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W Hiddemann

Publications and source records attributed to W Hiddemann.

448 records · Page 25Linked to original sources
PubMedDate not supplied

[Detection of aberrations in the karyotype of children with acute leukemia: a comparative analysis of cytogenetics and flow cytophotometry].

In the present study a comparative analysis of DNA flow cytometry and cytogenetics was performed in 257 children with acute leukemias to evaluate the comparability of both techniques for the detection of karyotype aberrations. DNA aneuploidies were detected in 88 (34%) patients while cytogenetic anomalies were revealed in 96 (37%) cases. From 76 patients (30%) with cytogenetically inevaluable metaphases 26 (35%) expressed aneuploid DNA stemlines. 67 (79%) of the 85 patients with normal karyotypes or normal modal chromosome numbers had a DNA index of 1.0 while DNA aneuploidies were identified in 18 cases (21%). 4 of 30 patients (13%) with pseudodiploid karyotypes revealed aneuploid DNA stemlines. While aberrations of the chromosome number by 1-3 chromosomes were combined with DNA aneuploidies in 9 of 35 cases (26%) only, all 31 patients with higher numeric chromosome changes also had aneuploid DNA stemlines. These data indicate that cytogenetics and DNA flow cytometry are complimentary methods for the detection of karyotype aberrations and should therefore be applied simultaneously.

Child↗
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[DNA aneuploidy in children with acute leukemia: I. Incidence and clinical significance within the scope of the BFM studies].

Analyses of the cellular DNA content were carried out in 226 patients with acute lymphoblastic leukemia (ALL) and in 61 children with acute myeloid leukemia (AML) to assess the incidence and clinical significance of DNA aneuploidies. All children were treated within the BFM studies ALL 79/81 and 81/83 as well as AML 78 und 83. DNA aneuploidies were identified in ALL in 39,8% and in AML in 36,1% of cases. Within the ALL group a significantly higher rate of aneuploid DNA stemlines was observed for non-T/non-B ALL with 44,1% as compared to T-ALL with 14,3% (p less than 0,01). In AML the morphologic subgroups M 1/2 revealed a lower frequency of 21,7% DNA aneuploidies than M 4/5 leukemias with 44,4%. The rates of complete remissions were not different between patients with and without DNA aneuploidy neither in ALL nor in AML. In the study ALL 79/81, however, a tendency towards longer remissions for patients with DNA aneuploidy was found (p = 0.053) which could not be confirmed at present by the study ALL 81/83. In both ALL trials patients with the lowest pretherapeutic risk-score revealed the highest rate of aneuploid DNA stemlines.

Aneuploidy↗
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[DNA aneuploidy in children with acute leukemia: II. Correlation with the phenotype of blasts, clinical picture and course of disease].

Analysis of the cellular DNA content was carried out in 162 children with ALL and 34 children with AML admitted to the university children's hospital Münster between 1979 and 1984. DNA aneuploidies were identified at a similar frequency in ALL (40%) and AML (44%). However, the degree of DNA aneuploidies (DNA-index) was significantly lower in aneuploid AML (median 1.09) than in aneuploid ALL (median 1.19). We found a significantly lower incidence of DNA-aneuploidies in T-ALL (3/21; 14%) as compared to non-T/non-B-ALL (60/137; 44%). No differences were found between children with and without DNA aneuploidy in PAS score and TdT activity. In non-T/non-B-ALL DNA aneuploidy is highly correlated with a long pretherapeutic history, with a low WBC and blast count and with a low serum LDH. Under the conditions of the ALL protocols BFM-79/81 and 81/83 no difference in the remission rate was found between the two patient groups. However, more relapses occurred so far within the group of children without DNS aneuploidy.

Acid Phosphatase↗
PubMedDate not supplied

European Surveillance of Infections in Cancer Patients--ESIC.

Major advances in cancer therapy result from development of multidrug chemotherapy regimens. Besides death from tumor progression, infections are currently one of the major causes of mortality and morbidity. Because of the risk of complications and mortality, the treatment for febrile neutropenia is admission to hospital and administration of broad-spectrum antibiotics. Response rates of initial antimicrobial treatment vary considerably (40-92%). Due to the heterogeneity of populations in randomized studies, comparison of efficacy and identification of risk factors is limited. This is the main reason why the European Society of Biomodulation and Chemotherapy (ESBiC) is conducting a surveillance study that concentrates more on the evaluation of risk factors than on the therapeutic outcome of prospective randomized antimicrobial regimens: European Surveillance of Infections in Cancer Patients (ESIC). The present contribution is to determine which cancer patients are at low risk for fever, and can benefit from first-line treatment with treatment options such as monotherapy as well as on an outpatient basis.

Anti-Bacterial Agents↗
PubMedDate not supplied

Phase II evaluation of 5-fluourouracil plus folinic acid and alpha 2b-interferon in metastatic colorectal cancer.

Biochemical modulation of 5-fluorouracil (5-FU) by folinic acid (FA) increases the response rate in patients with metastatic colorectal cancer compared to 5-FU alone. Phase II trials also demonstrated increased efficacy when interferon was added to 5-FU. In two consecutive trials, 76 patients were treated on days 1-5 with FA 200 mg/m2 plus interferon 5 x 10(6) U/m2 and 5-FU 350 mg/m2 as intravenous bolus injection (n = 33, regimen A) or 5-FU 500 mg/m2 as 2-hour infusion (n = 43, regimen B), repeated every 3 weeks with individual 5-FU dose escalation in steps of 50 (regimen A) or 100 mg/m2 (regimen B). In regimen A 5-FU dose reduction to 300 mg/m2 due to toxicity was necessary in 49% of the patients; in regimen B a 5-FU dose of 600 mg/m2 or above was tolerated by 70% of the patients. Dose-limiting toxicity was severe mucositis and/or diarrhea. Objective responses were observed in 5 of 33 patients (15%) in regimen A (3-28%, 95% confidence interval) and 7 of 41 patients (17%) in regimen B (5-29%, 95% confidence interval). Median time to progression was 4.7 and 4.8 months, and median survival 9.9 and 11.4 months for regimens A and B, respectively. Prolonged 5-FU administration over 2 h allows the administration of a higher 5-FU dose compared to bolus injection with no apparent improvement in antineoplastic efficacy. The addition of interferon to the combination of 5-FU plus FA in this dose and schedule does not seem to improve the response rate but appears to increase treatment toxicity.

Adult↗
PubMedDate not supplied

Expression of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P in epithelial tumors of the kidney and the urinary bladder.

The differential expression of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P was investigated in 11 renal cell carcinomas and 11 urinary bladder carcinomas and compared with their expression in non-neoplastic tissue preparations from the kidney (n = 9) and urinary bladder (n = 12). The glycoproteins were demonstrated immunohistologically in frozen sections and additionally, in some cases, in paraffin sections. MCA and BW 495/36-P positive cells were present in all preparations except for a grade I transitional cell carcinoma of the bladder, in which no MCA-expression could be detected. In the non-neoplastic renal tissue mainly the cells of the distal tubuli were stained by the antibodies against these two glycoproteins. Carcinoma cells of the kidney and of the urinary bladder showed an increased expression of both epitopes. CA 125, in comparison, was strongly expressed in 3 of the 11 urinary bladder carcinomas investigated but could only be shown in a few cells of a single renal cell carcinoma. Normal renal tissue showed no and the urinary bladder only very isolated CA 125 positive epithelial cells. Apart from this distribution, strong staining of the connective tissue fibers with CA 125 antibody was seen in all paraffin sections, but not in the frozen sections. This leads to the supposition that in these structures there is a CA 125 cryptantigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Tumor-Associated, Carbohydrate↗
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Immunocytochemical determination of the tumor-associated glycoproteins MCA, CA 125 and BW 495/36-P in urine of patients with epithelial tumors of the kidney and urinary bladder.

Pre-operative and, in some cases, post-operative urine samples from 29 patients with renal cell or urinary bladder carcinoma were compared to samples from 24 healthy persons and 10 patients with nephrolithiasis and 9 patients with other benign disorders of the efferent urinary tract. The specimens were examined for the presence of MCA, CA 125 and BW 495/36-P expressing epithelial cells. The urine concentrations of the soluble antigens MCA and CA 125 were determined simultaneously in urine samples from 35 patients with renal cell or urinary bladder carcinoma, 10 patients with cystitis and 30 healthy individuals. MCA and BW 495/36-P expressing epithelial cells were significantly increased in all pre-operative urine samples of the tumor patients compared to the group of healthy persons. This increase was also seen with CA 125-positive cells in patients with bladder carcinoma, not however in patients with renal cell carcinoma. BW 495/36-P positive cells were also found in both groups of tumor patients in greater numbers than in the patients with nephrolithiasis or other benign urinary tract disorders. Based on a specificity of 97% when compared to the control urine samples, the cytological determination of the antigens MCA, CA 125 and BW 495/36-P in urinary tract cells of all tumor patients revealed a sensitivity of 48%, 33% and 79% as well as a positive predictive value of 92%, 89% and 95%, respectively. The sensitivity of CA 125 increased to 67% upon isolated analysis of patients with bladder carcinoma. The majority of labelled cells were not identifiable as tumor cells morphologically and appeared as normal transitional epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Tumor-Associated, Carbohydrate↗
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Caspase-activation and induction of inducible nitric oxide-synthase during TNF alpha-triggered apoptosis.

Activation of the intracellular "death domain" (DD) of the 55kD-TNF alpha-receptor by TNF alpha initiates signal and effector cascades with pro- and anti-apoptotic function. Co-activation of the adjacent "NO-domain" is followed by induction of inducible nitric oxide-synthase (iNOS) and generation of nitric oxide radicals (NO.). Recently, we have shown NO.-generation to be essential for TNF alpha-induced apoptosis of various tumor cell lines. However, the impact of iNOS activation in relation to other promoters of apoptosis, such as the caspases, is still unclear. Caspase activation, iNOS induction and death rate were therefore investigated in TNF alpha-treated MCF-7 cells. Incubation with TNF alpha (+/- cycloheximide) led to activation of the caspase cascade and was followed by apoptosis. Simultaneously, TNF alpha stimulated induction of iNOS and generation of NO.. Caspase inhibitors DEVD-CHO, YVAD-cmk and YVAD-CHO effectively inhibited caspase activation and prevented apoptosis. Apoptotic cell death was decreased to a similar degree following inhibition of iNOS by L-nitro-arginine-methyl-ester (L-NAME). Cell death suppression by caspase inhibition did not result in reduced iNOS activity, as well as L-NAME-dependent prevention of apoptosis was not associated with caspase inactivation. Taken together, TNF alpha induces apoptosis in MCF-7 cells by initiating a two-sided effector pathway including iNOS-induction and activation of caspase 1- and 3-like proteases. Both mechanisms seem to be equally essential for the execution of the death program. The exact nature of their cooperation needs further clarification.

Adenocarcinoma↗
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Radioimmunotherapy of colorectal cancer in small volume disease and in an adjuvant setting: preclinical evaluation in comparison to equitoxic chemotherapy and initial results of an ongoing phase-I/II clinical trial.

The 5-year survival of colorectal cancer patients with distant metastases is below 30%, despite the development and use of a variety of chemotherapeutic regimens. Therefore, new therapeutic strategies are warranted. Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky disease, it may be a promising therapeutic alternative in limited and small volume disease. The aim of this study was, therefore, to compare, in a preclinical study, the therapeutic efficacy of RIT in colorectal cancer to equitoxic chemotherapy, as well as to evaluate, in a pilot clinical trial, its efficacy in small volume disease. Nude mice, bearing subcutaneous or metastatic human colon cancer xenografts, were injected either with the unlabeled or 131I-labeled monoclonal antibodies (MAbs), CO17-1A (which is a murine IgG2a directed against a 41-kD membrane glycoprotein) or F023C5 (which is an anti-CEA MAb of murine IgG1 subtype), or were administered 5-fluorouracil/folinic acid (5-FU/LV) at equitoxic doses. In a pilot clinical study, 10 colorectal cancer patients with small volume metastatic disease (all lesions < or = 3 cm) have been entered so far in an ongoing mCi/m2-based dose escalation study with the 131I-labeled F023C5. In the animals, the maximum tolerated activities (MTD) of 131I-labeled CO17-1A and F023C5 were 300 microCi and 600 microCi, respectively, corresponding to blood doses of approximately 15 Gy each. Accordingly, myelotoxicity was dose-limiting. The MTD in the chemotherapy group was 0.6 mg 5-FU/1.8 mg LV, given as intravenous bolus 1 h apart for 5 subsequent days. Whereas no significant therapeutic effects were seen with both unlabeled MAbs or 5-FU/LV chemotherapy, tumor growth was retarded significantly with both radiolabeled antibodies. In the metastatic model, chemotherapy prolonged life for only a few weeks, whereas RIT led to cures in 35-55% of the animals. As was the case in the animals, myelotoxicity seems to be dose-limiting in patients as well. Encouraging anti-tumor effects were observed, lasting for up to more than 12 months. These data suggest that radioimmunotherapy may be a viable therapeutic option in colorectal cancer patients with limited disease. Myelotoxicity is the only dose-limiting organ toxicity. Although most patients were treated below the MTD, anti-tumor effects are encouraging. Further studies are ongoing.

Animals↗
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Microalbuminuria during cisplatin therapy: relation with pharmacokinetics and implications for nephroprotection.

BACKGROUND: To assess the relation of cisplatin-induced nephrotoxicity to its pharmacology. PATIENTS AND METHODS: In 22 chemonaive patients (median age, 32 years) receiving 100-150 mg/m2 cisplatin for a total of 54 courses of therapy pharmacokinetics of ultra-filtrable platin were analyzed. Nephrotoxicity was sensitively assessed by nephelometric analyses of urinary marker-proteins. RESULTS: The parameters calculated for ultrafiltrable platin were (two-compartment-model): terminal half-life, 36 hours (coefficient of variation [CV], 22%); AUC, 12852 ng h/ml (33%); volume of distribution, 3531 (44%); total clearance, 285 ml/min (30%); renal clearance, 149 ml/min (23%); maximum concentration, 1720 ng/ml (66%); renal elimination, 57% of applied dose (26%). A pathological urinary excretion of albumin > 20 mg/l and alpha-1-microglobulin > 10 mg/l was detected in 39 out of 54 and 42 out of 54 cycles, respectively. The degree of albuminuria was related with urinary monoaquoplatin concentrations (p = 0.003). CONCLUSION: Nephrotoxicity of cisplatin appears to depend on the urinary monoaquoplatin concentrations which may be modulated by application of saline.

Adult↗
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Hepatic arterial infusion with oxaliplatin, folinic acid, and 5-fluorouracil in patients with hepatic metastases from colorectal cancer: role of carcino-embryonic antigen in assessment of response.

BACKGROUND: Therapy for patients with hepatic metastases from colorectal cancer (CRC) remains controversial and may be improved by regional oxaliplatin which proved to be effective when administered systemically to patients with advanced CRC. METHODS: During the current study, which aims to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetics of oxaliplatin applied as hepatic intra-arterial infusion combined with folinic acid and 5-fluorouracil in patients with hepatic metastases from CRC, serial levels of carcino-embryonic antigen were determined and their relationship to response to therapy was assessed. RESULTS: Toxicity mainly consisted of nausea, pain, mucositis, sensorial neuropathy, diarrhoea, and thrombocytopenia. The results of tumor marker analyses suggest that progressive disease may be detected early by increasing CEA levels and responsive disease may be characterized by low or decreasing values. CONCLUSIONS: Further analyses are warranted to determine the role of CEA in the assessment of response as compared to imaging techniques.

Aged↗
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Monoclonal B cell proliferation in lymphoproliferative disease associated with herpes virus type 6 infection.

Clonal gene rearrangements and aneuploidy are commonly recognized as characteristics of malignancy. We challenge this by an observation of a 3 1/2 year old boy with chronic benign lymphadenopathy, connatal splenomegaly and peripheral lymphocytosis. His brother and mother suffered from similar disease without progression. Cervical lymph node biopsy from our patient revealed a benign histology corresponding to the clinical course; however, clonal rearrangements of the JH and TCR gamma gene were demonstrated in lymph node cells and DNA aneuploidy in 11% of bone marrow cells. Immunohistology showed an inverse T-helper/T-suppressor cell ratio with polyclonal B cell increase and extensive lymphocyte activation. In situ hybridization demonstrated foci of lymphoid cells in the paracortical zone with expression of herpes virus type 6 genome. In addition, the patient, his brother and his mother showed serological evidence of active infection with the human herpes virus-6 (HHV-6). The association of HHV-6 infection, monoclonality and benign lymphoproliferation is discussed.

Antibody Formation↗
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Circadian variations of interleukin-2 receptors, serum thymidine kinase and beta-2-microglobulin in patients with non-Hodgkin's lymphoma and normal controls.

In this study we investigated whether circadian rhythms of interleukin-2 receptors (sIL-2R), serum thymidine kinase (sTK) and beta-2-microglobulin (beta 2M) are apparent, which may influence tumor marker detection. Blood was drawn every two hours over 24 hours from 6 patients with NHL, 3 healthy donors and three patients with non-hematologic disorders. The serum levels of the three markers were measured. The three normal volunteers showed circadian variations of sIL-2R, sTK and beta 2M best described by a sinusoidal curve. This rhythm could also be demonstrated in three of the six patients with NHL for all three markers. In three patients the circadian rhythm of one marker was disturbed. The three NHL-patients with consistent circadian rhythms in all three markers achieved a complete remission, whereas the patients with disturbed rhythm progressed under therapy. We showed that circadian variations of sIL-2R, sTK and beta 2M follow a sinusoidal circadian rhythm in normals and patients with NHL. Disturbance of this rhythm may be related to a worse prognosis.

Adult↗
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Deregulated simultaneous expression of multiple glucose transporter isoforms in malignant cells and tissues.

To evaluate the molecular and functional characteristics of upregulated glucose uptake in malignant cells, the expression of four glucose transporter (Glut) isoforms as well as glucose transport were determined in benign and malignant cell lines and tissues. In vivo distribution of Glut proteins was examined by immunocytochemistry in 30 breast cancer samples. In comparison with benign controls upregulation of Glut 1 mRNA and Glut 3 mRNA was shown. Glut 2 mRNA could not be detected. Glut 4 mRNA was found in various malignant cell lines in contrast to the physiological restriction of Glut 4 to terminally differentiated muscle and fat cells. While Glut 3 protein was not detectable in non-neuronal tissues, the degree of overexpression of Glut 1 and 4 corresponded to the expression level of the respective mRNAs. 57% of the breast cancer tissues showed positivity for Glut 1, 43% for Glut 4. Functional integrity of Glut 4 was demonstrated by preserved insulin-responsiveness. In cell lines, glucose transport activity was positively correlated with proliferation rate. Enhanced translocation of Glut 4 to the plasma membrane in correlation with high Ki-67 positivity in tissues pointed to the same association in vivo. C-myc overexpression had no detectable influence on Glut expression. In conclusion, malignant cells demonstrate quantitative as well qualitative changes of Glut expression and activity. Alteration of differentiation-adapted transcription and expression of cell-specific Gluts may represent a part of the transformation process and contribute to tumor progression.

Adult↗
PubMedDate not supplied

Early intensive and myeloablative adjuvant chemotherapy in women with high-risk breast cancer.

BACKGROUND: Women with breast cancer and > 10 positive lymph nodes have an unfavorable prognosis. The optimal combination and intensity of adjuvant chemotherapy is uncertain. Between July 1994 and December 1996 we treated 19 patients with early intensive followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation. PATIENTS AND METHODS: Patients were initially diagnosed with breast cancer and multiple positive lymph nodes. Induction chemotherapy consisted of two courses VP16, ifosphamide, cisplatin and epirubicin (VIPE) and one course of mitoxantrone, cyclophosphamide and thiotepa (MCT). Peripheral blood stem cells were mobilized after the first or second course of VIPE and retransfused two days after high dose chemotherapy. RESULTS: Stem cells were successfully collected in all patients. Major toxicities (WHO grade III and IV) were neutropenia, thrombocytopenia, alopecia, nausea, infections and mucositis. Hematopoietic recovery occurred in all patients with a median of 10 days for leukocytes and 13 days for platelets. No patient died of therapy-induced complications. The median observation time is 24 months. Two patients have relapsed, one with locoregional disease. The projected rate of patients with disease-free survival after three years is 88%. CONCLUSIONS: Early intensive and myeloablative chemotherapy followed by peripheral blood stem cell transplantation is a highly efficient and feasible protocol for high risk patients with breast cancer.

Adolescent↗