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Biomedical subjects

F Ries

Publications and source records attributed to F Ries.

At least 37 records · Page 2Linked to original sources
PubMed1997

Multidrug resistance: molecular and clinical aspects.

Clinical drug resistance, a common and compromising side-effect during anticancer chemotherapy, is an acquired cellular resistance simultaneously to several cytotoxic drugs. Expression of the multidrug resistance gene (mdr) is one of the most-studied potential underlying mechanisms. The human mdr gene family encompasses two homologous members, the first of which, called the mdr1 gene, is the best-characterized so far. The human mdr1 gene has been shown to encode a membrane P-170 glycoprotein that, on the basis of its structure, is considered to act as a drug-efflux pump excreting various drugs from cells. The human mdr1 gene is thus a major regulated gene playing an important role in the molecular mechanism of multidrug resistance. Its bipartite structure of two similarly organized halves is explained by a gene fusion event during evolution. However, the clinical significance of this particular feature, if it seemed obvious in the 1980s as a factor producing chemoresistance, is currently revised-being a marker of tumor aggressiveness rather than the cause of drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[New diagnostic approaches to deep venous thrombosis].

This review summarizes a number of recent articles reconsidering the use of phlebography as the golden standard for deep venous thrombosis. Compression ultrasound and color-coded duplex doppler seem to be reasonably sensitive to provide safety in detecting lower limb thrombosis while less invasive. A clinical risk factor panel may further enhance diagnostic security.

Humans↗
PubMed1997

Phase I/II clinical trial of epirubicin and paclitaxel followed by granulocyte colony-stimulating factor in a 2-week schedule in patients with advanced or metastatic breast cancer.

Anthracyclines and taxanes are the most potent cytotoxic agents available for treating breast cancer. With combined therapy (either epirubicin or doxorubicin with paclitaxel [Taxol; Bristol-Myers Squibb Company, Princeton, NJ]), response rates of 70% to 90% have been reported. To achieve a maximal dose intensity per week, we decided to combine epirubicin 100 mg/m2 with escalating doses of paclitaxel, at successive dose levels of 135, 150, 165, and 180 mg/m2 in a 2-week schedule, with administration of subcutaneous granulocyte colony-stimulating factor 5 microg/kg from days 2 through 10. To date, 16 patients have been included, with six patients treated at level 1 (100/135 mg/m2 epirubicin/paclitaxel), four at level 2 (100/150 mg/m2), four at level 3 (100/165 mg/m2), and two at level 4 (100/180 mg/m2). The median age of all subjects is 55 years (range, 41 to 65 years). Five patients had received chemotherapy in the adjuvant setting. Of 79 treatment courses, 78 are evaluable for toxicity. The mean number of courses per patient is six (range, two to six courses). At dose level 1, one episode of febrile neutropenia with grade 4 thrombocytopenia occurred. No grade 4 extrahematologic adverse event has been noted so far. At dose level 2, we achieved a dose intensity per week of epirubicin 50 mg/m2 and paclitaxel 75 mg/m2, as expected. At dose level 3, the dose intensity per week was 47.5 mg/m2 and 78.8 mg/m2, respectively (expected 50 and 82.5 mg/m2). The current response rate, evaluated in 14 of 16 patients, is four complete remissions and eight partial remissions, for an overall response rate of 85%. Two patients had stable disease. Granulocyte colony-stimulating factor following epirubicin/paclitaxel on a 2-week schedule permits a very high dose intensity per week for both drugs and produces a high response rate in patients with advanced or metastatic breast cancer.

Adult↗
PubMed1996

Epirubicin cardiotoxicity: a study comparing low- with high-dose-intensity weekly schedules.

Epirubicin is one of the less cardiotoxic alternatives to doxorubicin. We were interested in studying the cardiotoxic effect of the total cumulative dose, and weekly schedules of low compared to high dose intensity. Fifty-seven patients were treated with different epirubicin-containing regimens. We confirm the classical notion that total cumulative doses of less than 600 mg/m2 do not induce significant cardiotoxicity, whereas doses above 600 mg/m2 are associated with a trend towards cardiotoxicity. Patients receiving a high weekly dose intensity (> 40 mg/m2), however, did have a significantly lower incidence of cardiotoxicity than those receiving a low dose intensity per week (< 40 mg/m2) (22.8% versus 50%; P < 0.05). We identified the association of a dose intensity of more than 40 mg m-2/ week-1 and a cumulative dose of 400-899 mg/m2 or a dose intensity of less that 40 mg m-2/week-1 and a cumulative dose of less than 400 mg/m2 to have the lowest incidence rate of cardiotoxicity. We conclude from this study that epirubicin in weekly schedules of high dose intensity is not more cardiotoxic than in weekly schedules of low dose intensity.

Adult↗
PubMed1996

[Endovascular balloon occlusion test of the internal carotid artery with increased hemodynamic monitoring for determination of circulatory reserve before planned carotid occlusion].

PURPOSE: To evaluate stroke risk assessment of balloon test occlusion of the internal carotid artery (ICA) with enlarged haemodynamic monitoring prior to permanent ICA occlusion. MATERIAL AND METHODS: 24 patients with cervical metastasis (n = 18), cavernous meningiomas (n = 3) or inoperable cavernous aneurysms (n = 3) were examined. The test occlusion was monitored by EEG, neurological examinations and transcranial Doppler sonography of the ipsilateral middle cerebral artery with evaluation of the cerebrovascular reserve capacity. Additionally 99mTc-HMPAO-SPECT imaging was added showing the perfusion during test occlusion. RESULTS: In one (4%) patient the test occlusion had to be interrupted previously due to an acute neurological deficit. This patient and two (8%) patients with highly pathological test results in SPECT and TCD were excluded from permanent carotid occlusion. In 6 (25%) patients quantitative TCD monitoring could improve the stroke risk assessment by differentiating the patients in a low and high risk group. 6 (25%) patients were definitely occluded without haemodynamic complications, but two patients suffered from embolic infarctions which cannot be predicted by this procedure. CONCLUSIONS: The multimodal balloon test occlusion with enlarged haemodynamic monitoring allows haemodynamic stroke risk assessment prior to permanent occlusion of the ICA.

Adult↗
PubMed1996

ALS.

The cause of ALS is not known but there are four main hypotheses about its etiology. First, an excess of extracellular glutamate in the CNS of patients with ALS resulting from a defect in glutamate reuptake may have excitotoxic effects on motor neurons. Clinical trials suggest the antiglutamate agent riluzole improves survival of patients with the disease. Second, ALS may be an autoimmune disease, but immunologically-based treatments have been unsuccessful. The third hypothesis is that ALS results from a lack of neurotrophic growth factors. Preliminary results from clinical trials indicate recombinant human insulin-like growth factor I offers therapeutic promise. Finally, familial ALS is sometimes linked to a gene encoding a Cu/Zn-binding superoxide dismutase; the mutations in ALS are thought to result in gain of function of dismutase activity. The involvement of superoxide dismutase in sporadic ALS is unclear.

Amyotrophic Lateral Sclerosis↗
PubMed1996

What Does Multidrug Resistance (MDR) Expression Mean in the Clinic?

For 15 years, an overflowing literature has been published about MDR-1 gene expression in tumor cell lines and in cancerous tissues at various stages of disease and treatment (chemotherapy-naive, during treatment and at relapse). However, the clinical significance of this particular feature, if it seemed obvious in the 1980s as a factor responsible for the development of chemoresistance, is currently reconsidered. MDR-1 gene expression seems to be, at least in some instances, a hallmark of tumor cell aggressiveness and of chemoresistance rather than its cause, the mechanisms of which are probably far more complex. The failure of MDR reversal trials might result from the misunderstood or overvalued role of MDR expression in cancer cells rather than from a lack of control of pharmacological parameters. This review summarizes recent data and hypothesis about the expression of P-170 and its clinical significance in some important human tumor types, suggesting that it should rather be considered in the future as an adverse prognostic factor.

Journal Article↗
PubMed1995

The human mdr1 (multidrug-resistance) gene harbours a long homopyrimidine.homopurine sequence next to a cluster of Alu repeated sequences in intron 14.

In order to identify specific DNA sequences useful as 'genetic landmarks' in the construction of a complete map of the human mdr1 (multidrug-resistance) gene, we investigated the introns in the central region. In intron 14, we identified a long stretch of a homopyrimidine.homopurine sequence most probably adopting an unconventional DNA conformation, followed by a cluster of three Alu repeated sequences in an inverted orientation. Here, we describe the structure, formation and nucleotide sequence of these DNA elements.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Repetitive DNA sequences located in the central region of the human mdr1 (multidrug resistance) gene may account for a gene fusion event during its evolution.

The mdr1 gene, first member of the human multidrug-resistance gene family, is a major gene involved in cellular resistance to several drugs used in anticancer chemotherapy. Its product, the drug-excreting P-glycoprotein, shows a bipartite structure formed by two similar adjacent halves. According to one hypothesis, the fusion of two related ancestral genes during evolution could have resulted in this structure. The DNA sequence analysis of the introns located in the region connecting the two halves of the human mdr1 gene revealed a highly conserved poly(CA).poly (TG) sequence in intron 15 and repeated sequences of the Alu family in introns 14 and 17. These repeated sequences most likely represent "molecular fossils" of ancient DNA elements which were involved in such a recombination event.

Base Sequence↗
PubMed1995

[Multimodal carotid occlusion test for determining risk of infarct before therapeutic internal carotid artery occlusion].

UNLABELLED: In patients with head and neck carcinoma and extensive cervical metastasis, the topographic and functional relationship of the tumor to the carotid artery is highly important. In case of suspected carotid infiltration, the possibility of a carotid resection or a prosthetic replacement has to be considered preoperatively. Treatment of cavernous carotid aneurysms may also require sacrificing the internal carotid artery (ICA). An interdisciplinary test occlusion of the ICA was performed to assess cerebral collateral circulation prior to permanent carotid occlusion. MATERIALS AND METHODS: Fifty-two patients with cervical tumors (n = 45) or inoperable aneurysms (n = 7) were examined. The endovascular balloon test occlusion (BTO) of the ICA was combined with monitoring of the neurological status, cardiovascular status (EKG, blood pressure), cortical function (EEG), and single photon emission CT (SPECT) imaging of the regional cerebral blood flow (rCBF) with 99mTechnetium-HMPAO. In the last 24 patients, transcranial Doppler sonography (TCD) of the ipsilateral middle cerebral artery (MCA) was added for direct hemodynamic monitoring during BTO. In order to improve the diagnostic value of the test results and to simulate hemodynamic crisis, the cerebrovascular reserve capacity was then evaluated with acetazolamide (Diamox). RESULTS: BTO could be performed without neurological complications or carotid dissection. In eight (15%) patients BTO had to be interrupted previously due to neurological symptoms or a delta-EEG. These patients and patients with highly pathological test results in SPECT imaging (n = 9) or TCD (n = 3) were excluded from permanent carotid occlusion. Ten (19%) patients were definitely occluded without hemodynamic complications, but two patients suffered embolic infarctions, which can not be predicted by this procedure. In two patients with a severe hypoperfusion in SPECT imaging, the ICA had to be ligated under emergency conditions following a carotid rupture. Predictably, a hemodynamic infarction occurred postoperatively in both patients. CONCLUSIONS: The multimodal BTO with brain perfusion imaging (HMPAO-SPECT) and quantitative blood flow monitoring (TCD) allows a hemodynamic stroke risk assessment prior to permanent occlusion of the ICA. The procedure is important for planning of the therapeutic strategy and for the preoperative dialogue with the patient. Embolic ischemic complications can not be predicted.

Adult↗
PubMed1994

A four-drug combination chemotherapy with cisplatin, mitomycin, vindesine and 5 fluorouracile: a regimen associated with major toxicity in patients with advanced non-small cell lung cancer.

The purpose of this study was to determine the activity of a 4-drug combination chemotherapy: cisplatin, mitomycin C, vindesine and 5-fluorouracil (5-FU) in patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy consisted of the administration of cisplatin (30 mg/m2 d 1-4), mitomycin C (10 mg/m2 d 1), vindesine (3 mg/m2 d 1) and 5-FU (1 g/m2 d 1-4 by continuous intravenous infusion). In patients older than 70 years, and in those who received prior irradiation or chemotherapy, cisplatin and 5-FU were omitted on day 4. Courses were repeated every 4 weeks and evaluation of response was performed after the first 2 courses. In case of response, treatment was continued until best response or untolerable toxicity. Among 182 eligible patients, 75% had received no prior therapy; 41% had locoregional disease and 59% metastatic disease; 41% lost more than 5% of their pretherapy body weight. A 34% objective response rate was observed in the 164 evaluable patients (31% in all the eligible patients) including 4 complete and 52 partial responses. Patients with locoregional disease had a significantly better response rate than those with metastases (44% vs 27%). The overall median survival was 26 weeks. Significant hematological toxicity was documented but the most serious adverse event was the occurrence of 18 (10%) cardiac or sudden deaths. These toxic deaths were significantly associated with a 5% loss of body weight prior to therapy. The addition of 5-FU to combination of cisplatin, mitomycin C and vindesine does not improve antitumoral effect but results in very significant cardiac toxicity.

Adult↗
PubMed1994

A four-drug combination chemotherapy with cisplatin, mitomycin, vindesine and 5-fluorouracil. A regimen associated with major toxicity in patients with advanced non-small lung cancer. European Lung Cancer Working Party.

PURPOSE: To determine in patients with advanced non-small cell lung cancer the activity of a 4-drug combination chemotherapy. PATIENTS AND METHODS: Chemotherapy consisted of the administration of cisplatin (30 mg/m2 d 1-3 or 4), mitomycin C (10 mg/m2 d 1), vindesine (3 mg/m2 d 1) and 5-FU (1 g/m2 d 1-3 or 4 by continuous intravenous infusion. RESULTS: 182 were eligible patients. A 34% objective response rate was observed in the 164 evaluable patients. The overall median survival was 26 weeks. The most serious adverse event was the occurrence of 18 (10%) cardiac or sudden deaths. These toxic deaths were significantly associated with a > or = 5% loss of body weight prior to therapy. CONCLUSIONS: The regimen studied resulted in a very significant cardiac toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes.

Previous studies have shown that intravenous immunoglobulin (IVIg) therapy is useful prophylaxis against infection in patients with secondary hypogammaglobulinaemia due to a low-grade lymphoproliferative disease. This randomized double-blind study was undertaken to determine prospectively the dose regime required. 34 such patients received IVIg at either 500 or 250 mg/kg every 4 weeks for 1 year. There was no significant difference in the rates of serious infections between the two groups of patients, which were well matched for disease and laboratory parameters. The rates of infection seen were similar to those in IVIg groups of previous studies and strikingly different from those in the placebo group in the previously randomized placebo-controlled study.

Aged↗
PubMed1994

Phase II randomized trial comparing high-dose cisplatin with moderate-dose cisplatin and carboplatin in patients with advanced non-small-cell lung cancer. European Lung Cancer Working Party.

PURPOSE: A phase II randomized trial was conducted in patients with advanced non-small-cell lung cancer (NSCLC) to determine if the combination of moderate-dose cisplatin and carboplatin was active (primary end point) and could avoid the long-term limiting (renal, auditive, neurologic) toxicity of high-dose cisplatin, which prevents prolonged administration (secondary end point). PATIENTS AND METHODS: One hundred twenty-one patients, registered between April 1990 and September 1991, were randomized to receive high-dose cisplatin (120 mg/m2 intravenously [IV] on day 1) or a combination of moderate-dose carboplatin (200 mg/m2 IV on day 1 and moderate-dose cisplatin (30 mg/m2 IV on days 2 and 3). One hundred nine patients were eligible: 56 in the cisplatin arm and 53 in the combined arm; 52 and 47, respectively, were assessable for response. All had stage IV disease (or stage IIIB with pleural effusion) and none had received prior chemotherapy. RESULTS: There was a 23% objective response rate to cisplatin (23% of the eligible patients) and a 22% response rate to cisplatin plus carboplatin (21% of the eligible patients). The overall survival rate was not significantly different between the two study arms, but responders in the combined arm survived significantly longer than those in the high-dose cisplatin arm (respective median survival durations, 66 and 30 weeks). Although there was no difference between the arms for alopecia, emesis, and leukopenia, the combined arm was significantly associated with more thrombocytopenia (although rarely severe) and, more importantly, with less renal (19% v 36%), auditive (4% v 16%), and neurologic (0% v 16%) toxicity of any grade. CONCLUSION: The regimen combining moderate-dose cisplatin and carboplatin was active against advanced NSCLC and significantly less toxic than high-dose cisplatin.

Actuarial Analysis↗