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J Bergh

Publications and source records attributed to J Bergh.

At least 91 records · Page 5Linked to original sources
PubMed1997

Risk factors for local recurrence after conservative treatment in stage I breast cancer. Definition of a subgroup not requiring radiotherapy.

BACKGROUND: Risk factors for local recurrence after breast-conserving treatment of early breast cancer have not previously been evaluated in settings where mammography has been a major pathway to diagnosis of both primary tumour and recurrences or in patients treated surgically by a formal sector resection. PATIENTS AND METHODS: Three hundred eighty-one women with stage 1 primary breast cancer were randomised after a standardised sector resection to either a course of postoperative radiotherapy to 54 Gy to the breast (XRT group) or to surgery alone (non XRT group). At five years, 43 local recurrences, six of them in the XRT group, appeared. Patient characteristics collected from the medical records, histopathological characteristics determined by re-examination of slides, and mammographic characteristics from the pre-operative mammograms were evaluated as risk factors for recurrence by univariate and multivariate Cox proportional hazards models. Results are reported as relative hazards (RH) with 95% confidence intervals (95% CI). RESULTS: In the univariate analysis comedo cancer, RH 3.5 (95%, CI 18 6.7), lobular cancers RH 2.8 (95% CI 1.1 7.1), mammographic appearance as circular/oval shaped density, RH 2.3 (95% CI 1.1 4.51, and mammographic appearance as a stellate lesion with microcalcifications inside the lesion, RH 3.8 (95% CI 1.1-13.0) were identified as risk factors for local recurrence. Age, with a RH of 0.97 (95% CI 0.94 0.99) for each increasing year was inversely associated with risk. A multivariate analysis, which also took postoperative radiotherapy into account, only showed comedo cancers with a RH 2.6 (95% CI 1.3-5.0) and mammographic appearance of a stellate lesion with microcalcification inside the lesion RH 4.5 (95% CI 1.1-17.6) to be statistically significant. The estimates for age RH 0.98 (95% CI 0.95 1.01 and lobular cancers RH 2.5 (95%, CI 0.98 6.6) were marginally changed, with widened CIs. Patients > 60 years of age, without comedo or lobular carcinomas were found to be at low risk 15.9% at five years in Kaplan Meyer estimate) of local recurrence, even without postoperative radiotherapy. CONCLUSION: Low age, comedo and lobular cancers and mammographic appearance of the tumour as a stellate lesion with microcalcifications inside the lesion indicate an increased risk for local recurrence after sector resection in stage 1 tumours at five years. Patients > 60 years of age without comedo or lobular cancers are at low risk for local recurrence at five years even without postoperative radiotherapy.

Combined Modality Therapy↗
PubMed1997

The cost-effectiveness of routine postoperative radiotherapy after sector resection and axillary dissection for breast cancer stage I. Results from a randomized trial.

BACKGROUND: Cost-effectiveness of routine postoperative radiotherapy after breast-conserving surgery has not been prospectively evaluated earlier. In times of rationing of medical resources, valid assessments of cost-effectiveness are important for rational allocation of resources. PURPOSE: Cost and cost-effectiveness of routine postoperative radiotherapy was calculated in a prospective randomized trial comparing sector resection plus axillary dissection with (XRT group) or without (non-XRT group) postoperative radiotherapy in breast cancer stage I. Three hundred eighty-one patients were included. After a median follow-up of five years 43 local recurrences, six of them in the XRT-group occurred (P < 0.0001). No difference in regional and distant recurrence (P = 0.23) or survival (P = 0.44) was observed. PATIENTS AND METHODS: Direct medical costs as well as indirect costs in terms of production lost during the treatment period and travel expenses were estimated from data in the medical records and the national insurance registry of each patient. Average costs of different treatment activities and measures were estimated for the XRT-group and the non-XRT group respectively. From these estimates differences in costs and effectiveness between the groups were calculated and marginal cost-effectiveness ratios were estimated. For the construction of QALYs each life-year was quality-adjusted by a utility value depending on which health state the patient was considered to perceive. RESULTS: Taking into account the cost of primary treatment, the cost of follow-up, the cost of treatment of a local recurrence, travel expenses and indirect costs (production lost) excluding costs for treatment of regional and distant recurrence the cost per avoided local recurrence at five years was SEK 337,727 ($44,438, Pounds 27,018). Adjustment for quality of life showed a cost for every gained QALY to be SEK approximately 1.6 million, ($210,526, Pounds 128,000), range SEK 0.2-3.9 million ($26,315-513,158, Pounds 16,000-312,000). CONCLUSION: The cost of routine postoperative radiotherapy after sector resection and axillary dissection in breast cancer stage I per avoided local recurrence and gained QALY is high. The cost per gained QALY show great variation depending on utility value, which in this study was derived from external observers and not from the patients themselves. These results stress the importance of identifying risk factors for local recurrence, better understanding of impact on quality of life of a local recurrence and adding cost evaluations to clinical trials in early breast cancer.

Breast Neoplasms↗
PubMed1997

Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors.

We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo II. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo IIalpha and/or -beta, did not confer ICRF-159 resistance. Indeed, marked topo IIalpha down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo II inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo IIalpha, not topo IIbeta, is more likely to be the major in vivo target for ICRF-159.

Antineoplastic Agents↗
PubMed1997

Suramin in non-small cell lung cancer and advanced breast cancer. Two parallel phase II studies.

Suramin inhibits the growth of non-small cell lung cancer (NSCLC) and breast cancer in vitro by blocking the action of most known growth factors. The clinical efficacy of suramin was evaluated in patients with unresectable or relapsed NSCLC (n = 16) and advanced breast cancer (ABC) resistant to conventional therapies (n = 12). A plasma level > or = 200 micrograms/ml was maintained by three times weekly administrations using adaptive control with feedback. Treatment was continued until documented progression of disease or unacceptable toxicity. No clinical responses were observed in any patient. Median overall survival was 4.5 months in NSCLC and 9 months in ABC patients. Mean treatment duration was 6.6 weeks in NSCLC patients and 15.9 weeks in ABC patients. Treatment was discontinued due to disease progression in 14 patients, unacceptable adverse effects in 11 patients, while three patients refused to continue therapy. We cannot recommend this drug for further clinical trials in NSCLC and ABC.

Adult↗
PubMed1996

Decreased growth rate and tumour formation of human anaplastic thyroid carcinoma cells transfected with a human thyrotropin receptor cDNA in NMRI nude mice treated with propylthiouracil.

The effect of the human TSH-receptor (TSHR) on the growth of human anaplastic thyroid carcinoma cells lacking the endogenous expression of TSHR, was studied both in vitro and in vivo in NMRI nude mice. Cells from a human anaplastic thyroid carcinoma cell line (C643) were transfected with a TSHR cDNA, and clones were isolated after neomycin selection. The expression of a functional receptor protein was ensured by analysis of the specific binding of 125I-TSH and measurement of TSH-induced cAMP. Incorporation of [3H]thymidine and increase in cell number was slightly inhibited by TSH in TSHR-expressing cells in vitro. In order to investigate whether the regained expression of a functional TSHR protein in C643 cells could influence the in vivo growth, cells were injected subcutaneously into NMRI nude mice. To manipulate the endogenous level of TSH, animals were given 6n-propyl-2-thiouracil (PTU; resulting in a high TSH level), T4 (a low TSH level) or no treatment (as a control). There seemed to be a TSH induced inhibition of tumour growth, since tumours in mice treated with PTU grew after a longer take rate and with a slower growth rate. The present results suggest a TSH-mediated growth inhibition in the TSHR-transfected C 643 anaplastic thyroid carcinoma cells.

Animals↗
PubMed1996

The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry.

BACKGROUND: Mutations in the p53 tumor suppressor gene (also known as TP53) have been detected in a wide variety of human cancers. In breast cancer, the presence of p53 gene alterations has been associated with worse prognosis. PURPOSE: We compared a complementary DNA (cDNA)-based sequencing method and an immunohistochemical (IHC) method for their abilities to detect p53 mutations in breast cancer specimens. In addition, we determined the prognostic value of information obtained when these two methods were used. METHODS: Specimens from 316 primary breast tumors were evaluated for the presence of mutant p53 protein by use of the mouse monoclonal antibody Pab 1801 (that recognizes both wild-type and mutant forms of p53) and standard IHC methods. In addition, the entire coding region of p53 genes expressed in these tumors was screened for mutations by combining reverse transcription, the polymerase chain reaction, and DNA sequencing. Probabilities for overall survival (OS), breast cancer-corrected survival (BCCS; death from breast cancer is the considered event), and relapse-free survival (RFS) were estimated by use of the Kaplan-Meier method, and survival curves for different patient subgroups were compared by use of the logrank method. All reported P values are from two-sided tests. RESULTS: Sixty-nine (22%) of 316 tumors had p53 gene mutations detected by the cDNA-based sequencing method; only 31 (45%) of these mutations were located in evolutionarily conserved portions of the p53 coding region. Sixty-four tumors (20% of the total) had elevated levels of p53 protein as detected by IHC, suggesting the presence of mutations. Of the sequencing-positive tumors (i.e., p53 mutant), 23 exhibited negative IHC reactions, indicating that IHC failed to detect 33% of the mutations. Furthermore, 19 of the IHC-positive tumors were sequencing negative (i.e., p53 wild-type), suggesting a 30% false-positive frequency with IHC. Four tumors (1.3% of the total) could not be analyzed by the cDNA-based sequencing method, and three tumors (1% of the total) could not be analyzed by IHC. The 5-year estimates for RFS, BCCS, and OS were significantly shorter for patients with p53 sequencing-positive tumors than for patients with sequencing-negative tumors (P = .001, P = .01, and P = .0003, respectively). Patients with IHC-positive tumors showed reduced survival in all three categories when compared with those with IHC-negative tumors, but the differences were not statistically significant. CONCLUSIONS: Use of a cDNA-based sequencing method to determine the status of the p53 gene in primary breast cancers yielded better prognostic information than IHC performed with the Pab 1801 monoclonal antibody.

Adult↗
PubMed1996

Comparison of iodixanol and ioxaglate for adult aortography and renal/visceral angiography: a phase III clinical trial.

RATIONALE AND OBJECTIVES: We investigated whether iodixanol offers improved safety or tolerance compared with ioxaglate and evaluated whether iodixanol-enhanced radiographs are diagnostically comparable or superior to those produced with ioxaglate. Iodixanol is a new isosmotic hexa-iodinated nonionic contrast agent being evaluated for intravascular use. METHODS: Fifty-four adult patients undergoing renal or visceral angiography, aortography, or both were enrolled in a prospective, randomized, double-blind, two-center study in which iodixanol and ioxaglate were compared. Subjects were monitored for adverse events, injection-associated discomfort, and changes in laboratory parameters and vital signs. Efficacy was measured by the overall quality of angiographic enhancement. RESULTS: No serious adverse events occurred during this trial. Mild-to-moderate adverse events were more common in patients receiving ioxaglate (p = .041). Injection-associated pain was reported by three patients receiving ioxaglate and none receiving iodixanol (p = .093). Clinical laboratory and vital-sign data showed no differences between groups, and there was no difference in the overall quality of angiographic visualization (p = .711). CONCLUSION: Iodixanol resulted in improved safety and patient tolerability while providing images of equivalent diagnostic efficacy compared with ioxaglate.

Angiography↗
PubMed1996

Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.

PURPOSE: The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI), fluorouracil (5-FU), and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients. PATIENTS AND METHODS: Data from 21 women were collected over a total of 35 cycles. 5-FU (300 to 600 mg/m2) and CP (300 to 600 mg/m2) were administered as bolus injections, whereas EPI (15 to 60 mg/m2) was administered either as a bolus injection or as an infusion. The pharmacokinetics of the component drugs were monitored using a limited sampling scheme. Population pharmacokinetic models for each of the three drugs were developed using the program NONMEM. RESULTS: The data for 5-FU were best described by a one-compartment model with nonlinear elimination, where the maximal rate of elimination (Vmax) and the concentration at which the elimination was half-maximal (Km) were 105 mg/L.h and 27 mg/L, respectively. EPI concentration-time profiles showed a triexponential decline, with a mean terminal half-life of 24 hours and a clearance (CL) of 59 L/h. The elimination of 4-OHCP was monoexponential, with a mean half-life of 7 hours. The interindividual coefficients of variation (CVs) in CL were 30%, 22%, and 41% for 5-FU, EPI, and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in CL were 11%, 8%, and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found. CONCLUSION: Individualization of dosing of the FEC regimen using therapeutic drug monitoring and attempts to find concentration-response relationships may be successful, but requires that the exposure of all three drugs is considered simultaneously.

Adult↗
PubMed1996

Overview on human breast cancer with focus on prognostic and predictive factors with special attention on the tumour suppressor gene p53.

A long list of potential prognostic markers has been analysed for breast cancer, some of them will be reviewed in this article. The lymph node status is still the best prognostic marker. The lymph node status combined with information on tumour size, receptor- and proliferation status of the tumour should be analysed as standard for all breast cancer patients. Prognostic information for breast cancer patients has also been described for the membrane protein c-erbB2, the protease cathepsin D, plasminogen activators and inhibitors, certain oncogenes and tumour suppressor genes. Some of these factors also give potential additional information on the response to different oncological therapies, and are better denoted predictive factors. In this overview we shortly describe the above mentioned prognostic factors with major focus on the tumour suppressor gene p53 and its prognostic value and potential predictive value.

Apoptosis↗
PubMed1996

Effects of interferons and tumour necrosis factor-alpha on human lung cancer cell lines and the development of an interferon-resistant lung cancer cell line.

Thirteen human lung cancer cell lines, 7 representing small cell lung cancer (SCLC) and 6 different types of non-SCLC, were tested for sensitivity to tumour necrosis factor alpha (TNF-alpha) and interferon alpha and gamma (IFN-alpha and gamma) using an automated fluorometric microculture cytotoxicity assay (FMCA). One SCLC line (H-82) was found to be sensitive to IFN-alpha in short-term (72 h) culture, whereas after prolonged (5 days) culture two additional SCLC cell lines responded to IFN-gamma. TNF-alpha inhibited the growth of one large cell carcinoma cell line (H-157), whereas all SCLC lines were found to be insensitive. The combination of IFN-gamma and TNF-alpha produced no further response compared with the single agents used alone. By continuous cultivation of the IFN-alpha-sensitive cell line H-82 in the presence of increasing concentrations of IFN-alpha, an IFN-alpha-resistant subline (H-82) was established. This line displayed a high degree of resistance ( > 100 fold) to IFN-alpha and cross-resistance to IFN-gamma. There was no alteration in the number of IFN binding sites, in the growth rate, the expression of selected surface markers for SCLC or the expression of multidrug resistance markers in the H-82R subline compared with the parental H-82 cell line. The results demonstrate a heterogeneous response of SCLC cell lines to IFN-alpha and gamma and TNF-alpha with only a minority of the cell lines responding to these agents by growth inhibition. The IFN-alpha and gamma H-82R subline may serve as a valuable tool in future studies on the mechanisms of IFN antitumour activity.

Antigens, Neoplasm↗
PubMed1995

Functional hyaluronan receptors are expressed on a squamous cell lung carcinoma cell line but not on other lung carcinoma cell lines.

We investigated the production of hyaluronan and the presence of hyaluronan receptors in a panel of human lung carcinoma cell lines, consisting of small cell carcinomas (SCLC) and non-small cell carcinomas (non-SCLC). These transformed cell lines produced only minute amounts of hyaluronan, whereas normal lung fibroblasts synthesized high amounts. CD44 molecules (an integral membrane glycoprotein suggested previously to function as a hyaluronan receptor) were differentially expressed on non-SCLC cell lines but essentially not on the SCLC cell lines. In contrast, RHAMM molecules (receptor for hyaluronan-mediated motility) were preferentially expressed on SCLC cells. Although all the lung tumor cell lines expressed various amounts of CD44 and RHAMM, only the SCLC line U-1752 could bind [3H]hyaluronan. The binding sites were saturated with about 19,700 hyaluronan molecules (Mr 1.4 x 10(6)) bound per cell with a Kd of 0.16 x 10(-9) M. CD44 molecules were responsible for the binding activity since Hermes-1 antibodies that block the binding of hyaluronan to CD44 blocked the binding of [3H]hyaluronan to U-1752 cells. 4-Phorbol 12-myristate 13-acetate (PMA) treatment of U-1752 cells both increased the hyaluronan-binding activity in U-1752 cells as well as induced abrogation of cell-cell and cell-matrix interactions. Addition of hyaluronan inhibited the PMA-induced disassembly of the cells. The fact that CD44 molecules are able to bind [3H]hyaluronan only on the SCLC line U-1752 but not on other lung carcinoma cell lines may be of value as a marker for squamous cell carcinoma differentiation. Furthermore, the inhibitory effect of hyaluronan on the PMA-promoted cell disassembly suggest that hyaluronan surrounding squamous cell carcinoma cells may affect their migration and invasiveness.

Carcinoma, Non-Small-Cell Lung↗
PubMed1995

Expression of the 85-kd membrane protein in primary human breast cancer: relationship to hormone receptor levels, DNA ploidy, and tumor grade.

Using the monoclonal antibody (MAb) MRK20 the immunohistochemical expression of the 85-kd membrane protein (MP)/cell adhesion molecule (CAM) CD36 was investigated in tumors from 41 patients with untreated breast adenocarcinoma. DNA ploidy as measured by flow cytometry and estrogen (ER) and progesterone receptor (PgR) tumor contents also were determined. Immunohistochemistry on frozen tissue showed expression of 85-kd MP localized to the carcinoma cells in tumors from 16 patients (39%). These samples also displayed variable staining of the capillary endothelium. Twenty-one samples (51%) showed 85-kd MP expression in small blood vessels. Thus, a total of 37 of 41 tumors (90%) were MAb MRK20 positive in carcinoma and/or mesenchymal cells. Expression of 85-kd MP in carcinoma cells was negatively associated with expression of ER (P < .05) and PgR (P < .01) receptors and positively associated with nondiploid tumors (P < 0.05) and tumor grade (P < .05). Axillary lymph node status, tumor size, and (patient) age were not associated with expression of 85-kd MP. In cytological smears obtained by fine-needle aspiration (FNA) cytology from 19 of the samples, expression of 85-kd MP in carcinoma cells showed a good correlation with tumor cell positivity in the corresponding histological section. Expression of 85-kd MP in breast carcinoma cells thus was associated with some recognized adverse prognostic factors. Future studies of its pathophysiological and prognostic roles in breast cancer seem warranted.

Adenocarcinoma↗
PubMed1995

Increased radioresistance of an in vitro transformed human small cell lung cancer cell line.

After 4-6 months in continuous culture the human small cell lung cancer (SCLC) cell line, U-1906, changed its radiobiological characteristics spontaneously. The cell line became more radioresistant indicating an increased repair capacity. This change was accompanied by a more adherent growth pattern, a higher clonogeneity, a decrease in the cytokeratin (tissue polypeptide antigen) content and increased glucagon and neuron-specific enolase (NSE) production. Other parameters such as the estramustine-binding protein (EMBP) and the proliferation associated antigen Ki-67 were unaltered. This spontaneous transformation in vitro of U-1906 may reflect a clinically important in vivo phenomenon of SCLC, which frequently develops resistance both to radio- and chemotherapy.

Carcinoma, Small Cell↗
PubMed1995

The cytotoxic activity of Taxol in primary cultures of tumour cells from patients is partly mediated by Cremophor EL.

In patient tumour samples the activity in vitro of Taxol corresponded fairly well to the known clinical activity and Taxol showed low cross-resistance to standard cytotoxic drugs. However, the Taxol solvent Cremophor EL--ethanol was considerably active alone, whereas paclitaxel formulated in ethanol was less active. Taxol thus seems to contain two components active against patient tumour cells in vitro.

Antineoplastic Agents↗
PubMed1995

Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy.

The complete coding region of the p53 gene was sequenced from 316 consecutively presented breast cancers, of which 97 were lymph node positive and 206 were node negative. The p53 status was related to prognosis and effect of adjuvant therapy. In all, 69 individual mutations, 29 in node-positive tumours, were demonstrated throughout the whole coding sequence. The mutation sites were partly different for node-positive and node-negative patients. p53 mutations in the evolutionary conserved regions II and V were associated with significantly worse prognosis. Adjuvant systemic therapy, especially with tamoxifen, along with radiotherapy seemed to be of less value to p53 mutation- and lymph node-positive tumours.

Amino Acids↗
PubMed1995

p53 Status predicts survival in breast cancer patients treated with or without postoperative radiotherapy: a novel hypothesis based on clinical findings.

PURPOSE AND METHODS: Primary breast cancer tumors without axillary metastases from 206 consecutive patients in a population-based cohort were investigated with regard to the presence of an intact p53 gene using a cDNA-based sequencing method. Clinical follow-up data and outcome of node-negative patients without any adjuvant systemic therapy (n = 168) were related to locoregional radiotherapy and p53 status. RESULTS: Mutations in p53 occurred in 31 node-negative breast cancer patients who did not receive any systemic adjuvant treatment, but were treated with postoperative locoregional radiotherapy or nothing. Node-negative breast cancer patients with p53 mutations had significantly improved relapse-free survival (P = .0007), breast cancer-corrected survival (P = .01), and overall survival (P = .02) rates when treated with locoregional radiotherapy. In node-negative breast cancer patients with wild-type p53, there was no statistically significant difference in outcome between patients who received locoregional radiotherapy and those who did not. Cox proportional hazards models indicate that mutant p53 is associated with worse prognosis independent of response to radiotherapy and that response to radiotherapy is qualitatively different in tumors with p53 mutations compared with those with wild-type p53. CONCLUSION: Our clinical findings define a group of breast cancer patients in whom locoregional radiotherapy improves relapse-free, breast cancer-corrected, and overall survival. The outcome for irradiated node-negative breast cancer patients with p53 alterations indicates that irradiation can induce cell death even in the presence of p53 mutations.

Adult↗