into the [1,2-bis(3-hydroxyphenyl)ethylenediamine]dichloroplatinum(II)-complexes with K2PtCl4 (1-PtCl2 - 4-PtCl2) is described.

Antineoplastic Agents↗
PubMed1989

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl) ethylenediamine]dichloroplatinum(II)-complexes, Part II: Biological properties.

The activity of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine] dichloroplatinum(II)-complexes (1-PtCl2,R,S; 2-PtCl2, R,R/S,S; 3-PtCl2, R,R; 4-PtCl2, S,S) on several tumor models (MDA-MB 231 breast cancer cell line; P 388 leukemia, mouse; L 1210 leukemia, mouse; L 5222 leukemia, rat; Ehrlich ascites tumor, mouse--wildtype; cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.) is described. For comparison the analogous [1,2-bis(4-hydroxyphenyl)ethylendiamine]dichloroplatinum (II)-complexes (5-PtCl2, R, S; 6-PtCl2, R,R/S,S; 7-PtCl2, R,R; 8-PtCl2, S,S) and cisplatin are used. 1-PtCl2 to 4-PtCl2 (OH in 3,3'-positions) show their maximum antitumor effect at lower doses than 5-PtCl2 to 8-PtCl2 (OH in 4,4'-positions). 2-PtCl2 and 6-PtCl2 (R,R/S,S) are more active than 1-PtCl2 and 5-PtCl2 (R,S). 4-PtCl2 and 8-PtCl2 (S,S) are superior to 3-PtCl2 and 7-PtCl2 (R,R). On the L 5222 leukemia 2-PtCl2 (R,R/S,S), 4-PtCl2 (S,S) and 8-PtCl2 (S,S) markedly surpass cisplatin. Strong effects are produced by 2-PtCl2 to 4-PtCl2 on the Ehrlich ascites tumor (wildtype, cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.). The combination of 4-PtCl2 with cisplatin results in a weakly synergistic effect.

Animals↗
PubMed1989

Phase I study of recombinant human tumor necrosis factor alpha in advanced malignant disease.

A phase I study with recombinant human tumor necrosis factor alpha (rhuTNF-alpha; Knoll AG, Ludwigshafen, FRG) in patients with advanced malignant disease was undertaken to evaluate drug toxicity (organ specificity, time course, predictability, reversibility, maximal tolerated dose), effectiveness, antigenicity and pharmacokinetics. TNF was administered as a test dose followed by daily i.v. infusions for 5 days, every 3 weeks (single i.v. infusion lasting 10 min, TNF dissolved in 50 ml 5% human albumin). Dosage was increased in groups of 3 or 4 patients from 0.04 mg/m2 to 0.28 mg/m2. A total of 19 patients with different cancers, including seven large-bowel carcinomas, three chronic myelogenous leukemias, three hypernephromas, two small-cell lung cancers, one malignant melanoma, one malignant lymphoma, one rhabdomyosarcoma and one fibrosarcoma were treated. Major side-effects were chills and fever (maximum 40.4 degrees C, median 38.7 degrees C, 19/19), headache (12/19), nausea and vomiting (12/19) and pronounced (greater than 20%) hypotension (4/19). Acute side-effects could be diminished by paracetamol or indomethacin pretreatment, and with one possible exception no tachyphylaxis to TNF was noted. Mild renal toxicity was seen during TNF treatment. Pharmacokinetic studies showed a serum half-life (t1/2) ranging from 11 min to 17 min for doses from 0.04 mg/m2 to 0.16 mg/m2 and prolonged clearance with t1/2 ranging from 54 min to 70 min in the 0.20-0.28 mg/m2 dose range. No objective antitumor effects were observed in this phase I study.

Adenocarcinoma↗
PubMed1989

Sequential combination chemotherapy (CABOPP/VIM) for the treatment of high-grade malignant non-Hodgkin lymphoma.

In 42 patients with high-grade malignant non-Hodgkin lymphomas, a new treatment program was used in an attempt to improve results without increasing toxicity. Two effective but relatively well tolerated and non-cross resistant drug combinations were given sequentially according to the response of disease. Therapy was started with a combination consisting of cyclophosphamide, doxorubicin, bleomycin, vincristine, procarbazine and prednisone (CABOPP). In patients with complete remission after a maximum of 4 cycles of CABOPP, this regimen was continued for a total of 6 cycles. In patients with progressive disease or with only a partial remission after 4 cycles of CABOPP, therapy was switched to a combination consisting of etoposide, ifosfamide and methotrexate (VIM). Complete remission (CR) was achieved in 86% of patients. Sixty-nine percent achieved CR with CA-BOPP alone and 17% after changing to VIM. The CR rate was 100% in patients with stage I or II and 78% in those with stage III or IV of disease. The projected survival at 2 years is 66%. Fifty-six percent of patients with CR are predicted to have continued CR at 2 years. Thus, CABOPP/VIM appears to be an effective and well tolerated program for the treatment of aggressive lymphomas. The value of this program, however, can only be established comparing it with other newly developed protocols in randomized studies.

Adolescent↗