Biomedical subjects

R Becher

Publications and source records attributed to R Becher.

At least 19 recordsLinked to original sources

PubMed2005

Mineral particles of varying composition induce differential chemokine release from epithelial lung cells: importance of physico-chemical characteristics.

Presently, little is known about the potential health effects of mineral particles other than asbestos and quartz. In this study, a human epithelial lung cell line (A549), primary human small airway epithelial cells (SAECs) and primary rat type 2 (T2) cells were exposed to stone quarry particles of two size fractions (<10 and <2.5 microm) from nine different rock samples. The ability to induce the release of chemokines from lung cells was investigated and compared with the particles' mineral and element composition and the amount of soluble elements. The stone particles induced the release of only low levels of interleukin (IL)-8 from A549 cells. In contrast, some of the other particles induced the release of high levels of macrophage inflammatory protein (MIP)-2 from T2 cells, and high levels of IL-8 from SAECs. Differences in particle surface area could account for differences in activity between the <10 and <2.5 microm fractions of six out of the nine rock samples. For two samples the <2.5 microm fraction was most active and for one sample the <10 microm fraction was most active. Content of the mineral plagioclase displayed a strong, negative correlation with the potential to induce MIP-2, whereas the mineral pyroxene was positively correlated with MIP-2 induction. However, neither plagioclase nor pyroxene content was sufficient to explain differences in bioactivity between the particles. No statistically significant correlation was found between the amounts of total or soluble elements and MIP-2 release. In conclusion, the results suggest that mineral particles with a high content of plagioclase have a low potential to induce a pro-inflammatory response. However, a particular mineral or element responsible for eliciting strong increases in chemokine release could not be identified. Thus, at present it appears that analysing mineral and element content is insufficient to predict stone particle bioactivity, and that biological testing is a necessity.

Animals↗

PubMed2001

Rat lung inflammatory responses after in vivo and in vitro exposure to various stone particles.

Rat lung alveolar macrophages and type 2 cells were exposed for 20 h in vitro to various stone particles with differing contents of metals and minerals (a type of mylonite, gabbro, feldspar, and quartz). The capability to induce the release of the inflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2) was investigated. We found marked differences in potency between the various particles, with mylonite being most potent overall, followed by gabbro, and with feldspar and quartz having an approximately similar order of lower potency. The results also demonstrated differences in cytokine release pattern between the two cell types. For all particle types including quartz, type 2 cells showed the most marked increase in MIP-2 and IL-6 secretion, whereas the largest increase in TNF-alpha release was observed in macrophages. To investigate possible correlations between in vitro and in vivo inflammatory responses, rats were instilled with the same types of particles and bronchoalveolar lavage (BAL) fluid was collected after 20 h. The results demonstrated a correlation between the in vitro cytokine responses and the number of neutrophilic cells in the BAL fluid. The BAL fluid also showed a strong MIP-2 response to mylonite. However, this was the only particle type to give a significant cytokine response in the BAL fluid. We further examined whether a similar graded inflammatory response would be continued in type 2 cells and alveolar macrophages isolated from the exposed animals. Again a differential cytokine release pattern was observed between type 2 cells and macrophages, although the order of potency between particle types was altered. In conclusion, various stone particles caused differential inflammatory responses after both in vitro and in vivo exposure, with mylonite being the most potent stone particle. The results suggest the alveolar type 2 cell to be an important participant in the inflammatory response following exposure to particles.

Animals↗

PubMed2000

Role of signal transduction pathways in lung inflammatory responses.

A variety of cell types participate in lung inflammation. Macrophages and epithelial cells play an important role in the inflammatory process by releasing cytokines in a complex cell to cell network. Interleukins are important mediators of this cell signalling. The interleukins IL-6 and IL-8 are released from epithelial cells in response to noxious agents such as particles, bacterial and fungal toxins and various chemicals. Though the involvement of, e.g. NF-IL-6 (C/EBP-beta) in the regulation of interleukins has been reported, the role of different signal transduction pathways in the regulation of these mediators has not been thoroughly investigated in lung epithelial cells. The involvement of different signal transduction pathways in the release of inflammatory markers is discussed with special emphasis on the effect of lung toxic compounds in human and rat lung epithelial cells.

Animals↗

PubMed1999

Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy: results of a randomized trial. Essen Breast Cancer Study Group.

The purpose of this randomized phase III trial was to study whether medroxyprogesterone acetate (MPA) maintenance treatment prolongs the time to progression in advanced breast cancer patients responding to an induction chemotherapy. Patients with progressive advanced breast cancer previously untreated with anthracylines and progestins were given epirubicin (30 mg/m2) and ifosfamide (2 g/m2) on days 1 and 8 at 3-weekly intervals. Patients without disease progression after 6 cycles of chemotherapy were randomly assigned to receive, until progression, either no treatment or MPA at a daily total dose of 500 mg. Ninety patients were randomized: 46 to the MPA arm and 44 to the observation arm. Median time to progression was longer in the MPA arm: 4.9 months versus 3.7 months in the intent-to-treat analysis (p = 0.02), and 4.9 months versus 3.0 months in the secondary efficacy analysis (p = 0.012). Seven patients were removed from MPA due to side effects. The changes in patient-rated quality of life scores were similar in both groups. The median length of survival from randomization was 17.4 months for patients receiving MPA and 18.3 months for patients randomized to observation (p = 0.39). In conclusion, in patients with advanced breast cancer achieving remission or non-progression with 6 cycles of epirubicin and ifosfamide chemotherapy, MPA maintenance treatment led to a significant, though modest, prolongation of the time to progression without affecting overall survival of the study patients.

Aged↗

PubMed1999

Cis-acting sequences from the rat cytochrome P450 2B1 gene confer pulmonary and phenobarbital-inducible expression in transgenic mice.

Specific cytochrome P450 enzymes show tissue-specific induction, and different regulatory units for expression of these enzymes have been identified. The regulation of the phenobarbital (PB)-inducible P450 genes has been relatively well characterized in terms of PB induction, but less so with regard to tissue-specific expression. CYP2B2 is not expressed in the rat lung, whereas cytochrome P450 2B1 (CYP2B1) is a dominating enzyme in the same tissue. The constitutive expression of CYP2B1 and CYP2B2 in liver is low, but inducible by PB, whereas the pulmonary expression of CYP2B1 is not induced by PB. This indicates utilization of different regulating mechanisms in the two organs. A gene construct consisting of the structural gene for LacZ coupled to a 1.3-kb 5' fragment of the rat CYP2B1 gene was used to generate transgenic mice in order to further elucidate the mechanism behind tissue-specific expression and PB induction of the CYP2B1 gene. Using reverse transcriptase-polymerase chain reaction on total RNA extracted from lung and liver tissue, a lung-specific transcription of the transgene was observed. Transcription of the construct was also observed in livers from PB-treated transgenic animals. By histochemical staining of lung sections with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal), we demonstrated expression at the protein level in bronchiolar cells. In conclusion, our results revealed that the region extending to -1. 3 kb in the 5' flanking region of the CYP2B1 gene included sequences that could partly account for the lung-specific transcription of CYP2B1 and the hepatic induction of CYP2B1 transcription by PB.

Animals↗

PubMed1999

Fluoride-induced interleukin-6 and interleukin-8 synthesis in human epithelial lung cells.

Exposure to fluorides has been associated with asthmatic symptoms among workers in the aluminium industry. In a recent experimental study hydrogen fluoride (HF) was found to induce a weak inflammatory response in humans. In the present study the potential of sodium fluoride (NaF) and HF to induce cytokine response was examined and how these responses are modulated by Al3+ in a human epithelial lung cell line (A549). Dose-response experiments showed a maximal release of IL-6 and IL-8 at a concentration of 5 mM NaF 24 h after addition. The responses to HF were of a similar magnitude as for NaF. Time-course experiments showed a NaF-induced IL-6 response at 5 h, whereas an IL-8 response was observed after 10 h. Cycloheximide treatment completely abolished the NaF-induced cytokine responses. A marked increase in the mRNA level for IL-6 was observed already 2 h after exposure to 5 mM NaF, and presumably is a prerequisite for the subsequent increase of IL-6. The fluoride-induced effects on IL-6 and IL-8 release were strongly reduced by pretreatment with deferoxamine (an Al3+-chelator), and enhanced by addition of Al3+. This indicates that an AlF4-- complex, a known activator of GTP-binding proteins, is involved in fluoride-induced IL-6 and IL-8 responses in A549 cells.

Aluminum Chloride↗

PubMed1998

Regulation of CCSP (PCB-BP/uteroglobin) expression in primary cultures of lung cells: involvement of C/EBP.

The Clara-cell secretory protein (CCSP) is a cell-specific differentiation marker for the bronchiolar Clara cell. Isolated rat Clara and alveolar type 2 cells kept in primary culture proliferate and dedifferentiate, providing the opportunity to study differentiation-dependent mechanisms. In freshly isolated Clara cells, high levels of CCSP and the corresponding mRNA were detected. During culture in vitro, these levels decreased. In the type 2 cell fraction, low levels of CCSP were detected, which decreased further during culture. A promoter fragment of the rat CCSP gene encompassing the sequence from -188 to +53 was able to drive high-level expression of reporter genes in transfected Clara cells. Reporter gene expression in transfected type 2 cells was markedly lower, and no expression could be detected in alveolar macrophages. Expression of transcription factors previously described to stimulate CCSP expression appeared not to parallel CCSP levels in the primary Clara cells. However, expression of the transcription factor C/EBP alpha correlated with the CCSP expression pattern. In electrophoretic mobility shift assays, we were able to demonstrate binding of C/EBP alpha from rat Clara cell nuclear extracts to an element located 85 bp upstream of the start site of transcription. Overexpression of C/EBP alpha increased expression from the CCSP -188 promoter fragment up to fivefold in NCI-H441-cells and 30-fold in A549-cells, establishing the functional importance of C/EBP alpha. Our results show that primary cultures of Clara cells constitute a useful model for investigating terminal airway differentiation and suggest a role for C/EBP-factor(s) in this process.

Animals↗

PubMed1998

The role of enteroclysis in the diagnosis of unexplained gastrointestinal symptoms: a prospective assessment.

The purpose of this prospective study performed at a non-university hospital was to assess the role of enteroclysis in the diagnosis of unexplained gastrointestinal symptoms such as abdominal pain, gastrointestinal bleeding, and chronic diarrhea done following inconclusive imaging or endoscopic procedures. 184 consecutive patients were subjected to enteroclysis over 25 months. 84 (46%) had abdominal pain, 52 (28%) gastrointestinal bleeding, and 48 (26%) chronic diarrhea. Findings were categorized as normal and abnormal (subdivided into main, i.e., explanatory of symptoms; and secondary, i.e., not explanatory of symptoms). Main findings were further divided into those exclusively detected by enteroclysis and those confirmed by this procedure. Normal enteroclysis investigations were obtained in 159 (86%) patients and abnormal in 25 (14%). Main findings were present in 19 (10%) patients, in ten (5%) of them exclusively detected by enteroclysis. Secondary findings were present in six (3%) patients, also detected only by enteroclysis. The highest rate of main findings exclusively detected by enteroclysis related to patients with chronic diarrhea (8%), compared with 6% and 2% with abdominal pain and gastrointestinal bleeding, respectively. For the inspection of the small bowel, enteroclysis shall remain the gold standard for detecting abnormal findings in the small bowel until user-friendly enteroscopes are developed.

Abdominal Pain↗

PubMed1997

Use of fluorescence in situ hybridization and comparative genomic hybridization in the cytogenetic analysis of testicular germ cell tumors and uveal melanomas.

Fluorescence in situ hybridization (FISH) with specific DNA probes and comparative genomic hybridization (CGH) are molecular cytogenetic methods that provide powerful supplementations of classical cancer cytogenetics. We present two examples of successful application of these new techniques in solid tumors in which basic information about specific cytogenetic aberrations had been gained previously by conventional karyotyping. In the first, testicular germ cell tumors (TGCT), FISH analysis allowed further characterization of the i(12p) marker chromosome. By CGH, chromosomal subregions that may harbor genes important for tumorigenesis or progression could be identified. In the second, uveal melanoma, CGH enabled a retrospective study in which monosomy 3 was statistically proved to be a relevant marker for poor prognosis.

Chromosome Deletion↗

PubMed1997

The significance of trisomy 8 in de novo acute myeloid leukaemia: the accompanying chromosome aberrations determine the prognosis. German AML Cooperative Study Group.

Trisomy 8 is the most frequent numerical chromosome aberration in acute myeloid leukaemia (AML). It occurs either as the sole anomaly or together with other clonal chromosome aberrations. We investigated whether accompanying chromosome anomalies influence the clinical outcome in patients with trisomy 8 and de novo AML. Since 1986, in 713 AML cases treated according to the protocols of the German AMLCG trials, chromosome analyses have been successfully performed. The overall incidence of trisomy 8 was 7.6%. Complete clinical follow-up data were available for 51 patients who were divided into three different categories: group 1: trisomy 8 as the sole cytogenetic anomaly (n = 20); group 2: trisomy 8 in addition to favourable chromosome aberrations (t(8;21)(q22;q22), t(15;17)(q22;q21), inv(16)(p13q22)) (n = 10); and group 3: trisomy 8 accompanied by other anomalies, in most cases of complex type (n = 21). Complete remission (CR) rates were 70%, 90% and 67% for groups 1, 2 and 3, respectively. Event-free survival (EFS) at 3 years differed significantly between patients with trisomy 8 only (37.5%), patients with trisomy 8 in combination with favourable aberrations (55.0%) and patients with trisomy 8 and other accompanying anomalies, mostly complex chromosome aberrations (9.0%) (group 1 v group 2: P=0.12; group 1 v group 3: P=0.005; group 2 v group 3: P=0.05). In this study patients with +8 as the sole cytogenetic anomaly had an intermediate prognosis, patients with +8 in addition to favourable chromosome aberrations maintained a good clinical outcome, and patients with +8 in combination with other abnormalities showed the worst prognosis.

Acute Disease↗

PubMed1997

Genotoxic effects of cyclopenta-fused polycyclic aromatic hydrocarbons in different types of isolated rat lung cells.

The genotoxic effects of the environmental contaminants benz[j]aceanthrylene (B[j]A), benz[l]aceanthrylene (B[l]A) and benzo[a]pyrene (B[a]P), and the metabolism of radiolabelled B[j]A, were studied using rat lung microsomes and various types of isolated rat lung cells from control and Aroclor 1254 (PCB) treated animals. All three compounds (10 or 20 microg/plate) resulted in low, but detectable, levels of His+ revertants in the Salmonella assay when plated with control lung microsomes. The two cyclopenta polycyclic aromatic hydrocarbons (CP-PAH) B[j]A and B[l]A, gave increased levels of revertants when plated with microsomes from PCB-treated animals. Clara cells, type 2 cells and alveolar macrophages isolated from control rats were exposed to B[j]A, B[l]A or B[a]P (30 microg/ml, 1 h), but neither of the cell types showed any DNA damage when measured by alkaline filter elution. However, both B[j]A and B[l]A (30 microg/ml, 2 h) caused DNA adducts in all three cell types, measured by the 32P-post-labelling technique, whereas no B[a]P adducts were detected (30 microg/ml, 2 h). The total DNA adduct levels in Clara cells, type 2 cells and macrophages exposed to B[j]A were 0.085 +/- 0.033, 0.053 +/- 0.001 and 0.170 +/- 0.030 fmol/microg DNA, respectively, whereas the total levels in cells exposed to B[l]A were 0.140 +/- 0.070, 0.140 +/- 0.030 and 0.220 +/- 0.080 fmol/microg DNA, respectively. Cells exposed to B[j]A revealed only one adduct which corresponds with the B[j]A-1,2-oxide DNA adduct. Judged from high performance liquid chromatography (HPLC) analysis using radiolabelled B[j]A (30 microg/ml, 30 min), the major metabolite formed in control microsomes was B[j]A-1,2-diol. Thus, oxidation at the cyclopenta ring appears to be the most important activation pathway for B[j]A with control rat lung cells. Exposure of lung cells to CP-PAH (30 microg/ml, 2 h) isolated from PCB pretreated rats resulted in slightly increased DNA adduct levels in Clara cells and macrophages when compared to cells isolated from control rats. Furthermore, the adduct pattern had shifted, and no apparent B[j]A-1,2-oxide adduct could be detected on the thin layer chromatography (TLC) plate. In contrast, the major metabolite formed with microsomes from PCB-treated animals was still the B[j]A-1,2-diol.

Animals↗

PubMed1996

Prognostic implications of monosomy 3 in uveal melanoma.

BACKGROUND: A high proportion of patients with uveal melanoma die of metastatic disease. In a subgroup of uveal melanomas there is the loss of one chromosome 3. To assess the prognostic implications of this genetic anomaly, we studied 54 patients for a median of 3.4 years. METHODS: 180 patients underwent primary enucleation for malignant uveal melanoma at the Ophthalmology Department of the Universitätsklinikum Essen between 1987 and 1993. Tumour material was available for chromosome analysis and DNA preparation from 69 of these patients (for logistic reasons unlikely, we believe, to introduce bias). 15 patients were excluded from our study: nine because the methods for assessment of monosomy 3 were unsuccessful; five because of insufficient information about their relapse status; one because histopathological data were incomplete. Of the 54 remaining patients, the tumours of 16 were assessed for copy number of chromosome 3 by karyotype analysis, of 30 by comparative genomic hybridisation, and of eight by both techniques. Clinical status was assessed by contact with family doctor or a clinical check up. Statistical analysis was by the log-rank test and Cox proportional-hazard regression. FINDINGS: The tumours of 30 patients had monosomy 3. 17 (57%) of these patients relapsed with metastatic disease, and the 3-year relapse-free survival rate was 50%. By contrast, of the 24 patients whose tumours had retained both chromosomes 3, none developed metastatic disease. In univariate analysis monosomy 3 was the most significant (p < 0.0001) predictor of poor prognosis in uveal melanoma, followed by tumour location (p < 0.0007) and tumour diameter (p < 0.0021). Histopathological subtype, age, sex, extrascleral growth, and tumour thickness had no additional predictive value. INTERPRETATION: In uveal melanoma, monosomy 3 is a significant predictor of both relapse-free and overall survival.

Aged↗

PubMed1996

Detection of chromosomal DNA gains and losses in testicular germ cell tumors by comparative genomic hybridization.

To extend the results of conventional cytogenetic analysis of testicular germ cell tumors (TGCTs), we applied the new molecular cytogenetic method of comparative genomic hybridization (CGH), which enables the detection of chromosomal imbalances without the need for dividing cells. DNA from II TGCTs was studied by CGH. In all tumors examined, gain of 12p, mostly of the whole p arm, could be demonstrated. However, in three tumors, an amplification of 12p material restricted to the chromosomal bands 12p11.2-p12.1 was found. Further fluorescence in situ hybridization (FISH) analysis using a yeast artificial chromosome (YAC) that was previously mapped to that region revealed multiple copies of that chromosomal segment in interphase nuclei of these tumors. This finding is an important clue to the localization of candidate protooncogenes at 12p involved in TGCTs. Gains of small chromosomal regions at 2p, 4q, 6p, and 19p were also detected recurrently. Furthermore, gains of chromosomes 8, 14, 21, and X as well as loss of chromosome 13 were frequent findings. In conclusion, CGH provides new insights into genetic alterations of TGCTs. By using CGH, chromosomal subregions could be identified that may harbor genes involved in the pathogenesis of this malignancy.

Adolescent↗

PubMed1996

Pulmonary infiltrations. Sign of severe acute pancreatitis.

CONCLUSION: Pleural infiltrates are indicative of severe acute pancreatitis and a negative prognostic parameter for the course of the disease. BACKGROUND: The purpose of this study was to determine the frequency of pulmonary infiltrates in acute pancreatitis and their importance for evaluating the severity of the disease. METHODS: Incidence and localization of pulmonary infiltrates were evaluated in 140 patients with acute pancreatitis. Chest X-ray was obtained within 24 h, and a contrast-enhanced computed tomography within 72 h after admission. Ranson's prognostic parameters were estimated within the first 48 h. RESULTS: Patients with pulmonary infiltrates (n = 36, 26%) had a significantly higher Ranson's score and pancreatic necroses more frequently than patients without this complication, plus a higher mortality rate.

Acute Disease↗

PubMed1996

Environmental chemicals relevant for respiratory hypersensitivity: the indoor environment.

The allergenic constituents of non-industrial indoor environments are predominantly found in the biologic fraction. Several reports have related biological particles such as mites and their excreta, dander from pets and other furred animals, fungi and bacteria to allergic manifestations including respiratory hypersensitivity among the occupants of buildings. Also, bacterial cell-wall components and the spores of toxin-producing moulds may contribute to the induction of hypersensitivity, but the relevance for human health is not yet determined. The knowledge regarding hypersensitivity and asthmatic reactions after exposure to chemical agents is primarily based on data from occupational settings with much higher exposure levels than usually found in non-industrial indoor environments. However, there is evidence that indoor exposure to tobacco smoke, some volatile organic compounds (VOC) and various combustion products (either by using unvented stoves or from outdoor sources) can be related to asthmatic symptoms. In some susceptible individuals, the development of respiratory hypersensitivity or elicitation of asthmatic symptoms may also be related to the indiscriminate use of different household products followed by exposure to compounds such as diisocyanates, organic acid anhydrides, formaldehyde, styrene and hydroquinone. At present, the contribution of the indoor environment both to the development of respiratory hypersensitivity and for triggering asthmatic symptoms is far from elucidated.

Air Pollution, Indoor↗

PubMed1996

The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9.

The t(7;11)(p15;p15) translocation is a recurrent chromosomal abnormality associated primarily with acute myeloid leukaemia (FAB M2 and M4). We present here the molecular definition of this translocation. On chromosome 7 positional cloning revealed the consistent rearrangement of the HOXA9 gene, which encodes a class I homeodomain protein potentially involved in myeloid differentiation. On chromosome 11 the translocation targets the human homologue of NUP98, a member of the GLFG nucleoporin family. Chimaeric messages spliced over the breakpoint fuse the GLFG repeat domains of NUP98 in-frame to the HOXA9 homeobox. The predicted NUP98-HOXA9 fusion protein may promote leukaemogenesis through inhibition of HOXA9-mediated terminal differentiation and/or aberrant nucleocytoplasmic transport.

Amino Acid Sequence↗

PubMed1996

The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.

The recurrent translocation t(8;16)(p11;p13) is a cytogenetic hallmark for the M4/M5 subtype of acute myeloid leukaemia. Here we identify the breakpoint-associated genes. Positional cloning on chromosome 16 implicates the CREB-binding protein (CBP), a transcriptional adaptor/coactivator protein. At the chromosome 8 breakpoint we identify a novel gene, MOZ, which encodes a 2,004-amino-acid protein characterized by two C4HC3 zinc fingers and a single C2HC zinc finger in conjunction with a putative acetyltransferase signature. In-frame MOZ-CBP fusion transcripts combine the MOZ finger motifs and putative acetyltransferase domain with a largely intact CBP. We suggest that MOZ may represent a chromatin-associated acetyltransferase, and raise the possibility that a dominant MOZ-CBP fusion protein could mediate leukaemogenesis via aberrant chromatin acetylation.

Acetyltransferases↗

PubMed1996

Phase I/II study with a weekly 24-hour infusion of 5-fluorouracil plus high-dose folinic acid (HD-FU/FA) in intensively pretreated patients with metastatic breast cancer.

BACKGROUND: In metastatic breast cancer patients who have had prior exposure to anthracyclines, single agents induce less than 15% and combination chemotherapy less than 20%-30% of objective responses. Therefore more active and tolerable salvage regimens are needed. PATIENTS AND METHODS: Forty-three patients with advanced breast cancer pretreated with 1-5 (median 2) different chemotherapy regimens were entered into this phase I/II trial. Treatment consisted of folinic acid (FA) (500 mg/m2, i.v., 2-hour infusion) followed by a 24-hour infusion of 5-fluorouracil (FU) which was escalated from 1.5 g/m2 (dose level (dl 1)), to 1.8 g/m2 (dl 2) to 2.1 g/m2 (dl 3). Therapy was given as outpatient treatment once weekly times 6 followed by a 2-week rest. RESULTS: HD-FU/FA was well tolerated. No dose-limiting toxicity occurred at dl 1 or 2. Only 3/32 (9%) patients had WHO grade 3/4 toxicities (gastrointestinal toxicities, hand-foot-syndrome) at dl 3. The response rate for all 32 of the patients treated at dl 3 was 41% (13/32). In the 24 patients with anthracycline-refractory disease, a response rate of 41% (10/24) was achieved. The median remission duration was 11 months and the median survival time 19 months. CONCLUSIONS: This schedule of FU/FA is a safe outpatient treatment with substantial activity in intensively pretreated breast cancer patients.

Adult↗