Radiosensitivity: Gender and Order of Administration of G-CSF, An Experimental Study in Mice.

To elucidate the potential influence of stimulating bone marrow before cell-cycle-dependent irradiation, we sought to determine overall survival in mice receiving total-body irradiation (TBI) when administered granulocyte stimulating factor (G-CSF) at different time points. Gender differences were also studied. C57/BL/6J mice, aged 9-14 weeks, received 8 Gy TBI in a perspex cage using a linear accelerator. In each of five different experiments, three groups were studied: 1. one control group receiving TBI only; 2. one group treated with filgrastim [500 lg/kg subcutaneously/intraperitoneally (s.c./i.p.)] the day before TBI, followed by daily filgrastim injections postirradiation (1-5 days); and 3. one group treated with daily filgrastim injections only post-TBI (1-5 days). Each experimental group included male and female mice. Survival of the mice was monitored daily, and mice were euthanized when their condition deteriorated. A total of 293 mice were monitored for at least 37 days post-TBI. Control mice that received 8 Gy TBI showed a significant gender difference, with a median survival of 22 days in females and 17 days in males. Addition of G-CSF, irrespective of pre- or postirradiation, significantly improved survival, but in males the improvement was significantly better when G-CSF was not given before TBI. Improved survival in females was independent of the order of administration of GCSF. Multiple filgrastim injections were more effective than a single injection, and s.c. administration was not better than i.p. In conclusion, these findings indicate that male mice are more sensitive to TBI than females. Filgrastim improved survival in both genders irrespective of whether given pre- or postirradiation, but in males the improvement was significantly less if an injection was given before irradiation. These results suggest that, to prevent toxicity most effectively, GCSF should not be given before cytotoxic therapy. While a completely different experimental model was used here, these results may also be extrapolated to indicate that endocrine cell-cycle suppression therapy should not be given before or during cytotoxic therapy of hormone-dependent tumors (e.g., breast and prostate cancer), thus a reduction in the efficacy of cell-cycle-dependent therapy can be prevented.

Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy.

BACKGROUND: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. PATIENTS AND METHODS: Five hundred and twenty-five women below the age of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. RESULTS: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). CONCLUSION: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS.

A cumulative ozone uptake-response relationship for the growth of Norway spruce saplings.

Norway spruce saplings [Picea abies (L.) Karst.] were exposed during four growing seasons to different ozone treatments in open-top chambers: charcoal filtered air (CF), non-filtered air (NF) and non-filtered air with extra ozone (NF+, 1.4xambient concentrations). The CF and NF+ ozone treatments were combined with phosphorous deficiency and drought stress treatments. The total biomass of the trees was harvested at different intervals during the experimental period. The ozone uptake to current-year needles of the Norway spruce saplings was estimated using a multiplicative stomatal conductance simulation model. There was a highly significant correlation between the reduction of total biomass and the estimated cumulative ozone uptake, which did not vary when different thresholds were applied for the rate of ozone uptake. The reduction of the total biomass was estimated to 1% per 10 mmol m(-2) cumulated ozone uptake, on a projected needle area basis.

Impact of ozone and reduced water supply on the biomass accumulation of Norway spruce saplings.

Norway spruce saplings [Picea abies (L.) Karst.] were exposed during four growing seasons to two different ozone treatments in open-top chambers: charcoal filtered air (CF), and non-filtered air with extra ozone (NF+, 1.4xambient concentrations). Within each ozone treatment the saplings were either kept well watered or treated with a 7-8 week period with reduced water supply each growing season. The total biomass of the trees was measured in April and September during each of the last three growing seasons. NF+ significantly reduced the total biomass accumulation of Norway spruce saplings during the fourth growing season. No interaction between ozone and reduced water supply could be detected. The magnitude of the ozone impact after 4 years of exposure was an 8% reduction of the total plant biomass and a 1.5% reduction of the RGR. The reduced water supply reduced the total biomass 29% and the RGR 12%.

Timing of quality of life (QoL) assessments as a source of error in oncological trials.

AIM OF THE STUDY: To produce an empirical estimate of the nature and magnitude of the error produced by incorrect timing quality of life (QoL) measurements in patients receiving chemotherapy. DESIGN: In a multicentre trial, 283 patients were randomized to receive either docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). The QoL was assessed at baseline and before each treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The study design was retrospective. Data were analysed using t-tests. RESULTS: Erroneous timing affected the QoL findings in both treatment arms. At baseline, there were statistically significant differences in the MF group on the nausea/vomiting scale, with ill-timed assessment showing more symptoms, and in the T group on the physical functioning scale with ill-timed assessments indicating better QoL. The mean scores of correct vs. incorrect timings over the first 14 cycles showed statistically significant differences on several scales. In the MF group, ill-timed assessments indicated significantly worse physical functioning and global QoL, and significantly more of the following symptoms: fatigue, nausea/vomiting, insomnia, appetite loss, and constipation. In the T group, ill-timed assessment showed better physical functioning, less dyspnoea and more insomnia than correctly timed assessments. The reasons for erroneous timing were not always detectable retrospectively. However, in some cases the MF group, being in standard treatment, seemed to have followed a clinical routine not involving the active participation of the study nurse responsible, whereas patients in the experimental T group were more consistently taken care of by the study nurses. CONCLUSIONS: Incorrect timing of QoL assessments in oncological trials jeopardises both the reliability of the QoL findings within treatment and the validity of QoL outcome comparisons between treatments. This issue should be emphasized in the planning of both the study design and clinical routines.

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study.

BACKGROUND: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. METHODS: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. FINDINGS: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. INTERPRETATION: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

Acute hematologic feasibility of G-CSF supported dose-escalated FEC therapy as adjuvant treatment after breast cancer surgery.

A study of the feasibility of gradually increased epirubicin and cyclophosphamide dosage in an FEC regimen with G-CSF (granulocyte colony stimulating factor) support in 18 high-risk breast cancer patients as adjuvant treatment was carried out. The FEC regimen was initiated with 5-fluorouracil 600 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 900 mg/m2 together with G-CSF 5 micrograms/kg subcutaneously on days 2-15 q 3 weeks for nine cycles, increasing individually through four dose levels to a maximum of 5-FU 600 mg/m2 (not escalated), epirubicin 120 mg/m2 and cyclophosphamide 1800 mg/m2. Transient cytopenias were regularly observed without major clinical complications. Rapid recovery and a biphasic overshoot of granulocytes required individualization of G-CSF support. During the 6-month treatment period, a general decline in granulocytes, platelets and haemoglobin was observed, resulting in maximal dose intensity in the middle of the treatment period. Compared to a conventional FEC regimen (5-Fluorouracil 600 mg/m2, Epirubicin 60 mg/m2, Cyclophosphamide 600 mg/m2 q 3 w) without dose reductions, it was feasible to increase the dose of epirubicin by more than 50 per cent with an increased dose intensity between 25 and 70 per cent. The dose of cyclophosphamide was increased by more than 100 per cent. All patients suffered from complete alopecia and moderate nausea, but there was no acute cardiac or severe mucosal toxicity. It was concluded that intensified, G-CSF supported FEC therapy can be safely administered in an outpatient setting, provided the patients are thoroughly informed and adequately monitored. High-risk patients are enrolled in a study comparing the described regimen and a myeloablative regimen including peripheral stem-cell support. Breast cancer seems to respond to chemotherapy in a dose dependent manner, suggesting the use of dose intensified regimens (1,8,9,11). This approach is currently under investigation in studies comparing standard regimens with myelo-ablative regimens in high-risk primary breast cancer (3,10). In a Scandinavian multicenter study (2), two high dose regimens, G-CSF supported dose-escalated FEC and myeloablative cyclophosphamide-thiotepacarboplatin with peripheral stem cell support, are compared as adjuvant therapy in operable high-risk breast cancer. This phase I study was performed to assess the feasibility and achievable dose intensity of an individually dose-escalated FEC regimen not in previous use.

Gastrin release and gastric acid secretion in the rat infected with either Helicobacter felis or Helicobacter heilmannii.

Helicobacter pylori infection in humans has been shown to be associated with changes in gastric physiology, including exaggerated basal and meal-stimulated gastrin levels. This has been suggested to be due to the direct effects of the bacterium through inflammation and its urease enzyme. The gastric bacteria Helicobacter felis and Helicobacter heilmannii colonize the antrum of rats in large numbers and induce no significant inflammatory response. Thus, the direct effect of Helicobacter infection on gastric physiology, independent of gastritis, could be studied. Basal, freely fed and stimulated acid and gastrin levels were recorded from animals infected with H. felis, H. heilmannii or uninfected controls over a 30 week period. No significant difference was found between freely fed gastrin over 7 weeks or fasting gastrin over 24 weeks or basal and stimulated acid over 30 weeks between all three groups. Triple therapy did not alter gastrin or acid output. The antrum of all Helicobacter-infected rats was well colonized; triple therapy cleared H. felis but not H. heilmannii. Very little inflammation was seen in control or Helicobacter-infected animals. In conclusion, Helicobacter-induced effects on gastric physiology are unlikely to be due to direct bacterial effects, but are best explained by other factors (i.e. inflammatory damage).

Long-term exposure of Norway spruce, Picea abies (L.) Karst., to ozone in open-top chambers: IV. Effects on the stomatal and non-stomatal limitation of photosynthesis and on the carboxylation efficiency.

Rates of photosynthesis at different concentrations of CO2 (0-1850 µmol mol-1 ) were measured using one clone of Norway spruce, Picea abies (L.) Karst. exposed to three different concentrations of ozone for four seasons (1985-8) in open-top chambers. The treatments were non-filtered air+ozone (NF+), non-filtered air (NF) and charcoal-filtered air (CF). The measurements were made on shoots of four different age classes. No significant effects were found on photosynthesis or on leaf conductance to CO2 in current year shoots. In 1- to 3-yr-old shoots, leaf conductance to CO2 and rates of net photosynthesis at both 330 µmol mol-1 CO2 (Pn 330), and saturating concentrations of CO2 (Pn max), decreased with increasing shoot age and ozone concentration, although this was only significant for Pn 330 in 3-yr-old shoots. In current year shoots the intercellular concentration of CO2 was significantly higher in NF+-treated shoots compared with CF- and NF-treated shoots, while in the 2- and 3-yr-old shoots it was significantly higher in NF- and NF +-treated shoots compared with CF-treated shoots. The carboxylation efficiency significantly decreased in 2- and 3-yr-old shoots from the NF and NF+ treatments compared with shoots from the CF treatment. The gas phase limitation of photosynthesis decreased with increasing shoot age and ozone concentration.

Structure and function of rat parietal cells during treatment with omeprazole, SCH 28080, SCH 32651, or ranitidine.

For 2 weeks four groups of adult female rats were given daily peroral doses of 400 mumols/kg of one of the following inhibitors of gastric acid secretion: omeprazole, SCH 28080, SCH 32651, or ranitidine; additional control rats were given vehicle only. Six rats in each group were killed 2 h after the last dose and another six in each group at 48 h. Samples of the gastric corpus wall were processed for light and electron microscopy. The maximal reduction of stimulated acid secretion in parallel gastric fistula rats was 100%, 90%, 40%, and 85%, respectively. Forty-eight hours after the last dose only SCH 28080 produced significant inhibition of acid secretion. 'Vacuolation' of parietal cells was occasionally observed in paraffin sections. Such 'vacuoles', which were not found in plastic sections, probably represent dilated secretory canaliculi. A small number of lucid parietal cells--presumably in the process of desquamation--were seen in all groups of rats; their proportion was significantly higher 2 h after the last dose of ranitidine, SCH 28080, or SCH 32651 than in the controls. Forty-eight hours after the last dose the proportion of such degenerating parietal cells was about the same in all groups.