Biomedical subjects

H Hecker

Publications and source records attributed to H Hecker.

At least 55 records · Page 3Linked to original sources

PubMed1998

Safety and toxicity of amphotericin B in glucose 5% or intralipid 20% in neutropenic patients with pneumonia or fever of unknown origin: randomised study.

OBJECTIVE: To compare the feasibility of treatment, safety, and toxicity of intravenous amphotericin B deoxycholate prepared in either glucose or intralipid for empirical antimycotic treatment of neutropenic cancer patients. DESIGN: Single centre stratified, randomised non-blinded phase II study. SETTING: University hospital providing tertiary clinical care. SUBJECTS: 51 neutropenic patients (leukaemia (35), lymphoma (11), solid tumours (5)) with refractory fever of unknown origin (24) or pneumonia (27). INTERVENTIONS: Amphotericin B 0.75 mg/kg/day in 250 ml glucose 5% solution or mixed with 250 ml intralipid 20%, given on eight consecutive days then alternate days, as a 1-4 hour infusion. MAIN OUTCOME MEASURES: Feasibility of treatment, subjective tolerance (questionnaire), and objective toxicity (common toxicity criteria of the National Cancer Institute). RESULTS: Study arms were balanced for age, sex, underlying malignancy, renal and liver function, and pre- and concomitant treatment with antibiotics and nephrotoxic agents. No statistically significant or clinically relevant differences were found between the treatment groups for: daily or cumulative dose and duration of treatment with amphotericin B; incidence and time of dose modifications or infusion duration changes related to toxicity; dose or duration of symptomatic support with opiates, antipyretics, or antihistamines; renal function; subjective tolerance; most common toxicity scores; course of infection; and incidence of treatment failures. Patients treated with amphotericin B in intralipid were given fewer diuretics (P<0.05) and therefore had more peripheral oedema (P<0.01) and needed less potassium supplementation (P<0.05) than patients given amphotericin in glucose. Acute respiratory events were more common in the intralipid arm (P<0.05). CONCLUSIONS: Amphotericin B 0.75 mg/kg/day in intralipid given on eight consecutive days then alternate days provides no benefit and is associated with potential pulmonary side effects possibly because of fat overload or an incompatibility of the two drugs.

Adolescent↗

PubMed1998

Standard calculation of ethanol elimination rate is not sufficient to provide ethanol substitution therapy in the postoperative course of alcohol-dependent patients.

OBJECTIVE: Alcohol withdrawal syndrome (AWS) is a severe complication during postoperative treatment of alcohol-dependent patients. Besides the use of clomethiazole, clonidine, and benzodiazepines, there is another possible way to prevent AWS by deliberate administration of ethanol. The appropriate dosage of ethanol has not been known up to now and it could be defined according to the average ethanol elimination rate (EER) which, from forensic analysis, is known to be 15 mg/dl per h in a normal population. However, it is questionable whether these data are suitable for the calculation of the correct dosage in alcohol-dependent patients. DESIGN: Preliminary retrospective descriptive study. SETTING: Intensive care unit of a university teaching hospital. PATIENTS: 11 alcohol-dependent patients (9 males, 2 females, mean age 50.8 years, range 33 to 60 years). INTERVENTIONS: Ethanol substitution (ES) by parenteral application. MEASUREMENTS AND RESULTS: Ethanol kinetics were evaluated by repeated measurement of the blood ethanol concentration (BEC) over a period of at least 6 h parallel to the administration of ethanol. The average EER was found to be 28 mg/dl per h with a standard deviation of 11 mg/ dl per h. The minimum value was 18 mg/dl per h and the maximum 50 mg/dl per h. These EERs were significantly higher than the EERs known from forensic analysis. AWS was prevented in all 11 patients. CONCLUSIONS: Close control of BEC and precise adjustment of ethanol administration are necessary prerequisites for ES. The standard EER is not sufficient to define the appropriate ethanol dosage due to enormous variations in the ethanol metabolism of alcohol-dependent patients.

Adult↗

PubMed1998

Predictors of respiratory function deterioration after transfer of critically ill patients.

OBJECTIVES: Critically ill patients are often transferred due to the growing number of diagnostic procedures required to be performed outside the intensive care unit. These transfers have proved to be very critical. The aim of this study was to evaluate predictors for the deterioration of respiratory function in critically ill patients after transfer. DESIGN: Prospective, clinical, observational study. SETTING: 1800-bed university teaching hospital. SUBJECTS: 98 mechanically ventilated patients were investigated during transfer. MEASUREMENT AND MAIN RESULTS: Before transfer, all patients were classified according to the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Therapeutic Intervention Scoring System (TISS). Haemodynamics and arterial blood gases were measured at 11 different times. Arterial oxygen tension (PaO2), fractional inspired oxygen (FIO2), PaO2/FIO2 ratio, lowest PaO2/FIO2 ratio, minimal PaO2 and maximal FIO2, APACHE II score, TISS before transfer, age and duration of transfer were analysed as potential predictors for deterioration of respiratory function after transfer. Variables were analysed using Classification and Regression Trees and Clustering by Response. In 54 transports (55%) there was a decrease in the PaO2/FIO2 ratio, and a decrease of more than 20% from baseline was noted in 23 of the transferred patients (24%). Age > 43 years and FIO2 > 0.5 were identified as predictors for respiratory deterioration. CONCLUSIONS: Our predictors were able to indicate deterioration after transfer correctly in 20 of 22 patients (91%), combined with a false-positive rate in 17 of 49 (35%).

APACHE↗

PubMed1998

The number connection tests A and B: interindividual variability and use for the assessment of early hepatic encephalopathy.

BACKGROUND/AIMS: The number connection tests A and B are regarded as sensitive psychometric measures for the assessment of early hepatic encephalopathy. Review of the studies dealing with the diagnostic sensitivity of the number connection tests, however, shows that the scoring of the number connection tests results differs between studies. Most groups define the limits of the normal range by studying small control groups. Others use scores given in the literature without ensuring the comparability of the test versions used. Thus, there is a need for normative data for the number connection test results and for re-evaluation of the sensitivity of the tests using valid scores. METHODS: In this study the number connection tests A and B were administered to 249 healthy volunteers (age: 18 to 76 years) to analyze the influence of age, education and occupation on their results. In addition, the age-corrected normative data were applied to 169 patients with grade 0-I hepatic encephalopathy. The specificity and sensitivity of age-corrected and age-independent normative data of the number connection tests were compared. RESULTS: There was a significant influence of age and education on the number connection test results, but only a negligible effect of occupation. Application of the age-corrected normative data to the test results of the patients with grade I hepatic encephalopathy significantly decreased the sensitivity of the number connection tests for hepatic encephalopathy compared to widely used age-independent normal ranges, but also increased the specificity. CONCLUSION: The use of standardized versions of the number connection tests and age-related normative data is recommended.

Acute Disease↗

PubMed1998

Trypanosoma evansi and T. equiperdum: distribution, biology, treatment and phylogenetic relationship (a review).

Trypanosoma evansi and T. equiperdum were compared regarding their ultrastructure, their mammalian hosts, way of transmission, pathogenicity, diagnosis and treatment, and biochemical and molecular characteristics. Electron microscopic investigation revealed no ultrastructural differences between the two species except that there were more coated vesicles in the flagellar pocket of T. equiperdum. Biological, biochemical and molecular studies were reviewed and exhibited many similarities between T. evansi and T. equiperdum. The most prominent differences between the two species are the presence of maxicircles in T. equiperdum, which are missing in T. evansi, and the route of transmission. While T. evansi is transmitted by biting flies, T. equiperdum is transmitted from one equine host to another during copulation when mucous membranes come into contact. Otherwise the two species are remarkably similar. The phylogenetic relationship between the two species and T. b. brucei is being discussed, and the hypothesis is proposed that T. evansi arose from a clone of T. equiperdum which lost its maxicircles.

Animals↗

PubMed1998

Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer.

PURPOSE: To determine whether high-dose infusional fluorouracil (FU) is effectively modulated by leucovorin (LV), interferon (IFN) alpha-2b, or both when given to patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients (n = 236) with progressive, measurable disease were randomized to three groups and received FU 2,600 mg/m2 as a 24-hour continuous infusion (CI) weekly for 6 weeks with 2 weeks rest (FU24h) and LV 500 mg/m2 as a 2-hour infusion before FU or IFN 3 x 10(6) U subcutaneously 3 times weekly or both. Treatment continued until progressive disease or unacceptable toxicity was observed. Pairs of treatment arms were analyzed sequentially to detect equivalence or a 25% difference in response rates. RESULTS: The rate of objective remission in patients who received FU24h/LV (44%; 40 of 91) was significantly higher than in patients who received FU24h/IFN (18%; 16 of 90; P < .05). The response rates of patients who received FU24h/LV versus FU24h/LV/IFN (27%; 13 of 49) were statistically equivalent. Significant differences were observed for time to tumor progression (TTP) (FU24h/LV, 7.1 months; FU24h/IFN, 3.9 months; FU24h/LV/IFN, 6.3 months; global P value < .009) and survival (16.6 months, 12.7 months, 19.6 months, respectively; global P value < .04). Unpredictable and life-threatening toxicity in the FU24h/LV/IFN arm required dose reduction of FU to 2,000 mg/m2/day and early stoppage of this arm. Toxicity was manageable in patients who received both FU24h/LV (grade 3 to 4 diarrhea, 21%) and FU24h/IFN (grade 3 to 4 diarrhea, 15%). CONCLUSION: Response rate, TTP, and overall survival were superior for LV-containing regimens compared with IFN modulation alone. The addition of IFN to high-dose infusional FU plus LV offers no advantage and may increase toxicity. The regimen of high-dose infusional FU24h/LV warrants further evaluation in patients with metastatic colorectal cancer.

Adult↗

PubMed1997

Prognostic factors and staging systems in childhood hepatoblastoma.

The objectives of this study were to investigate clinical and patho-histological characteristics of childhood hepatoblastoma on their value as prognostic factors, and to evaluate the predictive impact of different staging systems for liver tumors on 72 patients treated in the German Pediatric Liver-Tumor Study HB89. Statistical analysis was performed by comparing patients' disease-free survival with characteristics and stages. Multivariate analysis was done by the Cox proportional-hazards model, the recursive partitioning and amalgamation model (RECPAM) and the model of clustering by response (CBR). The following characteristics were significantly related with prognosis: tumor involvement of one vs. both liver lobes, multifocal disseminated vs. unifocal growth pattern in the liver, distant metastases, vascular invasion, fetal vs. embryonal differentiation, and serum alpha-fetoprotein; patients with values of < or = 100 ng/ml or > or = 1,000,000 ng/ml had a worse outcome than those with 100 to 1,000,000 ng/ml. Multivariate analysis with the 3 models revealed that tumor-growth pattern, serum alpha-fetoprotein and, in the Cox and CBR models, vascular invasion also are independent prognostic factors, permitting the allocation of hepatoblastoma patients to 1 of 2 prognostic groups for differential therapy. Post-surgical staging and the conventional TNM system for liver carcinoma had a high predictive value, in contrast to a TNM system proposed by the UICC for testing on childhood liver tumors. We therefore propose that the TNM system for liver carcinoma be applied for comparison of treatment results in hepatoblastoma.

Child↗

PubMed1997

[Total cavopulmonary anastomosis for definitive palliation of complex univentricular cardiovascular systems--potential preoperative risk factors].

The modified Fontan operation for definitive palliation has been performed in an increasing number of patients with various forms of a functionally univentricular heart. To eliminate the influence of different surgical techniques only patients after total cavopulmonary anastomosis (TCPA) were included in this retrospective analysis of preoperative risk factors. The age at operation in 72 patients varied from 7 to 219 months (median 54 months); 29 patients had been younger than 4 years. Forty-nine patients presented with a complex form of a functionally univentricular heart; associated systemic- or pulmonary venous anomalies were found in 22 patients, AV valve abnormalities in 42 patients with AV valve incompetence in 21 patients. Preoperative hemodynamic data revealed an elevated mean pulmonary artery pressure (> 15 mm Hg), increased pulmonary arteriolar resistance (> 3 U.m2) or end-diastolic ventricular pressure (> 12 mm Hg) in 23 patients. The overall mortality was 9.7% (7/72 patients). Variables with significant influence on postoperative mortality were associated systemic- and pulmonary venous anomalies. AV-valve incompetence and prolonged cardio-pulmonary bypass time. Age at operation, preoperative pulmonary arteriolar resistance, systemic- and pulmonary blood flow did not influence postoperative mortality. Even in patients with a complex form of a univentricular heart with associated anomalies and borderline preoperative hemodynamics TCPA can be performed with an acceptable risk.

Adolescent↗

PubMed1997

Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Study Committee of the Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric Oncology and Haematology.

The Cooperative German Paediatric Liver Tumour Study HB89 was conceived to evaluate the efficiency and toxicity of ifosfamide, cisplatin and doxorubicin (IPA) in children with resectable and non-resectable hepatoblastoma (HB) and to determine late sequelae including tubular nephropathy of tumour treatment. The study also assessed the results of a surgical strategy, which adapts the procedure at the initial operation to the tumour's extension in the liver. The relationship of the tumours' histological differentiation to response to chemotherapy was also examined. Patients with a HB restricted to one liver lobe underwent primary resection. Larger tumours were initially treated with IPA chemotherapy and resected at second-look surgery. All patients received IPA adjuvantly after tumour resection. The IPA regimen consisted of ifosfamide 3.5 g/m2 (over 72 h days 1-3), cisplatin 100 mg/m2 (over 5 days 4-8) and doxorubicin 60 mg/m2 (over 48 h, days 9-10). Median follow-up of survivors was 64 months (range 28-82). Long-term disease-free survival (DFS) was for stage I: 21/21; stage II: 3/6; stage III: 28/38; and stage IV: 2/7 (overall 75%). Severe surgical complications occurred in 15% (4/27) of primary and 21% (8/38) of secondary resections with no lethality. 44/45 stage III/IV HB displayed PR after two IPA courses. Drug resistance developed in 8/12 tumours after four or five chemotherapy courses. Acute toxicity was observed in 34/242 (14%) IPA courses. Late sequelae were found in 7/54 (13%) of survivors, and subclinical renal tubulopathy occurred in 7/41 investigated patients (17%). Despite a more favourable prognosis in pure fetal and predominantly fetal histology, statistical analysis revealed no relationship between tumour differentiation and response to chemotherapy. In conclusion, IPA chemotherapy in combination with delayed surgery was highly effective in the treatment of HB.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Distinct mechanisms of immunosuppression as a consequence of major surgery.

Altered host defense mechanisms after major surgery or trauma are considered important for the development of infectious complications and sepsis. In the present study, we demonstrate that major surgery results in a severe defect of T-lymphocyte proliferation and cytokine secretion in response to coligation of the antigen receptor complex and CD28. During the early postoperative course, reduced cytokine secretion was observed for interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha, which are associated with the Th1 phenotype of helper T lymphocytes, and for IL-4, the index cytokine of Th2 cells. During the late postoperative course, T-cell cytokine secretion increased to normal levels. Production of the anti-inflammatory cytokine IL-10 was altered, with different kinetics being selectively elevated during the late postoperative course. In contrast, the capacity of peripheral blood monocytes to present bacterial superantigens and to stimulate T-cell proliferation was normal or enhanced after surgery despite a significant loss of cell surface HLA-DR molecules. Thus, the level of major histocompatibility complex class II protein expression does not appear to predict the antigen-presenting capacity of monocytes obtained from surgical patients with uneventful postoperative recovery. Secretion of IL-1beta and IL-10 by endotoxin-stimulated peripheral blood monocytes was increased at different time points after surgery. Major surgery therefore results in a distinct pattern of immune defects with a predominant defect in the T-cell response to T-cell receptor- and CD28 coreceptor-mediated signals rather than an impaired monocyte antigen-presenting capacity. Suppression of T-cell effector functions during the early phase of the postoperative course may define a state of impaired defense against pathogens and increased susceptibility to infection and septic complications.

Aged↗

PubMed1996

Diltiazem increases blood concentrations of cyclized cyclosporine metabolites resulting in different cyclosporine metabolite patterns in stable male and female renal allograft recipients.

1. Six male and six female stable renal allograft recipients under cyclosporine immunosuppression and without concomitant therapy with drugs known either to induce or inhibit CYP3A enzymes were included in the study and received 180 mg day-1 diltiazem for 1 week in a two-period cross-over fashion. Cyclosporine (352 +/- 56 mg day-1) was given in two daily oral doses. The daily doses were not changed during the study. Blood samples were collected for 12 h after receiving cyclosporine alone and after receiving diltiazem in addition for 1 week. Cyclosporine and nine of its metabolites were quantified using h.p.l.c. 2. Co-administration of diltiazem caused a 1.6 fold increase of the AUC (0, 12 h) of cyclosporine and a 1.7 fold increase of the AUC(0, 12 h) of its metabolites. Analysis of the metabolite patterns showed an over-proportional increase of the AUC(0, 12 h) of the cyclized metabolites AM1c (2.6 fold) and AM1c9 (2.2 fold). The AUC(0, 12 h) values of cyclosporine and the hydroxylated metabolites increased less than two fold. 3. Differences of the AUC(0, 12 h) values of cyclosporine with and without diltiazem were significantly higher in female than in male patients (P < 0.02). The differences in the AUC(0, 12 h) values of the metabolites, especially AM1c, tended to be higher in female patients as well. 4. It is concluded that coadministration of diltiazem not only increases the blood concentration of cyclosporine but also those of its metabolites, leads to a shift of the metabolite pattern towards cyclized metabolites, and that the pharmacokinetic changes under diltiazem administration are more prominent in female than in male patients.

Adult↗

PubMed1996

[Importance of duplex velocity histograms in the diagnosis of liver cirrhosis].

PURPOSE: A prospective study was carried out to determine the diagnostic value of velocity histograms of hepatic veins in patients with liver cirrhosis and healthy subjects. METHODS: The hepatic veins of ten healthy subjects and ten patients with liver cirrhosis were examined by the Doppler method. The velocity histogram measures the velocity variation at a defined area in the duplex tracing. Within this tracing, the peak, mean, mode and velocity range were measured. RESULTS: A velocity range of 0.02 +/- 0.015 m/s was examined in healthy subjects, and a range of 0.06 +/- 0.013 was examined in liver cirrhosis patients (p < 0.001). The other measurement options showed no significant changes between the healthy subjects and the liver cirrhosis patients (p < 0.05). CONCLUSIONS: Until now, differentiation of the hepatic vein tracings was possible only on a qualitative basis. With the assessment of the velocity range it is possible to obtain a more objective differentiation between the duplex tracing in hepatic veins of liver cirrhosis patients and healthy subjects.

Adult↗

PubMed1996

Prediction of permanent work disability in a follow-up study of early rheumatoid arthritis: results of a tree structured analysis using RECPAM.

The objectives of this study are: (a) to determine the occurrence of permanent work disability (PWD) in early rheumatoid arthritis (RA); (b) to identify prognostic groups of patients; (c) to assess the employment rates for these groups over time. Seventy-three gainfully employed consecutive out-patients with early RA (> or = 5 ARA 1958 criteria, disease duration < or = 12 months) at time one (T1) were re-examined at time two (T2) after a mean follow-up of 6 yr (S.D. +/- 2 yr). Potential risk factors, identified at T1, for PWD at T2 were entered in a tree structured survival analysis using RECPAM (RECursive Partition and AMalgamation). Cumulative 3 yr employment rates (3-yrER +/- S.E.M.) were computed from the resulting Kaplan-Meier curves. At T2, PWD occurred in 27 of the 73 patients (37%). The fastest decline in the employment rate was found within the first 3 yr of the disease onset, with a 3-yrER reduced to 73 +/- 5%. The group with the poorest prognosis (n = 14; 3-yrER 14 +/- 9%) was defined by age > or = 50 yr with either ESR > or = 60 mm/h or the combination of modified functional class (1-7) > or = 4 with a disease duration > or = 7 months. An intermediate group (n = 38; 3-yrER 79 +/- 6%) was defined by (a) age > or = 50 yr and low or moderate disease activity, (b) age < 50 yr and more strenuous job-related physical requirements, (c) age < 50 yr and less strenuous work, but joint count > or = 15. No case of PWD occurred in 21 individuals aged < 50 yr with a joint count < 15 and less physically demanding jobs. PWD occurs early in a substantial number of patients with RA. RECPAM defines risk profiles that can readily be applied in actual clinical situations and allow an estimation of the risk of PWD at different time points using the resulting Kaplan-Meier curves.

Adult↗

PubMed1995

Properties of the histones and functional aspects of the soluble chromatin of epimastigote Trypanosoma cruzi.

The amino acid composition of all histones of Trypanosoma cruzi was analyzed, and the terminology of the histones of higher eukaryotes adopted. One chromatin associated protein, previously considered to be a variant of histone H1, could not be clearly identified, and shows features of core histones as well as of histone H1. An improved method for the isolation of intact nuclei and the production of soluble chromatin in T. cruzi was established. The chromatin of T. cruzi is relatively instable and histone H1 is easily lost during experimental manipulations. Histone H1 dissociates completely at a relatively low NaCl concentration of 380 mM, leading to an open nucleosome filament which does not condense. The influence of histone H1 of T. cruzi and of rat liver on the compaction pattern of the chromatin was investigated by homologous and heterologous reconstitution experiments, and analysed by electron microscopy. It could be shown that histone H1 of T. cruzi induces nucleosome filaments of T. cruzi as well as those of rat liver to condense. The same is true for histone H1 of rats. It can be concluded that T. cruzi has a functional histone H1.

Amino Acids↗

PubMed1995

Influence of the selection of angiographic projections on the results of coronary angiographic follow-up trials. International Nifedipine Trial on Antiatherosclerotic Therapy Investigators.

In recent years follow-up trials on coronary artery disease with angiographic end points analyzed quantitatively have gained increasing relevance and popularity. There is no consensus, however, on the method of calculation of progression or regression from multiple angiographic projections. Therefore the influence of the selection of angiographic projections on the outcomes of such trials was investigated with the data of the International Nifedipine Trial on Antiatherosclerotic Therapy. In 348 patients with coronary artery disease, repeated coronary angiograms were compared in multiple identical angiographic projections. Changes in angiographic parameters were averaged over the 1063 stenoses analyzed. Five methods of evaluation of multiple projections in the individual stenoses were applied, resulting in different extents of overall progression, or even regression of coronary artery disease (p < 0.01). It is concluded that in quantitative coronary angiographic follow-up trials changes should be averaged over all angiographic projections available for a stenosis to avoid overestimation of progression or regression.

Analysis of Variance↗

PubMed1995

Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89.

Clinical data and tumor histology of 37 patients with advanced and/or metastatic hepatoblastoma (32 stage III and 5 stage IV) treated according to the protocol of the German Cooperative Pediatric Liver Tumor Study HB-89 from 1988 to 1992 were studied for prognostic factors. Twenty-three patients (73%) were free of tumor 9 months to 5 years (median, 36 months) after treatment, whereas 4 experienced progressive disease, 7 had local relapse, and 3 had recurrent metastases. None of 2 patients with primary lymph node involvement or 5 with primary metastases remained disease-free. Chemotherapy with ifosfamide, cisplatin, and adriamycin was effective in reduction of tumor to resectability in 33 (89%) patients. Drug resistance developed in 6 of 11 patients treated with four or more courses of chemotherapy as could be shown by monitoring of serum-alpha-fetoprotein (AFP) and serial investigations of tumor expansion with sonography and computed tomographic (CT) scan. Only 1 of these patients survived after a liver transplantation. Completeness of tumor resection at second- or third-look laparotomy was significantly related to disease-free survival (P < .0001). Patients with initial serum-AFP values < 100 ng/mL or > 1,000,000 ng/mL had a worse outcome than those with immediate levels (P = .044). The rate of decrease of serum-AFP during chemotherapy was significantly related to prognosis (P = .003). Growth pattern of tumor within the liver (ie, defined nodes versus diffusely disseminated) (P = .011) and vascular tumor invasion (P = .026) were valuable prognostic factors, whereas tumor volume, local infiltration of surrounding tissue, histological subtypes, and epithelial differentiation were not significantly related to the outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Partial amino acid sequence and functional aspects of histone H1 proteins in Trypanosoma brucei brucei.

Trypanosoma brucei brucei, a protozoan parasite of wild and domestic animals in Africa, is related to the pathogenic agent of human sleeping sickness. Four H1 histone proteins were isolated from nuclei of procyclic culture forms and cleaved with proteases. Amino acid sequence analysis of purified fragments indicated the presence of variants which displayed sequence identities as compared to the C-terminal domain of human H1. Substitutions of amino acids and posttranslational modifications of the histones in T b brucei H1 may influence protein conformation and histone-histone as well as histone-DNA interactions in the chromatin of the parasite. Digestion of soluble chromatin with immobilized trypsin at low and high ionic strengths indicated an internal localization of H1 in the condensed chromatin. The influence of histone H1 of T b brucei on the compaction pattern of the chromatin was investigated by dissociation and reconstitution experiments. Electron microscopy revealed that trypanosome H1 was able to induce condensation of the chromatin of the parasite and of rat liver into dense tangles. After dephosphorylation of H1, 30 nm fibers were induced in rat liver chromatin, while the resulting fibers were distinctly thinner in T b brucei. It can be concluded that the absence of 30 nm fibers in T b brucei chromatin cannot be explained by the divergent variants and posttranslational phosphorylations of H1 only but rather by the influence of both, the divergent core histones, previously described, and H1 properties.

Amino Acid Sequence↗

PubMed1995

Interferon-alpha does not improve the antineoplastic efficacy of high-dose infusional 5-fluorouracil plus folinic acid in advanced colorectal cancer. First results of a randomized multicenter study by the Association of Medical Oncology of the German Cancer Society (AIO).

BACKGROUND: High-dose 5-FU given weekly as a 24-h infusion in combination with folinic acid (FA) has been associated with low toxicity and a high response rate. Interferon-alpha (IFN) either alone or in combination with FA has also improved treatment results by modulating 5-FU activity. We therefore initiated a randomized multicenter trial comparing the ability of FA or IFN to modulate infusional 5-FU. The statistical design using a sequential analysis allows us to report on the comparison of 5-FU/FA vs. 5-FU/FA/IFN while randomization of patients into 5-FU/FA vs. 5 FU/IFN continues. METHODS: Chemotherapy-naive patients with advanced progressive colorectal cancer and measurable metastatic lesions were randomized to receive 5-FU 2600 mg/m2 i.v. as a 24-h infusion, combined with either FA 500 mg/m2 as a 2-h infusion (A), or IFN 3 x 10(6) U s.c. 3 x/week (B), or the combination of FA plus IFN as in arms A and B (C). Treatment arms were repeated weekly for 6 weeks followed by a 2-week rest period. These 8-week cycles were administered until tumor progression. Because of the occurrence of 2 toxic deaths among the first 17 patients treated in arm C, 5-FU was reduced to 2000 mg/m2 for all patients in arm C. Sequential analysis according to Whitehead for objective response was planned with alpha = 0.05/3 and a power of 80% (beta = 0.2) to detect a difference of > or = 25% (delta = 0.25) or equivalence of response rates. For pairwise comparison of treatment arms a minimum of 30 patients per arm and a maximum of 90 patients per arm were expected in case of equivalence or difference. RESULTS: An interim analysis was performed after the first 93 of 149 randomized patients were evaluable for response and toxicity (A 31 pts, B 33 pts, C 29 pts). Despite the 5-FU dose reduction in arm C, 28% of patients experienced grade 3/4 toxicity (CTC) including diarrhea, mucositis and handfoot syndrome compared to 16% in arm A and 12% in arm B (not significant). No treatment related toxic death occurred in arms A or B, but 3 patients (10%) in arm C died of diarrhea and septicemia. Among patients treated with 5-FU/FA objective tumor response occurred in 12/31 patients (39%) (21%-56%, 95% confidence interval) (3 CR, 9 PR), no change in 13/31 (42%) and PD in 6/31 (19%) patients. Eleven of 29 patients (38%) (20%-56%, 95% confidence interval) receiving 5-FU/FA/IFN achieved complete (3 patients) or partial (8 patients) remissions, 10/29 patients (34%) had stable disease and 8/29 patients (28%) tumor progression. According to the sequential analysis the rates of objective responses observed in patients treated with 5-FU/FA or 5-FU/FA/IFN were equivalent. CONCLUSION: This interim analysis allows the conclusion that infusional 5-FU plus FA/IFN is no more active than infusional 5-FU plus FA alone. However, 5-FU/FA/IFN despite 5-FU dose reduction was associated with unacceptably high toxicity, including 10% deaths. Therefore, further investigation of this regimen is not justified. The study is continued with the comparison of 5-FU/FA vs. 5-FU/IFN.

Adult↗