Introduction Endometrial cancer patients with high grade tumours, deep myometrial invasion, or advanced stage disease have a poor prognosis. Randomized studies have demonstrated prevention of loco-regional relapses with radiotherapy with no effect on overall survival. The possible additive effect of chemotherapy remains unclear. Two randomized clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival in high-risk endometrial cancer. The two studies were pooled. Methods Patients (n=540; 534 evaluable) with operated endometrial cancer FIGO stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. Results In the NSGO/EORTC study, combined modality treatment was associated with a 36 % reduction in the risk for relapse or death (HR 0.64, 95 % CI 0.41-0.99; P=0.04); two-sided tests were used. The result from the MaNGO-study pointed in the same direction (HR 0.61), but was not significant. In combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in overall survival. In combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P = 0.07) and cancer-specific survival was significant (HR 0.55, CI 0.35-0.88; p=0.01). Conclusion Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and high risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

The 24-h expression of seven clock genes (Bmal1, Clock, Per1, Per2, Cry1, Cry2, and CK1 ) was assayed by in situ hybridization in the suprachiasmatic nucleus (SCN) and the pars tuberalis (PT) of the pituitary gland, collected every 4 h throughout 24 h, from female Soay sheep kept under long (16-h light͞8-h dark) or short (8-h light͞16-h dark) photoperiods. Locomotor activity was diurnal, inversely related to melatonin secretion, and prolactin levels were increased under long days. All clock genes were expressed in the ovine SCN and PT. In the SCN, there was a 24-h rhythm in Clock expression, in parallel with Bmal1, in antiphase with cycles in Per1 and Per2; there was low-amplitude oscillation of Cry1 and Cry2. The waveform of only Per1 and Per2 expression was affected by photoperiod, with extended elevated expression under long days. In the PT, the high-amplitude 24-h cycles in the expression of Bmal1, Clock, Per1, Per2, Cry1, and Cry2, but not CK1 , were influenced by photoperiod. Per1 and Per2 peaked during the day, whereas Cry1 and Cry2 peaked early in the night. Hence, photoperiod via melatonin had a marked effect on the phase relationship between Per͞Cry genes in the PT. This supports the conclusion that an ''external coincidence model'' best explains the way photoperiod affects the waveform of clock gene expression in the SCN, the central pacemaker, whereas an ''internal coincidence model'' best explains the way melatonin affects the phasing of clock gene expression in the PT to mediate the photoperiodic control of a summer or winter physiology.

The a-emitter 211 At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity. Methods: Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. 211 At was labeled to MX35 F(ab9) 2 using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with 211 At-MX35 F(ab9) 2 (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. g-camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo. Results: Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% 6 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 6 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 6 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 6 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 6 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 6 1.6 mGy/(MBq/L) (mean 6 SD). No adverse effects were observed either subjectively or in laboratory parameters. Conclusion: This study indicates that by intraperitoneal administration of 211 At-MX35 F(ab9) 2 it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity. The lifetime risk of ovarian cancer is 1%22% in European and U.S. women. Despite seemingly successful cytoreductive surgery, followed by systemic chemotherapy, most patients will relapse and succumb. The relapse is most frequently localized in the abdominal cavity. New systemic chemotherapy regimens have not improved the outcome over the past decade, which prompted experimental intraperitoneal treatments, including radioimmunotherapy.Radioimmunotherapy with b-emitters has displayed promising results, although an international randomized phase III study of 90 Y-HMFG1 showed no improvement in survival or time to relapse (1). This disappointing result could be partly explained by the choice of radionuclide. The long range of this b-emitter results in poor irradiation of small tumor clusters, likely insufficient to eradicate peritoneal micrometastases. Furthermore, the relativel...

Melatonin-based photoperiod time-measurement and circannual rhythm generation are long-term time-keeping systems used to regulate seasonal cycles in physiology and behaviour in a wide range of mammals including man. We summarise recent evidence that temporal, melatonincontrolled expression of clock genes in specific calendar cells may provide a molecular mechanism for long-term timing. The agranular secretory cells of the pars tuberalis (PT) of the pituitary gland provide a model cell-type because they express a high density of melatonin (mt1) receptors and are implicated in photoperiod/circannual regulation of prolactin secretion and the associated seasonal biological responses. Studies of seasonal breeding hamsters and sheep indicate that circadian clock gene expression in the PT is modulated by photoperiod via the melatonin signal. In the Syrian and Siberian hamster PT, the high amplitude Per1 rhythm associated with dawn is suppressed under short photoperiods, an effect that is mimicked by melatonin treatment. More extensive studies in sheep show that many clock genes (e.g. Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the PT, and their expression oscillates through the 24-h light/darkness cycle in a temporal sequence distinct from that in the hypothalamic suprachiasmatic nucleus (central circadian pacemaker). Activation of Per1 occurs in the early light phase (dawn), while activation of Cry1 occurs in the dark phase (dusk), thus photoperiod-induced changes in the relative phase of Per and Cry gene expression acting through PER/CRY protein/protein interaction provide a potential mechanism for decoding the melatonin signal and generating a long-term photoperiodic response. The current challenge is to identify other calendar cells in the central nervous system regulating long-term cycles in reproduction, body weight and other seasonal characteristics and to establish whether clock genes provide a conserved molecular mechanism for long-term timekeeping.

The purpose of this study was to investigate whether oat beta-glucan is responsible for the increased bile acid excretion previously observed with oat-fiber diets. The excretion patterns in ileostomy subjects given diets containing oat-bran bread with and without added beta-glucanase, a beta-glucan-degrading enzyme, were compared. The effect of a beta-glucan-rich barley fraction on sterol excretion was also investigated. Nine ileostomy subjects were served four diets in random order, each diet for 2 consecutive days. Four different kinds of bread, mainly made from oat bran (OB diet, 12.5 g beta-glucan/d), oat bran with beta-glucanase (OBE diet, 3.8 g beta-glucan/d), barley (B diet, 13.0 g beta-glucan/d), or wheat flour (W diet, 1.2 g beta-glucan/d) were added to a basal diet. The 24-h excretion of bile acids was 53% higher in the OB diet period than in the OBE diet period (P < 0.05) and also was significantly higher than in the B and W diet periods (P < 0.05). Median (range) bile acid excretion was 851 (232-1550), 463 (123-1414), 755 (133-1187), and 606 (101-980) mg/d in the OB, OBE, B, and W diet periods, respectively. The excretion of cholesterol was significantly higher in the B diet period than in the OBE and W diet periods (P < 0.05), but the mechanism behind this effect of barley fiber is unknown. In oat bran, however, beta-glucan mediates an increase in bile acid excretion, which most probably explains the effect of oat fiber in lowering serum lipids.

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Objective: We examined the relation between intake of natural dietary plant sterols and serum lipid concentrations in a freeliving population. Design, setting and participants: Cross-sectional population-based study of 22 256 men and women aged 39-79 y resident in Norfolk, UK, participating in the European Prospective Investigation into Cancer (EPIC-Norfolk). Main exposure and outcome measures: Plant sterol intake from foods and concentrations of blood lipids. Results: Mean concentrations of total cholesterol and low-density lipoprotein cholesterol, adjusted for age, body mass index and total energy intake, decreased with increasing plant sterol intake in men and women. Mean total serum cholesterol concentration for men in the highest fifth of plant sterol intake (mean intake 463 mg daily) was 0.25 mmol/l lower and for lowdensity lipoprotein cholesterol 0.14 mmol/l lower than those in the lowest fifth of plant sterol consumption (mean intake 178 mg daily); the corresponding figures in women were 0.15 and 0.13 mmol/l. After adjusting for saturated fat and fibre intakes, the results for total cholesterol and low-density lipoprotein cholesterol were similar, although the strength of the association was slightly reduced. Conclusions: In a free-living population, a high intake of plant sterols is inversely associated with lower concentrations of total and low-density lipoprotein serum cholesterol. The plant sterol content of foods may partly explain diet-related effects on serum cholesterol concentration.

A high dietary intake of plant sterols was not associated with a lower risk of colon and rectal cancers in the Netherlands Cohort Study on Diet and Cancer.