Vascular endothelial growth factor and prognosis in patients with node-negative breast cancer

Vascular endothelial growth factor (VEGF) has emerged as one of the most important angiogenic growth factors from experimental in vitro and in vivo studies. In the present study, we investigated the relationship between VEGF expression and microvessel density (MVD) and defined their prognostic relevance on a series of 242 patients with node-negative breast cancer, using immunohistochemical methods. In parallel, estrogen and progesterone receptors were quantitatively assessed using the dextran-charcoal technique and cell proliferation was evaluated as S-phase cell fraction according to (3)H-thymidine-labeling index (TLI). The percentage of VEGF-expressing cells varied from 0-95% in the different tumors and was unrelated to menopausal status, tumor size or steroid receptor status. Conversely, a significant inverse relation was observed with patient age or tumor cell proliferation, albeit with very poor correlation coefficients. A significant relation was observed between VEGF expression and MVD (r(s) = 0.55, p < 0.001). Clinical outcome analyzed as a function of high and low VEGF expression showed slight differences in terms of both disease-free survival (DFS) and overall survival (OS) that never reached statistical significance. Moreover, the trend was paradoxically in favor of patients with highly VEGF-expressing tumors. Finally, DFS and OS curves, when analyzed as a function of VEGF expression or MVD, were superimposable. In conclusion, our study did not highlight a prognostic relevance of VEGF expression in patients with node-negative breast cancer, as already observed for MVD.     

Catecholamine production and tyrosine hydroxylase expression in peripheral blood mononuclear cells from multiple sclerosis patients: effect of cell stimulation and possible relevance for activation-induced apoptosis

Sympathoadrenergic mechanisms may play a role in multiple sclerosis (MS). We examined catecholamine (CA) levels and production and tyrosine hydroxylase (TH) expression in peripheral blood mononuclear cells (PBMCs) from MS patients, and the correlation between CA production and apoptosis in PBMCs. PBMCs from MS patients had increased norepinephrine (NE) levels. However, phytohaemagglutinin (PHA)-stimulated PBMCs from MS patients with active disease synthesized less dopamine (DA) than cells from both healthy controls and patients with inactive disease. PBMCs from patients with inactive disease showed lower expression of TH. Pharmacological inhibition of TH in cultured PBMCs stimulated with PHA reduced the percentage of apoptotic cells. Since a failure of activation-induced apoptosis in immune cells may be involved in MS, it is suggested that altered CA production by PBMCs may be implicated in such dysregulation.     

Trends in cancer mortality in Switzerland, 1980-2001.

Trends in cancer mortality in Switzerland were analysed over the period 1980-2001, on the basis of the World Health Organization database. Appropriately developed correction factors were utilized for the period before 1995, to allow for spurious trends introduced by the change between the 8th and the 10th revisions of the ICD. Steady declines in cancer mortality were observed, particularly from the mid-1980s onwards. Over the last decade, the fall in overall age-standardized (world standard) cancer mortality was 11.1% in men (from 158.1 in 1990-1991 to 140.6/100,000 in 2000-2001) and 7.6% in women (from 91.6 to 84.7/100,000), and the decline was larger in truncated rates from 35 to 64 years (-18.0 and -9.7%). In men, all major tobacco and alcohol neoplasms have declined until the late 1990s but have levelled off over the last few years, reflecting recent trends in alcohol and tobacco consumption. The fall in male lung cancer mortality was 20% over the last decade (from 42.9 to 34.3/100,000). In contrast, lung cancer mortality in women has steadily increased by 38% between 1981 and 1991 and by 47% between 1991 and 2001, to reach 10.7/100,000 at all ages and 18.3 at age 35 to 64, due to increased prevalence of smoking in subsequent generations of Swiss women. Other sites showing substantial declines include stomach and colorectum in both sexes, (cervix) uteri and breast in women. Likewise, prostate cancer showed modest favourable trends after 1995. Steady declines were observed for leukaemias, Hodgkin's disease and testicular cancer, namely, the neoplasms most influenced by therapeutic improvements, while trends in lymphomas and myeloma showed no clear pattern.     

Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells.

Betulinic acid is a triterpene with selective cytotoxicity against melanoma, neuroectodermal and malignant brain tumor cell lines. In this study the betulinic acid activity was evaluated, in comparison with doxorubicin, on different human neoplastic and non-neoplastic cell lines and on proliferating normal lymphocytes. Growth inhibition was evident in all the neoplastic cell lines independently on p53 status and histotype. Antiproliferative activity of betulinic acid was related to a cytotoxic effect on two p53 wild-type and on one p53 mutant cell lines and to a cytostatic effect on one p53 mutant melanoma clone. At the same concentrations, normal cells were unaffected indicating a selective effect of this agent. A cytotoxic activity of doxorubicin was evident on all the tested systems. In vivo experiments, performed on one of these cell lines, confirmed the antineoplastic activity of this drug. These data support further preclinical studies of betulinic acid not confined to melanoma and neuroectodermal tumors independently of p53 status.     

Intensive, very short-term chemotherapy for advanced Burkitt's lymphoma in children.

PURPOSE: To improve the 63% event-free survival (EFS) achieved before 1986 in Murphy's stage III to IV Burkitt's lymphoma (BL), both chemotherapy and supportive care were intensified. PATIENTS AND METHODS: From May 1987 to February 2001, 60 children, median age 9 years (range, 2.1 to 17 years), with advanced BL were enrolled onto two sequential institutional studies. From 1987 to 1992, 30 patients were stratified according to the absence (regimen IA, n = 19) or presence (regimen IB, n = 11) of bone marrow (BM) or CNS involvement. After 5-week cytoreductive chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, high-dose (HD) methotrexate (MTX), and intrathecal MTX or cytarabine, HD cytarabine and cisplatin were provided as a 4-day continuous infusion. Regimen IB was intensified by adding etoposide and HD ifosfamide and escalating MTX doses. Since 1992, regardless of BM or CNS status, 30 patients have been placed on regimen II, which is identical to IB but without ifosfamide. The scheduled duration of regimen II was 45 days. RESULTS: EFS and disease-free survival at 5 years are 81% +/- 5% and 87% +/- 5%, respectively, for 59 assessable patients (73% +/- 8% and 85% +/- 7% for regimen IA + IB, 89% +/- 6%, EFS and disease-free survival, for regimen II; median follow-up, 6.7 years; range, 0.6 to 13.5 years). Six patients, two of whom were receiving regimen II, died as a result of initial treatment failure or relapse, and five patients, none receiving regimen II, died as a result of treatment-related complications. CONCLUSION: This 45-day intensive chemotherapy program is the shortest schedule for disseminated BL and overcomes previously recognized risk factors such as BM and CNS infiltration.     

Long-term outcome of patients with monostotic Ewing's sarcoma treated with combined modality

One hundred and twenty-one consecutive patients with monostotic Ewing's sarcoma (ES) were treated according to three consecutive combined modality programs from 1974 to 1986. Their 3-year progression free survival (PFS) rate from diagnosis of 59% was identical to the event free survival (EFS) rate, since all the 50 events occurring within 3 years from diagnosis were tumor recurrences. Primary tumor was treated with radiotherapy in 75 cases, surgical resection plus radiotherapy in 38, and radical surgery in 8. Chemotherapy was given to all patients and each program included adriamycin, vincristine, and cyclophosphamide ± dactinomycin. Median follow-up was 12 years, ranging from 6 to 19 years. The PFS rate decreased to 49% at 6 years and plateaued at 46% after the 7th year from diagnosis, even though some relapses were observed as late as 14 years from diagnosis. Second malignancies developed in 7 patients free from progressive ES and were represented by osteogenic sarcoma in previously irradiated bone in 4 cases and by breast carcinoma in 3. No other event but tumor relapse or second malignancy occurred in this series. EFS rate was 47% at 6 years and 39% at 12 years, further decreasing in the following years because of a number of late events. A continuous PFS longer than 7 years may be consistent with cure in the majority of patients with monostotic ES. However, these patients should be followed indefinitely because of risk of second malignancies. © 1994 Wiley-Liss, Inc.     

Platelet antibody determination by platelet factor 3 assay

Summary Platelet antibody determination by the PF3 test was carried out in 96 thrombocytopenic patients with various disorders, 31 repeatedly transfused patients with or without thrombocytopenia and 24 patients with autoimmune disease (SLE andmyasthenia gravis) without thrombocytopenia. The frequency of a positive test was greatest in the patients with ITP (61%), SLE (50%) or a history of numerous blood transfusions (60%). The patients withmyasthenia gravis also showed a considerable frequency (20%) of platelet antibodies detectable by the PF3 test. The PF3 test is less sensitive than the serotonin release test in detecting autoantibodies, but it is more sensitive than aggregometry in detecting isoantibodies and drug-related antibodies.     

Fluorescence assay of tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin in mice bearing solid tumors

Summary The tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin was studied in comparison with that of their parent compounds, daunorubicin and doxorubicin, in mice bearing transplanted tumors. The doses administered were equal or equitoxic to those of their parent compounds. The levels of total fluorescence due to initial drugs and metabolites were determined on tissue extracts by fluorometry. After administration of equal doses of daunorubicin and 4-demethoxydaunorubicin, the calculated Cxt values of 4-demethoxydaunorubicin equivalents were higher than those for daunorubicin in all the organs tested except the heart. In animals treated with equitoxic doses, lower 4-demethoxydaunorubicin levels were found in all the organs tested. In mice treated with equitoxic doses of doxorubicin and 4-demethoxydoxorubicin, 4-demethoxydoxorubicin reached higher drug concentrations than doxorubicin in spleen and liver, whereas in all the other organs tested lower drug levels were found. The rate of drug disappearance from organs was slower in animals treated with 4-demethoxyderivatives than in those treated with their parent drugs.