A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer.

BACKGROUND: Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy. In a phase II study in the second-line in patients with metastatic colorectal cancer (mCRC), we found that chronomodulated XELOX (XELOX(30Chron)) was a well-tolerated regimen with potentially reduced toxicity. PATIENTS AND METHODS: One hundred and forty-one patients with unresectable mCRC were enrolled in a randomized study comparing standard XELOX (XELOX(30)), arm A, and XELOX(30Chron), arm B-both with short-time infusion of oxaliplatin-with the primary aim of reducing overall toxicity. RESULTS: Overall toxicity grade 2-4 was 90% versus 85%, P = 0.47 and grade 3-4 was 31% versus 37%, P = 0.6 in arm A and B, respectively. We found no significant differences in median overall survival (17.6 versus 15.5 months; P = 0.068) and median progression-free survival (8.9 versus 8.8 months; P = 0.7). The incidence of grade 3 neuropathy was 16% in arm A and 19% in arm B (P = 0.7) after a cumulative dose of oxaliplatin of 1000 mg/m(2). CONCLUSION: XELOX(30Chron) does not reduce toxicity or improve efficacy. A 30-min infusion of oxaliplatin is safe and does not increase the severity of chronic neuropathy.

Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil.

BACKGROUND: Oxaliplatin in combination with capecitabine prolongs survival in patients with metastatic colorectal cancer (mCRC). Chronomodulation might reduce toxicity and improve efficacy. PATIENTS AND METHODS: A phase II study examining chronomodulated XELOX(30) (XELOX(30chron)): oxaliplatin: 130 mg/m(2) on day 1, as a 30-min infusion between 1 and 3 p.m. Capecitabine: total daily dose of 2000 mg/m(2), 20% of the dose between 7 and 9 a.m. and 80% of the dose between 6 and 8 p.m. in patients with mCRC resistant to irinotecan. Seventy-one patients were enrolled. Response rate was 18%; median progression-free survival 5.1 months and median overall survival (OS) 10.2 months. Platelet count and performance status were significantly correlated to OS in multivariate analyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2% of patients, respectively, other grade 3 toxic effects were as follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experienced grade 4) and palmoplantart erytem 9%. CONCLUSION: XELOX(30chron) is a convenient second-line regimen with efficacy and safety profile similar to other oxaliplatin schedules. To further investigate chronomodulated XELOX, we have started a Nordic randomised phase II study comparing XELOX(30) and XELOX(30chron) as first-line therapy in patients with mCRC.

Influence of epigallocatechin gallate and phenolic compounds from green tea on the growth of Oenococcus oeni.

AIMS: To investigate the effect of phenolic compounds on the growth of Oenococcus oeni. METHODS AND RESULTS: Oenococci are usually grown in media often supplemented with complex additives such as tomato juice. In order to improve our knowledge about the growth requirements of oenococci, we added several juices and leaf extracts such as green tea to the culture media and screened them for growth-stimulating substances to substitute complex supplements such as juices by more defined components. We found that also green tea could cause a growth stimulation of Oenococcus oeni strain B2. CONCLUSIONS: Further experiments showed that the stimulating effect was as a result of the phenolic compounds of green tea, especially epigallocatechin gallate (EGCG). On the other hand, EGCG could also inhibit the growth of O. oeni strain B2 just depending on its concentration. SIGNIFICANCE AND IMPACT OF THE STUDY: Individual catechins should have a minor influence on the growth of oenococci during wine making as their concentration in grapes is <30 mg kg(-1) grape. Whether there is a synergistic effect of the different catechins in wine has to be investigated.

Patient preference for oral or intravenous chemotherapy: a randomised cross-over trial comparing capecitabine and Nordic fluorouracil/leucovorin in patients with colorectal cancer.

Until recently, fluorouracil (F) and leucovorin (L) had been considered the standard therapy for patients with colorectal cancer. However, several studies have shown that oral therapy with UFT/L or capecitabine is as effective as intravenous (i.v.) therapy and in addition it is claimed that patients prefer oral to i.v. therapy as long as efficacy is not compromised. In a previous crossover study by Borner et al., it was shown that 26 out of 31 patients preferred oral therapy with UFT/L to i.v. FL (Mayo regimen) [Borner M, Schöffski P, de Wit R, et al. Patient preferences and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002;38:349-58]. The objective of the present study was to investigate patient preference between i.v. FL and oral capecitabine using the design described by Borner. The Nordic FL schedule is a bolus regimen with efficacy comparable to other i.v. regimens and at the same time a very tolerable and easy administered regimen. We randomised 60 patients with colorectal cancer (53 patients received adjuvant therapy and seven patients received palliative therapy) to start therapy with either oral capecitabine or Nordic bolus FL. After 6 weeks of therapy (two courses of capecitabine or three courses of Nordic FL) patients were crossed over to the other regimen. After having completed 12 weeks of therapy the patients (49 evaluable patients) were asked to choose one of the regimens for a further 12 weeks of therapy. Patients had more side-effect when treated with capecitabine and a total of 30 out of 49 (61%) preferred the Nordic FL regimen and 19 (39%) preferred capecitabine. We conclude that patients prefer the regimen with less toxicity and that it is of minor importance whether the medication is administrated orally at home or i.v. at the hospital.

Nucleotide sequence, genetic organization and expression strategy of the double-stranded RNA associated with the '447' cytoplasmic male sterility trait in Vicia faba.

The entire nucleotide sequence of the double-stranded (ds) RNA associated with the unconventional '447' cytoplasmic male sterility (CMS) trait in Vicia faba was determined from overlapping cDNA clones and by RT-PCR. Confirming previous observations, it was found that the negative-strand was continuous and 17,635 nt long, while the positive-strand featured an interruption, probably a nick, that could potentially define two subgenomic RNAs of 2735 nt and 14,900 nt, with the smaller RNA being located on the 5' side. The entire positive-strand could encode a single in-frame ORF starting at the first AUG at position 42-44 and ending with a TGA at 17,517-17,519. This long potential polypeptide with a predicted molecular mass of 654,109 is the largest described to date in the plant kingdom and contains conserved amino acid sequence motifs typical of viral helicases and RNA-dependent RNA polymerases (RDRP). Only limited sequence homology was detected with the ORF B encoded by the hypovirulence-associated dsRNA of chestnut blight fungus, a dsRNA replicon similarly contained in host-derived membranous vesicles and considered to share a common ancestry with potyviruses. By contrast, the helicase and RDRP domains were in the same respective arrangement and shared extensive sequence homologies with those identified in the polyprotein encoded by the dsRNA isolated from Japonica rice, another dsRNA replicon featuring a specific nick in the positive-strand. Although no proteolytic self-cleavage activity has yet been demonstrated, it appears likely that this long ORF is a polyprotein that undergoes proteolytic maturation, with one of the polypeptides derived by self-cleavage being the determinant of the CMS trait.

A brief history and current status of metal-and ceramic surface-conditioning concepts for resin bonding in dentistry.

The bond strength of resin to metal or ceramic surfaces has been increased with the introduction of various surface-conditioning techniques. The principles of currently used conditioning methods and clinical trials with these methods are summarized. The advances in surface-conditioning methods have increased bonding to a high level; however, interpretation of the literature review indicates that chemical bonding by means of recently introduced techniques provides better results than does mechanical bonding.

Unusual structure of the double-stranded RNA associated with the '447' cytoplasmic male sterility in Vicia faba.

The 16.7 kbp dsRNA specific to the '447' cytoplasmic male sterility (CMS) line of Vicia faba was labelled in vitro with [alpha-32P]ATP and poly(A) polymerase, and by T4 RNA ligase-mediated addition of [32P]pCp. Analysis of the reaction products under denaturing conditions revealed in both cases extensive labelling of a 4.5 kb ssRNA, already detected in previous experiments in which the RNA-dependent RNA polymerase associated with the dsRNA was allowed to pursue RNA synthesis on preinitiated complexes. Mobility shift analysis of total pCp-labelled dsRNA revealed not two but three different 3' termini. The most prominent sequencing pattern corresponded to the 4.5 kb ssRNA, indicating that this RNA species has a preferentially accessible, free 3' OH extremity. Northern blot analysis of the denatured dsRNA confirmed that the 4.5 kb ssRNA is a subgenomic mRNA and detected its counterpart of about 12 kb. Nearly all 16.7 kbp dsRNA molecules featured an interrupted positive-sense strand, indicating a marked prevalence of transcription over replication complexes. This unusual strategy of transcription by a strand displacement mechanism, following initiation at an internal discontinuity, is compared with that of other dsRNA viruses or defective viruses, and is discussed in relation to the expression of the CMS trait.

Cytotoxic treatment of metastatic breast cancer. Which drugs and drug combinations to use?

Although the optimal efficacy of cytotoxic therapy plateaued in the 1970s, no consensus yet exists regarding which cytotoxic combination to offer as first-line therapy for metastatic breast cancer. Comparison of a combination of CAF/CEF with other cytotoxic combinations reveals that an anthracycline-containing regimen not only increases response rate, but also improves time to progression and survival. Regarding appropriate duration of cytotoxic therapy, randomized trials indicate that therapy in excess of 6 months is beneficial. Although the main objective of cytotoxic therapy in patients with metastatic disease is to palliate symptoms at the least toxic cost, the finding that adjuvant cytotoxic therapy improves survival provides a clinical and ethical rational for continued research into new drugs and combinations in the hope that new strategies can be employed not only against metastatic breast cancer but may be applied with benefit also in the adjuvant situation.

[Tensile strength of dental porcelains]. / Festigkeit dentalkeramisicher Massen.

Flexural, compressive and tensile strength as well as the modulus of elasticity of 15 different dental ceramics were evaluated. Conventional dental ceramics differed insignificantly in their mechanical properties. By testing new products like Cerec 2 and especially In-Ceram there was found an evident increase in inner strength. For comparison the strength of some other new ceramics as Dicor increased slightly related to conventional ceramics.

[Bond strength of etched In-Ceram(R) to tooth enamel]. / Haftfestigkeit von geätztem In-Ceram(R) an Zahnschmelz.

Laminate veneers of porcelain may be suitable for the correction of enamel anomalies of incisors. They are, however, within the mouth subjected to high mechanical loads, aggressive humidity and abrupt temperature changes. Consequently high strength porcelain and a stable bond between the veneer and the enamel are mandatory. To prepare a retentive surface microscopic investigations reveal that etching of In-Ceram porcelain is less effective than etching of Biodent porcelain, which we investigated as a reference material. This is in accordance with the observed insufficient bond strength between In-Ceram porcelain and enamel. Therefore we conclude that under the environmental condition of the mouth In-Ceram porcelain, even if it is layered with Vitadur porcelain, can not be durably bonded to enamel at present.

The double-stranded RNA associated with the '447' cytoplasmic male sterility in Vicia faba is packaged together with its replicase in cytoplasmic membranous vesicles.

The 447 male sterility trait in Vicia faba is strictly correlated with the presence of well-defined membranous vesicles or 'cytoplasmic spherical bodies' not found in fertile isogenic maintainer plants, and by the occurrence of a discrete high molecular weight double-stranded RNA. We have purified these cytoplasmic membranous vesicles and find that they contain the dsRNA together with an RNA-dependent RNA polymerase whose activity depends upon the presence of Mg2+, requires the four-nucleoside triphosphates and is unaffected by inhibitors of cellular transcriptases, e.g. alpha-amanitin and Actinomycin D. The dsRNA can be labelled in vitro by incubating the cytoplasmic vesicles with radioactive NTPs, and the RNA synthesized in vitro is also in a double-stranded form as judged by its resistance to RNase digestion at high salt and its behaviour upon CF-11 chromatography. Treatment of the vesicles with a non-ionic detergent releases the dsRNA in the form of a complex with the RNA-dependent RNA polymerase. The enzyme can still carry out the specific synthesis of dsRNA in these solubilized complexes. The cytoplasmic vesicles therefore isolate this vertically transmitted, self-replicating dsRNA from the cellular milieu: the possible mode of action and relevance of this novel genetic element to the 447 cytoplasmic male sterility trait are discussed.

[Specific adhesive bonding of air-brushed alloy surfaces]. / Spezifische adhärente Kleubung abgestrahlter Legierungsoberflächen.

In vitro test have been conducted to examine if NiCr, CoCr and PdAg alloys air-brushed with aluminium oxide (grain size 250 microns) can be bonded in such a way that the bond resists humidity. After 150 days in water at 37 degrees C the high initial bond strength values of NiCr or CoCr alloys bonded with the modified bis-GMA adhesive Panavia remained unchanged. In the PdAg alloy specimens bonded with Panavia, the initial bond strength were approx. 60% lower than those of the NiCr and CoCr alloys, and were further reduced by approx. 33% after 150 days. As soon as after 15 minutes, the modified bis-GMA adhesive is cured to such an extent that functional loading of the bond interface is possible.