Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial.

BACKGROUND: This paper evaluates the prognostic and predictive impact of protein expression of various molecular markers in high-risk breast cancer (HRBC) patients with >9 involved lymph nodes, who received different chemotherapy dose-intensification strategies within a prospective randomized WSG AM-01 trial. MATERIALS AND METHODS: Paraffin-embedded tumors from 236 patients, who were randomly assigned to dose-dense conventional chemotherapy with four cycles of E(90)C(600) followed by three cycles of C(600)M(40)F(600) every 2 weeks (DD) or a rapidly cycled tandem high-dose regimen with two cycles of E(90)C(600) every 2 weeks followed by two cycles of E(90)C(3000)Thiotepa(400) every 3 weeks (HD), were available for retrospective central pathological review (116 HD/120 DD). Expression of estrogen receptor (ER), progesterone receptor (PR), MIB-1, epidermal growth factor receptor, and Her-2/neu was evaluated immunohistochemically using tissue microarrays. Results were correlated with follow-up data and treatment effects by proportional hazard Cox regression models (including interaction analysis). RESULTS: After a median follow-up of 61.7 months, 5-year event-free survival (EFS) as well as overall survival (OS) rates for the 236 patients were significantly better in the HD arm: EFS: 62% versus 41% [hazard ratio (HR) = 0.60, 95% CI 0.43-0.85, P = 0.004]; OS: 76% versus 61% (HR = 0.58, 95% CI 0.39-0.87, P = 0.007). In multivariate analysis, HD, tumor size <3 cm, positive PR, negative MIB-1 staining, and grade 1/2 were associated with favorable outcome. Interaction analysis showed that regarding predictive effects, triple negative (ER/PR/Her-2/neu) and G3 tumors derived most benefit from HD. CONCLUSION: Tandem HD improves both EFS and OS in HRBC. This therapy effect may be partly attributable to superior efficacy in the subgroup of triple-negative tumors and/or G3 with their poor prognostic marker profile.     

Primary leiomyosarcoma of the spinal leptomeninges

A case of leiomyosarcoma of the spinal leptomeninges is presented, with clinical, radiological, light microscopic and immunohistochemical data. The probable origin of the tumor from a pluripotent mesenchymal cell is discussed.     

Stenosed kinking of the left main coronary artery combined with an aneurysm of the ascending aorta

Stenosed kinking of the left main coronary artery is described in a 60-year-old man with an aneurysm of the ascending aorta and severe aortic valve insufficiency. An elective complete ascending aorta replacement using a valved composite graft was performed along with a shortening and direct implantation of the left main coronary artery. The right coronary artery was reimplanted as a Carrel-button.     

Down-regulation of retroviral transgene expression during differentiation of progenitor-derived dendritic cells

OBJECTIVE: Hematopoietic progenitor cells are a promising source for generation of genetically modified dendritic cells. A prerequisite for using these cells in therapeutic approaches is stable vector-mediated transgene expression during and after cell maturation. We investigated the expression of enhanced green fluorescence protein (EGFP) mediated by retroviral vectors in dendritic cells and other hematopoietic cells differentiated in vitro. MATERIAL AND METHODS: CD34(+) cells were efficiently transduced with retroviral vector constructs known to mediate different expression levels due to distinct cis-acting elements. EGFP(+) cells were purified by cell sorting and differentiated to monocytes, granulocytes, dendritic cells, and erythrocytes. Coexpression of EGFP and cell type-specific markers was analyzed by flow cytometry. RESULTS: Transgene expression from various retroviral vectors was silenced exclusively in dendritic cells, but not in other mature myeloid cells. Loss of EGFP was most pronounced in cells initially displaying low expression levels. This was confirmed by using a retroviral vector coding for a variant of EGFP with significantly reduced half-life. In contrast, a majority of dendritic cells showed stable expression when a self-inactivating retroviral construct using an internal cytomegalovirus promotor was used. CONCLUSIONS: We suggest that expression from the retroviral long terminal repeat is silenced during dendritic cell differentiation in vitro. High levels of stable transgene product in progenitor cells may mask a loss of expression. An improvement of retroviral vectors mediating stable transgenic expression is necessary for therapeutic approaches using gene-modified dendritic cells.     

NO reduces PMN adhesion to human vascular endothelial cells due to downregulation of ICAM-1 mRNA and surface expression

Reperfusion damage is largely due to the adherence of polymorphonuclear leukocytes to the endothelium initiated by adhesion molecule upregulation. The reduced endothelial nitric oxide release during ischemia may be involved in the upregulation of intercellular adhesion molecule 1. In this study, we tested if nitric oxide donors suppress polymorphonuclear leukocyte adherence to activated endothelial cells by inhibition of the intercellular adhesion molecule 1 surface expression. Confluent human umbilical vein endothelial cells were stimulated with tumor necrosis factor alpha (300 U/mL) after preincubation with increasing concentrations of the nitric oxide donors CAS 1609 (0.005-5 mM/L) and 3-(4-morpholinyl)-sydnonimine (0.01-1 mM/L). Intercellular adhesion molecule 1 surface expression was measured in a cell surface enzyme-linked immunosorbent assay, intercellular adhesion molecule 1 mRNA by Northern analysis. Human saphenous vein endothelial cells were transfected with the inducible nitric oxide synthase gene and stimulated with tumor necrosis factor alpha (300 U/mL). Fluorescein green-labeled polymorphonuclear leukocytes adhering to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells were quantified by epifluorescent microscopy. The intercellular adhesion molecule 1 surface expression of activated human umbilical vein endothelial cells/human saphenous vein endothelial cells was significantly diminished to 40 to 60% of the maximum after treatment with CAS 1609, 3-(4-morpholinyl)-sydnonimine, or transfection with the inducible nitric oxide synthase gene. Intercellular adhesion molecule 1 mRNA was diminished by CAS 1609 and 3-(4-morpholinyl)-sydnonimine in the same manner. The functional relevance of our data was shown by reduction of polymorphonuclear leukocyte adherence to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells following treatment with CAS 1609 and 3-(4-morpholinyl)-sydnonimine or transfection with inducible nitric oxide synthase. Tumor necrosis factor-induced polymorphonuclear leukocyte adherence was abolished by blocking antibody against intercellular adhesion molecule 1. Thus, exogenous or endogenous substitution of nitric oxide diminishes the expression of endothelial intercellular adhesion molecule 1 and its mRNA following tumor necrosis factor alpha stimulation. This results in a reduced polymorphonuclear leukocyte adherence to activated endothelium.     

Morphometric relationships between tooth and face shapes

The shape of a patient's face is commonly used as a reference to select the shape of the maxillary central incisors in edentulous patients. The validity of this relationship has not been proved. The objective of this clinical study was to determine whether a relationship exists between maxillary central incisors and face shapes. Casts were made of the maxillas of 50 men and 50 women. A standardized digital photographic procedure was used to record frontal views of each subject's face and of the maxillary central incisors of the dental casts. The shapes of the maxillary central incisors were compared with the face forms. Shape matches were evaluated according to their Hausdorff distance (HDD). The function h(A,B) is called the directed HDD from shape A to shape B (this function is not a true distance). It reflects the distance of the point of shape A that is farthest from any point of shape B and vice versa. The similarity of both shapes is given as a non-negative number. The value 0.0 indicates that the figures are identical (after scaling and shifting). Higher values indicate that shapes differ more substantially. Significant differences on the 5% level were calculated using the non-parametric Mann-Whitney U and Kruskal-Wallis tests. The face shape from the chin margin to the eyebrow line (superior edges of the eyebrows) produced a better match than the one from the chin to the hairline (P < 0.0001). On average, the maxillary central incisors displayed a variability (0.084 +/- 0.028) that was higher by a factor of 1.9 than the face shapes (chin margin to the eyebrow line, 0.045 +/- 0.015). In the interindividual comparison, the shapes of the maxillary central incisors of women displayed a significantly smaller HDD than the ones of the men (P < 0.0001).     

A modified ultra-rush-protocol of allergen immunotherapy in children and adolescents with insect venom allergy

BACKGROUND: In Germany the prevalence of insect venom allergy in the population is about 5 %, 10-40 deaths are reported every year. With a success rate of 95 % venom immunotherapy (SIT) has a convincing protective effect. The purpose of this study was to investigate the safety of the original ultra-rush-protocol in children and reduce from 9 to 8 doses by avoiding a second application of 100 micro g insect venom. METHODS: Nineteen children and adolescents with insect venom allergy were treated according to the modified ultra-rush-protocol. The first 5 children were hyposensitized according to the original protocol suggested by Brehler et al., the remaining 14 children (age 6-18 years) received only 8 injections (0.01/0.1/1/10/20/40/80/100 micro g). 5 patients were discharged on the second day four hours after the final application of 100 micro g insect venom. RESULTS: Extensive reddening due to inflammation was found in injection spot in 5 patients. Four patients had an amplified wheal formation. No systemic reactions were observed. The maintenance therapy was well tolerated. CONCLUSION: The modified ultra-rush-protocol increases compliance by short inpatient stay. In addition the modified hyposensitization was sure and well tolerated.