Low Hartmann’s procedure or intersphincteric proctectomy for distal rectal cancer: a retrospective comparative cohort study

Purpose

Two non-restorative options for low rectal cancer not invading the sphincter are the low Hartmann’s procedure (LH) or intersphincteric proctectomy (IP). The aim of this study was to compare postoperative morbidity with emphasis on pelvic abscesses after LH and IP.

Methods

All patients that had LH or IP for low rectal cancer were included in three centres between 2008 and 2014 in this retrospective cohort study. Follow-up was performed for at least 12 months.

Results

A total of 52 patients were included: 40 LH and 12 IP. Median follow-up was 29 months (IQR 23). There were no differences between groups in gender, age and ASA classification. Seven patients in the LH group (18%) and four patients in the IP group (33%) developed a complication within 30-day postoperative with a Clavien-Dindo classification grade III or higher (P = 0.253). Four out of 40 patients (10%) in the LH group and two out of 12 patients (17%) in the IP group developed a pelvic abscess (P = 0.612). Reinterventions were performed in 11 (28%) patients in the LH group and five (42%) patients in the IP group (P = 0.478), with a total number of reinterventions of 13 and 20, respectively. Six and 15 interventions were related to pelvic abscesses, respectively.

Conclusion

Pelvic abscesses seem to occur in a similar rate after both LH and IP. Previous reports from the literature suggesting that IP might be associated with less infectious pelvic complications compared to LH are not supported by this study, although numbers are small.

     

Lack of evidence that nebivolol is a β₃-adrenoceptor agonist

Nebivolol is a selective β?-adrenoceptor antagonist which, in addition, displays endothelium-dependent vasodilating properties in humans and other species. β?-adrenoceptors have been proposed to be a molecular target of nebivolol-induced vasodilatation. Therefore, we have investigated possible β?-adrenoceptor agonism by nebivolol for relaxation of the human and rat urinary bladder (prototypical β?-adrenoceptor-mediated responses) as well as for cAMP accumulation in Chinese hamster ovary cells stably transfected with the human β-adrenoceptor subtypes. Nebivolol concentration-dependently relaxed both human and rat isolated urinary bladder strips but with low potency, similar to that reported for vasodilatation. However, nebivolol-induced bladder relaxation in either species was not inhibited by the β?-adrenoceptor antagonist SR 59,230A (10μM), although this compound inhibited the isoprenaline-induced relaxation with the expected potency. In radioligand binding studies nebivolol had lower affinity for human β?-adrenoceptors than the other two β-adrenoceptor subtypes, but this low affinity was in line with its potency to relax the bladder or isolated blood vessels. In functional studies nebivolol even in high concentrations did not stimulate cAMP formation via any of the three cloned human β-adrenoceptors or in rat bladder smooth muscle cells. Taken together these data demonstrate that nebivolol can relax not only vascular but also urinary bladder smooth muscle. However, they do not support the hypothesis that nebivolol is an agonist at cloned human β?-adrenoceptors or in rat or human urinary bladder.     

Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3

The aim of this study was to characterize the in vitro hepatic uptake kinetics of sodium fluorescein (NaFluo) and identify the transporters involved. NaFluo exhibited saturable uptake kinetics in suspended rat and human hepatocytes as reflected by K_m values of 22.5 and 14.1 µM, and V_max values of 98.3 and 5.8 pmol/(million cells ? min), respectively. Coincubation with known inhibitors (e.g. rifampicin) of organic anion transporting polypeptide (OATP/Oatp; SLCO gene family) significantly decreased NaFluo uptake in hepatocytes. In contrast, neither inhibitors/substrates of the organic cation transporter or organic anion transporter family nor depletion of extracellular sodium resulted in significant inhibition of NaFluo uptake. To explore the contribution of individual uptake transporters, NaFluo uptake was determined in Chinese hamster ovary cells transfected with OATP1B1, OATP1B3, and OATP2B1. Transporter‐mediated uptake of NaFluo was observed in OATP1B1‐ and OATP1B3‐transfected cells (K_m = 4.2 and 10.9 µM; V_max = 30.9 and 135 [pmol/(mg protein ? min)], respectively). NaFluo can be used as a probe substrate to study Oatp/OATP1B‐mediated drug interactions in fluorescence‐based in vitro transport assays of rat and human liver. Labeling of drugs or bile salts with a fluorescein moiety can be expected to result in fluorescent conjugates with substantially altered hepatic uptake characteristics as compared with the unconjugated compounds. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:5018–5030, 2011     

Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars

l-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.     

Emerging drugs for functional dyspepsia

INTRODUCTION: Functional dyspepsia (FD) is a highly prevalent condition with a major impact on quality of life and high socio-economic and healthcare costs. To date, no treatment of established efficacy in FD is available. AREAS COVERED: This review of the literature summarizes recent progress in drug development for FD. Gastroprokinetics are considered therapeutically relevant in FD, although it has been difficult to prove symptomatic benefit. Recently studied drugs include 5-HT(4) receptor agonists (tegaserod), motilin receptor agonists (GSK962040 and others) and ghrelin receptor agonists (TZP-101, TZP-102). Fundic relaxant drugs are a novel approach to FD therapy. Recently studied drugs include 5-HT(1A) receptor agonists (buspirone, tandospirone, R137696) and acotiamide (or Z-338 or YM443), a first-in-class muscarinic M(1)/M(2) receptor antagonist and cholinesterase inhibitor. Extensive Phase II studies support the potential efficacy of acotiamide, especially for postprandial distress syndrome. In refractory cases, psychotropics are considered and recently studied agents include venlafaxine, which in a large multi-center study did not confirm efficacy, and a combination preparation of flupenthixol/melitracen, which showed potential efficacy in a small study. EXPERT OPINION: While many new prokinetic drugs are in the early stages of evaluation, acotiamide emerges as the drug with a promising efficacy profile. Convincing evidence for the efficacy of psychotropics is lacking.     

Alpha-internexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy: European organization for research and treatment of cancer trial 26951

BACKGROUND:

Although it has been demonstrated that the neuronal intermediate filament alpha‐internexin (INA) is closely related to 1p19q codeletion in gliomas, its prognostic and predictive value has not yet been confirmed in a prospective trial. The authors of this report assessed the prognostic significance of INA expression and its correlation with relevant clinical and molecular characteristics in the prospective, randomized European Organization for Research and Treatment of Cancer (EORTC) 26951 trial of adjuvant procarbazine, lomustine, and vincristine (PCV) in patients with anaplastic oligodendroglial tumors (AOTs).

METHODS:

INA immunohistochemistry expression in tumors from 92 patients who were included in the EORTC 26951 trial was analyzed independently by 2 observers and was correlated with relevant clinical characteristics, including progression‐free survival (PFS) and overall survival (OS), and with molecular features, including 1p/19q codeletion, isocitrate dehydrogenase 1 and 2 gene (IDH1/IDH2) mutation, and O‐6 methylguanine‐DNA methyltransferase (MGMT) promoter methylation status.

RESULTS:

INA expression was observed in 33 tumors and was strongly correlated with 1p/19q codeletion, IDH1 mutations, and MGMT promoter methylation. It was associated with significantly better PFS and OS independent of the treatment received. By using Cox proportional hazard modeling for OS with stepwise selection, INA expression, patient age, and performance status were identified as independent prognostic factors. The results indicated that INA expression may have an impact on the efficacy of combined radiotherapy plus PCV.

CONCLUSIONS:

In a homogeneously treated group of patients with grade III AOTs, INA expression had strong favorable prognostic significance for OS and may have predictive value for sensitivity to chemotherapy. Cancer 2011. © 2011 American Cancer Society.     

Comprehensive CADM1 promoter methylation analysis in NSCLC and normal lung specimens

Methylation-mediated silencing of the tumour suppressor CADM1 has been functionally linked to lung cancer development. We aimed to determine whether CADM1 promoter methylation is a candidate early detection marker for lung cancer. To this end frozen tissue samples of 36 non-small cell lung cancers, 26 corresponding tumour distant normal tissue samples as well as 6 samples of normal lung from non-lung cancer patients were tested for DNA methylation at three different regions within the CADM1 promoter (M1, M5 and M9) using methylation specific PCR followed by methylation specific reverse line blot analysis.Sixty-four percentage of tumour samples tested positive at the M1 region, 47% at M5 and 74% at the M9 region, compared with 65% (M1), 23% (M5) and 46% (M9) of paired normal tissue samples. Methylation of each of these promoter regions was also detected in the majority of non-lung cancer control samples. Dense methylation, defined as methylation at ≥2 promoter regions, was detected in 66% of tumour samples compared with 38% of paired normal tissues and 67% of non-lung cancer control samples. Within the small subgroup of female patients dense methylation was found in all tumour samples but only 22% of paired normal samples. Neither methylation of individual sites nor dense methylation was correlated with disease free survival. In conclusion, CADM1 promoter methylation is a frequent event in NSCLC as well as normal lung, both of lung cancer and non-lung cancer patients. Hence, CADM1 methylation analysis is unlikely to have diagnostic value for the early detection of lung cancer in an unselected population. However, a diagnostic value for selected subjects, such as females, cannot be excluded.