Differential inhibition and potentiation by cell-permeant analogues of cyclic AMP and cyclic GMP and NO-containing compounds of exocytosis in human neutrophils

Summary The chemoattractants, N-formyl-L-methio-nyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), complement C5a and platelet-activating factor (PAF), induce ß-glucuronidase release and aggregation and an increase in cytosolic Ca²⁺ [Ca²⁺]_i in human neutrophils. We studied the roles of cAMP and cGMP in neutrophil avtivation, using their cell-permeant analogues, N⁶,2-O-dibutyryl adenosine 3:5-cyclic monophosphate (Bt2cAMP) and N² ,2-O-dibutyryl guanosine 3:5-cyclic monophosphate (Bt₂cGMP) and the NO-containing compounds, sodium nitroprusside (SNP), 3-morpholino-sydnonimine (SIN-1) and its prodrug, molsidomine (SIN-10). Bt₂cAMP, Bt₂cGMP, SIN-1 and SIN-10 but not SNP inhibited exocytosis induced by fMet-Leu-Phe. Superoxide dismutase potentiated the inhibitory effect of SIN-1. Bt₂cGMP and SNP potentiated C5a-induced ß-glucuronidase release, Bt₂cAMP, KCN, SIN-1 and SIN-10 being ineffective. KCN partially reversed the stimulatory effect of SNP, and in the presence of superoxide dismutase, SIN-1 potentiated C5a-induced exocytosis. PAF-induced ß-glucuronidase release was not affected by Bt₂cAMP, Bt₂cGMP, SNP and SIN-1. Bt₂cGMP was more effective than Bt2cAMP to inhibit aggregation and the increase in [Ca²⁺]_i induced by fet-Leu-Phe at submaximally effective concentrations. C5a-induced rises in [Ca²⁺]_i were not affected by Bt₂cAMP and Bt₂cGMP. Bt₂cAMP but not Bt₂cGMP inhibited the effect of PAF at submaximally effective concentrations on [Ca²⁺]_i. Our data suggest (I) that Bt2cGMP and Bt2cAMP differentially modulate neutrophil activation, that (II) NO-containing compounds partially mimick the effects of Bt₂cGMP on exocytosis and that (III) cGMP plays an inhibitory role in fMet-Leu-Phe- and a stimulatory role in C5a-induced ß-glucuronidase release. Send offprint requests to R. Seifert at the above address     

Computed tomography (CT) evaluation of breast cancer patients with osteolytic bone metastases undergoing palliative radiotherapy—a feasibility study

Twenty-five patients with osteolytic metastases had computed tomography (CT) scans before and 3 months after palliative radiotherapy. The median % density change following single 8 Gy, 20 Gy/5#, 30 Gy/10# were: 128 (range 98–255), 141 (79–342), and 145 (65–235), respectively. It is feasible to evaluate remineralization of osteolytic lesions with palliative radiotherapy.     

Effects of whole body hyperthermia (41.8 degrees C) on the frequency of tumor cells in the peripheral blood of patients with advanced malignancies.

PURPOSE: Combining heat with antineoplastic drugs has produced evidence of antitumor synergism. An increasing number of trials are investigating whole body hyperthermia (WBH) in combination with chemotherapy in patients with advanced malignancies. Here we investigated whether the hyperdynamic state of the circulation as a consequence of WBH may stimulate dissemination of malignant cells. EXPERIMENTAL DESIGN: WBH in combination with chemotherapy was administered by a radiant heat device to 20 consecutive patients with advanced epithelial malignancies. One WBH session lasted for approximately 4 h (90 min heating time, 60 min plateau at 41.8 degrees C, and 60-80 min cooling). Peripheral blood was drawn before WBH treatment (baseline), at the end of the plateau (1 h), and 24 h and 48 h thereafter. After removal of leukocytes using anti-CD45 magnetic beads, circulating tumor cells were detected immunocytochemically using the monoclonal antibody A45-B/B3, which binds to a common epitope present on various cytokeratins. RESULTS: The method used to detect tumor cells in the peripheral blood proved to be specific and very sensitive (detection limit 1 tumor cell per 1.7 x 10(5) peripheral blood mononuclear cell). Before WBH, 6 of 20 patients had cyto-keratin-positive cells in their blood. A treatment-induced increase in the number of circulating tumor cells became statistically significant at 24 h after WBH (P = 0.043) and was detected in a total of 9 patients, 5 of whom had no detectable malignant cells at baseline. There was no evidence of a correlation between an increase in the number of circulating tumor cells and increased metastasis frequency. CONCLUSIONS: Our findings suggest that WBH might induce a temporary release of tumor cells into the circulation, but this spread appears to be clinically not significant in patients with advanced malignancies.     

Expression of CEACAM6 in resectable colorectal cancer: a factor of independent prognostic significance.

PURPOSE: CEACAM6, CEACAM1, and human carcinoembryonic antigen (CEA) are coexpressed in normal colorectal epithelia, but show deregulated expression in colorectal cancers (CRC). Upregulation of CEACAM6 expression in hyperplastic polyps and early adenomas represents one of the earliest observable molecular events leading to colorectal tumors. The aim of our study was to evaluate the prognostic relevance of CEACAM6, CEACAM1, and CEA tissue expression in patients with CRC. PATIENTS AND METHODS: Immunohistochemical analysis was carried out on tissue microarrays from 243 paraffin-embedded biopsies from a randomized controlled clinical trial (Swiss Group for Clinical Cancer Research [SAKK] 40/81) of adjuvant fluorouracil-based chemotherapy with CEACAM-specific monoclonal antibodies. The median follow-up was 8 years. Overall survival (OS) and disease-free survival (DFS) were calculated using Kaplan-Meier estimates and hazard ratios (HRs) estimated using Cox proportional hazards models. RESULTS: Tissue expression of CEACAM6, CEACAM1, and CEA was enhanced in 55%, 58%, and 94% of patients, respectively. Multivariate Cox analysis including sex, age, tumor site, stage, differentiation grade, treatment, and nodal status as covariates showed that CEACAM6 overexpression independently predicted poor OS (HR, 1.86; P =.0100) and DFS (HR, 2.00; P =.0028), whereas CEACAM1 or CEA were not significantly related to these outcomes. The data did not provide evidence for or against the hypothesis that the CEACAM6 effect on survival differs according to treatment. CONCLUSION: Expression of the cell adhesion molecule CEACAM6 in CRC is an independent prognostic factor allowing subdivision of patients into low- and high-risk groups. Whether CEACAM6 or CEA and CEACAM1 might be useful as predictive markers of chemotherapy benefit remains unclear.     

Quality of Life in the General Norwegian Population, Measured by the Quality of Life Scale (QOLS-N)

The main aim of the present study was to derive norms or reference values from the general Norwegian population for the Norwegian version of the Quality of Life Scale (QOLS-N). In addition, associations between socio-demographic and health variables on the level of quality of life were examined. The sample consisted of 1893 subjects from a total of 4000 randomly selected Norwegian citizens representative of the entire Norwegian population, aged 19-81. The subjects received a mailed questionnaire containing the QOLS-N. Results show that the mean quality of life score was 84.1 (SD 12.5). Women reported a higher quality of life than men. People with higher levels of education reported a higher quality of life. Those who were married or cohabitating reported the highest quality of life and those who were unemployed reported a lower quality of life than those who worked. In addition, people reporting long-term diseases or health problems scored significantly lower on quality of life. These results could serve as reference values for the level of quality of life, as measured by the QOLS-N in the Norwegian population.     

Hirntumoren im Kindesalter

About 380 children younger than 16 years of age are diagnosed with a brain tumor in Germany every year. Compared to adults, different types of brain tumors are found in children. The diagnosis is often delayed in spite of presentation with characteristic symptoms. Unspecific persistent symptoms must be followed by further diagnostics. Since the 1980s, multimodal therapeutic regimens have been developed systematically by the Society for Pediatric Oncology and Hematology (GPOH) in the context of treatment optimalization trials. Neurosurgery, chemotherapy and irradiation are applied according to histology, stage of metastasis, and the age of the children. Currently, 80–90% of children diagnosed with a brain tumor in Germany are treated according to the respective trial in the context of the ‘treatment network HIT’. The principle aims are improved survival and quality of life, and the reduction of therapy-associated toxicity and late-effects. In this article, typical clinical symptoms, diagnostic recommendations and current treatment strategies are described.     

Cost-effectiveness of telbivudine versus lamivudine for chronic hepatitis B

Background and aimChronic hepatitis B is a highly prevalent disease worldwide, leading to serious consequences if not properly treated. Six treatment options for chronic hepatitis B are currently provided by the Brazilian public health system. Telbivudine is a nucleoside analogue that is neither included in the Brazilian clinical protocol nor in the therapeutic guidelines for chronic hepatitis B.ObjectiveThe aim of this study was to evaluate the cost-effectiveness of telbivudine for the viewpoint of the Brazilian public system, comparing it to lamivudine.MethodsA Markov model was used to project lifetime complications and costs of treatment with lamivudine or telbivudine for chronic hepatitis B in both HBeAg-positive and HBeAg-negative patients. To evaluate disease progression, probabilities and utilities of virologic response, virologic resistance, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, treatment, interruption of treatment, death and seroconversion were collected in systematic reviews. Costs were collected in DATASUS, ABC da Saúde and scientific literature.ResultsHigher rate of virologic response and seroconversion was obtained with telbivudine, and also higher values of quality adjusted life years. However lamivudine is associated with lower costs and also lower cost-effectiveness values. The incremental cost-effectiveness ratios for telbivudine, when compared with lamivudine, were US$ 30,575 and US$ 40,457, respectively for HBeAg-positive and HBeAg-negative patients.ConclusionsIn chronic hepatitis B lamivudine is a more cost-effective or even cost-saving strategy when compared with telbivudine