Assessing the translational feasibility of pharmacological drug memory reconsolidation blockade with memantine in quitting smokers.

RATIONALE: Preclinical reconsolidation research offers the first realistic opportunity to pharmacologically weaken the maladaptive memory structures that support relapse in drug addicts. N-methyl D-aspartate receptor (NMDAR) antagonism is a highly effective means of blocking drug memory reconsolidation. However, no research using this approach exists in human addicts. OBJECTIVES: The objective of this study was to assess the potential and clinical outcomes of blocking the reconsolidation of cue-smoking memories with memantine in quitting smokers. METHODS: Fifty-nine dependent and motivated to quit smokers were randomised to one of three groups receiving the following: (1) memantine with or (2) without reactivation of associative cue-smoking memories or (3) reactivation with placebo on their target quit day in a double-blind manner. Participants aimed to abstain from smoking for as long as possible. Levels of smoking and FTND score were assessed prior to intervention and up to a year later. Primary outcome was latency to relapse. Subjective craving measures and attentional bias to smoking cues were assessed in-lab. RESULTS: All study groups successfully reduced their smoking up to 3 months. Memantine in combination with smoking memory reactivation did not affect any measure of smoking outcome, reactivity or attention capture to smoking cues. CONCLUSIONS: Brief exposure to smoking cues with memantine did not appear to weaken these memory traces. These findings could be due to insufficient reconsolidation blockade by memantine or failure of exposure to smoking stimuli to destabilise smoking memories. Research assessing the treatment potential of reconsolidation blockade in human addicts should focus on identification of tolerable drugs that reliably block reward memory reconsolidation and retrieval procedures that reliably destabilise strongly trained memories

Determination of herbicides in human urine by liquid chromatography-mass spectrometry with electrospray ionization.

Aims: To determine the degree to which cigarette smoking predicts levels of cannabis dependence above and beyond cannabis use itself, concurrently and in an exploratory four-year follow-up, and to investigate whether cigarette smoking mediates the relationship between cannabis use and cannabis dependence. Methods: The study was cross sectional with an exploratory follow-up in the participants’ own homes or via telephone interviews in the United Kingdom. Participants were 298 cannabis and tobacco users aged between 16 and 23; follow-up consisted of 65 cannabis and tobacco users. The primary outcome variable was cannabis dependence as measured by the Severity of Dependence Scale (SDS). Cannabis and tobacco smoking were assessed through a self-reported drug history. Results: Regression analyses at baseline showed cigarette smoking (frequency of cigarette smoking: B = 0.029, 95% CI = 0.01, 0.05; years of cigarette smoking: B = 0.159, 95% CI = 0.05, 0.27) accounted for 29% of the variance in cannabis dependence when controlling for frequency of cannabis use. At follow-up, only baseline cannabis dependence predicted follow-up cannabis dependence (B = 0.274, 95% CI = 0.05, 0.53). At baseline, cigarette smoking mediated the relationship between frequency of cannabis use and dependence (B = 0.0168, 95% CI = 0.008, 0.288) even when controlling for possible confounding variables (B = 0.0153, 95% CI = 0.007, 0.027). Conclusions: Cigarette smoking is related to concurrent cannabis dependence independently of cannabis use frequency. Cigarette smoking also mediates the relationship between cannabis use and cannabis dependence suggesting tobacco is a partial driver of cannabis dependence in young people who use cannabis and tobacco

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Open versus closed lateral internal anal sphincterotomy in the management of chronic anal fissures: A prospective randomized study

Chronic anal fissure is a benign disorder that is associated with considerable discomfort. Surgical treatment in the form of lateral sphincterotomy has long been regarded as the gold standard of treatment. This study compared the open and closed techniques of lateral sphincterotomy in terms of their postoperative outcomes. A prospective, randomized comparative study was conducted between October 2010 and August 2012. A total of 136 patients were randomly assigned to each of two groups. Patients were followed up postoperatively for more than 1 year to assess any complications. The outcomes were compared among the two groups using the Chi-square test and Student t test. The mean age at presentation was 40.13 years. The male to female ratio was 1.47:1. The typical presentation was painful defecation. Fissures were most often located in the posterior midline and associated with a sentinel pile. Delayed postoperative healing was found in 4.4% of the group of patients undergoing open lateral sphincterotomy. The mean pain score and duration of hospital stay were lower with the closed technique. Closed lateral internal sphincterotomy is the treatment of choice for chronic fissures as it is effective, safe, less expensive, and associated with a lower rate of complications than the open sphincterotomy technique

Open versus closed lateral internal anal sphincterotomy in the management of chronic anal fissures: A prospective randomized study

Objective: Chronic anal fissure is a benign disorder that is associated with considerable discomfort. Surgical treatment in the form of lateral sphincterotomy has long been regarded as the gold standard of treatment. This study compared the open and closed techniques of lateral sphincterotomy in terms of their postoperative outcomes. Methods: A prospective, randomized comparative study was conducted between October 2010 and August 2012. A total of 136 patients were randomly assigned to each of two groups. Patients were followed up postoperatively for more than 1 year to assess any complications. The outcomes were compared among the two groups using the Chi-square test and Student t test. Results: The mean age at presentation was 40.13 years. The male to female ratio was 1.47:1. The typical presentation was painful defecation. Fissures were most often located in the posterior midline and associated with a sentinel pile. Delayed postoperative healing was found in 4.4% of the group of patients undergoing open lateral sphincterotomy. The mean pain score and duration of hospital stay were lower with the closed technique. Conclusion: Closed lateral internal sphincterotomy is the treatment of choice for chronic fissures as it is effective, safe, less expensive, and associated with a lower rate of complications than the open sphincterotomy technique