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Biomedical subjects

H H Hansen

Publications and source records attributed to H H Hansen.

At least 91 records · Page 5Linked to original sources
PubMed1994

[Development and treatment of renal insufficiency in multiple myeloma].

Renal insufficiency occurs in 55% of patients with multiple myeloma and is second only to infection as the most common cause of death in these patients. In acute renal failure, improvement can be achieved by correcting fluid balance or hypercalcaemia. Since 1968 chronic dialysis has been recommended as a worthwhile treatment. Haemodialysis and CAPD appear to be equally effective. One year survival in myeloma patients maintained on chronic haemodialysis was 53% while it is reported as 66-76% for myeloma patients not on dialysis. Transplantation may be a treatment option, but only in carefully selected patients. It has been suggested that chronic dialysis should be offered only if there has been a good response to chemotherapy. However, response to chemotherapy and duration of remission are unrelated to renal function and many patients require dialysis before any response to chemotherapy is known. Therefore almost all uraemic myeloma patients should start dialysis initially.

Acute Kidney Injury↗
PubMed1994

Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments.

The epipodophyllotoxins etoposide and teniposide are probably the most important drugs in the treatment of small cell lung cancer. The drugs are used in maximally tolerated doses, and the toxicity of the drugs precludes significant dose increments. The cellular target is the nuclear enzyme topoisomerase II which, in the presence of these drugs, causes an extensive fragmentation of DNA. The cell kill can be antagonized by distinct drug types. We have demonstrated previously that the intercalating drug aclarubicin and the cardioprotecting agent ICRF-187 antagonize the cytotoxicity of etoposide in vitro. We have studied possible ways of using this antagonism as a means of differentially protecting normal tissue. Here we demonstrate that the intercalating agent chloroquine prevents the introduction of topoisomerase II-mediated DNA breaks and thereby antagonizes the cytotoxicity of etoposide. This interaction depends on the extracellular pH. Chloroquine, in contrast to etoposide, is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. We propose that such a pH-dependent drug interaction may be useful in directing topoisomerase II drug effects toward solid tumors. Thus, by lowering the extracellular pH (pHe) from neutral (pHe = 7.4) to acidic (pHe = 6.0), [3H]chloroquine accumulation was decreased 5-fold in a human small cell lung cancer cell line, OC-NYH, and in murine leukemia L1210 cells. In parallel, the antagonism exhibited by chloroquine on etoposide cytotoxicity was pHe dependent. Thus, no protection by chloroquine was observed at pHe = 6.5, whereas at pHe = 7.4, etoposide cytotoxicity was almost completely antagonized with a 460-fold protection or more than eight doublings of the cell population. This exploitation of antagonist extracellular trapping by acidic pH is a novel model for regulation of anticancer drug effects.

Amsacrine↗
PubMed1994

Anticoagulant therapy in deep venous thrombosis. A randomized controlled study.

Ninety patients with venographically proven deep venous thrombosis(DVT) but without clinical signs of pulmonary embolism(PE) were randomized into two different treatment regimens to compare the safety and efficacy of continuous intravenous heparin and oral anticoagulant(AC) treatment versus non-AC treatment. All patients in the two treatment groups were actively mobilized from the day of admission and wore graduated compressing stockings. In the non-AC-group the patients were treated with phenylbutazone for ten days. Treatment with heparin was maintained for 6 days and oral AC treatment was given from the third day and continued for 3 months. Venography was repeated after 30 days. A perfusion-ventilation lung scan was performed on day 1-2, 10 and 60. In fifty-nine patients a revenography was performed, twenty nine in the AC-group and thirty in the non-AC group. For distal veins regression was found in nine and eight respectively (4.4% in favour of AC, 95% confidence limit 27.5% to -18.7%) and in proximal veins regression was found in five and eight, respectively (10.9% in favour of AC, 95% confidence limit 32.0% to -10.1%). No difference in lung scans was found after 10 days (0.8% in favour of AC, 95% confidence limit 21.5% to -19.9%) or after 60 days (3.3% in favour of non-AC treatment, 95% confidence limit 21.8% to -28.5%). In the AC group the incidence of bleeding complications was 8.3%. No side-effects of phenylbutazone was found. The present controlled clinical study demonstrated no effect of AC-treatment on DVT progression in actively mobilized patients wearing graduated compressing stockings when compared to a non-AC treated group receiving analgetic therapy with phenylbutazone. However, the patient population of the study is relatively small with wide confidence intervals for differences between groups. Before more general recommendations can be made, a large scale placebo-controlled study is needed to evaluate the possible effect of AC-treatment in DVT patients, who can be mobilized from the first day.

Administration, Oral↗
PubMed1994

Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma.

The urokinase pathway of plasminogen activation is involved in proteolytic degradation of various tissues, including dissolution of the extracellular matrix and basement membranes during the process of cancer cell invasion. We have studied the prognostic value of urokinase-type plasminogen activator (uPA) and type-1 plasminogen activator inhibitor (PAI-1) in tumor extracts from 106 patients with adenocarcinoma of the lung. uPA and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays. No correlation was found between uPA and PAI-1 (r = 0.23). High PAI-1 levels were significantly associated with short-duration overall survival (P = 0.017), while uPA levels showed no significant association with overall survival. Relating the levels of PAI-1 to other prognostic factors such as stage and age, no significant correlations were found. The prognostic impact of uPA and PAI-1 were investigated together with other prognostic factors in Cox multivariate analysis. PAI-1 was found to be an independent prognostic variable for survival, the relative risks being 1.5 (low versus medium PAI-1 values (95% confidence interval, 1.2-1.8) and 2.2 (low versus high (95% confidence interval, 1.8-2.6)). In patients with stage I disease (69 patients) high levels of PAI-1 were significantly associated with poor prognosis compared to low levels (P = 0.037). These data indicate that PAI-1 is a potentially important prognostic factor in pulmonary adenocarcinoma and may as such be used to select patients with low stage and poor prognosis for adjuvant therapy subsequent to complete surgical resection.

Adenocarcinoma↗
PubMed1994

Observer variation in the interpretation of ventilation-perfusion lung scintigraphy.

The diagnosis of pulmonary embolism (PE) remains one of the most difficult in clinical medicine, and the diagnostic value of lung scintigraphy has been questioned. To evaluate the observer variation in the interpretation of ventilation-perfusion lung scanning in the diagnosis of PE, 87 lung scintigrams from consecutive patients with phlebography-proven deep venous thrombosis and without clinical signs of PE were randomly mixed with 50 reference lung scintigrams from patients with PE symptoms. The scintigrams were reevaluated blind by two experienced clinical physiologists. Each observer evaluated each lung scintigram twice and recorded whether the lung scan was normal or abnormal. If it was abnormal, the location and number of segment defects were registered. The intraobserver agreement, including number and location of segments, ranged from 0.77 to 0.85 and for the diagnosis of PE from 0.88 to 0.92 with a kappa of 0.80-0.84. The values for the interobserver agreement for the diagnosis of PE were 0.73-0.80 with a kappa of 0.56-0.67. It is concluded that in the interpretation of ventilation-perfusion lung scintigraphy the use of a simple scheme-deciding whether there is segmental ventilation-perfusion mismatch or not-has a good reproducibility with a high kappa for inter- and intraobserver variation and can serve as a simple routine method for diagnosing PE.

Double-Blind Method↗
PubMed1994

In vivo inhibition of etoposide-mediated apoptosis, toxicity, and antitumor effect by the topoisomerase II-uncoupling anthracycline aclarubicin.

A number of clinically important drugs such as the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26), the anthracycline daunorubicin and doxorubicin (Adriamycin), and the aminoacridine amsacrine exert their cytotoxic action by stabilizing the cleavable complex formed between DNA and the nuclear enzyme topoisomerase II. We have previously demonstrated in several in vitro assays that the anthracycline aclarubicin (aclacinomycin A) inhibits cleavable-complex formation and thus antagonizes the action of drugs such as VP-16 and daunorubicin. The present study was performed to validate these in vitro data in an in vivo model. At nontoxic doses of 6 and 9 mg/kg, aclarubicin yielded a marked increase in the survival of non-tumor-bearing mice given high doses of VP-16 (80-90 mg/kg) in six separate experiments. In therapy experiments on mice inoculated with Ehrlich ascites tumor cells, aclarubicin given at 6 mg/kg roughly halved the increase in median life span induced by VP-16 at doses ranging from 22 to 33 mg/kg. An attempt to determine a more favorable combination of VP-16 and aclarubicin by increasing VP-16 doses failed, as the two drugs were always less effective than VP-16 alone. The way in which VP-16-induced DNA strand breaks lead to cell death remains unknown. However, VP-16 has been reported to cause apoptosis (programmed cell death) in several cell lines. To ascertain whether the protection given by aclarubicin could have a disruptive effect on the apoptotic process, we used the small intestine as an in vivo model. Whereas VP-16-induced apoptosis in crypt stem cells was detectable at a dose as low as 1.25 mg/kg, aclarubicin given at up to 20 mg/kg did not cause apoptosis. Indeed, aclarubicin caused a statistically significant reduction in the number of cells rendered apoptotic by VP-16. The present study thus confirms the previous in vitro experiments and indicates the value of including an in vivo model in a preclinical evaluation of drug combinations.

Aclarubicin↗
PubMed1994

Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial.

We performed a randomised single blind trial of high-dose dexamethasone as an adjunct to radiotherapy in patients with metastatic spinal cord compression from solid tumours. After stratification for primary tumour and gait function, 57 patients were allocated randomly to treatment with either high-dose dexamethasone or no steroidal treatment. Dexamethasone was administered as a bolus of 96 mg intravenously, followed by 96 mg orally for 3 days and then tapered in 10 days. A successful treatment result defined as gait function after treatment was obtained in 81% of the patients treated with dexamethasone compared to 63% of the patients receiving no dexamethasone therapy. Six months after treatment, 59% of the patients in the dexamethasone group were still ambulatory compared to 33% in the no dexamethasone group. Life table analysis of patients surviving with gait function showed a significantly better course in patients treated with dexamethasone (P < 0.05). Median survival was identical in the two treatment groups. Similar results were found in subgroup analysis of 34 patients with breast cancer as the primary malignancy. Significant side-effects were reported in 3 (11%) of the patients receiving glucocorticoids, 2 of whom discontinued the treatment. We conclude that high-dose glucocorticoid therapy should be given as adjunct treatment in patients with metastatic epidural spinal cord compression.

Adult↗
PubMed1994

Serum neuron-specific enolase (S-NSE) in progressive small-cell lung cancer (SCLC).

Clinical decision making is based on results from qualitative and quantitative information. To provide quantitative data, various laboratory variables are widely used in the clinical evaluation of patients with small-cell lung cancer (SCLC). The tumour marker serum neuron-specific enolase (S-NSE) and the routine laboratory parameter serum lactate dehydrogenase (S-LDH) have been investigated, mostly separately. Few studies have compared their importance in SCLC, especially in progressive disease (PD). The present investigation was undertaken to evaluate S-NSE for diagnostic efficacy in PD and compare it with S-LDH. In 27 patients in a treatment trial of SCLC, regular follow-up laboratory values were prospectively obtained. Chemotherapy was given according to trial protocols, and all clinical evaluation followed the WHO recommendations. At re-evaluation all but three values had normalised (two S-NSE, one S-LDH). S-NSE at progression was increased in 93% of the patients and S-LDH in 59%. The efficacy of S-NSE to discriminate between response and PD was superior to S-LDH (0.92 vs 0.70). There was no additive effect of the two parameters in prediction of PD, and the discriminating power was higher for S-NSE than for S-LDH (P < 0.0008). The disease status-related marker increments in relation to upper reference limits, i.e. the signal-noise relation, were higher for S-NSE than for S-LD. Both of the markers carry information on PD. S-NSE is, however, clearly superior to S-LDH in reflecting disease status during therapy. This prompts us to conclude that S-NSE should replace S-LDH as prognostic factor and disease activity monitor in SCLC.

Biomarkers, Tumor↗
PubMed1994

Fucosyl-GM1 in small-cell lung cancer. A comparison with the tumour marker neuron-specific enolase.

BACKGROUND: Recently, the ganglioside Fucosyl-GM1 (FucGM1) has been described as a possible new tumour marker for small-cell lung cancer (SCLC). FucGM1 has been detected in 75% to 90% of SCLC tumours by immunohistochemical analysis and in about 50% of sera from SCLC patients. Neuron-specific enolase (NSE) is a glycolytic enzyme which is expressed in the majority of SCLC tumours and patient sera. PATIENTS AND METHODS: Sera from 156 patients with SCLC were analyzed for FucGM1 with a scintillation proximity assay (SPA), which is a simple and sensitive analysis. Sera were analyzed before the initiation of chemotherapy, and twenty patients were monitored during and after treatment. The concentration of FucGM1 was compared to the tumour marker NSE and related to clinical data and survival. RESULTS: Sixty-three per cent of the patients were positive for FucGM1. The concentrations did not correlate with NSE or clinical data including stage of disease, organ site of metastases or ABO blood group status. Nor did the expression of FucGM1 correlate with survival. As a monitor of clinical response, a correlation was found in 8 out of 20 patients. Eighty-four per cent of the patients were positive for NSE; and 97% were positive for either FucGM1 or NSE. CONCLUSION: We conclude that FucGM1 does not have a clinical role as a tumour marker for patients with SCLC at diagnosis or during treatment.

Adult↗
PubMed1994

Recent advances in diagnosis and treatment of small cell and non-small cell lung cancer.

Despite much effort and many published reports, progress in diagnosing and treating lung cancer has been slow. The use of monoclonal antibodies for detection of metastasis and neuroendocrine markers for subclassification of non-small cell lung cancer into different prognostic groups may be useful in future staging and treatment. Dose-intensive chemotherapy in small cell lung cancer is still experimental, which is also the case for prophylactic cranial irradiation. Adjuvant chemotherapy for completely resected patients with non-small cell lung cancer may be associated with a marginal survival benefit, which also seems to hold true for patients with advanced disease when compared with untreated control subjects solely receiving supportive care. The modest survival benefit is achieved at the cost of increased toxicity. Neoadjuvant treatment remains a controversial issue, one of the major problems being the lack of an effective standard systemic therapy in non-small cell lung cancer.

Brain Neoplasms↗
PubMed1994

Silent pulmonary embolism in patients with deep venous thrombosis. Incidence and fate in a randomized, controlled trial of anticoagulation versus no anticoagulation.

OBJECTIVES: A high frequency of asymptomatic pulmonary embolism (PE) in patients with deep venous thrombosis (DVT) has been reported, but information about the outcome of the patients with PE remains sparse. The aims of the present study were to assess the prevalence of silent PE in patients with symptomatic, venographically proven DVT, and to evaluate the natural history of silent PE. DESIGN: Consecutive patients from one centre of primary care were included in a randomized, open study with blinded control. All patients gave written, informed consent. SUBJECTS: Eighty-seven consecutive patients with venographically proven DVT and with a perfusion-ventilation lung scintigraphy performed within 48 h of the DVT diagnosis were included. On the 10th and 60th days the lung scintigraphy was repeated in 80 and 60 patients, respectively. All the patients were followed for 3 months in the out-patient clinic. INTERVENTIONS: All patients were ambulated from the first day and were allocated randomly to no anticoagulant (non-AC) therapy or to AC therapy with intravenous heparin infusion for at least 6 days and oral AC therapy for 3 months. RESULTS: Forty-three of these patients had a high probability lung scintigraphy for PE. Distal vein and femoral vein thrombosis embolized in 33 and 53% of patients, respectively. The progression rate after 60 days was 3% in both the AC and the non-AC group and after 10 days the rates were 13 and 8%, respectively. CONCLUSIONS: A high frequency of silent PE in patients with DVT both above and below the knee is demonstrated. AC treatment did not influence the resolution rate of PE or the rate of clinical PE in a 3-month follow-up period.

Adolescent↗
PubMed1994

Comparison of clinical neurological function and CT response during chemotherapy for initial brain metastases from small cell lung cancer.

We compared the clinical neurological and functional response with changes in CT during systemic combination chemotherapy in 20 patients with initial brain metastases from small cell lung cancer (SCLC). Seven patients died within four weeks from start of chemotherapy, leaving 13 patients for evaluation of treatment response. Eight patients improved to or maintained a high neurological score, meaning no or insignificant neurological deficits or disability. Three patients had a stable neurological score, and 2 patients deteriorated. The median duration of the clinical response was 20 weeks. Based on changes in CT four patients had complete remission, six had partial remission, and two showed no change. One patient had a rapid deterioration of her clinical condition and died without CT control. Five patients with late CNS relapse were treated with second-line cranial irradiation inducing clinical improvement in three. Median survival was 11 weeks, and in assessable patients, excluding early deaths, 28 weeks. In conclusion initial brain metastases respond to systemic chemotherapy as readily as extracranial locations of SCLC, and in many patients prolonged neurological and CT remission can be achieved.

Aged↗
PubMed1994

Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study.

PURPOSE: To evaluate the efficacy and safety of gemcitabine, a pyrimidine antimetabolite with activity against solid tumours. PATIENTS AND METHODS: Eighty-two patients with unresectable stage IIIa to IV non-small-cell lung cancer (NSCLC) were entered. The first 54 patients received gemcitabine 800 mg/m2, and subsequent patients 1,000 mg/m2, as a 30-minute intravenous infusion on days 0, 7, and 14. Courses of therapy were repeated every 28 days. Twenty percent dosage escalation was permitted after course no.1 if World Health Organization (WHO) toxicity was < or = 1. RESULTS: Sixteen (20%; 95% confidence interval [CI], 12% to 31%) of 79 patients assessable for response had independently validated partial responses, with a median duration of 7 months. The overall median survival duration was 7 months. Gemcitabine improved disease-related symptoms (70% patients) and increased WHO performance status (44%). Toxicity was generally mild and reversible. Patients experienced little WHO grade 3 and 4 toxicity, with anemia in four (5%), thrombocytopenia in one (1%), leukopenia in six (7%), and neutropenia in 18 (22%). Infection occurred in nine patients (12%) during the study (four were neutropenic), but there were no episodes of WHO grade 3 or 4 infection. WHO grade 3 and 4 biochemical toxicity occurred with transient elevations of transaminases in 10 patients (12%). Two patients had transient WHO grade 3 elevation of serum creatinine levels, and two developed acute renal failure 4 and 6 weeks after the last dose of gemcitabine. There was no WHO grade 4 symptomatic toxicity. WHO grade 3 vomiting occurred in 31 patients (38%) and grade 3 alopecia in one (1%). Flu-like symptoms were associated with gemcitabine administration in 36 patients (44%). Twenty-six patients (32%) experienced fever (1% WHO grade 3), 33 (40%) ankle edema not associated with cardiac failure, 31 (38%) lethargy, and 11 (13%) dyspnea. CONCLUSION: Gemcitabine is an active new agent in the treatment of NSCLC. This schedule was associated with little alopecia or myelosuppression. Gemcitabine warrants further investigation in other malignancies and in combination with other agents.

Adult↗
PubMed1994

Lung cancer.

In SCLC, combination chemotherapy including agents such as etoposide, teniposide, cisplatin, carboplatin, doxorubicin, vincristine and cyclophosphamide continues to be the backbone of therapy. Epipodophyllotoxin derivatives, together with cisplatin or carboplatin are being increasingly used as part of the initial therapy. Complete plus partial responses to combination chemotherapy occur in 80-90% of all patients with a median duration of 9-11 months. Median survival in these studies is at present 11-16 months, depending on the initial tumour stage. At this point, 5-year survival is around 5% and includes a small fraction of patients (1%) initially presenting with extensive disease. The optimum duration of treatment is still uncertain, but the tendency is to shorten the duration of treatment to 6-9 months. The results of intensifying the treatment with the use of hematopoietic growth factors have hitherto been disappointing. The results of several phase II studies stress the importance of dose scheduling of etoposide in SCLC, with continuous treatment of 5 days' duration or more being superior. The therapeutic results for squamous cell carcinoma, adenocarcinoma, large cell carcinoma and mesothelioma are essentially unchanged. The treatment of patients with these types of lung cancer should continue to be considered experimental, since no standard chemotherapy has as yet been developed, neither when given as single modality nor in combination with surgery or radiotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Different modes of anthracycline interaction with topoisomerase II. Separate structures critical for DNA-cleavage, and for overcoming topoisomerase II-related drug resistance.

In contrast to the classic anthracyclines (doxorubicin and daunorubicin), aclarubicin (ACLA) does not stimulate topoisomerase II (topo II) mediated DNA-cleavage. This distinction may be important with respect to topo II-related drug resistance, and the aim of this study was to clarify drug-structures responsible for this difference. Various ACLA analogs were tested for: (a) interaction with purified topo II, (b) induction of DNA cleavage in cells, (c) cellular uptake and (d) cytotoxicity. A remarkable distinction was seen between analogs containing the chromophore aklavinone (AKV) (e.g. ACLA) which have a carboxymethyl group (COOCH3) at C-10 and drugs with a beta-rhodomycinone (RMN) chromophore with hydroxyl groups at C-10 and at C-11. Thus, RMN-containing analogs, including the aglycone RMN itself, effectively stimulated topo II-mediated DNA cleavage. In contrast, AKV-containing drugs inhibited DNA cleavage and antagonized cytotoxicity mediated by RMN-containing drugs. In OC-NYH/VM cells, exhibiting multidrug resistance due to an altered topo II phenotype (at-MDR), cross-resistance was only seen to the RMN-containing drugs whereas no cross-resistance was seen to the non-DNA cleaving AKV-containing compounds. Thus, our data show that one domain in the anthracycline is of particular importance for the interaction with topo II, namely the positions C-10 and C-11 in the chromophore, and further that at-MDR was circumvented by a COOCH3 substitution at position C-10. These findings may provide guidance for the synthesis and development of new analogs with activity in at-MDR cells.

Aclarubicin↗
PubMed1993

Phase II study of 4'-iodo-4'-deoxydoxorubicin in non-resectable non-small-cell lung cancer.

A total of 44 patients with previously untreated; non-resectable non-small-cell lung cancer (NSCLC) were treated with 4'-iodo-4'-deoxydoxorubicin (IDX), which is an analogue of doxorubicin with less cardiotoxicity. Patients received 80 mg/m2 i.v. every 3 weeks. Dose reductions were carried out for haematological toxicity. Response was assessed prior to each treatment according to WHO criteria. Among the 43 evaluable patients, 1 (2%; 95% confidence limits, 0-8%) achieved a partial response. Leucocytopenia of WHO grade 3 or 4 occurred in 64% of patients and corresponding thrombocytopenia grade 3 or 4 occurred in 30%. Of the 26 patients who were evaluated by measurements of the left ventricular ejection fraction (LVEF), 4 had a decline in LVEF of more than 15%, and 2 patients developed congestive heart failure. Myocardial biopsies were not done. In conclusion, IDX is not active in NSCLC at the applied dose and on the schedule used. Moreover, it does not seem possible to increase the dose intensity further due to the observed toxicity.

Carcinoma, Non-Small-Cell Lung↗