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Biomedical subjects

J Bergh

Publications and source records attributed to J Bergh.

At least 109 records · Page 6Linked to original sources
PubMed1995

Positron emission tomography studies in patients with locally advanced and/or metastatic breast cancer: a method for early therapy evaluation?

PURPOSE: To investigate if sequential positron emission tomographic (PET) scans with the glucose analog 18F-2-fluoro-2-deoxy-D-glucose (18FDG) and/or L-methyl-11C-methionine (11C-methionine) in patients with breast cancer could provide early information on the efficacy of polychemotherapy. PATIENTS AND METHODS: Sixteen patients with breast cancer (11 with locally advanced tumors, three with recurrent disease in the contralateral breast, two of them with distant and regional metastases, and two with distant metastases) underwent a baseline and two follow-up PET scans after the first and third/fourth polychemotherapy course. Tumor response was determined clinically/radiographically after three/four polychemotherapy courses. RESULTS: Five patients were investigated with 18FDG, seven with both 11C-methionine and 18FDG, and four with only 11C-methionine before polychemotherapy. 11C-methionine presented a more distinct visualization of primary/contralateral breast cancers in five of seven patients when compared with 18FDG. Twelve of 16 patients demonstrated a response using conventional methods after the third/fourth course of polychemotherapy. Eight of these 12 clinical responders had a significant decrease in tracer uptake at the first PET scan performed 6 to 13 days after the first polychemotherapy course, and these reductions were further augmented after the third/fourth course and corresponded to the conventional therapy evaluation (clinical examination, computed tomography [CT], ultrasonography, and mammography). CONCLUSION: Our data indicate that PET may be of clinical value in predicting response to chemotherapy in patients with locally advanced breast cancer and/or metastatic disease earlier than any other method used.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

High-dose therapy with autologous bone marrow stem cell support in primary and metastatic human breast cancer. A review.

A dose-response relationship has been demonstrated for metastatic human breast cancer. This increased response using moderately increased doses is generally not translated into an improved survival. The use of high-dose therapy to selected patients with metastases/recurrence responding to conventional doses of polychemotherapy may lead to an improved survival tail. Conventional doses of polychemotherapy in the adjuvant setting will reduce the relative mortality by around 25% 10 years after primary diagnosis. The use of high-dose therapy supported by autologous bone marrow stem cells may be markedly more effective in the adjuvant setting, especially to high-risk patients, compared with standard polychemotherapy. Several randomized studies are being planned or have already started in order to answer different aspects of this issue.

Antineoplastic Agents↗
PubMed1994

Estramustine-binding protein and specific binding of the anti-mitotic compound estramustine in astrocytoma.

Estramustine-binding protein (EMBP) is a M(r) 46,000 heterodimeric protein originally isolated from prostatic tissue. It has a demonstrated high affinity for, and selective binding of, estramustine, which is a derivative of 17 beta-estradiol and nornitrogen mustard with antimitotic activity. In this study, we have analysed the expression of an EMBP-like protein in astrocytoma specimens. Immunohistochemistry revealed a pronounced reactivity for EMBP in astrocytoma grades III-IV as well as in metastatic prostatic adenocarcinoma used as positive control. In astrocytoma grades I-II, the expression was weak. The EMBP-like protein was quantified by radioimmunoassay in astrocytoma tumor tissue with higher concentrations in malignant astrocytoma, grades III-IV, compared to grades I-II tumors. Western immunoblotting of immunoaffinity purified EMBP-like protein under nonreducing conditions revealed an immunoreactivity corresponding to M(r) 138,000 and 200,000, indicating a different structure of EMBP in astrocytoma compared to prostatic tissue. Specific binding and the presence of saturable binding sites for 3H-labeled estramustine were demonstrated in astrocytoma tissues expressing EMBP-like protein. Scatchard plot analysis showed a Kd at approximately 30 nM, which suggests a binding affinity for estramustine in the same range as previously reported for EMBP in the prostate. Moreover, the number of estramustine binding sites/g tumor as calculated from the Scatchard plots was well correlated with the EMBP levels determined in the radioimmunoassay. In conclusion, an EMBP-like protein is expressed in astrocytoma. This protein may be responsible for the specific binding of estramustine in the tumor tissue. Whether this specific binding of estramustine is of importance for the cytotoxic effect in glioma cells remains to be evaluated.

Astrocytoma↗
PubMed1994

Sector resection with or without postoperative radiotherapy for stage I breast cancer: five-year results of a randomized trial. Uppsala-Orebro Breast Cancer Study Group.

BACKGROUND: The effectiveness of routine postoperative irradiation following breast-conserving treatment of breast cancer has not previously been assessed in randomized clinical trials that have taken place in settings where mammography has been a major pathway to diagnosis or that have followed patients treated surgically by sector resection. PURPOSE: The aim of this study was to determine if treatment of stage I breast cancer by strictly standardized surgical technique with meticulous confirmation of a complete excision can reduce the local recurrence rate to an acceptable level without routine adjuvant radiotherapy. METHODS: In this trial conducted in Sweden, 381 women with stage I breast cancer were surgically treated by sector resection plus axillary dissection; then 184 women were randomly selected to receive postoperative radiotherapy to the breast (XRT group), and 197 women received no further treatment (non-XRT group). Patient accrual started in October 1981 and ended in September 1988. Criteria for eligibility were a unifocal cancer 20 mm or less in diameter (visible on mammogram) and radical excision and no histopathologic signs of axillary metastases. RESULTS: After median follow-up times of 65 and 63 months, the 5-year local recurrence rate was 2.3% (95% confidence interval [CI] = 0.1%-4.3%) in the XRT group and 18.4% (95% CI = 12.5%-24.2%) in the non-XRT group, respectively. The life-table curves were significantly different (P = .0001). The two treatment groups did not differ in overall survival: For the XRT group, the value was 91.0% (95% CI = 86.4%-95.4%); for the non-XRT group, it was 90.3% (95% CI = 85.8%-94.8%). The same was true for survival free from regional and distant recurrence: XRT group, 90.0% (95% CI = 85.3%-94.5%); non-XRT group, 87.1% (95% CI = 82.3%-92.0%). The rate of local recurrences was significantly higher in patients treated more recently (P. = 003). CONCLUSIONS: Sector resection plus radiotherapy to the breast very effectively achieves local tumor control. Surgery alone results in similar survival prospects, but the probability of local recurrence approaches 20% at 5 years. IMPLICATIONS: The increase in recurrence rate observed over time suggests that surgical technique and patient selection should be improved. The benefits of reduced cost and patient inconvenience that would result from the elimination of postoperative radiotherapy must be carefully weighed against the disadvantages of local recurrence. Longer term follow-up must be done to estimate the risk of cancer recurrence in these women 10 and 15 years later, and methods must be developed to identify those women who have a higher risk of recurrence. Finally, economic analyses of this and similar trials are needed to give empirical underpinnings for optimal use of radiotherapy.

Adult↗
PubMed1994

Detection of tumor-specific cytotoxic drug activity in vitro using the fluorometric microculture cytotoxicity assay and primary cultures of tumor cells from patients.

The semi-automated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) by viable cells, was employed for cytotoxic drug sensitivity testing of tumor cells from patients with hematological or solid tumors. In total, 390 samples from 20 diagnoses were tested with up to 12 standard cytotoxic drugs. The technical success rate for different tumor types ranged from 67 to 95%. Fluorescence was linearly related to cell number but variably steep depending on tumor type. Samples from most solid tumors thus showed higher signal-to-noise ratios than hematological samples. A wide spectrum of in vitro drug activity was obtained, with acute leukemias and non-Hodgkin's lymphomas being sensitive to almost all tested drugs, whereas renal and adrenocortical carcinomas were essentially totally resistant. Between these extremes were samples of breast and ovarian carcinomas and sarcomas. When in vitro response was compared with known clinical response patterns, a good correspondence was observed. The results indicate that the FMCA is a rapid and efficient method for in vitro measurement of tumor-specific drug activity both in hematological and in solid tumors. The assay may be suitable for new drug development and direction of phase-2 trials to suitable patients.

Antineoplastic Agents↗
PubMed1994

Isoenzyme-specific quantitative immunoassays for cytosolic glutathione transferases and measurement of the enzymes in blood plasma from cancer patients and in tumor cell lines.

Enzyme-linked immunoassays (ELISAs) based on the double-antibody sandwich technique have been developed for the quantitative analysis of the major human cytosolic class Pi, Mu and Alpha glutathione transferases (GSTs). The procedures were optimized with respect to antibody concentration for coating of plates as well as other parameters in order to achieve high sensitivity and accuracy. No cross-reactivity was detected between members of the three different classes of GSTs or among the Mu class GSTs M2-2, M3-3 and M4-4 with the ELISA for GST M1-1. The ELISAs have been applied to establish the cytosolic GST profiles of 10 cell lines and to monitor the plasma GST levels in cancer patients. The results revealed that the class Pi GST was the dominant isoenzyme in six (LS 174T, HCT-8, Hu 549 Pat, K-562, U-937 and Hu 549) out of nine tumor cell lines and immortalized hepatocytes (Chang Liver). The isoenzymes A1-1 and M1-1 were determined to be the major GST components in Hep G2 and HeLa cells, respectively. In a clinical study, the majority of the patients with urinary bladder cancer were found to have increased plasma levels of both GST A1-1 and GST P1-1 (10/15), while patients with renal cancer frequently showed increases only in GST P1-1 (5/8). The results demonstrate that the ELISAs are suitable for analyzing GST phenotypes in both normal and tumor cells and in monitoring plasma levels of GSTs in cancer patients.

Cross Reactions↗
PubMed1994

Expression of estramustine-binding protein in ependymomas and in human and developing rat ependymal cells.

The mainstays of primary treatment of ependymoma are aggressive surgery followed by radiotherapy. Although spreading occasionally occurs in the cerebrospinal pathways, chemotherapy is still not established and no ultimate drug has so far been found. Estramustine-phosphate (EMP), with a demonstrated effect on astrocytoma in vitro, has been shown to penetrate the blood-tumor barrier and to accumulate in human brain tumor tissue including ependymoma. It has been proposed that the cytotoxic effect of EMP depends on the presence of a binding protein, estramustine-binding protein (EMBP). In the present paper we have, for the first time, immunohistochemically demonstrated an EMBP-like protein in a series of ependymomas. Immunoreactivity was found within the cytoplasm of the tumor cells with a tendency to increase with increasing malignancy of the tumor. In addition, the occurrence of EMBP-like protein was demonstrated in human ependymal cells. In the rat brain, a weak immunoreactivity was detected in early fetal neuroepithelial cells while the staining intensity was increased in mature ependymal cells in late fetal, neonatal, and adult rat. Thus; immunoreactivity for an EMBP-like protein was demonstrated in ependymoma tissue, normal human ependyma and in the developing rat ependymal cells.

Adolescent↗
PubMed1994

Paclitaxel-induced cytotoxicity--the effects of cremophor EL (castor oil) on two human breast cancer cell lines with acquired multidrug resistant phenotype and induced expression of the permeability glycoprotein.

Paclitaxel (Taxol) is a new cytotoxic agent with considerable activity in phase II studies on metastatic breast cancer. Paclitaxel for clinical use is dissolved in the solvents cremophor EL and ethanol. In this study, we added paclitaxel, formulated either in cremophor EL and ethanol or only in ethanol, in increasing concentrations to two parental human breast cancer cell lines (ZR 75-1 and HS 578T) and their corresponding sublines with acquired doxorubicin resistance and P-glycoprotein expression. Paclitaxel dissolved either in ethanol or ethanol plus cremophor EL, resulted in steep and almost identical dose-response curves for the parental lines ZR 75-1 and HS 578T, respectively, independent of the solvent used. When paclitaxel was formulated only in ethanol the effects on the corresponding doxorubicin-resistant sublines were significantly reduced compared with paclitaxel dissolved in ethanol plus cremophor EL. These effects by cremophor EL may partly explain some of the antitumoral effects observed by paclitaxel in anthracycline failing patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Activity of cyclosporins as resistance modifiers in primary cultures of human haematological and solid tumours.

The semiautomated fluorimetric microculture cytotoxicity assay (FMCA) was used for evaluation of the ability of cyclosporin A (CsA) and its novel non-immunosuppressive derivative SDZ PSC 833 (PSC) to modify the response to doxorubicin or vincristine in vitro in different haematological and solid human tumour types. Primary cultures of 322 tumour samples were analysed. Both cyclosporins showed resistance-modifying activity in all haematological tumours tested, and in solid tumours activity was observed in ovarian carcinoma and childhood tumours. Little or no effect was found in the remaining tumour types, including breast, renal and adrenal cortical carcinomas and adult sarcomas. In most of the responsive cases the interaction between the modifier and the cytotoxic drug was synergistic. There was a tendency to higher activity in samples from previously treated patients, and an inverse relationship between degree of cytotoxic drug resistance and resistance-modifying activity was noted. No difference in potency between CsA and PSC could be discerned. The results indicate differential in vitro resistance-modifying activity of the cyclosporins depending on tumour type. The results also suggest that treatment with resistance modifiers should be considered also for primary therapy of drug-sensitive tumours. Drug resistance assays such as the FMCA may become useful in preclinical evaluation of resistance modifiers.

Antineoplastic Agents↗
PubMed1994

Acquired resistance to cisplatin and doxorubicin in a small cell lung cancer cell line is correlated to elevated expression of glutathione-linked detoxification enzymes.

A human small cell lung cancer cell line, U-1906, developed altered functional properties upon continuous in vitro cultivation. Cells obtained at late (U-1906 L) and early (U-1906 E) passages of cultivation differ in drug resistance to the cytostatic therapeutic agents cisplatin and doxorubicin. The U-1906 L cells are 1.6-fold and 1.3-fold more resistant to cisplatin and doxorubicin respectively, than are the U-1906 E cells. In the more resistant U-1906 L cells, the total glutathione (GSH plus GSSG) level is 40% lower, whereas the activities of GSH-linked enzymes such as GSH peroxidase and GSH transferases are significantly higher. Quantitative analysis with isoenzyme-specific ELISAs demonstrated increased concentrations of all three of the measurable GSTs, M1-1, M3-3 and P1-1, in the more resistant cells. The intracellular protein expression patterns of the U-1906 E and the U-1906 L cells are very similar as revealed by two-dimensional denaturing electrophoresis, but show significant alterations in the concentrations of some components. Two 35 kDa proteins of different pI values, the concentrations of which are increased in the U-1906 L cells, were both identified as glyceraldehyde-3-phosphate dehydrogenase, either by N-terminal or by internal amino acid sequence analysis. The present study demonstrates that the increased resistance of the U-1906 L cells may involve multiple detoxification mechanisms and that the contribution of the GSH-linked detoxification can be ascribed to the elevation of cytosolic GST isoenzymes, GSH peroxidase and glutathione reductase, rather than to the intracellular GSH concentrations.

Amino Acid Sequence↗
PubMed1994

Expression of the multidrug-resistance gene product in untreated human breast cancer and its relationship to prognostic markers.

The immunohistochemical expression of the 170-kDa permeability glycoprotein (P-gp) was investigated in 41 primary untreated breast carcinomas, using the monoclonal antibodies C219 and MRK16. DNA ploidy by flow cytometry and estrogen (ER) and progesterone receptor (PgR) contents were also determined. P-gp expression, as revealed by C219 or MRK16, was observed in 6 (14%) of the investigated cancers. P-gp expression had a tendency to occur in non-diploid, high-grade tumors as well as in patients with lymph node negative disease. However, except for lymph node status, these associations were not statistically significant. No positive statistical relationships were observed between other prognostic parameters (age, tumor size, and receptor status) and P-gp expression. Considering the great heterogeneity observed in previous studies and the low expression of P-gp observed hereby, the utility of P-gp immunostaining as a guide for therapy planning in patients with breast cancer remains uncertain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Expression of functional PDGF beta receptors in a human large-cell lung-carcinoma cell line.

In this study we have investigated a panel of lung-cancer cell lines, both of small-cell carcinoma and non-small-cell type, for the expression of receptors for platelet-derived growth factor. Although we found mRNA expression for the beta-type receptor on one small-cell and one non-small-cell line and alpha-type receptor mRNA expression on one small-cell-cancer cell line, only the beta receptors of the non-small-cell line (H-157) proved to be functional. Thus, the cell line H-157 displayed specific binding of 125I-PDGF-BB in addition to mRNA expression of the 6-kb transcript for the PDGF beta type receptor. Further evidence for the presence of functional PDGF beta receptors in H-157 cells was obtained from an in vitro kinase assay, which demonstrated a ligand-induced receptor autophosphorylation as well as the phosphorylation of a number of potential substrates associated with the activated receptor.

Carcinoma, Non-Small-Cell Lung↗
PubMed1993

Localization of hyaluronan in normal breast tissue, radial scar, and tubular breast carcinoma.

Hyaluronan (hyaluronic acid [HYA]) is one of the extracellular matrix components involved in normal cell physiology and is localized mainly in bodily fluids and connective tissues. Increased amounts of HYA in serum have been demonstrated in a number of neoplastic and inflammatory conditions, among them breast cancer. Tubular breast carcinoma (TC) and radial scar (RS) are two breast lesions that microscopically display characteristic stromal alterations and possess gross and microscopic similarities. Due to the importance of HYA as a component of the extracellular matrix, we investigated its presence in these lesions and in normal breast tissue. Using a biotinylated HYA-binding region for the in situ detection of HYA, we noted an increased amount of HYA in both TC and RS as compared with that in normal breast tissue specimens. A strong reactivity was observed predominantly around glandular structures and in the interlobular stroma of both TC and RS. Perivascular HYA staining also was distinctly observed in these lesions (TC and RS). Some HYA was observed in the connective tissue of the intralobular regions, around small blood vessels, and in the perivascular connective tissue of the normal breast. The distribution of HYA adjacent to the epithelium in the normal breast suggests a role for HYA in the interaction between epithelium and stroma of the normal breast. Its increase in the connective tissue of both TC and RS reflects the derangement of the stroma commonly observed in these conditions and supports the notion that these lesions may be associated.

Adenocarcinoma↗
PubMed1993

Phase I study of tauromustine administered in a weekly schedule.

Tauromustine was administered orally in weekly doses with interindividual dose escalation to patients with disseminated malignant melanoma. The dose in the first cohort of 6 patients was 20 mg/m2/week. The dose escalation was 5 mg/m2/week. The limit of tolerance was 55 mg/m2/week. 99 patients completed at least 8 weeks of treatment and eight dose levels were evaluated for toxicity. Reversible thrombocytopenia, and to a lesser degree leukopenia, were dose limiting. From a starting dose of 40 mg/m2/week, the long-term tolerated dose was 35 mg/m2/week, thus achieving a considerable increase of dose intensity without a significant increase of toxicity by employing this weekly schedule of tauromustine.

Administration, Oral↗
PubMed1993

Differential expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human lung carcinoma cell lines.

In the present investigation we have studied the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) in ten different human lung carcinoma cell lines, four small cell carcinomas and six non-small cell carcinomas. None of the small-cell lung carcinoma cell lines demonstrated expression of PD-ECGF/TP mRNA. However, four of six of the non-small cell carcinoma cell lines expressed the 1.8 kb PD-ECGF/TP transcript. The cell lines derived from the single squamous cell carcinoma and the two adenocarcinomas expressed the PD-ECGF/TP mRNA, and were found to have the corresponding protein both in cell lysates and conditioned media as determined both by immunoblotting and measurement of thymidine phosphorylase activity. Only one of three studied large cell carcinoma cell lines expressed low levels of PD-ECGF/TP mRNA, but the corresponding PD-ECGF/TP protein was not demonstrated by immunoblotting.

Carcinoma, Non-Small-Cell Lung↗
PubMed1992

[Should ultrasound examination be performed earlier in pregnancy?].

In 1991 33 perinatal deaths occurred at Rogaland hospital. Seven of the babies showed severely retarded growth (< 3 percentile) compared with the delivery date indicated by ultrasound. Five babies showed moderately retarded growth (from 3-10 percentile) and the remaining babies were not definitely growth retarded. For the three groups the delivery date indicated by ultrasound was on average 18, eight and five days later than the date estimated according to the rule of Naegele. A delivery date estimated by ultrasound at 18-19 weeks may cause serious misjudgements in cases of early retardation of growth. Earlier ultrasound examination is recommended for a more reliable estimated date of delivery. The author discusses ultrasound examination which differentiates estimation of delivery date and screening for malformation.

Congenital Abnormalities↗