[Expression of genes of potential importance in the response to chemotherapy in osteosarcoma patients]. / Expression von Genen mit möglicher prognostischer Bedeutung für das Ansprechen auf Chemotherapie bei Patienten mit Osteosarkom - Gene mit möglicher prognostischer Bedeutung beim Osteosarkom -

BACKGROUND: The prognosis of patients with osteosarcoma has considerably improved over the last 30 years, mainly due to developments in chemotherapy. However, almost half of the osteosarcomas do not respond to chemotherapy. Predictive markers for chemosensitivity at diagnosis are desirable. PATIENTS AND METHODS: In order to investigate the potential of some chemotherapy-associated genes with respect to their predictive value for chemosensitivity, the mRNA expression of 8 genes was evaluated in the osteosarcomas of 45 patients and correlated to the histological response to neoadiuvant chemotherapy. RESULTS: ERCC4, a member of the nucleotide excision repair system, showed a orrelation between expression and the histologically evaluated response to chemotherapy. The expression of the other investigated genes HER-2/neu, HSP 70, GST, DHFR, BCRP, ERCC1 and Mlh1 showed no significant correlation to response to chemotherapy. CONCLUSION: In our retrospective analyses, low expression of ERCC4 was shown to be related to poor response to chemotherapy. The potential value of ERCC4 as response predictor has to be investigated in a prospective study.

The influence of the amalgam alloy on the survival of amalgam restorations: a secondary analysis of multiple controlled clinical trials.

Data from 14 independent controlled clinical trials on the oral behavior of Classes 1 and 2 amalgam restorations, with a follow-up between five and 15 years, were re-evaluated by secondary analysis for the influence of alloy composition on the survival of amalgam restorations. For the analysis, 3119 restorations were available, which were made from 24 different alloys by a group of seven operators. The alloys were divided into four groups according to their zinc content (zinc-containing and zinc-free) and their copper content (conventional and high-copper). During the follow-up of the trials, the restorations were annually assessed for failures, which were classified as to (1) restoration-, (2) restorative process-, and (3) patient-related reasons. With the restoration-related failures, survival functions of the restorations were estimated by alloy and alloy group. The total number of failed restorations was 481, of which 77% were restoration-related and 14% process-related. Eighty percent of the restoration-related failures were due to some form of fracture of the amalgam. Restorations of conventional zinc-free alloys had the shortest survival. After 13 years, only 25% survived. Zinc and a high copper content had an equally favorable influence on the survival rate, which was 70% after 13 years when either was present. The highest survival rates were of restorations of zinc-containing high-copper alloys: 85% after 13 years. The zinc and copper contents of the alloy contributed to the corrosion resistance of the amalgams, which in turn influenced the survival of the restoration. The current ISO Standard 1559 on alloys for dental amalgam should be modified to account for these factors that influence the survival of amalgam restorations.

An estimation of the size distribution of amalgam particles in dental treatment waste.

Regulations have been adopted in several countries of the European Union which prescribe that dental treatment waste water must be discharged via an amalgam separator device. Since the effectivity of the device strongly depends on the size of the amalgam waste particles, this size was evaluated in waste water samples from eight dental offices. Per sample, all solid particles were separated from the waste water by pressure filtration, then dried and divided into six fractions by being sieved over five sieves with decreasing mesh width. Of the particles in each fraction, the density was determined by picnometry, the mass by weighing, and the area and width by image analysis. For this analysis, width was defined as the dimension perpendicular to the length of the particles. By combining the density, area, and width determinations of all fractions, we obtained mass distributions per waste particle width of the samples. The proportional amalgam mass of the distributions was estimated with the measured density of the particle fractions and with a number of assumptions for the density of amalgam particles only and of other waste particles only. Each waste sample has its own characteristics with respect to the mass and density of the particle fractions. The size distribution of waste particles has a bimodal shape and consists of a distribution of small (width, 2 to 90 microns) and large particles (width, 160 to 5500 microns). For small particles with a width up to 60 microns, the influence of the assumptions on the estimation of the proportion amalgam of the waste mass distribution is minor when compared with the sampling error. By averaging the estimations over the samples, one can estimate the weight of amalgam particles with a width < 10 microns and < 50 microns, respectively, between 4 and 15% and between 15 and 30%. The smallest particles comprising 5% of the amalgam mass have an estimated width of up to 15 microns.

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

Long-term levodopa treatment in Parkinson's disease is typically associated with "motor side effects" consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p = 0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p = 0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with > 50% substitution by bromocriptine exhibited half the risk observed in those with < 30% (p = 0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p = 0.046). In conclusion, partial substitution of levodopa by bromocriptine (> 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.

Gamma-1 to beta-1 phase transformation in retrieved clinical amalgam restorations.

A number of important reactions occur in clinical amalgam restorations. This investigation examined the extent of the gamma-1 to beta-1 transformation in a variety of amalgam restorations retrieved from clinical trials. Sixteen restorations of five brands of low Cu amalgams, 28 restorations of four brands of high Cu blended amalgams, and eight restorations of three brands of high Cu single particle amalgams were studied. The extent of the gamma-1 to beta-1 transformation was determined by the ratio of the integrated intensity of the 002 beta-1 peak to the 330 gamma-1 peak in x-ray diffraction patterns. These values were correlated with age, marginal deterioration grade, and residual Hg content. Restorations consistently contained more beta-1 than comparable laboratory controls. Blended high Cu amalgams generally contained more beta-1, which was correlated with better marginal grades. Beta-1 content was inversely related to residual Hg content. No other associations could be established. A model of the complex interactions between corrosion and transformations was developed.

Bromocriptine lessens the incidence of mortality in L-dopa-treated parkinsonian patients: prado-study discontinued.

L-Dopa supplemented by a peripheral decarboxylase inhibitor is considered the most potent therapeutic regimen prolonging active life in Parkinsonian patients. The long-term benefit of therapy is limited by adverse effects, such as dyskinesia and on-off phenomena, which can be mitigated by the concomitant administration of dopamine agonists, such as bromocriptine. In order to quantify the beneficial impact of early combination therapy, a controlled clinical trial (PRADO: PRA videl1 + DO pa) in patients with early Parkinson's disease was carried out, whereby L-Dopa monotherapy (in a fixed combination with benserazide (DoBe) was being compared with the same combination plus bromocriptine (DoBeBro). Patients were recruited and treated by 101 practising neurologists in the Federal Republic of Germany and in Hungary. Twenty seven clinical university centers cross-checked the patients at regular intervals. The trial started with 3 months of DoBe monotherapy (median dose of 375 mg L-Dopa for both randomized groups) followed by gradual substitution of DoBe by bromocriptine over 3 months in one of the groups (250 mg L-Dopa/10 mg bromocriptine). The target medication was maintained from study months 6 to 54. Parkinsonian symptoms were classified according to the Webster rating scale, the Hoehn and Yahr scale and the Zung Self-Rating Depression Scale. Adverse events and life status were checked at regular intervals. Special emphasis was given to motor performance tests. 587 patients (302 in the DoBe group and 285 in the DoBeBro group) were available for intention-to-treat analysis. Both groups were homogeneous at baseline in all observed parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

[Gingko biloba extract EGb 761 and pentoxifylline in intermittent claudication. Secondary analysis of the clinical effectiveness]. / Gingko-biloba-Extrakt EGb 761 und Pentoxifyllin bei Claudicatio intermittens. Sekundäranalyse zur klinischen Wirksamkeit.

Clinical trials on the efficacy of EGb 761 and pentoxifylline are summarized in the context of their methods and results and compared with each other. All placebo-controlled, randomized and double-blind studies with the major target objective of "pain-free walking distance" were selected. The pentoxifylline studies were adopted from a survey of the existing literature in the English language, which has been brought up to date via DIMDI research. The studies on both active substances are fraught with similar difficulties as to method, and are not different as regards their quality. The increase in walking distance is highly variable, especially in the pentoxifylline studies. On average through each and all of the studies on both preparations, an increase of 45% (EGb 761) or 57% (pentoxifylline) in relation to initial values is here found. No differences in the documentation of efficacy and the clinical efficacy were discovered between the two substances, both of which are registered as effective substances in the treatment of peripheral arterial occlusion (pAO) in accordance with the Federal German Drugs Law (Arzneimittelgesetz, AMG) of 1976.

Primary combination therapy of early Parkinson's disease. A long-term comparison between the combined regimen bromocriptine/levodopa and levodopa monotherapy--first interim report.

The aim of this multicenter randomized prospective study in patients with early Parkinson's disease is to differentiate over a 4-year period between levodopa/benserazide monotherapy and the corresponding combination with bromocriptine by the assessment of motorial side effects, therapeutical benefit and fine motorial skills. Although there is circumstantial evidence, that partial substitution of levodopa by bromocriptine carries benefit in preventing late levodopa-specific side effects and delaying the declining therapeutical benefit, so far no knowledge has been available how levodopa and the corresponding combination with bromocriptine would compare on a long-term basis. Such study appears all the more important since there are experimental findings consistent with a neurotoxic effect of levodopa on the one hand and some 'protective' impact of bromocriptine on the other. As to the practical procedure of the comparison, all patients were first treated with a levodopa monotherapy for 3 months. This was a platform for the consecutive randomized splitting of the patients into two groups receiving either continuing levodopa therapy or combination therapy, based upon at least 40 +/- 10% substitution of levodopa by bromocriptine. The investigation methods included, besides the usual clinical rating scales (Webster, Zung, Hoehn and Yahr), an apparative test series, the so-called 'MLS', which allowed a sensitive and reliable assessment of fine motorial skills. The results of the first 3 months of treatment with levodopa monotherapy before the consecutive splitting into the two treatment regimens demonstrate that the randomization was successful and that there were no significant differences, that potentially might interfere with the drug-specific evaluation afterwards. The results of the substitution phase show that combined treatment permitted a mean reduction of the levodopa dosage by 40%, without deterioration of therapeutic response. In addition, feasibility of the overall approach based upon a sophisticated interplay between the practising neurologists (101) and the centers (27) was demonstrated.

Dose-response curves in antihypertensive combination therapy: results of a controlled clinical trial.

We studied the dose-response relationship for hydrochlorothiazide + triameterene and verapamil, comparing monotherapy with combined treatment in 216 hypertensive patients over 3 weeks of active treatment following a 2-week washout period with placebo. The study was a double-blind, randomly allocated, clinical trial using a two-factorial analysis of variance design. The results showed that the highest dose (a combination of 160 mg verapamil with 25 mg hydrochlorothiazide and 50 mg triameterene) also had the maximum antihypertensive effect. We further conclude that multifactorial trial designs are the most useful designs for analyzing the effects of combination therapy and therefore should be used more often.

Efficiency of acitretin in combination with UV-B in the treatment of severe psoriasis.

Compared with the antipsoriatic retinoid etretinate, the new aromatic retinoid acitretin represents an important advance due to its rapid elimination kinetics. Since in psoriasis vulgaris retinoids are used predominantly in combination regimens, we investigated the therapeutic efficacy of acitretin and UV-B compared with placebo and UV-B in a double-blind, randomized multicenter trial in 82 patients with severe psoriasis. They were treated with 35 mg of the study medication during the first 4 weeks of therapy and 25 mg thereafter, concomitantly with UV-B irradiation in increasing energy doses. Forty patients who underwent therapy with acitretin and UV-B and 38 patients who underwent therapy with placebo and UV-B were evaluated for efficacy. The target variables--psoriasis severity index and total UV-B dose--were reported at intervals of 2 weeks over a maximum period of 8 weeks. At the end of treatment, the psoriasis severity index decrease was 79% in the acitretin and UV-B group and 35% in the placebo and UV-B group. The response rate, defined as greater than or equal to a 75% decrease of the psoriasis severity index, was 60% for the combination treatment and only 24% for the control treatment. This treatment response was achieved with markedly lower cumulative UV-B energy. The median cumulative UV-B energy applied to reach 75% clinical improvement was 11.8 J/cm2 vs 6.9 J/cm2. Side effects showed a similar pattern in both groups. Our data show that the acitretin dramatically improves the results of UV-B treatment in patients with severe psoriasis. In addition, it markedly decreases the effective cumulative UV-B dose, thereby reducing the potential long-term hazards of UV irradiation. We conclude that the acitretin plus UV-B combination treatment represents a highly effective therapeutic regimen in severe psoriasis.

A controlled clinical study of amalgam restorations: survival, failures, and causes of failure.

The survival and modes of failure of amalgam restorations were investigated retrospectively. 2660 Class I or II lesions were restored and evaluated yearly or half-yearly for failures during the 30- to 84-month follow-up. Restorations with unacceptable margins were not counted as failures if no traces of secondary caries could be seen. 8% of the restorations were lost because of patient drop-out. Of the remaining restorations, 1% was replaced due to primary caries. Of the remaining number (2431), 9% failed because of all other reasons. The leading mode of failure was bulk fracture (4.6%), followed by tooth fracture (1.9%), and marginal ridge fracture (1.3%). For all other reasons, 0.8% of the restorations failed. Only two restorations were replaced because of secondary caries. The alloy selection in both conventional and high-copper categories significantly influenced the survival of the restorations for reasons directly related to the restoration.

Survival rates and reasons for failure of posterior composite restorations in multicentre clinical trial.

n a multicentre clinical trial consisting of 12 centres, 232 amalgam and 932 composite Class I and Class II restorations were placed in 447 adult patients. At the 4-year review 76 per cent of patients with 71 per cent of the restorations were retrieved. In 8 centres after 4 years and 4 centres after 5 years a total of 12 amalgam and 92 Occlusin restorations had been replaced, having been considered to have failed. The reasons for failure were classified into three types: Type 1, related to the restoration (loss of material, recurrent caries and unacceptable marginal adaptation); Type 2, related to the restorative process (pulpal involvement, primary caries, tooth fracture and unacceptable contact) and Type 3, caused by external factors. A greater proportion of the restorations of Occlusin were replaced than the restorations of amalgam. For the restorations of Occlusin the reasons for failure were: Type 1, 59 per cent; Type 2, 32 per cent and Type 3, 9 per cent. Loss of material and recurrent caries accounted for the failure of 35 and 13 restorations of Occlusin respectively. The main Type 2 reasons for failure of the restorations of Occlusin were pulpal involvement (16 restorations) and primary caries (9 restorations). The overall 4-year survival of Occlusin restorations relative to Type 1 and to Type 1 + Type 2 reasons for failure was 96 per cent and 93 per cent respectively. The centre was found to have a significant influence on the survival rate in both analyses.

Bulk fracture of amalgam restorations--a 5-year controlled clinical trial.

A controlled clinical study, containing 720 posterior amalgam restorations placed in a group of 103 adult patients by three dentists, was used for examination of the influences on the incidence of occlusal and approximal bulk fractures. These fractures were evaluated from black and white photographs, taken annually, of the occlusal surface of the restorations over a 5-year period, using a three point photo-rating scale for both fracture sites. The influence of the dentist as well as the influence of the alloy and tooth type were statistically analysed. The results of these analyses demonstrated that the dentist, as well as the alloy and tooth type, have a statistically significant influence on the incidence of bulk fracture of amalgam restorations.