Randomized comparison of progenitor-cell mobilization using chemotherapy, stem-cell factor, and filgrastim or chemotherapy plus filgrastim alone in patients with ovarian cancer.

PURPOSE: This was the first randomized study to investigate the efficacy of peripheral-blood progenitor cell (PBPC) mobilization using stem-cell factor (SCF) in combination with filgrastim (G-CSF) following chemotherapy compared with filgrastim alone following chemotherapy. PATIENTS AND METHODS: Forty-eight patients with ovarian cancer were treated with cyclophosphamide and randomized to receive filgrastim 5 microg/kg alone or filgrastim 5 microg/kg plus SCF. The dose of SCF was cohort-dependent (5, 10, 15, and 20 microg/kg), with 12 patients in each cohort, nine of whom received SCF plus filgrastim and the remaining three patients who received filgrastim alone. On recovery from the WBC nadir, patients underwent a single apheresis. RESULTS: SCF in combination with filgrastim following chemotherapy enhanced the mobilization of progenitor cells compared with that produced by filgrastim alone following chemotherapy. This enhancement was dose-dependent for colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU-E), and CD34+ cells in both the peripheral blood and apheresis product. In the apheresis product, threefold to fivefold increases in median CD34+ and progenitor cell yields were obtained in patients treated with SCF 20 microg/kg plus filgrastim compared with yields obtained in patients treated with filgrastim alone. Peripheral blood values of CFU-GM, BFU-E, and CD34+ cells per milliliter remained above defined threshold levels longer with higher doses of SCF. The higher doses of SCF offer a greater window of opportunity in which to perform the apheresis to achieve high yields. CONCLUSION: SCF (15 or 20 microg/kg) in combination with filgrastim following chemotherapy is an effective way of increasing progenitor cell yields compared with filgrastim alone following chemotherapy.

Metallothionein expression in epithelial ovarian cancer: effect of chemotherapy and prognostic significance.

BACKGROUND AND PURPOSE: Regimens containing platinum drugs continue to be amongst the most effective therapies for ovarian cancer. However, despite high initial response rates most patients relapse and die of their disease. Elevation of metallothionein has been implicated as a mechanism by which tumour cells become resistant to platinum anticancer drugs, although most of these studies have been carried out in vitro. This study was carried out to determine whether metallothionein expression was associated with response or survival in patients with epithelial ovarian cancer. METHODS: Metallothionein was determined by radioimmune assay using frozen ovarian tumour tissue taken either before or following cytotoxic chemotherapy. RESULTS: An increase in expression of metallothionein was seen in tumour tissue from patients who had undergone cytotoxic chemotherapy, although this did not attain significance. However, a preliminary study using biopsy material from the same patient, taken both before and after chemotherapy, showed a statistically significant increase in metallothionein. An analysis of these data showed that the level of metallothionein expression was not associated with survival or response. CONCLUSION: These data do not support the hypothesis that metallothionein expression is a determinant of response in ovarian cancer. There is some preliminary evidence from the study of paired samples which indicates that cytotoxic chemotherapy may increase metallothionein expression. An increase in metallothionein was also seen in the study using unmatched biopsies although this did not attain statistical significance, due in part to the large inter-patient variability in expression of this protein.

5T4 oncofetal antigen expression in ovarian carcinoma.

5T4 oncofetal antigen is defined by a monoclonal antibody raised against human placental trophoblast, and recognizes a 72 kD glycoprotein expressed in many different carcinomas but detected only at low levels in some normal epithelia. Analysis of the patterns of expression of 5T4 oncofetal antigen in colorectal carcinomas has indicated a significant association between the presence of the antigen in tumor cells and metastatic spread. The 5T4 antigen expression of 72 epithelial ovarian carcinomas has been investigated by immunohistochemistry; 71% of the carcinomas demonstrated positive 5T4 immunoreactivity in adenocarcinoma cells and/or associated stromal tissue. In order to assess any relationship to prognosis, the 5T4 phenotypes were analyzed with respect to various clinicopathologic features of the tumors and the clinical outcome of the patients assessed by survival and disease-free interval. There was a significant correlation between 5T4 expression and more advanced stage of disease (FIGO stages III and IV) (P < 0.001) and with poorly differentiated tumors (P = 0.036) compared to well or moderately differentiated tumors. Patients with tumors expressing 5T4 were less likely to respond well to adjuvant therapy (P = 0.030) and had a significantly worse outlook in terms of survival (P = 0.033) and disease-free interval (P = 0.033). This significance was not demonstrated as acting independently of FIGO stage and tumor differentiation.

Energy and the English Industrial Revolution.

Societies before the Industrial Revolution were dependent on the annual cycle of plant photosynthesis for both heat and mechanical energy. The quantity of energy available each year was therefore limited, and economic growth was necessarily constrained. In the Industrial Revolution, energy usage increased massively and output rose accordingly. The energy source continued to be plant photosynthesis, but accumulated over a geological age in the form of coal. This poses a problem for the future. Fossil fuels are a depleting stock, whereas in pre-industrial time the energy source, though limited, was renewed each year.

The fall of marital fertility in nineteenth-century France: exemplar or exception? (Part I).

PIP: In France, the decline in marital fertility began in 1800 and preceded the marital decline in other European countries by about 70 years. The French decline is generally regarded as differing from the decline in other European countries only in timing, and the decline in all these countries is attributed to the innovative use of modern fertility control methods, which once introduced, were widely and rapidly accepted. An alternative explanation for the early decline in French fertility is presented. It is argued that the fertility decline in France between 1800 and 1980 reflects an adjustment process. It was suggested that in a peasant society, in contrast to an industrial society, there are only a limited number of available economic niches, and economic pressures will be intense if the population growth rate increases rapidly. In order to keep the population growth rate in balance with the economic resources, the net reproductive rate (NRR) must be kept near unity. In France, unity was maintained by keeping the marital fertility rate in balance with the nuptiality and mortality rates. Data on the population growth rates, mortality rates, marital fertility rates, NRRs, and on life expectancy is presented to support this argument. In France, between 1700-1800, the population increased by 35% and between 1800-1900 by 38%. This increase was exremely small compared to that which occurred in other European countries. For example, in England the corresponding increases were 71% and 252%. These differences in growth were the result of differences in the marital fertility patterns of the 2 countries. Before 1800, marital fertility in France was similar to that of other European countries, but after 1800 the French rate declined rapidly. By 1840 it was 2/3 of the 1800 level, and by 1900 it was 1/2 of the 1800 level. In other European countries marital fertility did not begin to decline until the 1870s. The decline in France differed not only in timing, but in form. When these declines were plotted on a line graph, the differences in form were immediately apparent. The French decline was choppy, and there is even an increase in marital fertility between 1850-1870. In contrast, the decline in other European countries was sharp, consistent, and smooth. During the 1700s in France there was a marked increase in the age at marriage and in the proportion of never married individuals. By the late 1700s a strain in the nuptiality pattern was evidenced by a marked increase in the illegitimacy rate and in the number of premarital pregnancies among brides. Subsequently, there was an increase in the nuptiality rate. In addition, life expectancy leaped from 28-39 years between 1790-1820. To compensate for both the increase in nuptiality and the decline in mortality, couples apparently limited births. These efforts to keep the marital fertility rate, the mortality rate, and the nuptiality rate in balance are evidenced in the NRR which varied from only 0.97-1.08 throughout the 1740-1880 period. The adjustment explanation is supported by the fact that while the marital fertility rate varied between 1740-1880, the NRR rate; remained stable. A subsequent paper will analyze regional differences. In using a equilbrium model, it is necessary to determine if the unity observed in the national NRR is a statistical artifact, resulting from large regional differences canceling each other out at the national level.^ieng

The fall of marital fertility in nineteenth-century France: exemplar or exception? (Part II).

PIP: The focus in this second part of a two-part article is on the homogeneity of French demographic history in the nineteenth century. Specifically, the author examines trends at the regional and departmental level in light of the national tendency for changes in fertility, mortality, and nuptiality to offset one another and keep the intrinsic growth rate close to zero. The author relates regional patterns to the national experience as a whole and describes the gradual dissappearance of the demographic distinctiveness of France in the late nineteenth and early twentieth centuries.^ieng

Population history in the 1980s: the prospects for population history.

PIP: Changes in the approach and scope of the study of population history over the past few decades are examined. The development of family reconstitution and aggregative back projection as techniques used in historical demography is described, and the impact of these techniques on the range of investigation of population history is considered. Changing awareness of the significance of the relationship between demographic change and the socioeconomic system and of the importance of studying analyzing marriage and reproductive patterns is discussed.^ieng

Long-term breastfeeding. The secret bond.

More and more women are choosing to breastfeed their infants, and some women choose to breastfeed for several years. The purpose of this qualitative research was to explore and describe the feelings, concerns, conflicts, and relations of 12 women who breastfed their infants for more than one year. Data collection involved semistructured, in-depth interviews; data analysis was by the grounded-theory method. "Synchronization" and "reorientation" were revealed by data analysis to be key processes that explained the mothers' feelings and behaviors. Synchronization is a process in which the mother moves in pace with her child. Reorientation is a process in which the mother rearranges her lifestyle to focus on the child and his or her needs. As these two processes evolve, the mother develops a secret bond with her child to limit intrusion into their relationship. Phases of these processes are presented. This research will help health-care personnel to have a better understanding of the mothers' needs, beliefs, and priorities.

Glutathione-S-transferase activity and isoenzyme levels measured by two methods in ovarian cancer, and their value as markers of disease outcome.

A study has been carried out to investigate the cellular distribution and levels of glutathione-S-transferase isoenzymes (GST), acidic (pi), basic (alpha) and neutral (mu), in ovarian tumour biopsies, and to measure GST activity in the same tumour specimens. Two methods of assessing isoenzyme levels (immunohistochemistry and Western blot) were compared. Well-known important clinicopathological features were correlated with response to treatment, overall survival and progression-free survival for each of 97 patients from whom biopsies had been obtained. The glutathione-S-transferase isoenzyme levels were also correlated with overall and progression-free survival, and with the important clinicopathological features. As expected, there was a significant correlation between FIGO stage, histological grade of tumour, amount of residual disease after staging laparotomy, response to chemotherapy, and both overall and progression-free survival. Glutathione-S-transferase isoenzyme levels (acidic, basic and neutral) measured by Western blot were not found to be significantly correlated with any of the clinicopathological parameters tested. Using the immunohistochemistry method of detection there was a correlation between the GST acidic isoenzyme level and the amount of residual disease remaining after initial debulking surgery (higher levels were detected in the group with no residual disease, P=0.034), and also between the GST acidic isoenzyme level and the type of chemotherapy regimen used. Higher levels of the acidic isoenzyme were present in tumour biopsies taken from the patient group who had received a combination regimen (cyclophosphamide, carboplatin, ifosfamide and doxorubicin). The neutral and basic GST isoenzyme levels were not significantly correlated with any of the clinicopathological parameters. None of the GST isoenzyme levels were significantly correlated with response to treatment, overall survival or progression-free survival (using either method of detection). Similarly, glutathione transferase activity showed no significant correlation with prognosis or survival.

A study of ovarian cancer patients treated with dose-intensive chemotherapy supported with peripheral blood progenitor cells mobilised by filgrastim and cyclophosphamide.

We have shown that large numbers of haemopoietic progenitor cells are mobilised into the blood after filgrastim [granulocyte colony-stimulating factor (G-CSF)] alone and filgrastim following cyclophosphamide chemotherapy in previously untreated patients with ovarian cancer. These cells may be used to provide safe and effective haemopoietic rescue following dose-intensive chemotherapy. Using filgrastim alone (10 micrograms kg-1), the apheresis harvest contained a median CFU-GM count of 45 x 10(4) kg-1 and 2 x 10(6) kg-1 CD34+ cells. Treatment with filgrastim (5 micrograms kg-1) following cyclophosphamide (3 g m-2) resulted in a harvest containing 66 x 10(4) kg-1 CFU-GM and 2.4 x 10(6) kg-1 CD34+ cells. There was no statistically significant difference between these two mobilising regimens. We have also demonstrated that dose-intensive carboplatin and cyclophosphamide chemotherapy can be delivered safely to patients with ovarian cancer when supported by peripheral blood progenitor cells and filgrastim. Carboplatin (AUC 7.5) and cyclophosphamide (900 mg m-2) given at 3 weekly intervals with progenitor cell and growth factor support was well tolerated in terms of haematological and systemic side-effects. Double the dose intensity of chemotherapy was delivered compared with our standard dose regimen when the treatment was given at 3 weekly intervals. Median dose intensity could be further escalated to 2.33 compared with our standard regimen by decreasing the interval between treatment cycles to 2 weeks. However, at this dose intensity less than a third of patients received their planned treatment on time. All the delays were due to thrombocytopenia.

A randomised trial investigating the dose intensity of primary chemotherapy in patients with ovarian carcinoma: a comparison of chemotherapy given every four weeks with the same chemotherapy given at three week intervals.

BACKGROUND: The dose intensity of chemotherapy for patients with ovarian carcinoma remains a controversial issue. Few randomised trials have been conducted examining dose intensity using the same total dose of chemotherapy. This study was designed to investigate two schedules of chemotherapy using standard and higher dose intensity with both groups receiving the same total dose. PATIENTS AND METHODS: Patients with FIGO stage IC, II, III and IV epithelial ovarian carcinoma were randomised to receive cycles of cyclophosphamide (600 mg/m2) and carboplatin (300 mg/m2) alternating with doxorubicin (50 mg/ m2) and ifosfamide (5 g/m2) at either four-weekly (n = 47) or three-weekly (n = 97) intervals (1:2 randomisation). At randomisation patients were stratified according to histological grade and amount of post operative residual tumour (greater or less than 2 cm). The two arms of the study were well balanced in terms of the major prognostic features. RESULTS: There was no difference in either progression free survival or overall survival between the two arms. The median overall survival was 730 days for the three-weekly treatment and 740 days in the four-weekly arm (progression-free survival was 500 days and 483 days, respectively). The combined overall response rate (complete and partial response) in the 114 assessable patients was 65.7% (66.7% for the three-weekly treatment and 64% for the four-weekly treatment). These differences were not statistically different. CONCLUSIONS: A modest increase in the dose intensity of chemotherapy (1:3 fold) failed to improve the response rate, progression-free survival and overall survival in patients with ovarian carcinoma.