A Population-Based Study to Evaluate the Associations of Nodal Stage,Lymph Node Ratio and Log Odds of Positive Lymph Nodes with Survival in Patients with Small Bowel Adenocarcinoma

Purpose: This study aimed to determine the real-world prognostic significance of lymph node ratio (LNR) and log odds of positive lymph nodes (LOPLN) in patients with non-metastatic small bowel adenocarcinoma. Methods: Patients diagnosed with early-stage small bowel adenocarcinoma between January 2007 and December 2018 from a large Canadian province were identified. We calculated the LNR by dividing positive over total lymph nodes examined and the LOPLN as log ([positive lymph nodes + 0.5]/[negative lymph nodes + 0.5]). The LNR and LOPLN were categorized at cut-offs of 0.4 and −1.1, respectively. Multivariable Cox proportional hazards models were constructed for each nodal stage, LNR and LOPLN, adjusting for measured confounding factors. Harrell’s C-index and Akaike’s Information Criterion (AIC) were used to calculate the prognostic discriminatory abilities of the different models. Results: We identified 141 patients. The median age was 67 years and 54.6% were men. The 5-year overall survival rates for patients with stage I, II and III small bowel adenocarcinoma were 50.0%, 56.6% and 47.5%, respectively. The discriminatory ability was generally comparable for LOPLN, LNR and nodal stage in the prognostication of all patients. However, LOPLN had higher discriminatory ability among patients with at least one lymph node involvement (Harrell’s C-index, 0.75, 0.77 and 0.82, and AIC, 122.91, 119.68 and 110.69 for nodal stage, LNR and LOPLN, respectively). Conclusion: The LOPLN may provide better prognostic information when compared to LNR and nodal stage in specific patients.     

Effects of the tropical ginger compound, 1'-acetoxychavicol acetate, against tumor promotion in K5.Stat3C transgenic mice

ABSTRACT: The purpose of the current study was to determine whether a tropical ginger derived compound 1'-acetoxychavicol acetate (ACA), suppresses skin tumor promotion in K5.Stat3C mice. In a two-week study in which wild-type (WT) and K5.Stat3C mice were co-treated with either vehicle, ACA, galanga extract, or fluocinolone acetonide (FA) and tetradecanoyl phorbol acetate (TPA), only the galanga extract and FA suppressed TPA-induced skin hyperproliferation and wet weight. None of these agents were effective at suppressing pTyr705 Stat3 expression. However, ACA and FA showed promising inhibitory effects against skin tumorigenesis in K5.Stat3C mice. ACA also suppressed phospho-p65 NF-kappaB activation, suggesting a potential mechanism for its action.     

Design and synthesis of deuterated boceprevir analogs with enhanced pharmacokinetic properties

As part of an ongoing effort to apply the Deuterated Chemical Entity Platform (DCE Platform?) to clinically validated drugs, the synthesis of deuterated analogs of the hepatitis C virus protease inhibitor boceprevir was carried out. The devised synthetic routes allowed for site‐selective deuterium incorporation with high levels of isotopic purity. Application of the DCE Platform? to boceprevir enabled the identification of several deuterated analogs that display marked levels of in vitro metabolic stabilization. Most notably, analog 1g exhibits a near doubling of in vitro half‐life in human liver microsomal assays. The details of the convergent synthetic route to the boceprevir isotopologs and the results of the metabolic stability assays are described herein.     

Perforated tubercular enteritis of childhood: A ten year study

One hundred sixty seven children were operated at the Kalawati Saran Children Hospital for acute peritonitis during last 10 years (1978–88). Bowel perforation was seen in 123 cases. Nineteen cases had underlying Tubercular enteritis. Preoperative diagnosis was usually difficult. The terminal ileum was affected in 12 and the jejunum in 5 cases. Multiple perforations were seen in 3 cases. Postoperative mortality was high (12/19) and usually attributable to their poor preoperative status.     

Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin

AIMS: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.