Enantioselective Phase-Transfer-Catalyzed Synthesis of Spirocyclic Azetidine Oxindoles.

Spiro-3,2'-azetidine oxindoles combine two independently important pharmacophores in an understudied spirocyclic motif that is attractive for medicinal chemistry. Here, the enantioselective synthesis of these structures is achieved in up to 2:98 er through intramolecular C-C bond formation, involving activation of the substrate with a novel SF5-containing chiral cation phase-transfer (PT) catalyst. The products are readily elaborated/deprotected to afford medicinally relevant enantioenriched compounds. Control experiments suggest an interfacial PT mechanism, whereby catalytic asymmetric induction is achieved through the activation of the chloride leaving group.

Acid-Mediated Ring Expansion of 2,2-Disubstituted Azetidine Carbamates to 6,6-Disubstituted 1,3-Oxazinan-2-ones.

The ring expansion of 2-ester-2-arylazetidine carbamates can be achieved using Brønsted acids to form 6,6-disubstituted 1,3-oxazinan-2-ones. The reaction is rapid at room temperature with Boc or Cbz derivatives and proceeds with excellent yield (up to 96%) and broad substrate scope. Derivatives of drug compounds and natural products are incorporated. The combination of this ring expansion in a three-step N-H insertion/cyclization/expansion sequence is applied to directly access medicinally relevant scaffolds from acyclic precursors.

Rapid Assembly of Saturated Nitrogen Heterocycles in One-Pot: Diazo-Heterocycle "Stitching" by N-H Insertion and Cyclization.

Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2-disubstituted azetidines, pyrrolidines, piperidines, and azepanes bearing ester and diverse aryl substituents. A one-pot rhodium catalyzed N-H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m-haloamines (m=2-5) to rapidly assemble 4 -, 5 -, 6 -, and 7 -membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including examples with diazo compounds derived from biologically active compounds. The products can be functionalized to afford α,α-disubstituted amino acids and applied to fragment synthesis.

Development and Validation of a Disease-Specific Instrument to Measure Diet-Targeted Quality of Life for Postoperative Patients with Esophagogastric Cancer.

BACKGROUND: Patients who have undergone esophagectomy or gastrectomy have certain dietary limitations because of changes to the alimentary tract. This study attempted to develop a psychometric scale, named "Esophago-Gastric surgery and Quality of Dietary life (EGQ-D)," for assessment of impact of upper gastrointestinal surgery on diet-targeted quality of life. METHODS: Using qualitative methods, the study team interviewed both patients and surgeons involved in esophagogastric cancer surgery, and we prepared an item pool and a draft scale. To evaluate the scale's psychometric reliability and validity, a survey involving a large number of patients was conducted. Items for the final scale were selected by factor analysis and item response theory. Cronbach's alpha was used for assessment of reliability, and correlations with the short form (SF)-12, esophagus and stomach surgery symptom scale (ES(4)), and nutritional indicators were analyzed to assess the criterion-related validity. RESULTS: Through multifaceted discussion and the pilot study, a draft questionnaire comprising 14 items was prepared, and a total of 316 patients were enrolled. On the basis of factor analysis and item response theory, six items were excluded, and the remaining eight items demonstrated strong unidimensionality for the final scale. Cronbach's alpha was 0.895. There were significant associations with all the subscale scores for SF-12, ES(4), and nutritional indicators. CONCLUSIONS: The EGQ-D scale has good contents and psychometric validity and can be used to evaluate disease-specific instrument to measure diet-targeted quality of life for postoperative patients with esophagogastric cancer.

A placebo-controlled, double-blind, randomized, multicenter study to assess the effects of dronedarone 400 mg twice daily for 12 weeks on atrial fibrillation burden in subjects with permanent pacemakers.

PURPOSE: Dronedarone is a benzofuran derivative with a pharmacological profile similar to amiodarone but has a more rapid onset of action and a much shorter half-life (13-19 h). Our goal was to evaluate the efficacy of dronedarone in atrial fibrillation (AF) patients using dual-chamber pacemakers capable of quantifying atrial fibrillation burden. METHODS: Pacemakers were adjusted to optimize AF detection. Patients with AF burden >1% were randomized to dronedarone 400 mg twice daily (BID) or placebo. Pacemakers were interrogated after 4 and 12 weeks of treatment. The primary endpoint was the change in AF burden from baseline over the 12-week treatment period. Patients with permanent AF, severe/recently decompensated heart failure, and current use of antiarrhythmic drugs were excluded. AF burden was assessed by a core laboratory blinded to treatment assignment. RESULTS: From 285 patients screened, 112 were randomized (mean age 76 years, 60% male, 84% hypertensive, 65% with sick sinus syndrome, 26% with diabetes mellitus type II, 15% with heart failure). Baseline mean (SEM) AF burden was 8.77% (0.16) for placebo and 10.14% (0.17) for dronedarone. Over the 12-week study period, AF burden compared to baseline decreased by 54.4% (0.22) (P = 0.0009) with dronedarone and trended higher by 12.8% (0.16) (P = 0.450) with placebo. The absolute change in burden was decreased by 5.5% in the dronedarone group and increased by 1.1% in the placebo group. Heart rate during AF was reduced to approximately 4 beats/min with dronedarone (P = 0.285). Adverse events were higher with dronedarone compared to placebo (65 vs 56%). CONCLUSIONS: Dronedarone reduced pacemaker-assessed the relative AF burden compared to baseline and placebo by over 50% during the 12-week observation period.

A comparative study of survival after minimally invasive and open oesophagectomy.

BACKGROUND: Oesophageal cancer is increasing in incidence worldwide. Minimally invasive techniques have been used to perform oesophagectomy, but concerns regarding these techniques remain. Since its description by Cuschieri in 1992, the use of minimally invasive oesophagectomy (MIO) has increased, but still only used in a minority of resections in the UK in 2009. In particular, there has been reluctance to use minimally invasive (thoracoscopic and laparoscopic) techniques in more advanced cancers for fears regarding the adequacy of the oncological resection. In order to identify any factors that could affect survival, we undertook a retrospective analysis on all patients who underwent surgery in our department over an 8-year period. METHODS: A retrospective data analysis was undertaken on all patients who underwent oesophagectomy in a tertiary upper gastrointestinal surgery unit, from 2005 to 2012 inclusive. Data were collected from the departmental database and case note review, with follow-up and survival data to time of data collection. The survival data were analysed using univariate and multivariate Cox proportional hazard regression models to determine which variables affected survival. Variables examined included age, tumour position, tumour stage (T0, 1, 2 vs T3, 4), nodal stage (N0 vs N1), tumour histology, completeness of resection (R0 vs R1), use of neoadjuvant chemotherapy and operative technique (thoracoscopic/laparoscopic (MIO) vs laparoscopic abdomen/open chest (Lap assisted) vs Open. RESULTS: 334 patients underwent oesophagectomy between 2005 and 2012. Male to female ratio was 3.75:1, with a mean age of 64 years (range 36-87). There were 83 open oesophagectomies, 187 laparoscopically assisted oesophagectomies and 64 minimally invasive oesophagectomies. Following univariate regression analysis the following factors were found to be correlated to survival: use of neoadjuvant chemotherapy (Hazard Ratio 2.889, 95 % CI 1.737-4.806), T stage 3 or 4 (3.749, 2.475-5.72), Node positive (5.225, 3.561-7.665), R1 resection (2.182, 1.425-3.341), type of operation (MIO compared to open oesophagectomy) (0.293, 0.158-0.541). There was no significant relationship between age, tumour position or tumour histology and length of survival. When these factors were entered into a multivariate model, the independently significant factors correlated to survival were found to be T stage 3 or 4 (HR 1.969, 1.248-3.105), Node positive (3.833, 2.548-5.766) and type of operation (MIO compared to open) (0.5186, 0.277-0.972). CONCLUSION: Multiple small studies have found reduced pulmonary complication rates and duration of hospital stay when using a minimally invasive approach compared to open. Concerns in the literature over long-term outcomes, however, have led to limited utilisation of this method, especially in advanced disease. The data from this large study show significantly better survival following operations performed using minimally invasive techniques compared to open, however, we have not adjusted for some known or unknown confounding factors. International and national RCTs, however, will provide more information in due course.

Development and validation of a symptom scale to evaluate postoperative patients with esophagogastric cancer.

BACKGROUND: Postgastrectomy or esophagectomy symptoms can be a significant burden for patients. However, no standard scale for evaluating these symptoms has been established. We recently developed a postoperative symptom-specific scale. STUDY DESIGN: After a draft scale was prepared based on a pilot study, psychometric methods were used to assess its reliability and validity. This study involved specialized and multifaceted discussions by a team consisting of gastrointestinal surgeons, gastroenterologists, psychologists, and epidemiologic researchers. The draft questionnaire included 40 questions and 3 domains. A factor analysis was carried out to refine the items and subscale design. To assess the reliability, Cronbach's alpha and score distributions were estimated. To assess the criterion-related validity, the correlations with the Short Form (SF)-12, Gastrointestinal Symptom Rating Scale (GSRS), endoscopic findings, and nutritional indicators were analyzed. RESULTS: A total of 344 patients were enrolled in this study. In an exploratory factor analysis (principal factor method), the eigenvalue attenuation data showed 4 domains. The final scale, named the Esophagus and Stomach Surgery Symptom Scale (ES(4)), included 23 items and 4 domains; 7 items for cervico-thoracic symptoms, 6 for abdominal hypersensitivity symptoms, 4 for abdominal distention symptoms, and 6 items for systemic symptoms. Cronbach's alphas for these domains were 0.82, 0.81, 0.79, and 0.74, respectively. The scale scores were normally distributed, and there were significant associations with the endoscopic findings, nutritional indicators, the summary score of the SF-12, and the GSRS. CONCLUSIONS: The ES(4) scale has high psychometric validity and can evaluate the profiles and severity of postoperative symptoms. This scale is applicable as an outcomes measure for various interventional studies on esophagogastric surgery aimed at alleviating postoperative symptoms.

The effect of centralisation on the outcomes of oesophagogastric surgery--a fifteen year audit.

INTRODUCTION: Centralisation of oesophagogastric (OG) resectional services has been proposed to improve patient outcomes in terms of perioperative mortality and long-term survival. Centralisation of services occurred in Gloucester 5 years ago. The aim of this paper is to assess if local patient outcomes have benefited from centralisation. METHODS: All oesophagogastric resections performed in our unit over a 15-year period (10-years pre-centralisation and 5-years post-centralisation) were assessed retrospectively. Patient demographics, pathological details and date of death were identified. Perioperative mortality (30 and 90 day) and estimated Kaplan-Meier survival was compared for cases performed pre- and post-centralisation of services. RESULTS: 456 resections for cancer were performed in the 15-year period; 234 of these were performed pre-centralisation (mean 23.4, range 13-31) and 222 were performed post-centralisation (mean 44.4, range 40-50). Median survival rates for gastric cancer were 1.1 years pre-centralisation and 1.5 years post-centralisation (p = 0.147) and median survival for oesophageal cancer improved from 1.1 years to 2.1 respectively (p = 0.028). Combined OG 30-day mortality rates improved from 10.3% pre-centralisation to 3.6% post-centralisation (p = 0.006, Fisher's exact test). DISCUSSION: Centralisation of OG services in Gloucester has resulted in twice as many resections being performed locally. Median survival for patients with oesophageal cancer has increased by 1 year and the 30-day mortality rate following resection has reduced by almost two thirds. Although other factors (such as improvements in oncological treatments, staging and critical care management over the 15-year time period) have undoubtedly had roles to play in these improvements, the results of this study support the policy of centralisation of upper GI cancer services.

The effect of intraperitoneal local anesthesia in laparoscopic cholecystectomy: a systematic review and meta-analysis.

Intraperitoneal administration of local anesthesia is often used to improve pain relief after laparoscopic cholecystectomy. We have conducted a meta-analysis to establish the efficacy of this technique in reducing early postoperative abdominal pain. A systematic literature search revealed 24 randomized, controlled trials assessing intraperitoneal local anesthetic use in laparoscopic cholecystectomy that met inclusion criteria. Of these, 16 studies reported sufficient data to allow pooled quantitative analysis. The weighted mean differences (WMD) in visual analog pain score at 4 h after surgery were pooled using a random effects model. Overall, the use of intraperitoneal local anesthesia resulted in a significantly reduced pain score at 4 h (WMD, -9 mm; 95% confidence interval [CI], -13 to -5). Subgroup analysis suggested that the effect was greater when the local anesthetic was given at the start of the operation (WMD, -13 mm; 95% CI, -19 to -7) compared with instillation at the end (WMD, -6 mm; 95% CI, -10 to -2). No adverse events related to local anesthetic toxicity were reported. We conclude that the use of intraperitoneal local anesthesia is safe, and it results in a statistically significant reduction in early postoperative abdominal pain.

Leukocyte count as an independent predictor of recurrent ischemic events.

BACKGROUND AND PURPOSE: Inflammatory markers predict first-time ischemic events. We investigated whether leukocyte and differential counts predict recurrent events and ischemic events in high-risk populations, and whether such events are preceded by acutely exacerbated inflammation. METHODS: We studied 18 558 patients with ischemic stroke, myocardial infarction, or peripheral arterial disease who participated in the trial of Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), a study that compared the occurrence of ischemic stroke, myocardial infarction, or vascular death under randomized treatment with aspirin or clopidogrel. Leukocyte counts were frequently assessed during followup. RESULTS: Compared with the quartile with lowest leukocyte counts at baseline (<5.9x10(9)/L), patients in the top quartile (>8.2x10(9)/L) had higher risks for ischemic stroke (relative risk 1.30; P=0.007), myocardial infarction (relative risk 1.56, P<0.001), and vascular death (relative risk 1.51; P<0.001) after adjustment for other risk factors. Neutrophil counts contributed most to increased risk. Assessments of regression dilution effects based on replicate measurements show that these risk associations may underestimate the real associations by 30 to 50%. Treatment with aspirin or clopidogrel did not influence predictive effects by leukocytes. In the week before a recurrent event, but not at earlier time points, the leukocyte count was significantly increased over baseline levels (n=211; mean difference +0.46x10(9)/L; P=0.005). CONCLUSIONS: Leukocyte counts and mainly neutrophil counts are independently associated with ischemic events in these high-risk populations. An increase of leukocyte counts over baseline levels heralds a period of increased risk lasting about one week.