Increased survival time or better quality of life? Trade-off between benefits and adverse events in the systemic treatment of cancer.

INTRODUCTION: Primary objective of the study was to assess the relative weighting between benefit in survival time (SV), benefit in quality of life (QoL) and willingness to experience adverse events (AEs), in patient preferences for chemotherapy treatment. MATERIALS AND METHODS: We included cancer patients with current or past systemic treatment of cancer (STC) as well as physicians placed as hypothetical patients. Participants filled a choice-based conjoint analysis questionnaire with 19 choices among three STC scenarios with variable amounts of benefit in SV or QoL and different types AEs. RESULTS: One hundred patients (50 on curative and 50 on palliative intention treatment) and 114 physicians (61 oncologists and 53 non-oncologists) were included and asked about their preferred chemotherapy treatment. The relative weighting (sum 100%) of SV-QoL-AEs for making the choice in the 100 patients was SV35%-CV33%-AEs31% what was not significantly different from a random distribution (Goodness of fit Chi square P = 0.91) just as it was not for both subgroups, palliative (SV37%-QoL29%-AEs34%; GoF Chi square P = 0.55) and curative (SV34%-QoL36%-AEs30%; GoF Chi square P = 0.73) treatment. The observed distribution in the group of 114 physicians (SV46%-QoL31%-AEs23%) was significantly different from a random distribution (GoF Chi square P = 0.018) just as it was for both subgroups, medical oncologists (SV48%-QoL29%-AEs23%; GoF Chi square P = 0.006) and non-medical oncologists (SV44%-QoL33%-AEs23%; GoF Chi square P = 0.04). CONCLUSIONS: The three attributes (SV, QoL, and AEs) are considered in the same way by cancer patients to make choices on their STC. On the contrary, when placed as hypothetical patients, physicians prefer for themselves those treatments that provide more SV.

Acid lipase activity in neonatal rat liver cell types. Effect of starvation.

The acid lipase activity in the liver of neonatal (1-day-old) rats was studied. It was found that (i) in whole liver, the activity was 50% lower than in adult rats; (ii) in neonatal livers, the activity was 7.7-fold higher in hepatocytes than in hemopoietic cells; (iii) neonatal hepatocytes contained about 25% of the activity detected in adult hepatocytes; (iv) all the differences disappeared when expressed per mg of protein; and (v) starvation did not affect the activity either in adult or in neonatal rat liver.

Lipoprotein lipase in liver. Release by heparin and immunocytochemical localization.

We have previously demonstrated that infusion of Intralipid to rats causes a pronounced increase of the lipoprotein lipase activity in the liver. In this paper we study where in the liver this lipoprotein lipase is located. When isolated livers from Intralipid-treated rats were perfused with heparin, substantial amounts of lipoprotein lipase were released into the perfusate. The identity of the lipase activity was demonstrated by specific inhibition with antisera to lipoprotein lipase, and to hepatic lipase, respectively, and by separation of the two lipase activities by chromatography on heparin-Sepharose. We have also studied the localization of both enzymes by an immunostaining procedure based on post-embedding incubation of ultrathin tissue sections with specific antibodies which were then visualized using protein A-colloidal gold complexes. There was no marked difference in localization for the two enzymes which were both seen at the luminal side of endothelial cells, at the interdigitations of the space of Disse and inside both hepatocytes and endothelial cells. Thus, lipoprotein lipase is present in the liver in positions similar to where the functional pool of hepatic lipase is located and analogous to where lipoprotein lipase is found in extrahepatic tissues. These results raise the possibility that the enzyme has a functional role in the liver.

Lipoprotein lipase and hepatic lipase activities are differentially regulated in isolated hepatocytes from neonatal rats.

Lipoprotein lipase and hepatic lipase are members of the lipase gene family sharing a high degree of homology in their amino acid sequences and genomic organization. We have recently shown that isolated hepatocytes from neonatal rats express both enzyme activities. We show here that both enzymes are, however, differentially regulated. Our main findings are: (i) fasting induced an increase of the lipoprotein lipase activity but a decrease of the hepatic lipase activity in whole liver, being in both cases the vascular (heparin-releasable) compartment responsible for these variations. (ii) In isolated hepatocytes, secretion of lipoprotein lipase activity was increased by adrenaline, dexamethasone and glucagon but was not affected by epidermal growth factor, insulin or triiodothyronine. On the contrary, secretion of hepatic lipase activity was decreased by adrenaline but was not affected by other hormones. (iii) The effect of adrenaline on lipoprotein lipase activity appeared to involve beta-adrenergic receptors, but stimulation of both beta- and alpha 1-receptors seemed to be required for the effect of this hormone on hepatic lipase activity. And (iv), increased secretion of lipoprotein lipase activity was only observed after 3 h of incubation with adrenaline and was blocked by cycloheximide. On the contrary, decreased secretion of hepatic lipase activity was already significant after 90 min of incubation and was not blocked by cycloheximide. We suggest that not only synthesis of both enzymes, but also the posttranslational processing, are under separate control in the neonatal rat liver.

Decrease in the expression of hepatic lipase activity following partial hepatectomy.

Variations in hepatic lipase (HL) activity were studied for the first time in liver, plasma and adrenal glands of partially hepatectomized (70%), sham-operated and intact rats. Activity profiles performed during 7 days in liver, plasma and adrenal glands of sham-operated rats were similar to those obtained in intact animals. However, HL activity in intact animals appeared to be slightly higher during the first 24 hours. Following surgery, hepatectomized animals showed a reduction of about 300 U in liver HL activity which persisted for 7 days. Plasma HL activity of hepatectomized rats was undetectable at 6 hours post-surgery but in increased afterwards. A high correlation between liver and adrenal gland HL activity was found in hepatectomized but not in sham-operated animals. HL mRNA levels in hepatectomized rats showed a 40% decrease during the first 24 hours after surgery, but they returned to the normal range later. On the other hand, HL mRNA values increased in sham-operated rats but no increase in HL activity was detected in these animals. To conclude, our results show that HL activity decreases dramatically during hepatic regeneration due to a concomitant decrement in the expression of the gene that encodes the enzyme and to other undetermined factors.

Partial hepatectomy and/or surgical stress provoke changes in the expression of lipoprotein lipase and actin in liver and extrahepatic tissues.

The expression of lipoprotein lipase (LPL) and actin genes was examined in heart, muscle and white adipose tissue (WAT) and the expression of albumin and actin genes was examined in regenerating liver after 2/3 hepatectomy. Both surgical stress and partial hepatectomy (PH) affected LPL and actin mRNA levels in muscle and WAT, but not in heart. The changes in LPL mRNA suggest transcriptional regulation of the enzyme during hepatic regeneration. Our results show for the first time that the LPL gene expression in the different tissues studied is altered not only by the surgical stress, but also by PH per se. Actin expression is also affected in some tissues. In liver, PH and surgical stress altered the expression of albumin and total mRNA. The total mRNA of the other tissues studied did not change. The changes observed in LPL in different tissues, especially in WAT and muscle, may be responsible for some of the changes in lipidic metabolism, thus allowing for some plasma lipoproteins to be used as substrates by the LPL activity that arises in the liver during hepatic regeneration. The fatty acids derived from these lipoproteins would constitute not only an energy source but also the building material needed in the process of restoration of the lost hepatic mass. It is suggested that hormonal changes taking place after surgery are responsible for the variation in the levels of the different mRNAs studied.

Starvation enhances lipoprotein lipase activity in the liver of the newborn rat.

To determine to what extent lipoprotein lipase activity in the liver of the newborn rat depends on milk ingestion, its changes were studied during different nutritional conditions. Newborns were placed with nurse rats with or without ligated nipples and they were killed at 0,8 or 24 h of life. Lipoprotein lipase in newborns liver was characterized by its inhibition in the presence of 1.0 M NaCl, its specific elution at 1.5 M NaCl on heparin-Sepharose 4B column and its requirement for serum in the assay mixture to manifest its activity. In fed animals lipoprotein lipase activity and triacylglycerol content in liver as well as circulating triacylglycerols and ketone bodies increased progressively after birth. When newborns were kept starved the change in enzyme activity was significantly enhanced, whereas the increase found after birth in the other parameters disappeared. Starvation produced reduction in circulating RIA-insulin levels in the newborn rats. Results show that liver lipoprotein lipase activity in the newborn rat is controlled by a mechanism which resembles that of the enzyme in the adult heart and indicate that its presence facilitates the uptake by the liver of fatty acids from circulating triacylglycerols for their oxidation rather than deposit.

Effect of starvation on lipoprotein lipase activity in the liver of developing rats.

Liver lipoprotein lipase activity in neonatal (1- and 5-day-old) rats was 2-3-times than in the liver of adult rats. In mid-suckling (15-day-old) or weaned (30-day-old) animals, it was not significantly different from the low activity detected in adult rats. Starvation resulted in a 3-fold increase of lipoprotein lipase activity in the neonatal liver, but did not affect the activity in the liver of mid-suckling, weaned or adult rats. When isolated livers from both 1- and 5-day-old pups were perfused with heparin, a sharp peak of lipoprotein lipase activity appeared in the perfusate. In fed neonates, the peak area accounted for about 70% of the total (released + non-releasable) activity. In starved neonates, the proportion of heparin-releasable activity increased up to about 90%. These results indicate that neonatal rat liver lipoprotein lipase activity is markedly affected by changes in the nutritional status of the animal, and the effect is restricted to the vascular pool of the enzyme, as was reported in extrahepatic tissues from adult rats.

Neonatal extinction of liver lipoprotein lipase expression.

In contrast to the complete absence of lipoprotein lipase (LPL) mRNA in adult rat liver, fetal and neonatal rat liver contain substantial amounts of LPL mRNA, which is translated in active LPL protein as can be deduced from the presence of LPL activity in this organ. At this neonatal stage, both the relative abundance of LPL mRNA and LPL activity increased with starvation. During the suckling period, LPL mRNA and LPL activity gradually decreased until both parameters were undetectable. While the administration of L-thyroxine or hydrocortisone enhanced the disappearance of LPL mRNA, induced hypothyroidism delayed its disappearance. In adult animals induced hypothyroidism could not reactivate LPL mRNA production in the liver. The data presented suggest that liver LPL production responds to changes in the nutritional state and becomes extinguished during development, in a fashion reminiscent to the extinction of alpha-fetoprotein. This extinction of LPL gene expression is influenced by hormonal factors.

Effects of starvation on in vivo gluconeogenesis in hypo- and hyperthyroid rats.

Studies were performed on rats in vivo to determine whether starvation disrupts glucose metabolic balance after removal of the thyroid gland. Intact controls and thyroidectomized rats were injected daily with 0, 0.1, 1.8, or 25 microgram L-T4/100 g BW. Glucose spaces were similar in all groups. The disappearance of labeled glucose from blood was faster in the thyroidectomized rats injected with 25 microgram L-T4 than in the other groups. Starvation enhanced the production of [14C]glucose from [3-14C]pyruvate in all groups, but this effect occurred earlier in control rats and thyroidectomized rats given 1.8 or 25 microgram L-T4 than in thyroidectomized rats given either 0 or 0.1 microgram L-T4. Starvation also enhanced the appearance of radioactivity in liver glycogen 30 min after the injection of [3-14C]pyruvate in all groups, but this effect was lesser in thyroidectomized rats given 0, 0.1, or 25 microgram L-T4 than in other groups. The normal net production of glucose in fed thyroidectomized rats may be the result of a balanced equilibrium between reduced gluconeogenesis and glycolysis. Results obtained in thyroidectomized rats given 25 microgram L-T4 are discussed in terms of the augmented utilization of the newly formed glucose which compensates for their enhanced gluconeogenesis.

Involvement of catecholamines in the effect of fasting on hepatic endothelial lipase activity in the rat.

The effect of fasting on hepatic endothelial lipase activity in the liver of adult rats was investigated. We found that, both in male and female rats, fasting produced a progressive decrease of the hepatic endothelial lipase activity. Upon refeeding, the activity returned to control values in 48 h. In isolated livers from fed male rats, a sharp peak of hepatic endothelial lipase activity appeared in the perfusate upon heparin addition. It accounted for 75% of the total activity (heparin-released + residual) of the tissue. Fasting (24 h) decreased the heparin-releasable activity, and this effect was responsible for most of the decrease found in whole tissue. We suggest that the effect might be due to a decreased synthesis and/or secretion of the enzyme by hepatocytes, since isolated hepatocytes from fasted rats, incubated at 37 C, released 65% less activity to the incubation medium than hepatocytes from fed rats. Adrenaline, but not insulin, glucagon, dexamethasone, epidermal growth factor, or T3, decreased the amount of hepatic endothelial lipase activity released by hepatocytes isolated from fed rats. The effect of adrenaline appears to be mediated by alpha 1-receptors since phenylephrine but not isoprenaline reproduced, and prazosin but not propranolol blocked, the effect of the catecholamine. In the presence of cycloheximide, adrenaline also decreased the amount of activity released. We suggest that, in our incubation conditions (up to 3 h), the hormone affects the posttranslational processing of the enzyme. In vivo administration of prazosin blocked the effect of both noradrenaline and fasting on hepatic endothelial lipase activity in whole liver. Those results suggest that catecholamines are involved in the decreased hepatic endothelial lipase activity found in the liver of fasted rats, and points out the role of these hormones in the acute modulation of an enzyme involved in reverse cholesterol transport.

Hormonal regulation of lipoprotein lipase activity from 5-day-old rat hepatocytes.

Lipoprotein lipase (LPL) activity is known to be synthesized, active and functional in the 1-day-old rat liver: it peaks just at birth triggered by parturition. During suckling LPL mRNA, LPL synthesis and LPL activity are still high at 5 days and then fade reaching adult values at weaning. How LPL expression is gradually extinguished is not known. Therefore we studied the effect of different doses of several hormones on LPL activity released by incubated hepatocytes from 5-day-old rats. In the presence of heparin the release of LPL activity in the medium was linear until 3 h and was always significantly increased vs. without heparin. At 3 h in the presence of heparin the main hormonal effects were: dose-dependent increase (30-60%) with dexamethasone; dose-dependent increase (20-60%) with glucagon; dose-independent decrease (50-60%) with ethinylestradiol, testosterone, progesterone and prolactin; no effect with insulin; 20-40% increase with adrenaline < 1 mM but 40-50% decrease with noradrenaline < 10 microM. Increase of LPL release by glucagon and adrenaline agrees with the increased LPL expression we previously found in an undifferentiated hepatoma cell line when the adenylate cyclase/protein kinase A pathway was activated. The effect of glucagon is concordant with our previous observations that fasting increases liver LPL activity in neonatal rats. The high estradiol levels known to be present in male and female 9-19-day-old rats might contribute to liver LPL extinction during suckling.

Acquired lipoprotein lipase deficiency associated with chronic urticaria. A new etiology for type I hyperlipoproteinemia.

Type I hyperlipoproteinemia (type I HLP) is a rare disorder of lipid metabolism characterized by fasting chylomicronemia and reduced postheparin plasma lipoprotein lipase (LPL) activity. Most cases of type I HLP are due to genetic defects in the LPL gene or in its activator, the apolipoprotein CII gene. Several cases of acquired type I HLP have also been described in the course of autoimmune diseases due to the presence of circulating inhibitors of LPL. Here we report a case of type I HLP due to a transient defect of LPL activity during puberty associated with chronic idiopathic urticaria (CIU). The absence of any circulating LPL inhibitor in plasma during the disease was demonstrated. The LPL genotype showed that the patient was heterozygous for the D9N variant. This mutation, previously described, can explain only minor defects in the LPL activity. The presence of HLP just after the onset of CIU, and the elevation of the LPL activity with remission of the HLP when the patient recovered from CIU, indicate that type I HLP was caused by CIU. In summary, we report a new etiology for type I HLP - a transient decrease in LPL activity associated with CIU and with absence of circulating inhibitors. This is the first description of this association, which suggests a new mechanism for type I HLP.

Metabolic response to starvation at late gestation in chronically ethanol-treated and pair-fed undernourished rats.

To study the role of undernourishment in the negative effects of ethanol during pregnancy and to determine whether maternal ethanol intake modifies metabolic response to starvation at late gestation, female rats receiving ethanol in their drinking water before and during pregnancy (ethanol group) were compared with animals that received the same amount of solid diet as the ethanol group rats (pair-fed group) and with normal rats fed ad libitum (control group). All animals were killed on the 21st day of gestation, either in the fed state or after 24-hours fasting. The body weight of ethanol rats was lower than that of controls but higher than that of pair-fed rats. When compared with controls, ethanol and pair-fed rats had reduced fetal body weights, whereas fetal body length was reduced only in the former. In the fed state, blood glucose concentration was lower in the ethanol and pair-fed rats and fetuses than in controls. Twenty-four-hour starvation caused a reduction in this parameter only in control and ethanol mothers. In the fed state, maternal liver glycogen concentration was lower in ethanol and higher in pair-fed mothers than in controls. Blood beta-hydroxybutyrate levels were higher in ethanol-treated mothers than in the others, and 24-hour starvation increased this parameter in ethanol and control rats to a greater extent than in the pair-fed ones. Liver triacylglyceride concentration was higher in ethanol-treated mothers than in the other two groups, and starvation caused this concentration to increase in ethanol and control groups but not in the pair-fed group.(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating triacylglycerols, lipoproteins, and tissue lipoprotein lipase activities in rat mothers and offspring during the perinatal period: effect of postmaturity.

Mammary gland and adipose tissue lipoprotein lipase activities have been implicated in the changes of circulating triacylglycerol levels which occur in the mother at late gestation. In the newborn the temporal accumulation of triacylglycerols in the liver coincides with the appearance of a lipoprotein lipase peak. The relationships of these changes with the rise in circulating prolactin in the mother before parturition and the extrauterine nutritional status in the offspring were studied in a postmaturity model produced in the rat by subcutaneous injection of 7 mg progesterone/day to pregnant animals from the 20th day of gestation. Pregnant controls received the medium. Parturition occurred at day 21.5 of gestation in pregnant controls while it did not occur before the 23rd day in those receiving progesterone. At the 20th day of gestation, plasma triacylglycerol concentrations and all lipoprotein fractions (especially VLDL) were much higher in mothers not receiving progesterone than in age-matched virgins, and these differences disappeared at the 21st day of gestation. Lipoprotein lipase activity was maintained low in control mothers' adipose tissue until the 23rd postfecundation day while it greatly increased in mammary gland from parturition time. In progesterone treated mothers, both triacylglycerol and lipoprotein fractions (especially VLDL) in plasma were maintained elevated until the 23rd postfecundation day and adipose tissue and mammary gland lipoprotein lipase activities were maintained low until this time.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidermal growth factor interferes with the effect of adrenaline on glucose production and on hepatic lipase secretion in rat hepatocytes.

We studied the interaction of epidermal growth factor (EGF) and adrenaline in the control of several metabolic functions in isolated hepatocytes from fed rats. EGF did not modulate glucose release, urea production or hepatic lipase secretion, but interfered with the stimulatory effect of adrenaline on both glucose and urea production and also with the inhibitory effect of this hormone on hepatic lipase secretion. EGF also interfered with the effect of both angiotensin II and vasopressin on glucose release and on hepatic lipase secretion. While the effect of EGF interfering with the action of adrenaline on glucose release was potentiated in the absence of extracellular calcium, the effect on the inhibition of hepatic lipase secretion was abolished. These results suggest that EGF interfered with catecholamine actions in the liver at a site distal from the generation of the calcium signal.

Localization of lipoprotein lipase to discrete areas of the guinea pig brain.

Lipoprotein lipase is a key enzyme in lipoprotein metabolism present primarily in extrahepatic tissues with high turnover of fatty acids. Using immunocytochemistry we have explored where lipoprotein lipase is localized in guinea pig brain. The enzyme was found to be associated with neuronal cells and vascular endothelial surfaces. The distribution was strikingly uneven with intense reaction in some areas, and virtually no reaction in adjacent areas. The highest reactivity was in neocortex, in hippocampus, in Purkinje cells of the cerebellum and in some motor nuclei of the brainstem. The results suggest marked differences between individual brain areas in utilization of plasma lipoproteins.

Morphological recovery of hippocampal pyramidal neurons in the adult rat exposed in utero to ethanol.

Reduced numbers of dendritic spines on the secondary apical dendritic branches and basilar dendrites of CA1 and CA3 pyramidal neurons were observed in ethanol-treated rats during embryonic life aged 15 days when compared with age-matched controls. However, differences were no longer present at the age of 90 days. These results suggest that recovery of some morphological parameters of pyramidal hippocampal neurons may occur in rats exposed in utero to ethanol.

High liver lipoprotein lipase activity in hyperlipemic developing rats from undernourished pregnant mothers.

To study the potential relationship between circulating triacylglycerol (TAG) levels and lipoprotein lipase (LPL) activity in the newborn rat liver, pups from undernourished or normal control mothers were nursed by normal dams, and studied at 0, 1, 15 or 30 days of age. Plasma TAG levels and liver TAG concentration increased more in pups from undernourished mothers than they did in controls. At birth, liver LPL activity was similarly high in both groups but, whereas in controls it decreased progressively after birth, in pups from undernourished mothers it remained stable until 15 days of age. Results suggest that the hypertriglyceridemia present in pups from undernourished mothers may be responsible for the sustained high LPL activity in their liver which may enhance the hepatic uptake of circulating TAG.

Hepatic endothelial lipase activity in neonatal rat liver.

Hepatic endothelial lipase (HEL) activity is as high in the neonatal (1-day old) rat liver as in adults. Most of the HEL activity is located at the capillaries since 75% of the total activity is released by heparin or collagenase perfusion. The residual activity (non-releasable) is located in hepatocytes and not in hemopoietic cells, which are the major cell type in neonatal liver. Per mg of protein, the HEL activity is 50% higher in neonatal than in adult hepatocytes. We suggest that neonatal hepatocytes have an increased capacity to synthesize and secrete HEL activity, so maintaining a high activity in the whole organ. It might contribute to the hepatic uptake of cholesterol from circulating lipoproteins, in a period in which endogenous cholesterol synthesis is known to be inhibited in the liver.