Biomedical subjects

R Becher

Publications and source records attributed to R Becher.

At least 37 records · Page 2Linked to original sources

PubMed1996

Differential distribution of Met and epidermal growth factor receptor in normal and carcinogen-treated rat liver.

Transforming growth factor-alpha (TGF-alpha) and hepatocyte growth factor (HGF) are strong hepatocyte mitogens and important regulators of liver regeneration. The TGF-alpha receptor EGFr appears primarily to mediate a proliferative signal, whereas mitogenic, motogenic, and morphogenic effects have been attributed to activation of the HGF receptor Met. We have studied the localization of Met and EGFr in normal and carcinogen-treated rat livers. Oval cells and preneoplastic lesions were induced by diethylnitrosamine initiation, followed by promotion with 2-acetylaminofluorene combined with a partial hepatectomy. Different liver cell populations and their receptor expression were characterized by two-color immunofluorescence and confocal laser scanning microscopy. Hepatocytes were detected by keratin K8 staining, and oval cells and bile ducts were recognized by keratin K19 expression. Enzyme-altered preneoplastic lesions ere identified by expression of placental glutathione S-transferase (GST-pi). Staining for these cellular markers was combined with immunodetection of EGFr and Met. Normal liver exhibited strong staining for EGFr in hepatocytes, whereas blood vessels, bile ducts, and some sinusoidal cells were Met-positive. In carcinogen-treated livers, oval cells showed Met but not EGFr immunostaining. GST-pi-positive foci displayed EGFr immunostaining at a similar intensity as surrounding hepatocytes, whereas Met was not detected. Our data indicate that putative liver cells (oval cells) have a growth receptor phenotype similar to that of bile ducts, whereas preneoplastic live lesions appear hepatocyte-like. These results indicate that the preferential proliferation of preneoplastic liver lesions compared to surrounding hepatocytes is not associated with an altered EGFr or Met phenotype.

Animals↗

PubMed1996

Acute myeloid leukemia with translocation (8;21). Cytomorphology, dysplasia and prognostic factors in 41 cases. AML Cooperative Group and ECOG.

The translocation t(8;21) is one of the most common structural aberrations in acute myeloid leukemia (AML). Excellent response rates and a better relapse-free survival have been described. We analyzed specific morphologic and cytochemical features including dysplasia and other prognostic factors in 41 patients with AML and t(8;21) who underwent aggressive chemotherapy in two national cooperative group studies. Five patients were classified as AML M1 and 36 as AML M2 according to the FAB criteria. Auer rods were detected in 28 patients (68%), however in only 16 patients were they "thin and elongated" as has been described as typical for t(8;21). The presence or absence of Auer rods did not appear to be associated with disease-free survival in this sample. Dysgranulopoiesis was detected in 31/41 patients (90%); five of these patients additionally had dyserythropoiesis (12%). In six cases (15%), dysmegakaryopoiesis was seen in combination with dysgranulopoiesis. Only one patient had trilineage dysplasia. Dysplastic features had no influence on prognosis. Additional cytogenetic abnormalities were detected in 24/41 patients. Twelve male (48%) and four female (25%) had a loss of a sex chromosome. This was correlated with a better disease-free survival (p = 0.039). The complete remission rate (CR) to chemotherapy was 90%. The early death rate was 10%. Disease-free survival of the complete responders was 60% at two years with no relapses observed in ten patients with 2-6 years of follow up. This favorable disease-free survival was observed with a variety of post-induction regimens and t(8;21) had been detected as an independent factor for good prognosis. The need for very intensive therapy, such as bone marrow transplantation, is unanswered at this time.

Adult↗

PubMed1996

BCR rearrangement without juxtaposition of ABL in pre-T acute lymphoblastic leukaemia.

The incidence and clinical relevance of the Philadelphia (Ph) translocation t(9:22) (q34:q11) in T-lineage acute lymphoblastic leukaemia (ALL) are unknown. We describe a patient with pre-T-ALL and a clonal 22q-aberration detected by conventional cytogenetics, suggestive of a Ph translocation. However, fluorescence in situ hybridization (FISH) using BCR and ABL probes revealed a translocation with one breakpoint within the BCR gene on chromosome 22 without juxtaposition of ABL on chromosome 9. We discuss the diagnostic and possible pathogenetic implications of this Ph-like chromosomal aberration.

Chromosomes, Human, Pair 22↗

PubMed1996

Epirubicin and ifosfamide in metastatic breast cancer.

In a randomized, phase II trial, we evaluated the effectiveness of continued chemotherapy with epirubicin/ ifosfamide versus unmaintained treatment interruption in advanced metastatic breast cancer. Three hundred fifty-seven patients were enrolled and 331 were evaluable for response. Complete response was achieved in 25 patients (8%) and partial response in 121 patients (37%). Pretreatment status correlated significantly with response (complete and partial response). While 54% of unpretreated patients responded, only 42% of the patients responded who had been pretreated with adjuvant chemotherapy and 33% who had been pretreated in the metastatic stage of disease; 69 patients (21%) had disease progression. Of 11 patients pretreated in both the adjuvant and metastatic setting, only two responded. Toxicity of treatment was mild, with leukopenia being the treatment-limiting factor. Thrombocyte levels were not altered significantly by treatment. Thus, there seems to be room for dose escalation using granulocyte colony-stimulating factor. There was no considerable cardiotoxicity, central nervous system toxicity, or cystitis observed. The low rate of cardiotoxicity appeared to be related to dose fractionation of epirubicin. After randomization of patients to treatment interruption versus continuation of chemotherapy, a longer relapse-free survival was observed for patients who continued chemotherapy (mean relapse-free survival, 2+ months); however, this did not translate into prolonged survival. The cumulative scores of toxicity and quality of life parameters showed increasing superiority for treatment interruption. Therefore, a strategy of treatment until maximum response and subsequent treatment interruption seems to be superior to treatment continuation.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

The use of isolated lung cells in in vitro pulmonary toxicology: studies of DNA damage, apoptosis and alteration of gene expression.

Isolated lung cells constitute a valuable system for studying mechanisms involved in chemically induced toxicity in the lung. Different lung cells isolated from various species may be studied. Bronchiolar Clara and alveolar type 2 cells produce important lung-specific proteins, hold a major role in the metabolism of xenobiotics and serve as progenitor cells for other lung cell types. They are possible target cells in lung carcinogenesis. Alveolar macrophages play an important role in lung defence and in inflammatory responses. In the present study we have characterised chemically induced DNA damage, apoptosis, changes in cell cycle progression, transformation and alterations in gene expression in these specific lung cells isolated from rat, rabbit and human. Major differences between the cell types and the various species in the induction of DNA damage by chemicals were found, as measured by the 32P-postlabelling and alkaline filter elution techniques. Benzo(a)pyrene and hydrogen fluoride were found to induce apoptosis in the isolated cells as measured by microscopical analysis and flow cytometry. The function of various important tissue- or cell type specific proteins (CYP 2B1, Clara cell protein) and/or cellular signal transduction pathways constitute important targets that may be affected by exposure to toxic compounds. Using immunological and molecular techniques the differential expression of specific proteins/RNAs and their activity can be studied. Among other proteins, c/ebp is involved in the regulation of transcription at the end of signal pathways. The protein is differentially expressed in rat lung cells and thus could be suitable for studying differential toxic effects in various lung cells. In humans, bronchoalveolar lavage (BAL) fluid from human volunteers can be readily obtained and examined after exposure to different chemical compounds. An increase in the percentage of CD3-positive cells (T-lymphocytes) was found after exposure to hydrogen fluoride. The number of certain cell types and cytokines may be used to estimate the degree of inflammatory reaction. In conclusion, the use of in vitro data including the use of specific, primary human lung cell types may contribute considerably to the quality of risk assessment, together with in vivo data from animals and man.

Animals↗

PubMed1995

[Children's indoor environment. A study of Norwegian dwellings].

The indoor environment was investigated in 112 Norwegian dwellings where either healthy children or children with asthma were living. Compared with the official guidelines for indoor air quality, more than 50% of the children's rooms had unacceptable indoor air. Continuous monitoring of carbon dioxide showed unacceptably high levels in 69% of the children's bedrooms at night. Levels of volatile organic compounds exceeded the guideline in 53% of the dwellings. More than 60% of the children were exposed to environmental tobacco smoke, as identified by nicotine in hair and cotinine in urine samples. Levels of house dust mites in excess of the guideline were found in 45% of the dwellings. The results indicated a need to improve the indoor environment in the homes of children.

Air Microbiology↗

PubMed1995

Cytogenetics of twelve cases of uveal melanoma and patterns of nonrandom anomalies and isochromosome formation.

We present cytogenetic data of 12 new cases of uveal melanoma. One case showed a hypotetraploid chromosome number; the others were near-diploid. Underrepresentation or monosomy of chromosome 3 as well as multiplication of chromosomes 8, 8q, or regions of 8q was found in five cases. Both anomalies were observed in three cases. In two of these, multiplication of 8q resulted from isochromosome formation. The smallest multiplicated region seemed to be 8q23-24-->qter. Chromosome 6 anomalies were found in five cases without monosomy 3. Aberrations of chromosome 21 were seen in five cases and found to be the only cytogenetic change in two of them. These anomalies may define a subgroup of uveal melanoma. An anomaly of chromosome 1 was found in three cases. Anomalies of other chromosomes were detected in at most two cases each. Nonclonal centromeric or telomeric associations were seen in one case and different nonclonal ring chromosomes in another. Underrepresentation of chromosome 3 was seen exclusively in tumors with ciliary body involvement, while anomalies of chromosome 6 were detected only in pure choroideal melanomas. A review of the published cytogenetic data of untreated uveal melanoma supports our finding that monosomy 3 is frequently associated with multiplication of 8q but rarely with anomalies of chromosome 6, whereas the opposite is true for tumors with disomy 3, and that isochromosomes are closely associated with monosomy 3. Thus, cells with monosomy 3 seem to predispose to isochromosome formation.

Adult↗

PubMed1995

Painless acute pancreatitis mimicking pancreatic carcinoma.

Painful acute pancreatitis masking pancreatic carcinoma and painless acute pancreatitis with shock or coma as leading symptoms have been described before. We report a first case of almost-painless pancreatitis mimicking pancreatic carcinoma with spontaneous normalization of symptoms and biochemical as well as imaging procedure findings.

Acute Disease↗

PubMed1995

Acute toxicity of carbamide peroxide and a commercially available tooth-bleaching agent in rats.

Previous studies have indicated that tooth-bleaching agents contain potentially hazardous chemicals. The present study evaluates the acute toxicity of a commercially available tooth-bleaching agent and carbamide peroxide, which is the active bleaching ingredient. Rats were dosed by stomach gavage, i.e., via a stomach tube, with 5, 15, and 50 mg carbamide peroxide/kg body weight and 150 and 500 mg tooth-bleaching agent/kg body weight, corresponding to 15 and 50 mg carbamide peroxide/kg body weight. Animals were killed after either one or 24 h. Autopsies were performed, and the distal part of the esophagus and the stomach were removed and processed for light microscopy investigation. Liver and kidney were evaluated histologically in animals killed after 24 h. Carbamide peroxide gave dose-dependent ulcerations of the gastric mucosa, with the 15 mg/kg body weight as the lowest observed effect level. The lesions were clearly visible after one h and seemed to be healing after 24 h. The ulcerations of the gastric mucosa were more pronounced after exposure to the tooth-bleaching agent than those observed after a comparable dose of carbamide peroxide. This may be attributed to the hydrophobic gel and the content of a carbopol (which increases the tissue adherence and retards the release of oxygen) in the bleaching agent. No apparent injury was observed in livers and kidneys. An exposure limit based on the lowest observed effect level (15 mg carbamide peroxide/kg body weight) and a safety factor of 100 were established and utilized in a risk assessment which indicated that daily human exposure during a bleaching procedure may come close to or even exceed this limit.

Acrylic Resins↗

PubMed1995

Phase I/II study with paclitaxel in combination with weekly high-dose 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer: an interim analysis.

Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/II trial in outpatients: high-dose 5-FU (24-hour infusion)/FA (2-hour infusion preceding 5-FU) is given for 6 weeks (days 1, 8, 15, 22, 29, and 36), with paclitaxel (3-hour infusion) administered on days 1 and 22; 2 weeks' rest follows. Folinic acid 500 mg/m2 was administered throughout; the respective 5-FU doses for dose levels 1 through 3 were 1.5, 1.8, and 2.0 g/m2 with paclitaxel 135 mg/m2. Dose level 4 (500 mg/m2 FA, 2.0 g/m2 5-FU, and 175 mg/m2 paclitaxel) was chosen for phase II evaluation. To date, 46 patients with bidimensionally measurable disease (four each at dose levels 1, 2, and 3, and 34 at dose level 4) have been entered. The 12 patients treated at dose levels 1 through 3 were titrated to level 4 doses when phase II began; 35 patients are evaluable for response. The median age is 46 years, and the median number of metastatic sites is 2.5. Fourteen patients had received adjuvant chemotherapy, nine chemotherapy for metastasis, and 23 chemotherapy both adjuvantly and for metastasis. Of 31 anthracycline-treated patients, 27 had anthracycline-resistant disease. No dose-limiting toxicity appeared until dose level 4, when grade 3 or 4 leukopenia and diarrhea occurred in 15 and eight, respectively, of 108 cycles. Mild to moderate mucositis, hand-foot syndrome, myalgia, and nausea/vomiting occurred in 20% to 40% of cycles. One (3%) of the 35 patients had a complete response, 18 (51%) had partial responses, 14 (40%) had stable disease, and two (6%) had disease progression. Eleven (55%) of 20 evaluable patients with anthracycline-resistant disease responded (95% confidence interval, 34% to 76%). Median time to maximum response was 2 months, and the remission duration was 8+ months. Median survival time has not been reached. Paclitaxel and weekly high-dose 5-FU/FA was well tolerated and highly effective, even in patients with anthracycline-resistant metastatic breast cancer. The regimen can be administered safely to outpatients.

Adult↗

PubMed1994

Two subclones in a case of uveal melanoma. Relevance of monosomy 3 and multiplication of chromosome 8q.

Monosomy 3 and multiplication of 8q are nonrandom findings in uveal melanoma. We present a case in which two subclones could be detected. Both had monosomy 3 in common. Furthermore, a multiplication of chromosome 8 material was also seen in both subclones. However, it was based on different kinds of aberrations and was accompanied by further anomalies, such as loss of a Y-chromosome, an additional chromosome 7, and an additional marker chromosome, in only one clone. This finding allows some insight into the relevance of the most frequently found anomalies of chromosome 3 and 8 in uveal melanoma. As monosomy 3 occurred before any subclone differentiation, it must be an early, if not primary, event in the genesis of this tumor. Multiplication of chromosome 8, specifically of 8q, however, may contribute to the clonal evolution of this tumor.

Aged↗

PubMed1994

[Biological pollution of indoor air].

Biological pollution of indoor air can consist of viruses, bacteria, fungi, fungal spores, mites, dander and metabolic products from the microorganisms. The occurrence of such pollution can occasionally cause building-related adverse health effects. Allergens produced by house dust mites and in the dander of furred domestic animals are generally regarded to be among the most important causes of disease episodes in atopic individuals. Bacteria and fungi as such cause building-related disease more rarely. An exception is respiratory infections caused by Legionella bacteria. Other possible health effects of biological indoor air pollution have been suggested, but the data are inconclusive.

Air Microbiology↗

PubMed1994

Chromosomal gains and losses in uveal melanomas detected by comparative genomic hybridization.

Eleven uveal melanomas were analyzed using comparative genomic hybridization (CGH). The most abundant genetic changes were loss of chromosome 3, overrepresentation of 6p, loss of 6q, and multiplication of 8q. The smallest overrepresented regions on 6p and 8q were 6pter-->p21 and 8q24-->qter, respectively. Several additional gains and losses of chromosome segments were repeatedly observed, the most frequent one being loss of 9p (three cases). Monosomy 3 appeared to be a marker for ciliary body involvement. CGH data were compared with the results of chromosome banding. Some alterations, e.g., gains of 6p and losses of 6q, were observed with higher frequencies after CGH, while others, e.g., 9p deletions, were detected only by CGH. The data suggest some similarities of cytogenetic alterations between cutaneous and uveal melanoma. In particular, the 9p deletions are of interest due to recent reports about the location of a putative tumor-suppressor gene for cutaneous malignant melanoma in this region.

Adult↗

PubMed1994

Absence of N-ras mutations in myeloid and lymphoid blast crisis of chronic myeloid leukemia.

Mutations within N-ras oncogene codons 12, 13, and 61 occur in approximately 25-30% of patients with acute nonlymphocytic leukemia and at a lower frequency (6-20%) in patients with acute lymphocytic leukemia. Moreover, N-ras mutations have been described in patients with chronic myeloid leukemia (CML) in blast crisis but have not been observed during the chronic phase of the disease. In view of the morphological and clinical similarities between acute leukemia and the blast crisis of CML, the question was raised whether the presence of N-ras mutations is associated with the phenotype of acute leukemia. We investigated leukemic cells from 100 patients with CML for the presence of N-ras mutations in the mutational hot spot codons. The cases analyzed included 87 diagnosed with different types of blast crisis and 13 cases in accelerated or chronic phase of the disease. Fragments from N-ras exons I and II containing the codons of interest were amplified by polymerase chain reaction and analyzed for the presence of point mutations by three different technical approaches, including specific oligonucleotide hybridization, direct sequencing, and single-strand conformation polymorphism analysis. N-ras mutations were not detected in any of the CML patients investigated. Only one patient, in whom the initial diagnosis of CML-blast crisis had been revised to chronic myelomonocytic leukemia, displayed an N-ras mutation within codon 13. Our data strongly suggest that N-ras mutations do not play a role in myeloid or lymphoid blast crisis of CML.

Base Sequence↗

PubMed1994

No parallel between the biochemical course of acute pancreatitis and morphologic findings.

The clinical, biochemical (serum enzymes), and morphologic course of acute pancreatitis was studied in 83 consecutive patients from time of admission until 3 months after discharge. At discharge, all 75 surviving patients had no more symptoms of acute pancreatitis, even though amylase (in 11%) and lipase (in 25%) were still elevated, computed tomography (CT) findings still abnormal (in 81%), and necrosis amounting up to 50% of the gland still present (in 24%). There was no significant correlation between serum enzymes and CT findings at discharge. Three months later, with the exception of one patient with an acute relapse of the disease, all followed-up patients were free of symptoms and had normal serum amylase, whereas lipase was still elevated in 10%, and CT findings abnormal in 23%. Subsiding symptoms provided a more accurate picture of the patients' recovery than the biochemical markers, and even more so that the morphologic findings.

Acute Disease↗

PubMed1994

Presence of re-appearance of BCR-ABL-positive cells years after allogeneic bone marrow transplantation for chronic-phase chronic myelogenous leukemia in patients in hematological remission.

Allogeneic bone marrow transplantation (BMT) is considered to be the only curative therapy for chronic myelogenous leukemia (CML). The cytogenetic marker of CML, the Philadelphia (Ph) chromosome, or the molecular alterations caused by the BCR-ABL gene fusion can be used to monitor the success of treatment. A sensitive two-step reverse-transcription polymerase chain reaction (RT-PCR) was done to score BCR-ABL-mRNA-positive leukemic cells in frozen bone marrow samples of 15 CML patients retrospectively. These patients, 4 females, 11 males, had undergone BMT during the first chronic phase after a preparative regimen consisting of total body irradiation (TBI) and cyclophosphamide; median age at BMT was 38 years (range 20-49 years). At the time of this study, 8 patients were in cytogenetic and/or clinical remission. Seven patients relapsed after BMT; all presented with Ph-chromosome-positive metaphases and BCR-ABL-positive cells at the time of relapse. In only 1 patient in hematologic remission was no positive PCR analysis obtained in the two samples tested. However, 5 patients have remained or became Ph-chromosome and/or PCR-positive after BMT without clinical symptoms of disease. In samples from another patient, transient presence of leukemic cells was observed only early after BMT. Clinically, these patients were relapse free at days 3,055, 2,581, 2,252, 1,846, 1,839, 1,747, and 1,173 after BMT, respectively. Based on these data, the presence of single BCR-ABL-positive cells > 1 year after BMT has no prognostic significance.

Adult↗

PubMed1994

Bcr-abl-positive and -negative clonogenic cells in CML patients undergoing long-term interferon treatment.

Bone marrow (BM) and peripheral blood cell (PBC) samples of 11 Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) patients in long-lasting hematologic remission induced by interferon (IFN) treatment were examined for the presence of leukemic hematopoietic precursor cells. Southern blot analysis revealed residual leukemic cells in BM samples of four patients, whereas seven patients showed no aberrant bands. Reverse transcription polymerase chain reaction (RT-PCR), however, amplified bcr-abl-specific cDNA in unfractionated BM or PBC samples in all 11 patients. The patients demonstrating bcr rearrangements in Southern blots had either a mosaic pattern (three patients) of bcr-abl-negative and positive colony-forming precursors (CFU-GEMM, BFU-E, CFU-GM, CFU-Mega), or all colonies were derived from leukemic precursors (one patient). However, in soft agar cultures of four patients without aberrant bands in Southern blots, only colonies without amplifiable bcr-abl transcripts were detectable. In another patient, few bcr-abl-positive colonies were found after 44 months of treatment, but not after 53 and 56 months of therapy. In these patients, therefore, residual disease detectable by PCR analysis of unfractionated cell samples does not appear to reside in the colony-forming cell compartment. The prognostic implications of these observations and the nature of the remaining bcr-abl-positive cells within unfractionated cell samples remain to be determined.

Adult↗

PubMed1994

Pleural effusions: a new negative prognostic parameter for acute pancreatitis.

OBJECTIVE: To evaluate the incidence, localization, and size of pleural effusions in 133 patients with acute pancreatitis. METHODS: A contrast-enhanced computed tomographic scan was prospectively obtained within 72 h after admission. RESULTS: Patients with pleural effusions (66 = 50%) had significantly more severe morphological changes of the pancreas and necroses (independent of the size and localization of the effusions and etiology of the acute pancreatitis), more often had a pancreatic pseudocyst, and had a higher mortality rate than patients without this complication. CONCLUSION: Pleural effusions are indicative of severe acute pancreatitis and are a negative prognostic parameter for the course of the disease.

Acute Disease↗