Treatment of patients with advanced nonsmall cell lung carcinoma using docetaxel and gemcitabine plus granulocyte-colony stimulating factor

BACKGROUND: A combination regimen comprised of docetaxel, gemcitabine, and granulocyte-colony stimulating factor (G-CSF) was studied in patients with advanced nonsmall cell lung carcinoma (NSCLC) to determine its antitumor efficacy and tolerance. METHODS: Thirty-four patients with advanced measurable NSCLC (3 patients with Stage IIIB and 31 patients with Stage IV disease) were treated with an intravenous combination chemotherapy regimen comprised of docetaxel, 80 mg/m(2), on Day 1 and gemcitabine, 1000 mg/m(2), on Days 1 and 10; G-CSF, 5 microg/kg, was administered subcutaneously between Days 2 and 8. Treatment cycles were repeated every 3 weeks. All patients were evaluable for toxicity and response assessment. A total of 163 courses was administered. RESULTS: Objective tumor response was noted in 17 patients (50%; 95% confidence interval, 32. 5-67.5%), including 2 complete responses (6%) and 15 partial responses (44%). There was no change in 10 patients (29%) and 7 patients developed progressive disease. The median duration of response was 6.5 months (range, 3-15 months) and the median time to disease progression for all patients was 6.8 months (range, 1.8-18 months). The median overall survival time was 13.0 months (range, 2. 5-23+ months) with a 1-year survival rate of 55.8%. Myelosuppression was the most frequently encountered adverse reaction, although World Health Organization Grade 3 or 4 leukocytopenia and/or granulocytopenia occurred in only 18% and 24% of patients, respectively. Other toxicities generally were mild to moderate, and always fully reversible. CONCLUSIONS: With a response rate of 50% and a median survival time of 13 months, the drug combination described in the current study appears to have significant activity against advanced metastatic NSCLC. Due to its fairly good tolerance and ease of administration, further investigation of this regimen appears warranted.     

Detection of minimal residual disease in patients with cancer: a review of techniques, clinical implications, and emerging therapeutic consequences

The issue of minimal residual disease (MRD) manifesting itself by the presence of undetected disseminated isolated tumor cells in both tissues and hematopoietic autografts from patients with early-stage malignancies or from patients in clinical complete remission has been discussed widely during the last decade. Based on the current understanding of the pathogenesis of malignancy, disseminated tumor cells persisting after conventional oncologic treatment modalities or after reinfusion of contaminated autologous hematopoietic cells constitute the source of subsequent recurrence of disease. Accordingly, much emphasis is placed on the detection and characterization of disseminated isolated tumor cells in both basic and clinical research. This effort is aimed at a better understanding of the processes of metastasis and tumor dormancy and, ultimately, the estimation of prognosis, molecular monitoring, and the design of new therapeutic agents in oncology. In our review, we used computerized (MEDLINE, Embase) and manual searches to summarize laboratory and clinical data concerning MRD focusing on the issue of MRD in solid malignancies. We give a detailed overview of the methods used for the detection and molecular characterization of disseminated tumor cells and of the prevalence and prognostic significance of the detection of MRD in patients and hematopoietic autografts. Finally, we discuss the emerging therapeutic consequences of the detection of disseminated tumor cells, with special emphasis on the therapeutic potential of antibodies. We conclude that the detection of MRD represents a hallmark for the diagnosis, monitoring, and treatment of malignant conditions in future clinical trials.     

A relationship between repression of dimethylnitrosamine-demethylase by polycyclic aromatic hydrocarbons and their shape

The quantitative relationship between the ability of polycyclic aromatic hydrocarbons to repress the mixed-function oxidase, dimethylnitrosamine-demethylase, and a parameter expressing the shape of the hydrocarbon molecules, has been studied. The shape parameter represents the ratio of the longer to shorter sides of the minimum rectangular envelope around the structure, drawn proportionally to atomic dimensions. The shape parameter allows the prediction of the relative biological activity of 23 active and 4 inactive compounds.     

The antidepressant effect of running is associated with increased hippocampal cell proliferation

A common trait of antidepressant drugs, electroconvulsive treatment and physical exercise is that they relieve depression and up-regulate neurotrophic factors as well as cell proliferation and neurogenesis in the hippocampus. In order to identify possible biological underpinnings of depression and the antidepressant effect of running, we analysed cell proliferation, the level of the neurotrophic factor BDNF in hippocampus and dynorphin in striatum/accumbens in 'depressed' Flinders Sensitive Line rats (FSL) and Flinders Resistant Line (FRL) rats with and without access to running-wheels. The FRL strain exhibited a higher daily running activity than the FSL strain. Wheel-running had an antidepressant effect in the 'depressed' FSL rats, as indicated by the forced swim test. In the hippocampus, cell proliferation was lower in the 'depressed' rats compared to the control FRL rats but there was no difference in BDNF or dynorphin levels in striatum/accumbens. After 5 wk of running, cell proliferation increased in FSL but not in FRL rats. BDNF and dynorphin mRNA levels were increased in FRL but not to the same extent in the in FSL rats; thus, increased BDNF and dynorphin levels were correlated to the running activity but not to the antidepressant effect of running. The only parameter that was associated to basal level of 'depression' and to the antidepressant effect was cell proliferation in the hippocampus. Thus, suppression of cell proliferation in the hippocampus could constitute one of the mechanisms that underlie depression, and physical activity might be an efficient antidepressant.     

Exposure to PCBs and p,p'-DDE and human sperm chromatin integrity

Persistent organochlorine pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (p,p'-DDE), the major metabolite of dichlorodiphenyltrichloroethane (DDT), are stable lipophilic compounds widely found in the environment and in the general population. They can enter the food chain, and their negative impact on male reproduction is currently under active scrutiny. To explore the hypothesis that environmental exposure to these compounds is associated with altered sperm chromatin structure integrity in human sperm, we conducted a study of 176 Swedish fishermen (with low and high consumption of fatty fish, a very important exposure source of POPs). We determined serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and p,p'-DDE, and we used the sperm chromatin structure assay (SCSA) to assess sperm DNA/chromatin integrity. When CB-153 serum levels (individual dose range, 39-1,460 ng/g lipid) were categorized into equally sized quintiles, we found an association with the DNA fragmentation index (%DFI). A significantly lower %DFI was found in the lowest CB-153 quintile (< 113 ng/g lipid) compared with the other quintiles; there was a similar tendency, although not statistically significant, between %DFI and p,p'-DDE. These results suggest that POP exposure may have a slight negative impact on human sperm chromatin integrity.     

Expression of calcipressin1, an inhibitor of the phosphatase calcineurin, is altered with aging and Alzheimer's disease

Protein phosphatase 2B (calcineurin) activity has been shown to be decreased in Alzheimer's disease and is a possible mechanism(s) for the hyperphosphorylation of tau and subsequent neurofibrillary tangle formation. Recently, mRNA expression of Down's syndrome Critical Region 1 gene, which encodes the protein calcipressin (an endogenous inhibitor of calcineurin), was found to be upregulated in both Down's syndrome and Alzheimer's disease. Calcipressin is induced by oxidative stress and Abeta in vitro, further establishing a link in the pathology of both diseases. Using immunohistochemistry techniques, calcipressin protein expression in the pyramidal neurons of the temporal lobe was shown to increase with aging (r2=0.5658; p=0.0313), and also in moderate to severe Alzheimer's disease compared to control patients (t=3.872; p=0.0017). In addition, there was a positive correlation between the total number of calcipressin-positive pyramidal neurons and the number of neurofibrillary tangles in the temporal cortex (r2= 0.5955; p=0.0249). As there was an 88% increase in nuclear calcipressin in Alzheimer's disease (p=0.0001), the relationship between cellular localization of calcipressin and neurofibrillary tangle formation was investigated, which revealed a decrease in neurofibrillary tangle-bearing neurons that contain nuclear calcipressin (t=4.874; p=0.0028) and further demonstrates that the cellular regulation of calcipressin is altered in Alzheimer's disease.     

The treatment of advanced chronic lower limb ischaemia with marrow stem cell autotransplantation

INTRODUCTION: Conventional methods of critical leg ischaemia treatment are of limited efficacy. Amputation, as an ultimate solution, is not so rare. The results of marrow stem cell therapy as a potential novel approach to peripheral artery disease management were presented in 2002 by Tateishi-Yuyamy. AIM: To assess efficacy and safety of critical lower limb ischaemia treatment with marrow stem cell autotransplantation. METHODS: Ten patients suffering from chronic leg ischaemia in Fontaine IV stadium were involved in the study. They did not require emergency amputation and had previously been unsuccessfully treated with conventional therapy. Autologic marrow stem cells were condensated by a separator from bone marrow samples taken from the iliac crest. The cells were delivered intramuscularly by repeated injections into the pedal and tibial regions. The number of CD34 and AC133 positive mononuclear cells in each sample was evaluated by flow cytometry. After two weeks and one, two, three and twelve months the following parameters were measured: Laser Doppler Flux (LDF), percutaneous oxygen partial pressure, ankle-brachial index (ABI), visual analgesic scale (VAS), analgesic therapy requirement and ulceration area. Also, lower leg angiography and scintigraphy were performed. RESULTS: An improvement of the peripheral blood flow assessed by Laser Doppler Flux and percutaneous oxygen partial pressure was found. Pain severity decreased in the majority of patients. Amputation was required in three patients in whom the therapy failed. No side effects of the therapy were observed. The clinical effect of the treatment did not correlate with the amount of cells injected. CONCLUSION: Marrow stem cell autotransplantation into the ischaemic lower limb seems to be a potentially effective method of peripheral perfusion enhancement. Further studies are needed to clarify the underlying mechanisms of such improvement.     

Quantitative assessment of mRNA TGF-beta1 in liver tissue in connection with serum mean daily level of TGF-1 in chronic hepatitis B patient

Monitoring of fibrosis process with the use of histopathologic studies on liver's bioptates is limited, so it is attempted to find reliable, obtained with less invasive methods, sensitive and reflecting fibrosis dynamics markers of this process. The aim of the study was simultaneously to assess liver's expression as well as circadian and mean daily TGF-betal concentration in serum of patients with chronic hepatitis type B in comparison to control group. Studies were performed on 50 patients (9 women, 41 men) aged 45.9 +/- 2.3 years with chronic hepatitis type B. Control group consisted of 20 patients (mean age 38.6 +/- 3.7 years), in which so called minimal changes without fibrosis were observed in histophatologic bioptate of liver. Blood for studies was collected every 4 houres during the day. Serum concentration of TGF-betal was assessed with the use of ELISA method, and expression of mRNA TGF-betal in liver with QRT-PCR method. No significant difference between circadian as well as mean daily serum TGF-betal concentration beetwen control group and the group with chronic hepatitis type B was shown. Increased expression of mRNA, TGF-betal in bioptate of liver of patients with chronic hepatitis type B in comparison to control group was noted. In "minimal changes" control group presence of significant positive correlation between expression of mRNA TGF-beta1 in liver and concentration of this cytokine in serum was shown, in the group of patients with chronic hepatitis B this connection was not noted.