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J Bergh

Publications and source records attributed to J Bergh.

At least 73 records · Page 4Linked to original sources
PubMed1999

Clinical studies of p53 in treatment and benefit of breast cancer patients.

This article describes p53 as a prognostic and predictive factor, together with some information on how best to determine the p53 status. By December 1998, 13,000 articles on p53 were identified on Pub Med, the National Library of Medicine. Within one week a further 62 articles were recorded making it difficult to give the complete p53 story. This review article will focus on discussing p53 in relation to its predictive potential. So far, no firm conclusions can be made based on the articles studied. This may be, in part, because many studies have used less than optimal techniques for determination of the p53 status, together with the fact that the studies lacked power to detect a potential difference in outcome from specific therapy in relation to p53 status.

Adenocarcinoma↗
PubMed1999

Pharmacokinetic models for the saturable distribution of paclitaxel.

Paclitaxel pharmacokinetics are nonlinear with saturable metabolism and saturable distribution to the tissues. The saturable distribution has in previous pharmacokinetic modeling been described as a saturable transport process, whereas the present study was undertaken to investigate alternative explanations. Using a sparse sampling scheme (on average 3.3 samples per profile), 101 plasma concentration-time profiles in 22 female patients with metastatic cancer of the breast or ovary were monitored. It was found that the observed data could be equally well described by saturable tissue binding as well as by capacity-limited tissue transport. The data were better described by a model where equilibrium was achieved with drug in the central rather than in the peripheral compartment. Models where the binding was assumed to be an instantaneous or a noninstantaneous process were tried, but the data did not allow resolution between these two possibilities. The value at which the saturable transport was half-maximal was 0.55 microM. The K(d) values of the binding models were 0.06 to 0.12 microM. These are close to the values reported as a threshold for drug toxicity of paclitaxel, suggesting a possible connection between the binding sites involved in the pharmacokinetics and the mechanism responsible for the toxicity. For all models, a saturable elimination of paclitaxel was included using the Michaelis-Menten model. K(m) for the elimination ranged in the different models from 2.5 to 5.6 microM.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Prognosis in women with a carcinoma in situ of the breast: a population-based study in Sweden.

We studied the risk of invasive breast cancer and breast cancer death after a breast carcinoma in situ during a period when mammography screening became a nationwide practice and when breast conservation was introduced. In a study base including all 4661 women registered to the Swedish Cancer Registry for a first carcinoma in situ between 1960 and 1992, we selected a cohort of 3398 women diagnosed between 1980 and 1992. The recruitment period was chosen according to the reporting routines for the registry. The corrected survival was 97.4% after 10 years. The risk of invasive cancer was similar in the ipsilateral and contralateral breast. Women diagnosed between 1989 and 1992 ran a relative risk of 0.1 (95% confidence interval, 0.0-0.9) of dying of breast cancer, as compared with women diagnosed from 1980-1982. Residence in counties where mammography screening was available was associated with a relative risk of 0.2 (95% confidence interval, 0.0-2.1) for breast cancer death in the age groups screened. Screening mammography may have contributed to the improvement of prognosis over this time period. This study cannot distinguish between lead time effects and a "true" improvement in prognosis. The increased use of breast conservation was not associated with a worse prognosis in the group as a whole. The study indicates that at least 50% of invasive cancers occurring after treatment for in situ lesions may be new cancers.

Adult↗
PubMed1998

Homozygous deletions at 3p12 in breast and lung cancer.

We have constructed a physical map of the region homozygously deleted in the U2020 cell line at 3p12, including the location of putative CpG islands. Adjacent to one of these islands, we have identified and cloned a new gene (DUTT1) and used probes from this gene to detect two other homozygous deletions occurring in lung and breast carcinomas: the smallest deletion is within the gene itself and would result in a truncated protein. The DUTT1 gene is a member of the neural cell adhesion molecule family, although its widespread expression suggests it plays a less specialized role compared to other members of the family.

Breast Neoplasms↗
PubMed1998

Comparison between p53 protein measurements using the luminometric immunoassay and immunohistochemistry with detection of p53 gene mutations using cDNA sequencing in human breast tumors.

The p53 mutational status of 226 representative primary breast cancer samples, derived from a population-based cohort, was analyzed using cDNA-based sequencing. The results were compared with those obtained with immunohistochemistry (IHC) on microwave-treated paraffin sections and the p53 specific luminometric immunoassay (LIA) on cytosols, all from the same individuals. Thirty-seven mutations were found using cDNA sequencing and were categorized into A) missense mutations in the evolutionarily conserved regions; B) missense mutations outside the evolutionarily regions; and C) deletions, insertions and nonsense mutations. Using optimal cut-off values, LIA detected 15 of 16 missense mutations in category A, in which IHC detected all 16. In category B, 10 of 13 and 7 of 13 mutations were detected, respectively. Some of the samples in category A had a very high p53 protein content when measured with the LIA, the reason for this being discussed. IHC detected 0 of 5 stop codon and 0 of 3 deletions/insertions mutations, while the LIA method detected 2 of 5 stop codon mutations and 1 of 3 deletion/insertion mutations. Compared with cDNA sequencing, protein analyses using optimal cut-off values resulted in an overall sensitivity and specificity of 64.9% and 89.9%, respectively, for the LIA method. Corresponding values were 72.2% and 92% for IHC. In addition, patients from whom p53 mutations could be detected by cDNA sequencing had a statistically significant (p = 0.0137) shorter survival, which was not readily apparent using the alternative LIA or IHC approaches at optimal cut-off values.

Breast Neoplasms↗
PubMed1998

Tailored chemotherapy to equal toxicity: is it possible?

Conventional dosage of chemotherapy based on body surface area in patients with normal organ functions will result in marked interindividual variations in systemic exposure to the cytostatics used. This will result in over- and undertreatment of the individual patient associated with unwarranted toxicity and suboptimal outcome. The intention to modify dosage is motivated by a possible correlation between toxicity and outcome. New dosage strategies with individual tailoring of the therapy should be investigated with the aim of increasing the efficacy of therapy without increasing its toxicity. Pharmacokinetic monitoring using the limited sampling procedure could be one alternative, another toxicity-guided dosage. The dosage scheme used for tailored FEC polychemotherapy (six dose levels), based on therapy to equivalent haematological toxicity, has been clinically applicable in the multicentre setting for both adjuvant and preoperative therapy. In the adjuvant setting it has resulted in the delivery of significantly higher epirubicin and cyclophosphamide doses without increasing acute toxicity to the same extent; in two out of three patients no difference in acute toxicity could be verified for the highest two dose levels compared with the lower dose levels. In short, we could obtain better results with our present arsenal of cytostatics if we used them better.

Antineoplastic Agents↗
PubMed1998

Skeletal metastases from breast cancer: uptake of 18F-fluoride measured with positron emission tomography in correlation with CT.

OBJECTIVE: To characterise the uptake of 18F in skeletal metastases from breast cancer using positron emission tomography (PET) and to relate these findings to the appearance on CT. PATIENTS AND DESIGN: PET with 18F and CT were performed in five patients with multiple skeletal metastases from breast cancer. The CT characteristics were analysed in areas with high uptake on the PET study. Dynamic PET imaging of the skeletal kinetics of the 18F-fluoride ion were included. RESULTS: The areas of abnormal high accumulation of 18F correlated well with the pathological appearance on CT. Lytic as well as sclerotic lesions had markedly higher uptake than normal bone, with a 5-10 times higher transport rate constant for trapping of the tracer in the metastatic lesions than in normal bone. CONCLUSION: PET with 18F-fluoride demonstrates very high uptake in lytic and sclerotic breast cancer metastases.

Aged↗
PubMed1998

A general model for time-dissociated pharmacokinetic-pharmacodynamic relationship exemplified by paclitaxel myelosuppression.

BACKGROUND: Hematologic toxicity after cancer chemotherapy and other drug effects that occur late compared to the exposure are usually modeled with use of some summary exposure variable such as the area under the concentration-time curve (AUC model) or the time of exposure above a threshold concentration (threshold model). An underlying assumption for both of these models is that the drug exerts a direct effect while present in the body and that it is the time integral of this direct effect that is related to the ultimate observed effect, either linearly (AUC model) or by a step function (threshold model). We propose a more general model that allows this relationship to be characterized by a nonlinear continuous function. METHODS: Data on survival fraction of neutrophiles and time course of leukopenia from 92 courses of paclitaxel therapy in 21 patients with breast or ovarian cancer was related to paclitaxel concentration-time profiles with the AUC, threshold, and general models. The properties of the general model were also investigated with use of simulations. RESULTS: For both pharmacodynamic end points, the general model described the data significantly better than the AUC or threshold models. CONCLUSION: The general model is an extension to the present way of relating concentration-time profiles to late-effect measures, and it may provide an improved description of the concentration-response relationship and more accurate predictions of the ultimate effect when doses and schedules are varied. It can explain complex relationships between concentration-time profiles and the observed effect, and predictions from it lack some of the counterintuitive properties that the AUC or threshold model have when extrapolations are made.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Radiotherapy of breast cancer after breast-conserving surgery: an improved technique using mixed electron-photon beams with a multileaf collimator.

BACKGROUND AND PURPOSE: Loco-regional radiotherapy after breast cancer surgery significantly reduces the risk of recurrences. An increase of cardiac deaths for irradiated breast cancer patients has been reported in some studies, especially for women with tumours in the left breast. The aim of this study was to compare retrospectively the conventionally used technique using two opposed tangential photon beams with a modified technique using a combination of photon and electron beams to find an optimal technique with respect to dose homogeneity in the breast and surrounding regional lymph nodes and a minimal dose in the organs at risk. MATERIALS AND METHODS: Thirty patients with stage II breast cancer who received different types of adjuvant systemic therapy were included in the investigation. Comparative dose planning of two techniques was performed, i.e. an isocentric technique with two photon beams with coplanar medial beam edges and a technique with one electron and three photon beams with a common isocentre for all beams aided by a multileaf collimator. RESULTS: The mixed technique was selected for eight of 12 patients with left-sided breast cancers because of significantly lower doses to the heart. However, the decision-making was influenced by many factors such as dose coverage of the target volume combined with minimizing of the doses to the organs at risk and the contralateral breast. CONCLUSION: The use of the mixed technique will optimize the loco-regional radiotherapy after breast-conserving surgery for many left-sided breast cancers.

Adult↗
PubMed1998

Higher spontaneous apoptotic index in small cell compared with non-small cell lung carcinoma cell lines; lack of correlation with Bcl-2/Bax.

Spontaneous apoptosis was assessed in ten small-cell (SCLC) and five non-small cell (NSCLC) lung carcinoma cell lines by the TUNEL assay and chromatin cleavage. TUNEL staining showed significantly higher apoptotic index (AI) in SCLC (2-20%) compared with NSCLC lines (0.2-1%) in untreated exponentially growing cells. Six out of ten SCLC and none of the NSCLC showed DNA fragmentation when analysed by agarose gel electrophoresis. Field inversion pulse gel electrophoresis was used in a subset of cell lines and showed the presence of high molecular weight fragments in untreated SCLC lines U-1285 and U-1906 cells, but not in the NSCLC line U-1810. Important molecular determinants of apoptosis were studied by Western blot. Bcl-2 was detected at highest level in SCLC. There was no correlation between the ratio Bcl-2/Bax and AI in all tested cell lines. Neither p53 nor c-Myc protein status correlated to AI. Pro-caspase-3 was expressed in all cell lines without correlation to AI and no difference between the SCLC and NSCLC groups was found. In conclusion, this study shows a high degree of spontaneous apoptosis in SCLC lines compared to NSCLC lines unrelated to Bcl-2/Bax ratio.

Apoptosis↗
PubMed1998

Enhanced expression of neuropeptides in human breast cancer cell lines following irradiation.

Previously, we have observed that the expression of the neuropeptides bombesin (BN-), the mammalian counterpart being gastrin-releasing peptide (GRP), and substance P (SP) in intact normal tissues, such as salivary and laryngeal glands, increases in response to irradiation. In the present study, the aim was to evaluate whether irradiation can have effects on individual cells that normally synthesize neuropeptides. In addition, since these neuropeptides are potentially mitogenic, we studied tumor cells. Therefore, the estrogen receptor-negative human breast cancer cell line MDA-MB-231 and its subline, with acquired doxorubicin resistance, MDA-MB-231 Dox were examined before irradiation and 4, 10, and 15 days after irradiation with 4 Gy (195 kV, 2 Gy fractions with 4 hours interval). Potential dose related changes were studied by delivering single doses of 2 or 9 Gy with the same technique. Immunohistochemical and radioimmunoassay (RIA) methods were used for detection of the SP and BN/GRP. Before, and at all time points following irradiation, a subpopulation in both cell lines displayed an intense immunostaining of SP and BN/GRP. A partial reorganization of the immunoreactive material was observed 10 days after irradiation. The RIA-analyses displayed signs of a dose-related increase, and a time-dependent transient and significant increase in the content of both peptides. The pattern of changes differed between the two peptides, and was especially pronounced in the doxorubicin resistant cells with regard to SP. Another neuropeptide, calcitonin gene related peptide (CGRP), was not detected in the cells used. The results suggest that irradiation has effects on a population of cultured neuropeptide-synthesizing cells. The occurrence and the specific changes obtained in the levels of neuropeptides, in response to irradiation, might imply an importance in the growth of breast cancer cells and in explaining repair processes following irradiation.

Antibiotics, Antineoplastic↗
PubMed1998

Dosage of adjuvant G-CSF (filgrastim)-supported FEC polychemotherapy based on equivalent haematological toxicity in high-risk breast cancer patients. Scandinavian Breast Group, Study SBG 9401.

BACKGROUND: Conventional dosages of cytostatics in mg/m2 will cause marked variations in systemic exposure, resulting in over- and under-treatment, at least with respect to side effects. PATIENTS AND METHODS: We are conducting a randomized adjuvant study for breast cancer patients younger than 60 years of age with > or = 70% risk of recurrence within five years. The first 89 consecutive patients who have received nine courses q three weeks of individually dose-escalated and G-CSF (filgrastim)-supported FEC (5-fluorouracil (5-FU), epirubicin, and cyclophosphamide) therapy given with ciprofloxacin prophylaxis were included in this analysis. Six different FEC dose levels were used for treatment at equivalent haematological toxicity. Dose modifications were based on white blood cell and platelet counts on days 8, 11/12, 15, and 22. RESULTS: Eighty-three of 89 patients completed all nine courses. The median epirubicin and cyclophosphamide doses were 782 mg/m2 (range 0-994 mg/m2) and 10.330 mg/m2 (range 0-14.460 mg/m2), respectively. Patients treated at the two highest dose levels experienced NCl grade 0 or 1 toxicities in 73% to 92% of the courses. Three patients have developed acute myeloid leukaemia, and two of them have demonstrated abnormalities compatible with topoisomerase II-poison-related karyotypic changes. CONCLUSIONS: Tailored adjuvant G-CSF-supported FEC polychemotherapy will make it possible for all patients to be treated at equivalent levels of haematological toxicity with significantly higher doses without a marked increase in other organ toxicities.

Aged↗
PubMed1998

High-dose chemotherapy with autologous stem cell support in patients with responding stage IV breast cancer.

Ninety-four patients underwent high-dose chemotherapy with stem cell support for stage IV breast cancer. The high-dose chemotherapy consisted of the Stamp V regimen in all patients comprising cyclophosphamide, thiotepa and carboplatin (CTCb). Twenty-three patients received sequential high-dose therapies with the first consisting of high-dose melphalan and the second of Stamp V. Two patients died from chemotherapy-related complications resulting in a transplant-related mortality at 100 days of 2.2%. The progression-free survival at 3 years was 36% in patients with no evidence of disease at the first course of high-dose therapy compared with 17% in patients with remaining disease at time of the high-dose therapy (P = 0.03). There was no difference in overall survival between patients with no evidence of disease and other patients. The source of stem cells, single or double courses of high-dose therapy, positive selection of CD34+ cells, or number of involved sites had no influence on either progression-free survival or overall survival. Further studies of more intensive induction chemotherapy followed by high-dose therapy with stem cell support are indicated.

Adult↗
PubMed1998

Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers.

PURPOSE: To investigate the prognostic and predictive value of c-erbB-2 overexpression in breast cancer in relation to other prognostic markers. PATIENTS AND METHODS: Paraffin-embedded tumors from 315 consecutive primary breast cancer patients were screened for c-erbB-2 protein (p185) overexpression by immunohistochemistry using the monoclonal antibody CB11. RESULTS: c-erbB-2 protein overexpression was detected in 19% of tumors and was associated with shorter 5-year overall survival (OAS) rate compared with c-erbB-2-negative cases in the total patient material (58% and 77%, respectively; P = .004) and in the 96 node-positive patients (31% and 61%, respectively; P = .02), but not in node-negative patients. For 47 node-positive patients treated with adjuvant tamoxifen and radiotherapy, the 5-year OAS was 13% for c-erbB-2 overexpression and 75% for c-erbB-2-negative patients (P = .00004). The frequency of c-erbB-2 overexpression decreased with age at diagnosis. The prognostic value of c-erbB-2 on OAS was independent of age, node status, tumor size, histopathologic grade, hormone receptor status, S phase, p53 status, and adjuvant treatment. c-erbB-2 status added prognostic information to p53-negative and low S-phase cases, but not to p53-positive and high S-phase cases. Correspondingly, these only added information to c-erbB-2-negative cases. CONCLUSION: c-erbB-2 protein overexpression may have a predictive value with regard to adjuvant therapy in node-positive patients, for whom adjuvant tamoxifen with radiotherapy appears insufficient in the presence of c-erbB-2 overexpression. Combination of conventional and newer tumor markers may identify patients with a worse prognosis within groups with a generally favorable prognosis.

Adult↗
PubMed1998

Assessment of sequence-based p53 gene analysis in human breast cancer: messenger RNA in comparison with genomic DNA targets.

The high prevalence of p53 mutations in human cancers and the suggestion from several groups that the presence or absence of p53 mutations might have both prognostic and therapeutic consequences point to the importance of optimal methods for p53 determination. Several strategies exploring this have been described, based either on mRNA or genomic DNA as a template. However, no comparative study on the reliability of the two templates has been performed. The principal aim of this study was to study the concordance of RNA- and DNA-based direct sequencing methods in detecting p53 mutations in breast tumors. In 100 tumors, 22 mutations were detected by both methods. Furthermore, one stop mutation, two splice-site mutations, and one intron alteration were found only by genomic sequencing. In addition, the comparative study suggests that cells with missense mutations have increased steady-state concentrations of p53-specific mRNA, in contrast to cells with a gene encoding a truncated protein.

Aneuploidy↗
PubMed1997

Alkaline single-cell gel electrophoresis and human biomonitoring for genotoxicity: a pilot study on breast cancer patients undergoing chemotherapy including cyclophosphamide.

Alkaline single-cell gel electrophoresis (the 'comet assay') was used to evaluate DNA damage in lymphocytes from 17 breast cancer patients before and 1-21 h after chemotherapy including cyclophosphamide (600-1800 mg/m2). In order to control for the experimental variability over time, freshly isolated lymphocytes from female mice given physiological saline or cyclophosphamide (150 mg/kg b.wt.) were included as 'internal standards' in each individual electrophoresis run. There was an upward tendency of DNA damage in the mouse lymphocytes over the study period, but cyclophosphamide was constantly found to induce significant damage at all time points investigated (1-48 h). Although patients given up to 11 prior cycles of chemotherapy showed the same basal level of DNA damage as the patients coming to the clinic for their first treatment, the chemotherapy given at the time of the present blood sampling was associated with significant DNA damage in most samples. Considerable interindividual variations were observed both before and after the treatment. DNA single-strand breaks and alkali-labile sites in peripheral lymphocytes as evaluated by the comet assay seem to be useful molecular biomarkers for exposure to DNA damaging agents when monitoring ongoing exposures, but less impressive when monitoring accumulated exposures, at least in patients given high doses of cyclophosphamide and other antineoplastic agents.

Adult↗