Preclinical models of advanced melanoma have shown that chronic indomethacin therapy combined with interleukin 2 (IL-2) can eradicate experimental metastases. A phase II trial was done in patients with advanced melanoma. Indomethacin and ranitidine were begun at least one week before IL-2. Of the objective responses in 3 patients, 2 were achieved on ranitidine and indomethacin alone, before start of IL-2. Indomethacin and ranitidine may be responsible for some responses in melanoma patients previously attributed to IL-2.

Cisplatin is generally accepted to be the most active cytotoxic agent for the treatment of ovarian cancer but the optimum dose remains unclear. We have performed a randomised trial to assess the importance of cisplatin dose in the treatment of advanced epithelial ovarian cancer. Patients were randomly assigned treatment with 50 mg/m2 (low dose) or 100 mg/m2 (high dose) cisplatin plus 750 mg/m2 cyclophosphamide, for a maximum of six cycles with intervals of 3 weeks. We planned to recruit 300 patients, but an interim analysis on the first 165 indicated a highly significant survival difference (p = 0.0008). Recruitment was therefore stopped and the trial patients were followed-up for 12 months longer. The relative progression rate (high-dose/low-dose) after 12 months' extra follow-up was 0.55 (95% confidence interval 0.37-0.81, p = 0.003) and the relative death rate 0.53 (0.34-0.81, p = 0.003). Overall median survival was 69 weeks in the low-dose group and 114 weeks in the high-dose group. Residual disease extent before chemotherapy had an important influence--patients with lesions of less than 2 cm did best; if given high-dose cisplatin their median survival was 3 years. 56 low-dose and 45 high-dose patients completed six cycles of chemotherapy; 15 and 9 patients, respectively, were withdrawn early because of progressive disease and treatment was stopped in 6 and 25, respectively, because of unacceptable side-effects or patient refusal. Toxic effects were significantly greater in the high-dose group, especially those on the nervous system and ears, alopecia, vomiting, and anaemia. Although the higher dose of cisplatin clearly leads to better results in terms of survival, its overall clinical benefit in the management of ovarian cancer will depend on further improvements in measures to alleviate toxic effects.

Studies with nicotine chewing gum and nicotine skin patches indicate that nicotine replacement can help people to give up smoking. The rapidity with which nicotine is absorbed when given as a nasal spray suggests that it might be effective for those for whom the other means of replacement are too slow. The efficacy and safety of a nasal nicotine spray as an adjunct to group treatment for stopping smoking were assessed in a randomised, double-blind, placebo-controlled trial in which 227 cigarette smokers attending the Maudsley Hospital Smokers Clinic received 4 weeks of supportive group treatment plus active nicotine (0.5 mg per shot) or placebo nasal spray. The main end-point was biochemically validated complete abstinence from smoking from the third week of group treatment until the 12-month follow-up. Side-effects were assessed by self-reports and, where necessary, by physical examination. Of subjects assigned to active treatment 26% (n = 30) were validated abstinent throughout the year, compared with 10% (n = 11) of those assigned to placebo (relative abstinence rate 2.6, 95% CI 1.5-4.5, p less than 0.001). The advantage of the active spray was greatest in the heaviest smokers. Plasma nicotine concentrations from the spray were typically between one-half and three-quarters of baseline smoking levels. Tobacco-withdrawal symptoms, craving for cigarettes, and weight gain in abstinent subjects were reduced by the active spray. Minor irritant side-effects were frequent in both active and placebo sprays, but only 2 subjects had the spray discontinued as a result. No serious adverse effects were encountered. Nasal nicotine spray combined with supportive group treatment is an effective aid to smoking cessation.

Previous studies of the effect of 6-monthly vitamin A supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebo-controlled trial of vitamin A supplementation in the Sudan among 28,753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200,000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 IU vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8.4/1000) in the vitamin A group and 112 (7.9/1000) in the placebo group (relative risk 1.06, 95% confidence interval 0.82-1.37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. The lack of an effect of large-dose vitamin A supplementation on mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Reducing poverty, improvements in sanitation, and access to adequate diets should remain the main goals to improve child survival.

It is possible to record the fetal electrocardiographic waveform (ECG) from the scalp electrode used in labour for detection of fetal heart rate. Animal and observational studies of changes in the ST waveform of the ECG during hypoxia suggest that a combination of heart rate and ST waveform analysis might improve the predictive value of intrapartum monitoring. In a randomised trial, we have studied intervention rates and neonatal outcome for high-risk labours monitored either by conventional cardiotocography (CTG) or by ST waveform analysis plus CTG. 1200 women with pregnancy of at least 34 weeks' gestation were assigned to the groups when the decision to apply a fetal scalp electrode was made. Neonatal outcome was assessed by umbilical-cord blood gas analysis, Apgar scores, resuscitation needed, and postnatal course. All recordings were retrospectively viewed by an observer unaware of clinical details to check adherence to the trial protocol. The addition of ST waveform monitoring to CTG substantially reduced the proportion of deliveries for fetal distress (ST + CTG 27/615 vs CTG 58/606; p less than 0.001). The groups did not differ in rate of operative delivery for other reasons, incidence of asphyxia at birth, or neonatal outcome. Metabolic acidosis and low 5 min Apgar scores were less common in the ST + CTG than the CTG group, but not significantly so. The only case of birth asphyxia in the ST + CTG group was identified by both heart rate and ST changes. The review of recordings showed that the reduction in intervention rate was among cases with CTG patterns classified as normal or intermediate, whereas there was no difference in intervention rates among cases with abnormal recordings. Our findings confirm that ST waveform analysis discriminates CTG changes in labour and that our protocol for interpretation is safe. Further randomised studies are warranted.

In the US Physicians' Health Study the early termination of the aspirin arm has provided the opportunity to test the hypothesis that low-dose aspirin (325 mg on alternate days) might affect the subsequent occurrence of peripheral arterial surgery. In the study, a randomised double-blind placebo-controlled trial among 22,071 healthy US male physicians aged 40-84, there were, during an average of 60.2 months of treatment and follow-up, 56 participants who underwent peripheral arterial surgery (20 aspirin, 36 placebo). The relative risk of peripheral artery surgery in the aspirin group was 0.54 (95% confidence intervals 0.30-0.95; p = 0.03). These data indicate that chronic administration of low-dose aspirin to apparently healthy men reduced the need for peripheral arterial surgery.

University of Wisconsin (UW) preservation solution has been reported to be beneficial for canine organ transplants and for human liver and pancreas transplants. To examine whether it affects renal graft survival, a randomised multicentre trial was conducted to compare its effect with that of EuroCollins solution on delayed graft function, renal function, and patient and graft survival in 695 recipients of cadaveric renal transplants. 352 kidneys were preserved with UW and 343 with EuroCollins solution. Delayed graft function occurred in 23% of the UW group and in 33% of the EuroCollins group (p = 0.003). Three factors other than type of preservation fluid were associated with a higher incidence of delayed graft function: older donor age, intracerebral haemorrhage in the donor, and oliguria in the donor. Renal function as indicated by serum creatinine concentration was better in the UW than in the EuroCollins group. Patient survival in the UW and EuroCollins groups after 1 year was 95% and 94%, respectively. In both groups, delayed graft function reduced 1-year graft survival by 15% (p = 0.0001). 1-year graft survival of UW-preserved kidneys was 6% higher than that of controls (88.2% vs 82.5%, p = 0.04). Delayed graft function is significantly associated with a reduction in 1-year graft survival. The preservation solution is the most important factor influencing development of delayed graft function, and UW solution is superior to EuroCollins solution in reducing occurrence of delayed graft function, improving graft function, extending graft survival.

Ondansetron, a selective serotonin-receptor antagonist, is an effective antiemetic for patients receiving high-dose cisplatin chemotherapy. However, no comparison has been made between a combination of a serotonin antagonist and dexamethasone, which also has antiemetic properties, with currently available antiemetic regimens. 289 consecutive cancer patients receiving cisplatin chemotherapy (much greater than 50 mg/m2) were randomised to receive one of the following intravenous antiemetic regimens: ondansetron 0.15 mg/kg, before and after cisplatin, + dexamethasone 20 mg before cisplatin (treatment A) or metoclopramide 3 mg/kg, before and after cisplatin, + dexamethasone + diphenhydramine 50 mg before cisplatin (treatment B). From day 2 to day 4, all patients received oral metoclopramide and intramuscular dexamethasone. 267 patients (136 receiving treatment A and 131 treatment (B) were available for analysis. Complete protection against emesis was achieved in 107 (78.7%) and 78 (59.5%) patients, respectively (p less than 0.002). Complete protection was also significantly superior for treatment A on day 2 (83.9% vs 68.0%; p less than 0.006). Complete protection from acute nausea (first 24 h) was achieved in 105 patients (77.2%) with treatment A and in 86 (65.6%) with treatment B (p less than 0.051); complete protection from nausea and emesis was achieved in 94 (69.1%) patients and 66 (50.4%), respectively (p less than 0.003). Patients receiving treatment B noted significantly more sedation than patients receiving treatment A (11.8% vs 2.1%; p less than 0.005). Extrapyramidal reactions were present only with treatment B (2.7%). Ondansetron + dexamethasone is more effective and better tolerated than metoclopramide + dexamethasone + diphenhydramine in the prevention of cisplatin-induced nausea and emesis.

Assessment of the physiological effects of physical and emotional stress has been hampered by a lack of suitable laboratory techniques. Since hypnosis can be used safely to induce specific emotional states of considerable intensity, we studied the effect on distal colonic motility of three hypnotically induced emotions (excitement, anger, and happiness) in 18 patients aged 20-48 years with irritable bowel syndrome. Colonic motility index was reduced by hypnosis on its own (mean change 19.1; 95% CI 0.8, 37.3; p less than 0.05) and this change was accompanied by decreases in both pulse (12; 8, 15) and respiration (6; 4, 8) rates (p less than 0.001 for both). Anger and excitement increased the colonic motility index (50.8; 29.4, 72.2; and 30.4; 8.9, 51.9, respectively; p less than 0.01 for both), pulse rate (26; 22, 30; and 28; 24, 32; p less than 0.001 for both), and respiration rate (14; 12, 16; and 12; 10, 14; p less than 0.001 for both). Happiness further reduced colonic motility although not significantly from that observed during hypnosis alone. Changes in motility were mainly due to alterations in rate than in amplitude of contractions. Our results indicate that hypnosis may help in the investigation of the effects of emotion on physiological functions; this approach could be useful outside the gastrointestinal system. Our observation that hypnosis strikingly reduces fasting colonic motility may partly explain the beneficial effects of this form of therapy in functional bowel disorders.

Streptococcus agalactiae transmitted to infants from the vagina during birth is an important cause of invasive neonatal infection. We have done a prospective, randomised, double-blind, placebo-controlled, multi-centre study of chlorhexidine prophylaxis to prevent neonatal disease due to vaginal transmission of S agalactiae. On arrival in the delivery room, swabs were taken for culture from the vaginas of 4483 women who were expecting a full-term single birth. Vaginal flushing was then done with either 60 ml chlorhexidine diacetate (2 g/l) (2238 women) or saline placebo (2245) and this procedure was repeated every 6 h until delivery. The rate of admission of babies to special-care neonatal units within 48 h of delivery was the primary end point. For babies born to placebo-treated women, maternal carriage of S agalactiae was associated with a significant increase in the rate of admission compared with non-colonised mothers (5.4 vs 2.4%; RR 2.31, 95% CI 1.39-3.86; p = 0.002). Chlorhexidine reduced the admission rate for infants born of carrier mothers to 2.8% (RR 1.95, 95% CI 0.94-4.03), and for infants born to all mothers to 2.0% (RR 1.48, 95% CI 1.01-2.16; p = 0.04). Maternal S agalactiae colonisation is associated with excess early neonatal morbidity, apparently related to aspiration of the organism, that can be reduced with chlorhexidine disinfection of the vagina during labour.

Selective decontamination of the digestive tract (SDD), by means of non-absorbable antibiotics, to prevent infection in intensive-care units (ICUs) remains controversial; there is evidence that the regimen reduces the incidence of secondary infection, but no convincing reduction in morbidity or mortality has been shown and the costs and effect on microbial resistance patterns need further study. In a double-blind, placebo-controlled trial, we have tried to find out whether SDD should be used routinely in all ICU patients at high risk of secondary infection. All patients admitted to the ICU who were thought likely to stay in the unit for at least 5 days and to need intubation for longer than 48 h were enrolled and randomly allocated to groups receiving placebo or SDD (amphotericin, colistin, and tobramycin applied to the oropharynx and enterally); all patients received intravenous cefotaxime for 72 h. Of 322 patients randomised, 83 were withdrawn (80 ICU stay or duration of intubation too short, 3 protocol violations). 239 medical, trauma, and surgical patients completed the trial period (114 SDD, 125 placebo). There were no differences between SDD and placebo groups in incidence of infection (30 [26%] vs 43 [34%] patients; p = 0.22), duration of ICU stay (mean 16.2 [14.3] vs 16.8 [12.3] days), hospital stay (29.9 [SD 25.0] vs 31.9 [22.2] days), or mortality (21 [18%] vs 21 [17%]). SDD substantially increased the costs of intensive care. Mechanisms other than bacterial colonisation of the gut may bring about substantial numbers of secondary infections in ICUs. Routine use of SDD in multidisciplinary ICUs cannot be recommended.