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Biomedical subjects

H Bojar

Publications and source records attributed to H Bojar.

At least 19 recordsLinked to original sources
PubMed2002

Gene expression profiles in the acutely dissected human aorta.

OBJECTIVES: heritable connective tissue abnormalities and arterial hypertension may predispose to aortic dissection. This study evaluates gene expression profiles in the acutely dissected human aorta. DESIGN, MATERIALS AND METHODS: Atlas Human Broad Arrays I, II, and III (Clontech) were used to compare gene expression in acutely dissected (6 patients) and normal ascending aortas (6 multiorgan donors). The tissues were also compared macroscopically. RESULTS: of 3537 genes analysed, 1250 (35%) were expressed in aortic tissue. For statistical analysis we focused on 627 genes, which had an intensity>0.95 of the mean patients or controls. Dissected and adjacent macroscopically intact aorta displayed similar gene expression patterns. On the contrary, 66 genes were expressed significantly different in dissected aorta, compared with undiseased control aorta of multiorgan donors. Genes, predominantly upregulated in dissection, are involved in inflammation, in extracellular matrix proteolysis, in proliferation, translation and transcription. Predominantly downregulated genes code for extracellular matrix proteins, adhesion proteins and cytoskeleton proteins. CONCLUSION: our results demonstrate for the first time the complexity of the dissecting process on a molecular level. The ultimate dissection seems to be the dramatic endpoint of a long-lasting process of degradation and insufficient remodelling of the aortic wall. Altered patterns of gene expression suggest a pre-existing structural failure of the aortic wall, resulting in dissection.

Acute Disease↗
PubMed2001

Novel lipophilic chloroquine analogues for a highly efficient gene transfer into gynecological tumors.

Liposomal vectors based on cationic lipids have been proven to be an attractive alternative to viral vectors in gene therapy protocols with regard to safety and manufacturing concerns. In order to improve the transfection efficiency we have synthesized two novel carboxycholesteryl-modified chloroquine analogues. Due to their potential endosomal buffering capacity these compounds enable the efficient transfection of various gynecological tumors and therefore are promising reagents in gene therapy applications.

Cell Survival↗
PubMed2001

Long-term prognosis of breast cancer patients with 10 or more positive lymph nodes treated with CMF.

The purpose of this investigation was to study the long-term prognosis of breast cancer patients with 10 or more positive lymph nodes after conventional chemotherapy treatment with cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Between 1984 and 1989, 1048 node-positive patients were treated with CMF in two separate trials conducted by the German Breast Cancer Study Group (GBSG). Subgroups either received radiotherapy or tamoxifen in addition. In this study, long-term prognosis in the subgroup of 141 patients with 10 or more positive lymph nodes was investigated. Univariate and multivariate Cox models were used to evaluate the effect of prognostic factors on event-free survival (EFS) and overall survival (OS). Both univariate and multivariate analyses revealed the progesterone receptor (PR) status as the dominating prognostic factor for both EFS and OS, resulting in a strongly increased risk of more than 2-fold for receptor-negative patients. A large number of positive lymph nodes also affected the prognosis for EFS. In univariate analysis, the degree of lymph node involvement (i.e. percentage of positive nodes out of all examined nodes), oestrogen status (ER) status, and tumour grade also showed significant effects. To conclude, the prognosis in the subgroup of patients with 10 or more positive lymph nodes is heterogeneous. Some surprisingly high survival rates have been observed in case series of breast cancer patients treated with high-dose chemotherapy which may be explained by patient selection. From the usual factors investigated in this study, the PR status showed the strongest effect, and, at least this factor should be taken into account in the design and analysis of trials for breast cancer patients with a poor prognosis.

Adult↗
PubMed2001

Local inflammation and devascularization--in vivo mechanisms of the "bystander effect" in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma.

Somatic gene therapy with the herpes simplex virus type I thymidine kinase gene/ganciclovir (HSV-Tk/GCV) system and murine retroviral vector producer cells (VPCs) was introduced as a new adjuvant treatment modality to treat tumor bulk and to prevent tumor recurrence in patients harboring malignant glioma. The single-center experience after treatment of 27 patients undergoing tumor resection followed by intracerebral VPC injection for HSV-Tk suicide gene therapy will be presented focused on findings of systematic and close MRI follow-up and a few histological specimens. The data indicate that hemorrhagic necrosis due to endothelial cell transfection mediated vessel necrosis and that local inflammatory immune response occurs frequently after gene therapy. These phenomena seem to be specific because none of the patients of a control group showed any similar features. The prognosis (time to progression, survival) of the patients with "bystander effects" after gene therapy was better, but compared to those patients without bystander effects, they were also privileged by a favorable constellation of prognostic factors. Therefore, the appearance of these neuroradiologic features cannot serve as an indicator for treatment effectiveness and outcome.

Adolescent↗
PubMed2000

Randomized trial on the effect of radiotherapy in addition to 6 cycles CMF in node-positive breast-cancer patients. The German Breast-Cancer Study Group.

In 1984 the GBSG started a multicenter randomized trial to compare the effectiveness of 6 cycles of cyclophosphamide, methotrexate and fluorouracil (CMF) with or without radiotherapy (RT) as adjuvant treatment in node-positive breast-cancer patients treated by mastectomy. During 5 years, 199 patients were randomized. After a median follow-up of about 9 years, the treatment groups 6 x CMF and 6 x CMF + RT were compared regarding time to recurrence and death. As the first event of failure, we observed locoregional recurrence in 22 patients, distant metastases in 66 patients, a secondary malignancy in 9 patients and death without previous event in 5 patients. For event-free survival (EFS), no significant difference was observed [relative risk (RR) 6 x CMF + RT vs. 6 x CMF 0.82, 95% confidence interval (CI) 0.55-1.21]. Event-specific analysis showed a significant decreased risk after radiotherapy for locoregional recurrence. The risk for distant metastases was estimated as slightly decreased and the risk for secondary malignancy and for death without previous event was estimated as increased in treatment group 6 x CMF + RT in comparison with treatment group 6 x CMF, but these effects were not significant. For overall survival (OS) and breast-cancer-specific survival (BCS), no significant treatment effect could be demonstrated. There is a beneficial effect of radiotherapy on locoregional recurrence. For EFS and BCS, a tendency in favour of radiotherapy is observed, but this is not significant; for OS, no difference can be demonstrated, but the power of the study is too low to detect small treatment effects.

Adult↗
PubMed2000

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients: an update based on 10 years' follow-up. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group started a multicenter randomized trial to compare six versus three cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) starting perioperatively and to investigate the additional effect of tamoxifen as adjuvant treatment in node-positive breast cancer patients treated with mastectomy. PATIENTS AND METHODS: From 1984 to 1989, 473 patients were randomized from 41 institutions. After a median follow-up of approximately 10 years for overall survival (OS) and 9 years for event-free survival (EFS), the treatment groups were compared with respect to OS and EFS. Results based on a median follow-up of 56 months have been published earlier. RESULTS: Estimated cumulative locoregional incidence rate after 10 years was 19.9%; the corresponding rate of distant recurrences was 41.3%. Concerning duration of chemotherapy, we did not find any difference between six and three cycles of CMF (EFS: relative risk [RR] in multivariate analysis = 0.95; 95% confidence interval [CI], 0.74 to 1.21 OS: RR = 0.90; 95% CI, = 0.69 to 1.18). Treatment with tamoxifen resulted in an improvement in outcome (EFS: RR = 0.81; 95% CI, 0.61 to 1.07, OS: RR = 0.74; 95% CI, 0.55 to 1.0) although it proved not significant. Number of positive lymph nodes and progesterone receptor were the dominant prognostic factors. CONCLUSION: In this study, we observed some tendency in favor of hormonal treatment, which is in agreement with the literature. Concerning duration of chemotherapy, the results of this study provide further evidence that a reduction to three cycles of CMF is possible without increasing the risk of recurrence or death. For a definitive conclusion, however, further investigations are required.

Adult↗
PubMed1999

Modelling the effects of standard prognostic factors in node-positive breast cancer. German Breast Cancer Study Group (GBSG).

Prognostic models that predict the clinical course of a breast cancer patient are important in oncology. We propose an approach to constructing such models based on fractional polynomials in which useful transformations of the continuous factors are determined. The idea may be applied with all types of regression model, including Cox regression, the method of choice for survival-time data. We analyse a prospective study of node-positive breast cancer. Seven standard prognostic factors--age, menopausal status, tumour size, tumour grade, number of positive lymph nodes, progesterone and oestrogen receptor concentrations--were investigated in 686 patients, of whom 299 had an event for recurrence-free survival and 171 died. We determine a final model with transformations of prognostic factors and compare it with the more traditional approaches using categorized variables or assuming a straight line relationship. We conclude that analysis using fractional polynomials can extract important prognostic information which the traditional approaches may miss.

Breast Neoplasms↗
PubMed1998

The effect of oral contraceptive use on the prognosis of node positive breast cancer patients. German Breast Cancer Study Group.

The effect of oral contraceptive (OC) use as a risk factor for breast cancer was recently assessed in a large meta-analysis, but currently available data on the prognostic effect are still insufficient. We investigated the relationship between OC use and standard prognostic factors and the effect of OC use on recurrence-free survival (RFS) and overall survival (OS) in 422 premenopausal pT1a-3aN + M0 patients from two trials of the German Breast Cancer Study Group (GBSG). 137 patients (32.5%) were OC users. They were younger on average (mean age 41.5 years versus 45 years for non-OC users) and the percentage of patients with smaller tumours was higher in the group of OC users. Based on 163 events for RFS and 103 events for OS, no significant effect of OC use on RFS and OS could be demonstrated in univariate and multivariate analyses. In our study of node positive breast cancer cases, OC users were younger and had smaller tumours. This may be an effect of earlier detection of breast cancer, but OC users did not have a better prognosis, both before and after adjustment for tumour size and other prognostic factors.

Adult↗
PubMed1998

Dual-parameter immunoflow cytometry in diagnosis and follow-up of patients with bladder cancer.

OBJECTIVES: The aim of this study was to evaluate the clinical significance of a dual-parameter immunoflow cytometry (DPI-FCM) assay in the detection of tumor cells in barbotage specimens of bladder cancer patients. METHODS: DPI-FCM is an automated method, based on the utilization of two monoclonal antibodies (mAbs) either used for a preselection of urothelial cells (mAb Due AUT 2) or the analysis of the expression of a differentiation antigen within the preselected urothelial cells (mAb Due ABC 3). The ratio of ABC 3-positive urothelial cells was used to discriminate between the normal and malignant state of the urothelium. At the time of examination 40 patients had endoscopically overt bladder tumors. Another 30 patients without endoscopically visible tumors were examined before routine rebiopsy. Thirty barbotage specimens from patients with diseases not related to bladder cancer were examined as controls. RESULTS: Overall, the sensitivity of DPI-FCM in patients with endoscopically overt and invisible residual tumors was 95 and 83%, respectively, regardless of concomitant urinary tract infection. The sensitivity of DPI-FCM for both patient groups was 86, 95 and 94% for tumor grades 1, 2 and 3, respectively. The specificity of the method in 30 patients with no history of bladder cancer was 93%. CONCLUSIONS: DPI-FCM appears to be a highly reliable method of recognizing tumor cells in bladder barbotage specimens even in patients with concomitant urinary tract infection. The procedure may be of value in monitoring bladder cancer patients for tumor recurrence.

ATP-Binding Cassette Transporters↗
PubMed1998

WAF1/p21 regulates proliferation, but does not mediate p53-dependent apoptosis in urothelial carcinoma cell lines.

The WAF1/p21 gene product is an inhibitor of cyclin-dependent kinases which can be induced by the tumor suppressor p53 and mediate some of its effects, or function in p53-independent pathways of cell cycle regulation. Although a potential tumor suppressor gene, WAF1/p21 is expressed in bladder cancer. To elucidate the function of p21 in tumor cells we have investigated in urothelial carcinoma cell lines: i) WAF1/p21 mRNA and protein expression, ii) the biological effects of p21 overexpression or down-regulation and (iii) whether p21 can be induced by p53. WAF1/p21 mRNA levels examined in four cell lines were comparable to bladder mucosa. One cell line, HT1376, failed to express p21 protein due to a frame shift mutation. Overexpression of WAF1/p21 cDNA inhibited clone formation in three cell lines, whereas transfection with antisense WAF1 increased clone sizes and numbers. WAF1 sense clones showed diminished cell proliferation compared to the parental cell line. Apoptosis- induced wild-type p53 was not inhibited by overexpression of antisense WAF1/p21. In a cell clone derived from line VMCub1 by stable transfection with wild-type p53 under the control of a metallothionein promotor, p21 was induced along with p53 upon activation of the promoter with zinc chloride. This induction was accompanied by a decrease in cell proliferation but by little apoptosis. These data suggest that p21 inhibits proliferation in a p53-dependent or independent manner but does not mediate p53-induced apoptosis in urothelial carcinoma cells.

Apoptosis↗
PubMed1996

Effect of recombinant human granulocyte colony stimulating factor (R-metHuG-CSF) as an adjunct to large-field radiotherapy: a phase I study.

PURPOSE: To test the feasibility of recombinant human granulocyte colony stimulating factor application during large-field radiotherapy. METHODS AND MATERIALS: Fifteen patients with clinically and histologically proven malignancy who received large-field radiotherapy entered this study. Administration of recombinant granulocyte colony stimulating factor (G-CSF) at a dose of 300 microgram subcutaneously was started on Friday and was continued on Saturday and Sunday after the first radiotherapy treatment, which began on the Monday before. In this way four courses of G-CSF were applied every Friday, Saturday, and Sunday during the radiotherapy period. Absolute neutrophil cell (ANC) and blood counts were monitored twice a week and compared to a second group of 15 patients who received large-field radiotherapy without G-CSF. Before and at the end of every cycle of G-CSF, ANC, blood counts, and biochemistry were measured. We compared the myelotoxicity of the patients treated with G-CSF with 15 patients without G-CSF treated at the same period with large-field radiotherapy, in match pair technique. RESULTS: G-CSF increased the ANC throughout the period of irradiation, and the treatment time needed for competing radiotherapy was shorter in the group who received G-CSF. Fourteen of 15 patients who received G-CSF treatment completed large-field radiotherapy without pause. Only 1 of 15 patients not receiving G-CSF was able to receive radiation treatment on schedule. Patients receiving G-CSF completed treatment with the mantle-field technique in 24 days and those with the abdominal bath technique in 26.5 days. Conversely, patients treated without G-CSF completed treatment with the mantle-field technique in 30.5 days and those with the abdominal bath technique in 36 days. The most frequent side effect was musculoskeletal pain. CONCLUSION: The prophylactic application of G-CSF during large-field radiotherapy before the onset of neutropenia was feasible in this schedule. Whether or not this shortening of treatment duration will translate into an improvement in efficacy is not clear.

Adult↗
PubMed1995

Dual-parameter immunoflow cytometry--a new technique in the noninvasive diagnosis of bladder cancer.

The introduction of monoclonal antibodies into the diagnosis of transitional cell carcinoma (TCC) has been a further step toward the use of biological parameters to support conventional cytological diagnosis of this tumor entity. Several investigators have demonstrated the high sensitivity and good specificity of immunocytology. Nevertheless this technique is hampered by the inconvenient and time-consuming microscopic analysis. The purpose of this study was to combine the advantages of immunocytology with the capabilities of an automated flow-cytometric system. Since all monoclonal antibodies (mAbs) currently used for immunocytology cross-react with granulocytes a preselection of urothelial cells becomes necessary for immuno-flow cytometry (immuno-FCM). Based on earlier analyses mAb Due AUT 2, reactive against urothelium and not against granulocytes, was chosen to preselect for urothelial cells. mAb Due ABC 3 was used to discriminate between normal and malignant urothelial cells. Initial experiments including 10 barbotage specimens from patients with histologically proven TCC and concomitant urinary tract infection yielded a high sensitivity (90%) of immuno-FCM. In 10 control patients with malignancies other than bladder TCC and benign diseases ABC 3 expression was not increased. Flow-cytometric examination of irrigation specimens from 10 patients with a history of bladder cancer but without cystoscopic and cytologic evidence of tumor recurrence showed abnormal results in 6 patients. Rebiopsy and/or cystectomy confirmed tumor recurrence in 5 of these patients and in 1 patient with negative immuno-FCM. Ongoing prospective trials will further define the clinical impact of this approach in the diagnosis and follow-up of patients with bladder cancer.

Antibodies, Monoclonal↗
PubMed1994

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group (GBSG) started a multicenter randomized clinical trial to compare the effectiveness of three versus six cycles of 500 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, and 600 mg/m2 fluorouracil (CMF) on day 1 and 8 starting perioperatively with or without tamoxifen (TAM) (3 x 10 mg/d for 2 years). The aim of the trial was to compare recurrence-free and overall survival between the different treatment modalities. PATIENTS AND METHODS: During 5 years, 41 institutions randomized 473 patients (3 x CMF: 145; 3 x CMF + TAM: 93; 6 x CMF 144; 6 x CMF + TAM: 91). Until March 31, 1992, median follow-up time was 56 months with 197 events for disease-free survival and 116 deaths observed. This provides a power of approximately 80% to detect a potential treatment difference corresponding to a relative risk (RR) of 0.67 for recurrence-free survival. Treatment modalities and various patient characteristics were evaluated by means of a multivariate Cox regression analysis. RESULTS: No significant difference in recurrence-free survival was observed with respect to hormonal therapy (RR = 0.75 TAM v no TAM; 95% confidence interval [CI], 0.54 to 1.04; P = .08) as well as duration of chemotherapy (RR = 0.90 of 6 x CMF v 3 x CMF; 95% CI, 0.67 to 1.19; P = .45). Similar results were obtained for overall survival. The multivariate analysis revealed a significant prognostic impact of the number of positive lymph nodes and the progesterone receptor level on recurrence-free survival. Compliance with chemotherapy within the range of 85% to 115% of the target dose was achieved in 94% and 78% of the patients randomized to 3 x CMF and 6 x CMF, respectively. Sufficient compliance with TAM was reported for 141 patients (93%). CONCLUSION: At this stage of follow-up, six courses of CMF are not superior to three courses with respect to recurrence-free survival.

Adult↗
PubMed1994

[The significance of clinical prodromes for dosage estimation after whole-body radiation exposure].

BACKGROUND: The triage of victims after radiation injury is complicated by missing dose values and the fact that most tissues react after a latency period. PATIENTS AND METHODS: We evaluated 63 patients undergoing total body irradiation as conditioning regime before bone marrow transplantation in order to find a relation between prodromal symptoms and dose. RESULTS: Emesis after radiation exposure hints to doses greater than 1.5 Gy. A rise of body temperature above 37 degrees C up to five hours after exposure is related to doses exceeding 2.5 Gy, while an acute onset of diarrhoea is an indicator of a severe accident with more than 9 Gy. CONCLUSION: Besides blood counts and chromosome analyses a careful evaluation of prodromal symptoms can help to classify the severity of radiation accidents.

Acute Disease↗
PubMed1993

[A study of the quantitative dual-parameter flow cytometry analyses of cellular antigens on transitional cells for the diagnosis of bladder cancer].

To establish a quantitative dual-parameter flow cytometry (FCM) analysis of cell surface antigens, possible obstacles caused by contaminated leucocytes in a specimen and staining and measuring conditions were investigated using human bladder cancer cell lines, 5637, T24 and SW1710. The first monoclonal antibody (MoAb) used to select urothelial cells in a specimen was applied with the second MoAb used to discriminate between normal and transformed urothelial cells. MoAbs Due AUT 2 and CD45 appeared to be suitable for the selection of urothelial cells, while Due ABC 3 and Due ABC 5 were applied to detect transformed cells. Tumor cell-leucocyte suspension was simultaneously stained with combinations of these MoAbs. The results demonstrated that Due AUT 2 and CD45 effectively eliminated contaminated leucocytes by means of positive and negative selection of the urothelial cells, respectively. Based on these experiments, dual-parameter FCM analyses of bladder washing from 5 patients with bladder cancer were performed using MoAbs Due AUT 2 and Due ABC 3. The results indicated that by dual-parameter FCM distinct antigenic features of transitional cells could be investigated even if considerable amounts of contaminated leucocytes were present. The clinical impact of this approach is a subject of ongoing trials.

Antibodies, Monoclonal↗
PubMed1993

[Radiotherapy following a breast-preserving operation in breast carcinoma].

Between 1980 and 1988, 116 patients with invasive breast cancer were treated by limited surgery with axillary node dissection followed by radiation therapy. Radiotherapy was performed by individually computerized treatment planning. The target volume dose was 50 Gy to the whole breast followed by an electron boost of 10 Gy to the tumor bed. The median follow-up period was 59 months. The actuarial overall survival rate is 93%, and the disease-free survival 75.2%. Ten (8.6%) breast recurrences occurred. Analysis of clinical and pathological prognostic factors revealed that local control was impaired by young age, negative hormone receptors, G3-4 tumors and intraductal growth. The recurrence rate for T3- and T4-tumors was 12.5%.

Adult↗
PubMed1990

The synthetic androgen mibolerone induces transient suppression of the transformed phenotype in an androgen responsive human prostatic carcinoma cell line.

The synthetic androgen mibolerone elicits a set of distinct changes in the behaviour of an androgen responsive human prostatic carcinoma cell line (LNCaP). Inhibition of cell proliferation, induction of morphological change and of a prostate specific mRNA, and inhibition of colony formation in soft agar are induced by very low concentrations of mibolerone. The natural androgen dihydrotestosterone is much less effective. The changes in growth characteristics and morphology are reverted by excess antiandrogen, i.e. cyproterone acetate or hydroxyflutamide. Cell lines lacking androgen receptors (PC-3, DU 145 and MRC-5) are completely unresponsive to mibolerone. Taken together, our results indicate androgen receptor mediated suppression of the transformed phenotype in LNCaP cells.

Androgen Antagonists↗