Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours.

To evaluate the toxicity, pharmacological and biological properties of ATN-161, a five -amino-acid peptide derived from the synergy region of fibronectin, adult patients with advanced solid tumours were enrolled in eight sequential dose cohorts (0.1-16 mg kg(-1)), receiving ATN-161 administered as a 10-min infusion thrice weekly. Pharmacokinetic sampling of blood and urine over 7 h was performed on Day 1. Twenty-six patients received from 1 to 14 4-week cycles of treatment. The total number of cycles administered to all patients was 86, without dose-limiting toxicities. At dose levels above 0.5 mg kg(-1), mean total clearance and volume of distribution showed dose-independent pharmacokinetics (PKs). At 8.0 and 16.0 mg kg(-1), clearance of ATN-161 was reduced, suggesting saturable PKs. Dose escalation was halted at 16 mg kg(-1) when drug exposure (area under the curve) exceeded that associated with efficacy in animal models. There were no objective responses. Six patients received more than four cycles of treatment (>112 days). Three patients received 10 or more cycles (> or =280 days). ATN-161 was well tolerated at all dose levels. Approximately, 1/3 of the patients in the study manifested prolonged stable disease. These findings suggest that ATN-161 should be investigated further as an antiangiogenic and antimetastatic cancer agent alone or with chemotherapy.

A phase I study of the oral combination of CI-994, a putative histone deacetylase inhibitor, and capecitabine.

BACKGROUND: This study was conducted to determine the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetics of the putative histone deacetylase inhibitor CI-994 in combination with capecitabine. PATIENTS AND METHODS: Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. Capecitabine was administered in twice daily divided doses, and CI-994 was given as a single daily dose. In schedule A, 26 patients were treated with capecitabine 1650 mg/m2/day and CI-994 for 2 weeks of a 3-week cycle. In schedule B, six patients received capecitabine 1650 mg/m2/day for two 3-week cycles and CI-994 for 5 of 6 weeks. In schedule C, 22 patients were treated with capecitabine 2000 mg/m2/day and CI-994 for 2 of 3 weeks. RESULTS: At the MTD, the principal dose-limiting toxicity was thrombocytopenia. The pharmacokinetics of CI-994 were unaltered by capecitabine, and there was no correlation between body surface area and major pharmacokinetic parameters. Platelet count nadir was best predicted by the observed maximal concentration (C(max)) of CI-994. CONCLUSIONS: The recommended phase II dose is 6 mg/m2 (or 10 mg) of CI-994 in combination with capecitabine 2000 mg/m2/day for 2 weeks of a 3-week cycle.

Quantitative assessment of brainstem development in Joubert syndrome and Dandy-Walker syndrome.

Key features of Joubert syndrome include developmental delay, hypotonia, hyperpnea and apnea, oculomotor apraxia, and the presence of the molar tooth sign on axial imaging through the brainstem isthmus--the junction of the pons and mesencephalon. Interestingly, 1 in 10 patients with Joubert syndrome has abnormal cerebrospinal fluid collections misdiagnosed as Dandy-Walker variants. Because of important differences in patient management, genetic counseling, and prognosis between these conditions, we undertook a study to determine if the brainstem isthmus is normal in Dandy-Walker syndrome. Using standard landmarks, we evaluated development of the isthmus in normal subjects and in subjects with Joubert syndrome and Dandy-Walker syndrome. Four of five brainstem measures increased with age in normal subjects. In subjects with Joubert syndrome, the depth and length of the interpeduncular fossa were increased, and the width of the isthmus was decreased. In subjects with Dandy-Walker syndrome, the width of the brainstem isthmus was normal, and the molar tooth sign was absent. Although the pons can be hypoplastic in Dandy-Walker syndrome, we conclude that the pontomesencephalic junction is normal. Thus, the molar tooth sign can effectively distinguish between Joubert and Dandy-Walker syndromes. Genetic heterogeneity or epigenetic factors may account for abnormal cerebrospinal fluid collections in some cases of Joubert syndrome.

Possible role of high-dose corticosteroids in the treatment of cat-scratch disease encephalopathy.

Approximately 2% of the estimated 24,000 patients in the United States who contract cat-scratch disease annually develop neurologic complications. Between 1989 and 1999, 36 patients were admitted to our hospital with cat-scratch disease; 25% had neurologic complications, and the majority experienced lengthy hospital stays. We describe a case of cat-scratch disease encephalopathy in a 4-year-old girl who responded to high-dose corticosteroid therapy. Further studies are warranted to determine if corticosteroid therapy shortens the duration of symptoms, lessens the severity of disease, and ultimately improves the outcome for patients with cat-scratch disease encephalopathy.

Realistic standards for quality assurance.

Standards are playing an increasingly important role in the field of quality assurance for dental and laboratory working conditions and performances. Evaluation, in terms of characteristics and importance, varies with the individual position and views of the respective institutions and authors but realistic standards are required to implement meaningful quality assurance measures.

11p deletions and breakpoints in squamous cell carcinoma: association with altered reactivity with the UM-E7 antibody.

The UM-E7 monoclonal antibody raised against the UM-SCC-I human squamous cell carcinoma (SCC) cell line identifies a cell surface antigen that is strongly expressed in normal tissues. The locus (MICI) controlling the expression of E7 and related cell surface antigens has been mapped to chromosome band 11p13. This band has been identified as a region of cancer-associated aberrations and as the probable locus of a tumor suppressor gene. Although E7 antigen expression is strong in normal keratinocytes, it varies among squamous carcinoma cell lines. Some SCC lines (12/26) exhibit weak expression of the E7 antigen, whereas other SCC cell lines (14/26) and 21 cell lines from other tumor types express the antigen strongly. On the basis of these observations and of mapping data, we postulated that low E7 antigen expression in a subset of SCC cell lines might be associated with chromosomal rearrangement or deletion involving the E7 locus on 11p. Fully evaluable karyotypes were prepared from 19 SCC cell lines, including 11 with weak and eight with strong E7 expression. Eight of the 11 lines with weak E7 expression had 11p abnormalities. Four of these contained 11p deletions, and four others had a breakpoint in 11p. In contrast, none of the cell lines in the group with strong E7 expression had an 11p deletion, although one had a rearrangement with an 11p breakpoint. In the four tumors with visible 11p deletions, the smallest region of overlap corresponded to the 11p13-p14 region. The mean log10 50% endpoint E7 titer in the group with 11p deletions or breakpoints was nearly two orders of magnitude lower than that of the lines with no 11p abnormality (1.95 +/- 0.53) (P less than 0.02). Our results indicate that the UM-E7 antibody identifies tumors with 11p13-p14 deletions and other 11p rearrangements and that the 11p region is a site of nonrandom chromosome rearrangement in a subset of human squamous cancers. The strong association of loss of antigen expression with visible 11p deletion or rearrangement in some tumors suggests that other tumors with this phenotype may contain submicroscopic lesions of 11p13-p14.

Serologic type conversion of a herpes simplex virus type 1 (HSV-1) to an HSV-2 epitope caused by a single amino acid substitution in glycoprotein C.

A monoclonal antibody to herpes simplex virus type 2 glycoprotein C (gC-2) did not recognize wild-type herpes simplex virus type 1 gC (gC-1) but did recognize a mutant gC-1 molecule. This conversion from a type 1 to a type 2 epitope was shown to be due to a single amino acid substitution in gC-1.

[Is the German dental industry ready for the future?]. / Ist die deutsche Dentalindustrie für die Zukunft gerüstet?

The future perspectives of the German dental industry will depend on the individual productivity of the different manufacturers and especially on the political and economic development of Europe as a whole. National, European and international standarization will play an important role with work safety and environment protection as center points. Not innovations but the consolidation of product fabrication selection and use - with quality assurance as a common objective of the dental world - will be one of the major challenges in the near future.