Polymorphisms in the dopamine D2 receptor (DRD2 C/T and DRD2 A/G) and in dopamine beta hydroxylase (DBH A/G) have been implicated in modulation of smoking and other reward-seeking behaviours. We hypothesized that these alleles would predict the outcome of nicotine patch therapy for smoking cessation. In 1991-93, we performed a randomized controlled trial of the nicotine patch on 1686 heavy smokers (> or = 15 cigarettes/day). In 1999-2000, we contacted 1532 of the 1612 subjects still available; 767 (50%) completed a questionnaire and gave a blood sample. In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation. At 1 week, the patch was more effective for smokers with DRD2 CT/TT genotype [patch/placebo odds ratio (OR) 2.8, 95% confidence interval (CI) 1.7-4.6] than with CC (OR 1.4, 0.9-2.1; P for difference in ORs 0.04). Smokers with both DRD2 CT/TT and DBH GA/AA genotypes had an OR of 3.6 (2.0-6.5) compared to 1.4 (1.0-2.1) for others (P = 0.01). At 12 weeks, the ORs for these genotypic groups were 3.6 (1.7-7.8) and 1.4 (0.9-2.3), respectively (P = 0.04). There was no association between patch effectiveness and DRD2 exon 8. Short-term effectiveness of the nicotine patch may be related to dopamine beta-hydroxylase and dopamine D2 receptor genotype. Our results support the need for further investigation into personalized therapies for smoking cessation based on individual genotype.

Objectives To summarize, in a systematic review, the evidence for the effect of stopping smoking on recurrence, cancer-specific and all cause-mortality among smokers with newly diagnosed bladder cancer. Materials and methods Two electronic databases and the reference lists of identified primary studies and reviews were searched. Studies were included if a hazard ratio and its confidence intervals could be extracted. A predefined set of study characteristics was extracted which defined whether studies were giving valid prognostic data on the effects of smoking in reasonably homogenous cohorts. The results of studies were synthesized qualitatively. Results Fifteen relevant studies were identified; former and current smokers were combined in many studies. Many studies produced information on prognosis that was confounded by the mixing of incident and prevalent cases. Only three studies examined the influence of smoking on prognosis in only incident cases, most of whom had superficial disease. Of these, only one was of high quality. These three studies and the other 12 showed suggestive evidence that continued smoking or a lifetime of smoking constitutes a moderate risk factor for recurrence and death, and that stopping smoking could favourably change this. However, the evidence base for this is weak because of the methodological shortcomings and because most studies' results were not statistically significant. A lifetable model showed that if stopping smoking altered the prognosis, the size of the benefit would be clinically worthwhile. Conclusions There is suggestive evidence that stopping smoking might favourably alter the course of bladder cancer, but this is insufficient for clinicians to inform patients that doing so will improve their prognosis, and for providing specialized services to assist in stopping smoking to patients with bladder cancer.

Few studies have investigated abstinence beyond three years among participants who stop smoking during trials of nicotine replacement therapy, 1-3 and even fewer have followed up smokers who failed to quit during such trials. We carried out an eight year follow up of people who had participated in a randomised controlled trial of the nicotine patch. Participants, methods, and resultsParticipants were the 1686 patients from general practices in Oxfordshire who took part in a double blind randomised controlled trial of the patch in 1991-2. 4 5 At entry they smoked ≥ 15 cigarettes a day and were aged 25-64 years. Participants wore the patches for 12 weeks. The main outcome was abstinence from smoking for one year, confirmed at 12, 24, and 52 weeks by a salivary cotinine concentration ≤ 20 ng/ml (89% of cases) or expired carbon monoxide ≤ 10 ppm (11%).In 1999-2000, we contacted 1532 of the 1625 living participants. We sent two follow up letters and phoned non-responders. In total 840 participants completed a questionnaire giving demographic details and information about smoking. The mean time from enrolment in the trial to follow up was 8.3 (SD 0.35) years, with a range of 7.4-9.3 years. Responders were more likely to be women (59.0% v 51.7%; P=0.005) and were more likely to have stopped smoking during the trial than non-responders (13.2% v 5.5% quit for one year; P < 0.0001). Reported abstinence at follow up was confirmed by a plasma cotinine concentration ≤ 20 ng/ml. Responders reported for how long they had been abstinent. We assumed that all those lost to follow up were still smoking.Of the 153 participants who had stopped smoking for a year in the original trial, 83 were still not smoking at follow up, giving an eight year abstinence rate of 83/1625 (5%; 95% confidence interval 4% to 6%) and a relapse rate of 70/153 (46%; 38% to 54%) (table). Relapse was similar in active and placebo groups: the active/placebo odds ratio (OR) for continuous abstinence up to follow up was 1.39 (0.89 to 2.17; P=0.19) compared with 1.45 (1.04 to 2.03; P=0.03) for quitting for a year in the trial.Of the 1472 who did not quit for a year in the trial, 116 (8%; 7% to 9%) were abstinent at follow up. Of these, 89 (6%; 5% to 7%) had abstained for a year or more, and 27 for less than a year (median 4 months). Overall at follow up therefore, 172 (11%; 9% to 12%) of trial participants had been abstinent for a year or more, 29 (2%) had been abstinent for less than a year, and 1424 (88%) were smoking. CommentEight years after taking part in a randomised trial of the nicotine patch, just under half of the 9% who had stopped smoking for a year had relapsed, leaving 5% of all trial participants continuously abstinent for eight years. Previous studies have reported that a third to a half of all those who stop during a trial relapse by three or four years.1-3 Use of the nicotine patch conferred a 39% increase in the odds of continuous abstinence compared with placebo. The increase was not significant, but our original trial was not powered to ...

Periconceptual exposure to subfertility treatments is increasingly common, raising concerns about the possibility of malformations in the offspring. The authors conducted a case-control study to determine whether subfertility or its treatment was associated with increased risk of neural tube defects (NTDs). Cases were 694 women diagnosed with an NTD-affected pregnancy in Oxfordshire or West Berkshire, England, between 1970 and 1987. Cases were individually matched on maternal year of birth and year of index pregnancy to controls randomly selected from a computerized database. Data on demographic, reproductive, and obstetric factors were abstracted from patient hospital records. Overall, the period prevalences of subfertility and of subfertility treatment were 7% and 3%, respectively, No evidence was found that the risk of NTD-affected pregnancies was increased by either subfertility (odds ratio (OR) = 1.2, 95% confidence interval (CI): 0.7, 2.1) or its treatment (OR = 0.9, 95% CI: 0.4, 2.0). After adjustment, NTD-affected pregnancies were associated with female offspring (OR = 2.3, 95% CI: 1.8, 3.1), multiple birth (OR = 4.8, 95% CI: 1.2, 18.8), and higher numbers of pregnancies (p for trend = 0.005). The findings from this large, population-based study were wholly consistent with those from smaller studies that found no increased risk of NTD associated with exposure to fertility treatments but reported associations with various pregnancy outcomes.

The overall effectiveness of nicotine replacement therapy could be greater if the therapy were targeted at those most likely to respond. Variants of the dopamine D2 receptor (DRD2 32806 C/T) have been implicated in the initiation and maintenance of smoking, 1 2 and these variants may also be related to response to nicotine replacement therapy.3 Additionally, mechanisms of nicotine addiction may differ in men and women. 4 With this evidence in mind, we examined whether the response to nicotine replacement therapy is modified by sex and genotype. Participants, methods, and resultsA randomised controlled trial of nicotine patches in 1991-2 recruited 1686 heavy smokers ( ≥ 15 cigarettes a day).5 The participants wore patches for 12 weeks. Abstinence from smoking was confirmed at one week by expired carbon monoxide concentration ≤ 10 ppm, and at 12, 24, and 52 weeks by salivary cotinine concentration ≤ 20 ng/ml (89% of cases) or by expired carbon monoxide concentration ≤ 10 ppm.In 1999-2000, we contacted 1532 of the 1625 participants still alive; the mean time from trial to follow up was 8.3 years. In all, 752/1532 (49%) gave a blood sample from which DRD2 32806 was successfully typed. Reported abstinence at follow up was confirmed by plasma cotinine concentration ≤ 20 ng/ml. Throughout, non-respondents were assumed to be smoking.Participants were older than non-participants (mean age at entry to trial, 43.0 years v 41.5 years; P = 0.002), more likely to be female (59% (445/752) v 53% (410/780); P = 0.01), and more likely to have quit for a year in the trial (11% (82) v 4% (33), P < 0.0001); 744 (99%) reported their racial background as white.The variant T allele of the dopamine D2 receptor DRD2 32806 (CT or TT genotype) was found in 41% (183/445) of women and 41% of men (127/307). Within each sex, there was no difference between the genotype groups in age, number of cigarettes a day, or dependency score.We measured effectiveness of the patches by the relative odds of abstinence for active and placebo patches over five cumulative time periods: one week, 12 weeks, 24 weeks, 52 weeks, and to follow up. Treatment by genotype and sex, and their interaction, was examined in a full logistic regression model. The three way interaction by genotype by sex was significant for all time periods (P = 0.009, P = 0.03, P = 0.006, P = 0.006, P = 0.004 respectively), and we therefore analysed the data for men and women separately.In women, the effectiveness of the patches differed with genotype at all time points (table). In men the genotype groups did not differ significantly at any time. In men with CC genotype an apparent trend in effectiveness was in an implausible direction, the patches being most effective long after therapy had stopped. In both sexes, when active and placebo groups were combined, the quit rate was not related to genotype. CommentIn women the effectiveness of nicotine patches seems to be related to genotype. Women with the variant T allele of the dopamine D2 receptor DRD2 32806 showed considerable benefit from...