Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015.

BACKGROUND: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P). PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m(2) i.v. on days 1, 15 and 22); FA (200 mg/m(2) i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m(2) i.v. bolus, then 22-h, 600 mg/m(2) infusion) or CAPIRI: irinotecan (250 mg/m(2) i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m(2) b.i.d. on days 1-15 and 22-36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.). RESULTS: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months). CONCLUSION: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.

Corticotropin-releasing hormone-induced adrenocorticotropin and cortisol secretion depends on sleep and wakefulness.

Twenty-four-hour profiles of pituitary-adrenocortical secretory activity in humans are characterized by a distinct decrease in hormone secretion after sleep onset and a strong increase during the early morning hours. It is a widely accepted notion that this pattern of hormone secretion is driven by intrinsic circadian oscillators, and the contributions of sleep and wakefulness have been greatly neglected. Here, we examined whether there is a sleep-dependent inhibition of stimulated ACTH and cortisol release during early nocturnal sleep, which is dominated by slow wave sleep (SWS). We administered human CRH (hCRH; 50 micrograms), the main corticotropin secretagogue, to 14 healthy men during the first SWS period after sleep onset and another time in the same night during a period of stage 2 sleep in the second half of sleeping time. To discriminate possible circadian influences from influences of sleep, on a second night another two injections of hCRH were administered at identical points during the night to the same subject, who was kept awake. Exclusively during sleep, but only during SWS in the beginning of sleep time, ACTH and cortisol responses to hCRH were blunted. The results demonstrate an inhibiting influence of sleep on stimulated ACTH and cortisol secretion, with this effect restricted to the early part of sleep.

Nocturnal adrenocorticotropin and cortisol secretion depends on sleep duration and decreases in association with spontaneous awakening in the morning.

It is still discussed controversially to what extent the nocturnal activity of the hypothalamus-pituitary-adrenocortical system depends on sleep and awakening in the morning. Therefore, we investigated the association of plasma ACTH and cortisol levels with undisturbed nocturnal sleep and spontaneous awakening in 14 healthy male subjects (between 2300 h and 1100 h). Between sleep onset and 476.9 min after sleep onset mean plasma cortisol level was significantly (P < 0.01) higher (210 +/- 15 vs. 155 +/- 9 nmol/L) in the group with a shorter (476.9 +/- 15.0 min; n = 7; mean +/- SEM) than in the group with a longer total sleep time (596.9 +/- 14.4 min; n = 7). Spontaneous awakening in the morning was not linked to the presence of any specific sleep stage or to rising plasma ACTH and cortisol levels. However, spontaneous awakening was followed by a brief rise in plasma ACTH and cortisol in both groups. Thereafter, during wakefulness plasma ACTH and cortisol abruptly declined in all subjects irrespective of the time of awakening. The slope of the plasma ACTH and cortisol curves differed significantly (ACTH: P < 0.001; cortisol: P < 0.002, for all subjects) comparing the time after awakening (until 1100 h) with a time interval of identical length before awakening. We conclude that the duration of sleep and nocturnal ACTH and cortisol secretion are interrelated. Furthermore, the data suggest that the endogenous early morning activation of the hypothalamus-pituitary-adrenocortical system is terminated by mechanisms closely associated with awakening.

Influences of corticotropin-releasing hormone, adrenocorticotropin, and cortisol on sleep in normal man.

We studied the effects of the hormones of the hypothalamus-pituitary-adrenocortical axis on sleep processes in normal men. In one experiment, 10 men received placebo, cortisol (6 mg/h), and ACTH (0.55 U/h) as continuous iv infusions from 2200-0700 h on 3 separate nights. In another experiment, placebo and CRH (30 micrograms/h) were administered to another 10 men in the same manner. The mean plasma cortisol levels were comparable during the cortisol and ACTH infusions (552 vs. 668 nmol/L). During both infusions, the time spent in rapid eye movement (REM) sleep was significantly (P less than 0.01) reduced compared to that during the placebo infusion, and the cortisol infusion significantly (P less than 0.05) enhanced the time spent in slow wave sleep (SWS). The CRH dose used only moderately increased plasma ACTH and cortisol levels; the changes in SWS and REM sleep during CRH infusion were in the same direction as occurred during the cortisol infusion, but were not significant. These results suggest that cortisol has a sleep modulatory effect. The decrease in REM sleep during the ACTH infusion may be mediated by the rise in endogenous cortisol. However, ACTH specifically altered sleep, in that it inhibited the cortisol-induced increase in SWS. Peripherally administered CRH had no intrinsic influence on sleep.

Different regulation of adrenocorticotropin and cortisol secretion in young, mentally healthy elderly and patients with senile dementia of Alzheimer's type.

Previous studies suggest that an alteration of the neuroendocrine system may particularly occur in senile dementia of Alzheimer's type (SDAT). In the present study the reactivity of the hypophyseal-adrenocortical axis (HPA) in the elderly was assessed by hormonal stimulation of the hypophysis. Twelve young men (aged 21-24 yr), 15 mentally healthy elderly (aged 65-90 yr), and 12 patients with SDAT (aged 60-84 yr) received an iv bolus injection containing 50 micrograms CRH and 0.5 IU lysine vasopressin after a baseline period of 2 h. ACTH, cortisol, and dehydroepiandrosterone secretion was monitored over a period of 2 h before and after the injection. The baseline ACTH concentrations were increased in both groups of elderly, the baseline cortisol levels were not different in either group. The peak ACTH and cortisol levels were significantly elevated in the mentally healthy elderly, whereas senile demented patients showed a rise comparable with that in the young subjects. Moreover, in the demented patients the post-stimulus decline in plasma ACTH levels seemed to be delayed. Dehydroepiandrosterone was significantly lowered in subjects of all ages. Our results demonstrate an enhanced reactivity of the HPA in mentally healthy elderly. This is possibly due to a diminished sensitivity of the feedback regulation to glucocorticoids. However, SDAT patients had, compared to healthy elderly subjects, an attenuated response to CRH/lysine vasopressin and a prolonged ACTH secretion, indicating alterations of the HPA in this disease.

Human adrenal cells express tumor necrosis factor-alpha messenger ribonucleic acid: evidence for paracrine control of adrenal function.

Tumor necrosis factor (TNF) is gaining increasing importance in clinical medicine. It plays a role in the interaction of the immune system with the hypothalamic-pituitary-adrenal axis. In the present study various morphological methods, including immunohistochemistry, electron microscopy, and in situ hybridization were applied to characterize the localization and distribution of TNF in the human adrenal gland. Double immunostaining revealed an astonishing degree of intermingling of steroid-producing cells and chromaffin cells. Macrophages could be found in all regions of the adrenal gland, but particularly in the transition zone of cortex and medulla. The steroid-producing cells of the inner zone of the cortex express major histocompatibility complex class II molecules. On the ultrastructural level, immune cells, steroid cells, and catecholamine-producing cells were found in direct contact. The combination of immunohistochemistry and in situ hybridization was optimally suited to define the exact cellular source of TNF in the human adrenal. TNF is produced in macrophages, but above all in 17 alpha-hydroxylase-positive cells (steroid-producing cells) in the zona reticularis and medulla. No signal was found in chromaffin cells. TNF may induce major histocompatibility complex class II in human adrenal gland in a paracrine or autocrine manner. It is concluded that TNF may have an important role in normal human adrenal physiology.

Nocturnal wakefulness inhibits growth hormone (GH)-releasing hormone-induced GH secretion.

Recent studies have suggested that spontaneous release of GH as well as GH secretion stimulated by exogenous GHRH are influenced by central nervous mechanisms that regulate sleep and wakefulness. Here, the effect of nocturnal wakefulness on GH secretion stimulated by i.v. administration of GHRH was examined in two experiments in healthy men. On all nights, GHRH (1 microgram/kg BW) was injected after the subjects had slept for about 2.5 h to minimize interference of endogenous release of GH during early sleep with the response to exogenous GHRH. Both experiments included a control condition to assess GH secretory responses to GHRH during undisturbed sleep and an experimental condition to assess the effect of wakefulness. In the control conditions, subjects slept throughout the night, and GHRH was administered 170 min after sleep onset. In the experimental condition of Exp I (n = 10), subjects were awakened 150 min after sleep onset and stayed awake. GHRH was given 20 min after awakening. In the experimental condition of Exp II (n = 8), subjects were awakened 30 min after GHRH treatment, which was administered 170 min after sleep onset. GHRH administrations during sleep fell into epochs of stage 2 sleep or rapid eye movement sleep. GH secretion and sleep characteristics before GHRH administrations were comparable for experimental and control conditions of both experiments. GH secretory responses were inhibited when the subject was awake at the time of GHRH administration compared to GH responses during undisturbed sleep. Awakening the subject 30 min after GHRH administration abruptly interrupted the initiated GH secretory response. The results demonstrate a profound inhibitory effect of nocturnal awakenings on GHRH-induced GH secretion. They indicate that the GH secretory response to GHRH is strongly determined by central nervous system sleep-wake activity.

Systemic growth hormone does not affect human sleep.

Subsequent to sleep onset, GH concentrations increase markedly, suggesting a stimulatory influence of sleep on GH secretion. However, results have been inconsistent as to whether GH conversely exerts a significant influence on sleep. Hence, the effects of exogenous administration of GH and of GH secretion stimulated by GH-releasing hormone (GHRH) on sleep were reexamined in 3 experiments in healthy male volunteers. In Exp I, 12 men participated on 3 experimental nights, receiving a constant iv infusion of 5 IU GH (between 2100-0700 h), an im bolus injection of 5 IU GH at 2100 h, and placebo. In Exp II, the effects of a short iv infusion of a high dose of 48 IU GH (between 2345-2315 h) on sleep were evaluated in 3 men. In Exp III, the effects of continuous infusion of 30 micrograms/h GHRH (between 2200-0700 h) on sleep were compared to the placebo condition in 10 men. Experiments were double blind, within-subject, cross-over comparisons and included an adaptation night before experimental nights. On all nights, the subjects went to bed at 2300 h and were awakened at 0700 h. Administration of GH elevated plasma GH and somatomedin-C levels throughout the night (P < 0.005). Neither im administration of 5 IU GH nor iv administration of 5 and 48 IU GH had any effect on the total sleep time or the time spent in different sleep stages during the whole night or in the first and second halves of sleep time. Infusion of GHRH increased nocturnal GH secretion (P < 0.005), but the episodic pattern of GH secretion was maintained. However, sleep remained unchanged during GHRH infusion. From these results we conclude that in healthy man, systemic GH has no physiological role for sleep regulation.

Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man.

A recent study in humans, animal studies, and in vitro data have suggested that interleukin-6 (IL-6) stimulates the secretory activity of the hypothalamus-pituitary-adrenocortical (HPA) axis. In a phase II study, one female and six male patients with metastatic renal cell carcinoma received IL-6 to evaluate a possible antitumor effect of IL-6. This offered the possibility of investigating the influence of IL-6 on the HPA axis in man. The subjects were studied 1 day before, on day 1, and on day 21 of IL-6 therapy (150 micrograms administered sc every day at 0900 h). Blood samples were taken at 0900, 1100, 1300, 1600, and 2000 h the day before, on day 1 of IL-6 therapy, 24 h after the first IL-6 injection, and on day 21 of IL-6 treatment. Plasma ACTH and cortisol levels promptly followed the rise of IL-6, which peaked 4 h after administration. They were significantly (P < 0.05) higher at 1100 and 1300 h on day 1 of IL-6 therapy compared with the corresponding plasma levels the day before IL-6 treatment. Cortisol concentrations remained significantly increased at 1600 and 2000 h after IL-6 administration. Twenty-four hours after the first IL-6 administration, IL-6, ACTH, and cortisol levels had reached preinjection values. Although plasma cortisol levels were similar on days 1 and 21, ACTH levels were lower on day 21 (than on day 1), but significantly elevated at 1100 h compared with levels on the day before the first IL-6 injection. Results confirming the very recent data of another study demonstrate a stimulating effect of IL-6 on the HPA axis in man. They support the notion that IL-6 is one of the cytokines involved in the interaction between the immune system and the HPA axis.

Interleukin-6 messenger ribonucleic acid expression in human adrenal gland in vivo: new clue to a paracrine or autocrine regulation of adrenal function.

Interleukin-6 (IL-6) is an important mediator in the interaction of the hypothalamo-pituitary-adrenal axis with the immune system. Recently, a direct influence of IL-6 on adrenal steroidogenesis has been demonstrated. Therefore, we designed a study to determine whether IL-6 is expressed within the normal human adrenal gland. The combination of in situ hybridization and specific immunostaining was eminently suited to identify the cell types producing IL-6. IL-6 messenger ribonucleic acid occurred in the inner zone of the adrenal cortex in anti-17 alpha-hydroxylase-positive steroid cells. Also, CD68-positive macrophages in the zona reticularis showed a positive signal. No reaction was seen in chromaffin cells. We conclude that under normal conditions, IL-6 is expressed in specialized adrenocortical cells. Therefore, IL-6 may play an important role as a paracrine or autocrine factor in a local immune-adrenal interaction.

Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men.

Interleukin-6 (IL-6) is a proinflammatory cytokine that has been shown to mediate, in addition to immune reactions, various endocrine and central nervous components of the acute phase response. In this context, the present study aimed to specify the contributions of IL-6 to the regulation of pituitary-adrenal secretory activity and GH and TSH secretion, as well as to the regulation of central nervous sleep and mood in healthy men. Effects of a low dose of IL-6 (0.5 microgram/kg body weight) were assessed, inducing plasma IL-6 concentrations closely comparable with those typically observed after infectious challenge. Each of the 16 male subjects participated in two 14-h sessions (between 1800 and 0800 h), receiving either placebo or human recombinant IL-6 sc at 1900 h. Blood was collected repeatedly to determine plasma hormone levels, serum concentrations of cytokines, and C-reactive protein. Moreover, mood was assessed, and sleep recordings were obtained between 2300 and 0700 h. The cytokine induced a prolonged increased in plasma concentrations of ACTH and cortisol (P < 0.001), but led to a decrease in TSH concentrations (P < 0.01). In response to IL-6, subjects reported fatigue and felt more inactive and less capable of concentrating than after placebo. Sleep architecture was altered significantly by the cytokine. Slow-wave sleep was decreased during the first half and increased during the second half of sleep. Rapid eye movement sleep during the entire nocturnal sleep time was significantly decreased. After IL-6, body temperature rose slightly. C-reactive protein concentrations were dramatically increased 12.5 h after substance administration (P < 0.001). IL-6 did not affect serum concentrations of IL-2, IL-8, interferon-alpha, and interferon-gamma. The results underscore the importance of IL-6 in the cascade of cytokines for the neuroendocrine response during the acute phase reaction. In addition, IL-6 appears to be involved in changes of sleep and behavior accompanying infection and inflammatory disorders.

Influences of partial REM sleep deprivation and awakenings on nocturnal cortisol release.

Decreasing endogenous plasma cortisol levels during rapid eye movement (REM) sleep have been recently reported, suggesting a diminished or absent secretory activity of the adrenals during this period. On the other hand, episodes of light sleep (Stage 1) and intermittent wakefulness have been found to be associated with increasing plasma cortisol levels. The present experiments in 10 adult men were designed to examine whether or not REM sleep inhibits adrenocortical activity and if short periods of wakefulness increase nocturnal cortisol release. Somnopolygraphic recordings were obtained from each subject under three experimental sleep conditions: a baseline night, an REM deprivation night in which the subject's sleep was disturbed contingent upon the occurrence of REM, and a control night in which sleep was disturbed both during REM deprivation and non-REM (NREM) epochs, i.e., mostly during Stage 2 sleep. This last condition was introduced to distinguish the effects of REM deprivation from those of arousals that may per se act as stressful stimuli for cortisol release. Contrary to expectation, we found that both REM sleep deprivation and arousals in NREM epochs reduced rather than enhanced mean plasma cortisol levels as compared with baseline conditions. These findings do not support the hypothesis of an inhibitory effect of REM sleep on cortisol secretion, though present data do not refute this hypothesis. The awakenings, or the light sleep subsequent to sleep disturbance, appear to have no stimulatory effect on adrenocortical secretion. Awakenings during sleep at night may even reflect the activity of mechanisms inhibiting sleep-related increases in plasma cortisol concentration.

Sleep disruption alters nocturnal ACTH and cortisol secretory patterns.

Recent studies have provided evidence that nocturnal cortisol secretion is coupled to ultradian rhythms of sleep. The present study was designed to specify how exogenous and sleep-related endogenous factors influence nocturnal adrenocorticotropin (ACTH) and cortisol secretion. We compared the influences of (1) temporary sleep deprivation, (2) arousals continuously induced during sleep and, (3) undisturbed sleep (baseline) on pituitary-adrenocortical activity in 10 healthy men. Sleep deprivation (DS) and continuous arousals during sleep (AS) were introduced at the beginning of the second rapid eye movement (REM) sleep period which is an epoch close to the first significant nocturnal rise in plasma cortisol. Compared with the baseline nights, plasma cortisol significantly increased immediately after continuous arousals were started or the subject was awakened and remained awake. Despite this exogenously provoked first cortisol peak, average cortisol release during DS and AS was no higher than during undisturbed sleep. The arousal-induced cortisol burst was followed by a temporary inhibition of cortisol secretion, suggesting that once the subject is aroused (i.e., in stage 1 sleep or awake), the hypothalamus-pituitary-adrenal (HPA) system becomes highly sensitive to negative feedback inhibition. Spontaneously occurring endogenous cortisol peaks of comparable size during undisturbed sleep did not exhibit such a temporary inhibition of cortisol secretion. We hypothesize that sleep attenuates negative feedback inhibition within the HPA system, whereas wakefulness (or stage 1 sleep) reflects increased feedback sensitivity of this system.

Lack of efficacy of recombinant human interleukin-6 in patients with advanced renal cell cancer: results of a phase II study.

The present phase II study was undertaken to assess antitumoral activity, safety and tolerability of recombinant human interleukin-6 (rh IL-6) in patients with advanced renal cell cancer. Rh IL-6 was administered as a daily subcutaneous injection at a fixed dose of 150 micrograms/day for a maximum of 42 consecutive days. 12 patients with metastatic renal cell cancer without previous immunotherapy were enrolled and were evaluated for response. No objective clinical responses were observed in the trial. Toxicity was moderate and reversible and mainly comprised fever, influenza-like symptoms, fatigue and moderate hepatotoxicity. Anaemia, leucocytosis, thrombocytosis and induction of an acute phase response were observed in most patients. In conclusion, prolonged subcutaneous administration of rh IL-6 on an outpatient basis is safe and feasible. However, rh IL-6 exhibited no antitumoral activity in patients with metastastic renal cell cancer. Profound regulatory effects on haematopoiesis and inflammatory response of rh IL-6 were observed.

Delta-sleep-inducing peptide does not affect CRH and meal-induced ACTH and cortisol secretion.

Besides sleep-promoting properties, delta-sleep-inducing peptide (DSIP) has been reported to act as a corticotropin-releasing inhibiting factor in vitro and in vivo. We examined, first, the influence of DSIP on ACTH and cortisol release following stimulation with human corticotropin-releasing hormone (h-CRH; 1.0 microgram/kg body weight, and 0.5 microgram/kg body weight, respectively) in healthy young men (n = 5 in each condition). DSIP (total doses of 3 and 4 mg, respectively, vs. placebo) was infused intravenously between 30 min prior to and 90 min after CRH injections. Responses of ACTH and cortisol were almost identical during and after infusion of DSIP and placebo. In a second experiment, the influence of DSIP (4 mg, also administered as intravenous infusion) on meal-related ACTH and cortisol secretion was studied in another 10 men. Meal-related midday surge of ACTH and cortisol was also not affected by DSIP. Our data do not support an inhibitory role of DSIP on ACTH and cortisol secretion in man.

Immunohistochemical detection of CD5 with monoclonal antibody 4C7 on paraffin sections.

CD5 is useful for the classification of low-grade B-cell lymphomas, because it is aberrantly expressed in B-cell chronic lymphocytic leukemias/small lymphocytic lymphomas (B-CLLs/SLLs) and mantle cell lymphomas (MCLs), but not in the other well-described low-grade B-cell lymphomas. Therefore, we tested the utility of monoclonal antibody (MAb) 4C7 to detect CD5 on paraffin sections of 22 cases with low-grade B-cell lymphomas and 4 cases with high-grade B-cell lymphomas and compared the results with CD5 detection by analysis of fresh tissue with a fluorescent-activated cell sorting (FACS). After heat-induced epitope retrieval we could detect CD5 on paraffin sections in all MCLs and B-CLLs/SLLs, identical to the results of flow cytometry. Eleven of 12 cases that showed no CD5 expression by FACS analysis were also negative on paraffin sections. In only one case of a presumed blastoid MCL, CD5 was detectable by immunohistochemistry but not by FACS analysis. We conclude that MAb 4C7 against CD5 is a useful paraffin-reactive marker, especially to correctly identify MCLs on paraffin sections.

Immunohistochemical detection of CD10 with monoclonal antibody 56C6 on paraffin sections.

We tested a total of 174 paraffin-embedded hematolymphoid neoplasias to determine whether CD10 can be specifically and sensitivity detected on paraffin sections using monoclonal antibody 56C6 after epitope retrieval. For 32 cases, results of CD10 detection by immunohistochemistry were compared with flow cytometric data. In only 1 case of follicle center lymphoma, divergent staining results were found with the detection of CD10 by flow cytometry but not by immunohistochemistry. Altogether, 22 of 28 follicle center lymphomas, 2 of 6 hairy cell leukemias, 14 of 34 diffuse large B-cell lymphomas, 3 of 3 Burkitt lymphomas, 4 of 5 precursor B-lineage acute lymphoblastic leukemias, and 2 of 4 T-lymphoblastic lymphomas were CD10+. Decalcification of bone marrow biopsy specimens did not diminish the staining intensity. All other cases, including 10 acute myeloid leukemias and a range of low-grade B-cell lymphomas, were CD10-. CD10 is reliably detectable with antibody 56C6 on paraffin sections using epitope retrieval. The antibody is especially useful for the subclassification of acute leukemias and low-grade B-cell lymphomas.