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Biomedical subjects

E Fritz

Publications and source records attributed to E Fritz.

At least 19 recordsLinked to original sources
PubMed2000

Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization.

Interphase fluorescence in situ hybridization (FISH) studies of chromosomal region 13q14 were performed to investigate the incidence and clinical importance of deletions in multiple myeloma (MM). Monoallelic deletions of the retinoblastoma-1 (rb-1) gene and the D13S319 locus were observed in 48 of 104 patients (46.2%) and in 28 of 72 (38.9%) patients, respectively, with newly diagnosed MM. FISH studies found that 13q14 was deleted in all 17 patients with karyotypic evidence of monosomy 13 or deletion of 13q but also in 9 of 19 patients with apparently normal karyotypes. Patients with a 13q14 deletion were more likely to have stage III disease (P =.022), higher serum levels of beta(2)-microglobulin (P =.059), and a higher percentage of bone marrow plasma cells (P =.085) than patients with a normal 13q14 status on FISH analysis. In patients with a deletion of 13q14, myeloma cell proliferation (Ki-67) was markedly increased (22.0% +/- 6.9% compared with 15.6% +/- 8.2% in patients without the deletion; P =.0008). Evaluation of bromodeoxyuridine incorporation in 5 patients revealed that both rb-1-deleted and rb-1-normal MM subpopulations were proliferative. The presence of a 13q14 deletion on FISH analysis was associated with a significantly lower rate of response to conventional-dose chemotherapy (40.8% compared with 78. 6%; P =.009) and a shorter overall survival (24.2 months compared with > 60 months; P <.005) than in patients without the deletion. Multivariate analysis of prognostic factors confirmed the independent predictive value of 13q14 deletions for shortened survival. In conclusion, deletions of 13q14 are frequently detected by interphase FISH in patients with newly diagnosed MM, correlate with increased proliferative activity, and represent an independent adverse prognostic feature in MM. (Blood. 2000;95:1925-1930)

Adult↗
PubMed2000

Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients.

BACKGROUND: After two decades of interferon (IFN) treatment in myeloma patients and many randomised clinical trials, no definite proof of its benefits exists. This meta-analysis of all available relevant published data tests the differences between IFN and control arms in a large patient population and addresses the issue of cost-effectiveness. PATIENTS AND METHODS: Meta-analysis was performed on 17 trials among 2333 patients who received IFN-chemotherapy induction treatment or chemotherapy alone and on 13 trials among 1615 patients on IFN maintenance therapy or without treatment. Response rates and parameters of published Kaplan Meier relapse-free and overall survival curves were analysed. RESULTS: Patients in IFN arms showed significantly better results in all investigated parameters: IFN-chemotherapy induction treatment yielded 6.6% higher response rates (2P < 0.002) as well as 4.8-month and 3.1-month prolongations of relapse-free (P < 0.01) and overall survival (P < 0.01), respectively. Interferon maintenance therapy lead to 4.4-month (P < 0.01) and 7.0-month (P < 0.01) prolongations of relapse-free and overall survival, respectively. Meta-analysis of all IFN trials combined resulted in 4.6-month and 3.7-month IFN-related gains in relapse-free and overall survival, respectively. As early as 6 and 12 months after the start of IFN treatment, percentages of cumulative relapse-free and overall survival were always significantly higher in IFN trial arms. IFN drug expenses for a one-year survival gain, as determined from AUCs of best-fitted Gompertz functions of IFN and control survival curves, were estimated to be US$42,482.28 for induction therapy and US$18,968.16 for maintenance treatment. CONCLUSIONS: Significantly superior outcomes were consistently found in IFN trial arms by meta-analysis of published data. These results are in accordance with a concomittantly conducted meta-analysis on individual patient data but were much easier to accrue. Taking all our results into account. i.e., the consistently significant, although limited, improvement of clinical outcomes and its acceptable cost-effectiveness, IFN treatment of patients with multiple myeloma seems worthwhile to be considered.

Cost-Benefit Analysis↗
PubMed2000

Interferon in multiple myeloma--summary of treatment results and clinical implications.

Even though interferon (IFN) has been used in myeloma treatment for more than two decades, its efficacy is still controversial. Meta-analysis of randomized trials is based either on individual patient data or on published data. We performed meta-analyses on published and reported data using, in addition to the standard method, three independent methods of evaluating Kaplan-Meier curves. Thirty randomized trials on IFN induction or maintenance treatment were meta-analyzed. Combined IFN-chemotherapy induction treatment resulted in significant increases of repsonse rates (6.6%), as well as median relapse-free (4.8 months) and overall survival (3.1 months). IFN maintenance treatment prolonged median relapse-free survival by 4.4 months, median overall survival by 7.9 months. Drug costs of IFN per 1-year survival gain were US$ 42,236.19 for induction therapy and US$ 18,114.95 for maintenance treatment. To conclude, our results a are in accordance with those obtained from individual patient data by the Myeloma Trialists' Collaborative Group. Because of the consistent, though limited, improved trial outcomes, IFN treatment should be suggested to all myeloma patients who might benefit from it.

Antineoplastic Agents↗
PubMed2000

The yeast TEL1 gene partially substitutes for human ATM in suppressing hyperrecombination, radiation-induced apoptosis and telomere shortening in A-T cells.

Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.

Apoptosis↗
PubMed2000

Predictive role of interphase cytogenetics for survival of patients with multiple myeloma.

PURPOSE: Recent metaphase cytogenetic studies suggested that specific chromosomal abnormalities are of prognostic significance in patients with multiple myeloma (MM). Because the true incidence of chromosomal abnormalities in MM is much higher than that detected by metaphase analysis, we used interphase fluorescence in situ hybridization (FISH) to determine the prognostic value of specific chromosomal aberrations. PATIENTS AND METHODS: Bone marrow plasma cells from 89 previously untreated patients with MM were studied consecutively by FISH to detect the deletions of 13q14, 17p13, and 11q and the presence of t(11;14)(q13;q32). FISH results were analyzed in the context of clinical parameters (response to treatment and survival after conventional-dose chemotherapy), and a multivariate analysis of prognostic factors was performed. RESULTS: By FISH, the deletion of 13q14 occurred in 40 patients (44.9%), deletion of 17p13 in 22 (24.7%), and 11q abnormalities in 14 (15.7%; seven with t(11;14)). Deletions of 13q14 and 17p13 were associated with poor response to induction treatment (46.9% v 77.3% in those without deletions, P =.006 and 40.0% v 73.2%, P =.008, respectively) and short median overall survival (OS) time (24.2 v 88.1 months, P =. 008 and 16.2 v 51.3 months, P =.008, respectively). Short median OS time was also observed for patients with 11q abnormalities (13.1 v 41.6 months, P =.02). According to the number of unfavorable cytogenetic features (deletion of 13q14, deletion of 17p13, and aberrations of 11q) that were present in each patient (0 v 1 v 2 or 3), patients with significantly different OS times could be discriminated from one another (102.4 v 29.6 v 13.9 months, P <.001, respectively). CONCLUSION: For patients with MM who were treated with conventional-dose chemotherapy, interphase FISH for 13q14, 17p13, and 11q provides prognostically relevant information in addition to that provided by standard prognostic factors. This observation may be considered for risk-adapted stratifications of MM patients in future clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Neurological function during long-term therapy with recombinant interferon alpha.

In 14 patients with myeloproliferative disorders associated with thrombocytosis, neurological and neuropsychological function were monitored prior to therapy with recombinant human interferon alpha (rIFN; dose 25 mU/week; range 10-35 mU/week) and after 3, 6, 9, and 12 months of treatment. No overt neurological side effects were observed except 1 case of cerebral insult, probably not treatment-related. Attention, memory function, and tapping improved significantly. The P2-N3 amplitudes of visually evoked potentials increased during normalization of platelet counts. Muscular strength and the amplitude of the compound muscle action potential of the median and peroneal nerves increased significantly in an inversely dose-related fashion. In patients with myeloproliferative disorders, long-term therapy with low to intermediate doses of rIFN does not seem to impair neurological function, but rather is associated with enhanced muscle power and the level of mental arousal.

Aged↗
PubMed1999

Human fibroblasts transfected with an ATM antisense vector respond abnormally to ionizing radiation.

ATM, the gene mutated in ataxia-telangiectasia (A-T), mediates multiple cellular responses to DNA damage. A-T homozygotes have a high risk of cancer and exhibit spontaneous chromosomal instability, and cultured A-T cells react abnormally to ionizing radiation. We have developed an ATM antisense vector that confers an A-T phenotype on normal cells. An episomal antisense vector was created that contained a 1.3 kb segment of the ATM cDNA, and was transfected into normal human fibroblasts. Intracellular levels of ATM protein were typically reduced 10-fold in antisense-expressing (GM639-46alpha) clones. GM639-46alpha clones exhibited the low threshold for radiation-induced apoptosis, low clonogenic survival, and cell cycle defects normally seen in A-T cells. Transfection with the corresponding ATM sense strand vector had no effect on the behavior of normal cells, and neither vector affected the behavior of A-T cells. Our results demonstrate that interference with ATM gene expression recreates the A-T phenotype in normal cells, and provide functional evidence linking the ATM gene to cellular DNA damage responses. The ATM antisense vector should prove a useful tool for studying ATM function in a variety of normal, mutant, and malignant cell lines.

Apoptosis↗
PubMed1998

Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy.

In multiple myeloma (MM), previous studies showed that mutations of the p53 gene are rare events in patients with newly diagnosed disease, but it is not known whether deletions of p53 are of any significance in MM. To address this question, we used interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 and investigated bone marrow plasma cells from 72 patients with MM (59 patients = 81.9% before therapy). By FISH, deletions of p53, which were found to be predominantly monoallelic, were detected in 32.8% and 54.5% of patients with newly diagnosed and relapsed MM, respectively. Karyotypes from six of the patients with a p53 deletion by FISH showed a structural abnormality of 17p in only one of them. Additional FISH studies including a distal-17p probe (specific for the D17S34 locus) provided evidence for an interstitial deletion on 17p resulting in loss of p53 hybridization signals in myeloma cells. Among all 59 patients with newly diagnosed MM, presence of a p53 deletion was associated with stage III (P = .054), but not with other laboratory and clinical parameters. Patients with a p53 deletion had significantly shorter survival time compared with those without a deletion, both from the time of diagnosis (median 13.9 v 38.7 months; P < .0001) and from the time of initiation of induction treatment consisting of conventional dose chemotherapy (median 15.9 months v median not reached at 38 months; P < .0002). On stepwise multivariate regression analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival (P = .002). We conclude that a p53 gene deletion, which can be identified by interphase FISH in almost a third of patients with newly diagnosed MM, is a novel prognostic factor predicting for short survival of MM patients treated with conventional-dose chemotherapy.

Adult↗
PubMed1998

Gene for topoisomerase III maps within the Smith-Magenis syndrome critical region: analysis of cell-cycle distribution and radiation sensitivity.

Smith-Magenis syndrome (SMS) is caused by an interstitial deletion of chromosome band 17p11.2 averaging 4-5 Mb. This deletion is likely to contain a large number of genes, each of which could potentially contribute toward the clinical phenotype. We report that the gene for topoisomerase III (hTOP3) is commonly deleted in SMS patients and maps between D17S447 and D17S258 on the short arm of chromosome 17. Cellular studies of SMS patient lymphoblasts and their respective parental cell lines were undertaken to determine the consequences of haploinsufficiency of hTOP3. Our studies indicate that hemizygosity for hTOP3 does not appreciably affect cell-cycle kinetics or activation of ionizing radiation-sensitive cell-cycle checkpoints. Furthermore, the induction of apoptosis in response to ionizing radiation in SMS and parental cells was similar. Our studies suggest that haploinsufficiency of hTOP3 does not have a major impact on the behavior of cells from SMS patients and may not play a significant role in the SMS phenotype.

Abnormalities, Multiple↗
PubMed1998

Anemia in cancer patients.

Chronic anemia in cancer patients is caused by several pathophysiologic mechanisms. Reduced numbers of erythroid progenitor cells in the bone marrow and increased levels of inflammatory cytokines, which suppress erythropoiesis, result in a lower proliferative response of the erythron to erythropoietin stimulation. Erythropoietin production by the kidney in response to tissue hypoxia is often blunted; as a result, serum erythropoietin levels may be inappropriately low with regard to the degree of anemia. Red blood cell survival may be shortened; impaired iron utilization is manifested by enhanced retention of iron in the reticuloendothelial system. Chronic anemia also may be induced by cancer treatment, such as nephrotoxic chemotherapy.

Anemia↗
PubMed1998

Anemia of cancer patients: patient selection and patient stratification for epoetin treatment.

Epoetin alfa is being used to treat patients with symptomatic anemia of cancer and to prevent or postpone chemotherapy-induced anemia in cancer treatment. As only approximately 50% of unselected anemic cancer patients respond sufficiently to epoetin alfa treatment, careful patient selection according to reliable prediction criteria is of great importance. Predictions of response to epoetin alfa treatment are based either on the degree of blunted erythropoietin response to the anemic condition or on indicators of responsiveness during the early treatment phase. The most accurate predictions of responsiveness, however, are derived from combinations of predictive factors. Combinations of synergistically acting hematopoietic growth factors, particularly epoetin alfa and granulocyte colony-stimulating factor, are beneficial to selected patients with myelodysplastic syndrome and may prolong survival in certain cases. Correction of anemia in cancer patients is particularly important because highly significant correlations have been reported between hemoglobin levels and quality of life in these patients.

Anemia↗
PubMed1997

Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype.

Ataxia-telangiectasia (A-T) is a recessive human disease characterized by radiation sensitivity, genetic instability, immunodeficiency, and high cancer risk. We previously used expression cloning to identify CAT4.5, a human cDNA that partially suppresses multiple aspects of the A-T phenotype upon transfection into cultured cells. Sequencing CAT4.5 revealed a 1.1-kb intronic fragment followed by a related ORF of 2.5 kb that encodes the near full-length ORF for hTOP3, the first mammalian topoisomerase III to be identified. Endogenous expression of hTOP3 was found in all human tissues tested. Both pCAT4.5 and an antisense hTOP3 construct were able to inhibit spontaneous and radiation-induced apoptosis in A-T fibroblasts, whereas overexpression of a full-length hTOP3 cDNA did not. We postulate that topoisomerase III may be deregulated in A-T cells and that CAT4.5 complements the A-T phenotype via a dominant-negative mechanism. Furthermore, functional correction of hyper-recombination in A-T cells by CAT4.5 supports the hypothesis that the hTOP3 topoisomerase is involved in the control of genomic stability, perhaps in concert with the Bloom or Werner syndrome DNA helicases.

Apoptosis↗
PubMed1997

Patient preferences for interferon alfa in multiple myeloma.

PURPOSE: Interferon alfa treatment in multiple myeloma marginally improves relapse-free and overall survival. Often it does so at the expense of toxicity and financial cost. If patients are unwilling or unable to participate in the decision of whether to initiate such treatment, known patient preferences can serve as guidelines for the physician. We interviewed myeloma patients in the United States to obtain information that might facilitate medical decision-making. PATIENTS AND METHODS: Three hundred fifty-five myeloma patients throughout the United States were interviewed by telephone. Without identifying interferon alfa as the treatment agent, interviewers described potential adverse effects, financial cost, and self-injection procedures. The potential benefits of four treatment choices, derived from a meta-analysis of published data, were presented as gains in remission rate (+10%), remission duration (an additional 4 and 7 months, respectively, for induction and maintenance treatment), and overall survival (an additional 3 and 6 months, respectively, for induction and maintenance treatment). Patients' choices for or against use of the unidentified substance were recorded, and interferon was subsequently disclosed as the treatment. The profiles of patients making different choices were determined using multivariate regression techniques. RESULTS: Approximately half of the patients accepted the unidentified treatment if remission and/or survival improved by at least 6 months. Accepters were younger and more likely to have used interferon. Of patients who rejected the unidentified treatment, 25% to 50% would have been willing to accept it if the benefits were > or = 12 months. Test/retest reliability of all choices, determined in 36 cancer patients, was 0.896. CONCLUSION: In multiple myeloma, interferon therapy and, by inference, other treatments with comparable features are acceptable to approximately half of the patients if a 6-month gain in relapse-free or overall survival can be expected.

Adult↗
PubMed1997

Immunohistochemical evaluation of cathepsin D expression in colorectal cancer.

Determination of cathepsin D has been proven to be prognostically relevant in breast cancer. Cathepsin D, a lysosomal proteinase, is suggested to be causally involved in tumor invasion. In this study we investigated cathepsin D expression immunohistochemically in 106 colorectal adenocarcinomas with the intention to evaluate its prognostic significance in this type of cancer. The majority of colorectal adenocarcinomas (93/106) stained positive for cathepsin D, while normal colon was almost completely negative. A trend toward stronger staining intensity was found in Dukes' stage C and D tumors (p < 0.1), but cathepsin D expression was found to have no influence on survival in this tumor type nor did it correlate with other known prognostic factors, e.g., histological differentiation, lymph vessel invasion, or rate of proliferation. Staining of lymph node metastases did not differ significantly from that of their primary tumors. Stronger staining intensity of tumor tissue in the neighborhood of inflammatory cells may be due to paracrine activation.

Adenocarcinoma↗
PubMed1996

Maximal androgen blockade in combination with methotrexate for treatment of metastatic prostate cancer.

Recently attention has been focused on the optimal timing of chemotherapy within the treatment regimen for patients with metastatic prostate cancer, i.e., hormonal manipulation, preferably maximal androgen blockage (MAB) consisting of chemical/surgical castration followed by treatment with antiandrogens. We have conducted a randomized prospective clinical trial, investigating the efficacy and toxicity of MAB (orchiectomy followed by flutamide therapy) alone as compared to MAB combined with methotrexate (MTX, 50 mg/m2/week) in 53 patients with newly diagnosed stage IV(M1) prostatic cancer (UICC TNM Classification 1987). The observed remission rates (complete + partial) of 42.3% in the MAB + MTX arm and 29.6% in the MAB arm did not differ significantly. The response rates (complete + partial + stable disease) of 73.1% and 66.7% for MAB + MTX and MAB respectively, also showed no significant difference. Neither progression-free survival (median 18/5 and 23.8 months for MAB + MTX and MAB, respectively) nor overall survival (median: 37.4 and 36.1) months in the MAB + MTX and MAB arm, respectively) could be improved by the addition of MTX to MAB Only the extent of metastatic pain reported by the patients was consistently less under MAB + MTX than under MAB alone (P<0.1). Both treatment regimens were well- tolerated with slightly more undesirable effects in the MAB + MTX arm. Our results do not provide evidence for the achievement of marked gains by combining chemotherapy with endocrine therapy in newly diagnosed patients with stage IV (M1) prostate cancer.

Aged↗
PubMed1995

Recombinant human erythropoietin for the correction of cancer associated anemia with and without concomitant cytotoxic chemotherapy.

BACKGROUND: Chronic anemia is a common complication in patients with cancer, especially in those with advanced disease or who are under intensive chemotherapy. Because homologous blood transfusions involve some hazards, the safety and efficacy of recombinant human erythropoietin (r-HuEPO) in the treatment of anemic patients with cancer with and without concomitant chemotherapy were studied. METHODS: One-hundred two cancer patients with hemoglobin less than 11 g/dl, ferritin greater than 30 micrograms/l, and creatinine < 220 mumol/l were enrolled in the study, 94 were eligible for efficacy evaluation. Sixty-eight patients received chemotherapy (CT group) and 26 had no cytotoxic cancer treatment (NT group). Recombinant human erythropoietin was administered subcutaneously at a dose of 150 U/kg three times per week for 6 weeks; in nonresponders the dose was doubled for the subsequent 6 weeks. Response was defined as the achievement of a hemoglobin increase of 2g/dl. Clinical and laboratory parameters, including serum erythropoietin (EPO) levels, performance status, and quality of life, were investigated at baseline and monitored at regular intervals thereafter. RESULTS: Response was achieved by 52% and 62% of CT and NT patients, respectively. The highest response rates were observed in patients with lung cancer or with a histology of squamous cell carcinoma (both 80%). In responding patients, the symptoms of anemia subsided. They no longer needed blood transfusions after 4 weeks of therapy; and both their performance status and quality of life improved significantly. The NT patients achieved slightly more favorable results on lower weekly doses: 450 U/kg/week in NT versus 570 U/kg/week in CT patients. Serum EPO levels were higher in nonresponders at baseline and further increased during the course of treatment. Recombinant human erythropoietin was well tolerated by all patients. CONCLUSION: This multicenter study in a large patient collective shows that r-HuEPO treatment represents a safe and effective means to increase the red cell mass and eliminate the need for blood transfusions in approximately 50% of the patients with chronic anemia of cancer. Responding patients not only have increased levels of hemoglobin, but their performance status also improves significantly, and they enjoy a significantly enhanced quality of life.

Adult↗
PubMed1995

Quantification of Coxiella burnetii by polymerase chain reaction (PCR) and a colorimetric microtiter plate hybridization assay (CMHA).

A colorimetric microtiter plate hybridization assay (CMHA) for the quantitative determination of Coxiella burnetii DNA after amplification by externally controlled polymerase chain reaction (PCR) is described. The quantification assay is based on an enzyme linked immunosorbent assay (ELISA) format. Cloned DNA, representing a sequence complementary to an internal part of the diagnostic amplicon, was noncovalently attached to the wells of a microtiter plate. Biotinylated PCR product was hybridized to the immobilized capture probe. Bound product was detected via streptavidin horse-radish peroxidase. The devised nonisotopic technique allows specific, rapid, and convenient quantification of C. burnetii DNA. Additionally, it is compatible with standard laboratory ELISA equipment, making this assay amenable to automation and permitting processing of large sample numbers.

Bacterial Proteins↗