Recombinant human stem cell factor stimulates growth of a human glioblastoma cell line expressing c-kit protooncogene.

The growth of a panel of eight different human glioblastoma cell lines was examined in a human tumor cloning assay in agar, a tritiated thymidine uptake assay, and by counting cell numbers, in cultures performed in the absence or presence of increasing concentrations (1 to 100 ng/ml) of recombinant human stem cell factor (SCF). Growth of 7 of 8 cell lines was not significantly and reproducibly affected by recombinant human SCF. However, growth of the CRL 1620 cell line could be stimulated up to 5-fold by the cytokine. In contrast to the other cell lines investigated, CRL 1620 expressed the c-kit protooncogene assessed on the mRNA and protein level. Furthermore, SCF-induced proliferation of CRL 1620 cells was sensitive to the tyrosine kinase inhibitor erbstatin. Our data suggest that SCF can be operative in growth modulation of malignant cells outside the hematopoietic system, and this finding should be further studied for its possible clinical implications.     

Evaluation of late cardiotoxicity with pulsed Doppler echocardiography in patients treated for Hodgkin's disease

Summary. The impact of valvular, myocardial and pericardial abnormalities on cardiac haemodynamics in patients treated for Hodgkin's disease with COPP/ABVD with and without mediastinal irradiation was determined in 49 patients 2–10 years after induction therapy. Diagnostic procedures to evaluate cardiac function consisted of history, physical examination, exercise bicycle stress test, M-mode two-dimensional and pulsed Doppler echocardiography. No patient reported symptoms related to cardiomyopathy, and only one of the 49 had evidence of coronary heart disease. Pericardial thickening was seen on echocardiograms in 19/49 patients (38.8%), valvular thickening in 21/49 (42·9%), and reduced fractional shortening in 9/49 (18·4%). The Doppler-derived mean E and A (±SD) of transmitral flow were 0·75 ± 0·14 m/s and 0·56 ± 0·09 m/s, respectively, in patients receiving chemotherapy and 0·81 ± 0.19 m/s and 0·63 ± 0·20 m/s in those with additional mediastinal irradiation. There was no statistically significant difference between mean E and A in transmitral flow in patients treated for Hodgkin's disease and control subjects. Furthermore, the transtricuspid and hepatic vein flow velocities did not differ significantly. Although the present study demonstrates high frequencies of pericardial and valvular thickening in patients treated for Hodgkin's disease with the COPP/ABVD regimen with or without mediastinal irradiation, it showed no impact on cardiac flow velocities. The abnormalities might thus be of minor clinical relevance in these patients.     

Primary malignant melanoma of the esophagus

Summary A case of primary malignant melanoma of the esophagus in a 74-year-old male is described. There was a diffuse pigmentation of the lower third of the esophagus macroscopically. Sections from this area revealed melanocytes in the basal layer of the epithelium. This melanosis was not caused by malignant melanoma cells, but obviously by preexisting ectopic and pigmented melanocytes a condition for which the term esophageal melanocytosis is proposed. It is suggested that esophageal melanocytosis as well as the presence of junctional changes may determine the primary nature of malignant melanoma of the esophagus. Furthermore, in order to outline the histologic criteria and the pathological features of primary esophageal melanomas, 64 cases have been reviewed.     

Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study

The combination of intravenous (i.v.) vinorelbine and epirubicin is highly active in the treatment of metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated a regimen alternating i.v. and oral vinorelbine in combination with epirubicin as first-line chemotherapy of patients with MBC. In all, 49 patients with MBC received, as first-line treatment, a combination regimen consisting of i.v. vinorelbine 25 mg m(-2) plus epirubicin 90 mg m(-2) given on day 1, and oral vinorelbine 60 mg m(-2) on day 8 (or day 15 if neutrophils <1500 mm(-3)) every 3 weeks, in an open-label, multicentre phase II study. Treatment was to be repeated for a maximum of six cycles. The study population had a median age of 55 years, half of the patients had received prior adjuvant chemotherapy and 86% presented a visceral involvement. In all, 25 responses were documented and validated by an independent panel review, yielding response rates of 51% (95% CI: 36-66) in the 49 enrolled patients and 54.5% (95% CI: 39-70) in the 44 evaluable patients. Median durations of progression-free survival and survival were 8 and 20 months, respectively. Neutropenia was the main dose-limiting toxicity, but complications were uncommon, four patients having experienced febrile neutropenia and six having developed neutropenic infection. Other frequently reported adverse events included stomatitis, nausea and vomiting, which were rarely severe. No toxic death was reported. Among patients who received six cycles, global score of quality of life remained stable. This regimen alternating oral and i.v. vinorelbine in combination with epirubicin is effective and safe. Oral vinorelbine on day 8 offers greater convenience to the patient, and decreases the need for i.v. injection and reduces time spent in hospital. Therefore, oral vinorelbine is a convenient alternative to the i.v. form in combination regimens commonly used to treat MBC.     

Integrin alpha6beta1 role in metastatic behavior of human pancreatic carcinoma cells

The factors that determine the metastatic behavior of pancreatic tumor cells are incompletely understood. In this study, we first demonstrate differences in adhesion properties, integrin expression and in vivo integrin function in the metastatic tumor cell line PaTu 8988s compared with the non-metastatic cell line PaTu 8988t. Both cell lines were derived from the same original tumor and exhibit identical genetic fingerprints. Using in vitro adhesion assays performed on purified extracellular matrix components, adhesion of PaTu 8988s cells was significantly increased on the basal membrane component laminin and decreased on the interstitial matrix protein fibronectin compared to PaTu 8988t cells. By immunocytochemistry and flow cytometry, and in correspondence with their adhesive properties, the metastatic PaTu 8988s cells did express a distinct pattern of integrin subunits. Laminin-binding integrins alpha6 and beta4 were overexpressed in PaTu 8988s cells. Fibronectin-binding alpha5 integrins were present at higher levels in the non-metastatic PaTu 8988t cells, whereas the beta1 subunit expression did not differ. Adhesion to laminin or fibronectin was specific and was mediated via integrins alpha6beta1 and alpha5beta1, respectively. In addition, metastasis formation in vivo after injection of cells into the tail vein of nude mice was inhibited by preincubation of PaTu 8988s cells with antibodies directed against the integrin alpha6 or beta1. We conclude that alpha6beta1 integrins are overexpressed and functionally active in metastatic human pancreatic carcinoma cells, and participate in metastasis formation probably through binding to the basal membrane component laminin.     

Systemische 5-Fluorouracil-(Kombinatons)-Chemo- therapie bei Patienten mit metastasiertem kolorektalem Karzinom

Aufgrund der unüberschaubaren Fülle von Phase-I, -II und -III Studien bei Patienten mit metastasiertem kolorektalem Karzinom, der starken Variabilit?t der Applikation von 5-Fluorouracil und der biochemischen Modulatoren, des Wandels der Therapieendpunkte sowie aufgrund des hohen Budgetdrucks im Gesundheitswesen soll versucht werden, mit Hilfe der Erkenntnisse der Evidenz-basierten Medizin Standards in der systemischen Chemotherapie zu formulieren.     

Interleukin-2-activated killer cell activity in colorectal tumor patients: evaluation of in vitro effects by prothymosinα1

The effects of prothymosin 1 (Pro 1) in combination with interleukin-2 (IL-2) on peripheral blood lymphocytes from 50 colorectal tumor patients at different stages were studied with respect to immunocytotoxicity, adhesion to cultured SW620 colon carcinoma cells, secretion of cytokines and expression of adhesion and surface marker molecules. On average, the patients showed lower natural killer (NK) cell activity than healthy donors, which was associated with a lower adhesion capacity to the tumor target cells. The NK cell activity of the patients was inversely related to the tumor stage. The generation of lymphokine(IL-2)-activated killer (LAK) cell activity was found to be comparable on lymphocytes from healthy individuals and patients and was not correlated to tumor stage. Pro 1 stimulated patients' LAK cell activity only, primarily at the early stage (Dukes A/B). The Pro 1 effect was associated with an increased adhesion of lymphocytes to tumor target cells and an increased secretion of the deficient IL-2-induced IFN secretion. No significant effects on the low level of TNF secretion was noted. By flow cytometry, Pro 1 in combination with IL-2 augmented the expression of the NK cell markers CD56, CD16/56, the subset CD3/16/56 and CD25 on lymphocytes of the patients. In contrast, Pro 1 was equally effective by increasing the expression of CD18 and CD11a, on lymphocytes from the patients and from normal controls. In conclusion, Pro 1, in combination with IL-2, can partially normalize lymphocyte deficiencies of colon cancer patients in vitro. This potential might provide an experimental basis for applying Pro 1 or related thymic peptides in selected immunotherapies against colorectal tumors.Abbreviations Pro 1 prothymosin 1 - NK natural killer - LAK lymphokine-activated killer - IL-2 interleukin-2 - TNF tumor necrosis factor - IFN interferon - PBL peripheral blood lymphocytes - ELISA enzyme-linked immunosorbent assay