Stage-Specific Effect of Adjuvant Therapy Following Gastric Cancer Resection: a Population-based Analysis of 4,041 Patients

Background Adjuvant chemoradiotherapy improved survival in patients with resected gastric adenocarcinoma in the Southwest Oncology Group/Intergroup 0116 trial. Our objective was to examine the impact of adjuvant treatment on overall survival (OS) in the general population. Methods Patients 18–85 years old who had undergone resection of non-metastatic gastric adenocarcinoma between May 2000 and December 2003, were identified from the Surveillance Epidemiology and End Results (SEER) database. Patients who had received pre-operative irradiation, had unknown stage or radiation status, or had a survival of 3 months or less from the date of diagnosis were excluded. Survival of those who received post-operative irradiation was compared with those who did not; Kaplan-Meier methods and Cox proportional hazards models were used. Results Of 4,041 patients, there was improved survival for those receiving adjuvant irradiation for stages III and IVM0, with a median OS of 31 versus 24 months (P = 0.005) and 20 versus 15 months (P < 0.001), respectively, and a trend for improved survival in univariate analysis of stage II (P = 0.0535). In final adjusted analysis, adjuvant irradiation significantly improved OS in stages III (HR: 0.71, P = 0.0007) and IVM0 (HR: 0.66, P < 0.0001). Adjusted analysis using a propensity score suggested that the benefit of adjuvant irradiation was similar in stage-II and -III patients. However, there was no statistical improvement in survival for stage-Ib and -II patients who had received adjuvant irradiation. Conclusions In this population-based analysis, adjuvant radiotherapy for stage-III and IVM0 gastric cancer significantly improved OS. Analysis of stage-Ib and -II patients is limited by small numbers, but there may not be the same benefit.     

Surgical Management of Intrahepatic Cholangiocarcinoma - A Population-Based Study

Background Cholangiocarcinoma (CCA) is associated with poor survival and therapeutic nihilism. To date, there has not been an examination of the surgical management of CCA at a population level. Methods Using the Surveillance, Epidemiology and End Results (SEER) database, we identified all patients with intrahepatic CCA diagnosed between 1988 and 2003. Tumors categorized as a single, unilobar lesion with no evidence of vascular invasion were defined as localized. It was then determined whether patients received cancer directed surgery (CDS). Multivariable logistic regression was used to evaluate factors associated with CDS in patients with localized disease. The influence of CDS on overall survival (OS) was evaluated using Kaplan–Meier curves and Cox proportional hazards modeling. Results Only 446 (12%) of 3,756 patients with intrahepatic CCA underwent CDS. On multivariable analysis, non-Klatskin tumor (p < 0.01) and younger age (p = 0.02) was associated with CDS. Localized disease was strongly associated with CDS (p < 0.01); however, only 91 (37%) of these 248 patients underwent CDS. Of patients with localized disease, those who had CDS had significantly better survival than those who did not (p < 0.01), with median overall survival (OS) of 44 months versus 8 months, and five-year OS of 42% versus 4%, respectively. Conclusions Patients with localized CCA who are selected for CDS are strongly associated with improved survival, with rates approaching that found in single institution studies. However, many patients with localized tumors do not receive potentially curative cancer-directed surgery. Further study is warranted to address the barriers to the delivery of appropriate care to these patients. This study was presented in abstract form at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2007, and the Society of Surgical Oncology Annual Meeting 2007. Dr. Baxter is supported by a Canadian Institutes of Health New Investigator Award and an American Society of Clinical Oncology Career Development Award. Dr. Law is supported by a Career Scientist Award from the Ministry of Health and Long Term Care.     

Is Botulinum Neurotoxin Type A (BoNT-A) a Novel Therapy for Lower Urinary Tract Symptoms Due to Benign Prostatic Enlargement? A Review of the Literature

CONTEXT: The intraprostatic injection of botulinum neurotoxin type A (BoNT-A) is a minimally invasive but still-experimental treatment of lower urinary tract symptoms (LUTS) due to benign prostatic enlargment (BPE) based on an off-label use of the drug. OBJECTIVE: Report the mechanisms of action of BoNT-A on the prostate as well as the efficacy and safety of intraprostatic BoNT-A injection according to various injection protocols. EVIDENCE ACQUISITION: We searched the Medical Literature Analysis and Retrieval System Online (MEDLINE) database and the abstract volumes of the 2005, 2006, and 2007 European Association of Urology (EAU), American Urological Association (AUA) and International Continence Society (ICS) meetings for studies on intraprostatic BoNT-A injection. EVIDENCE SYNTHESIS: Five experimental studies and 10 clinical studies were found. The level of evidence is 1b for one study and 3 for the other studies, with grades of recommendation of A and C, respectively. The experimental studies report induced relaxation of the prostate, atrophy, and reduction of its size through inhibition of the trophic effect of the autonomic system on the prostate gland. In the clinical studies, all patients had LUTS due to BPE and prostate volume varied from <20ml to >80ml. The dose varied from 100U to 300U of Botox((R)). The injection was performed transperineally, transrectally, or transurethrally under general, local, or without anesthesia. The follow-up period ranged from 3 mo to 19.8 mo. All studies reported an improvement of maximum urinary flow rate, quality-of-life index and reduction of International Prostate Symptoms Score, prostate-specific antigen (PSA) level, post-void residual volume, and prostate volume. Local or systemic side effects were rare. Only patients with retention needed a urethral drainage catheter. CONCLUSIONS: BoNT-A intraprostatic injection provides improvement in patients with LUTS due to BPE refractory to medical treatment. However, there is a need for large placebo controlled-studies and long-term results. So far the therapy is still experimental.     

The humerus is the best place for bone lengthening

The aim of this study was to examine the effectiveness of lengthening the humerus in children and young adults. Between 1984 and 2005, the Orthopaedic Department of Semmelweis University elongated 11 humeri (ten patients) for reasons of congenital hypoplasia (four cases), osteomyelitis (three cases), epiphyseolysis, growth plate closure after irradiation and obstetrical paralysis (one case each). The study cohort consisted of five females and five males, with an average age at the time of surgery of 17.8 years (range: 12-31 years). In every case, the lengthening was performed with a unilateral Wagner fixator. The lengthening protocol was 1 mm distraction daily (callotasis) after a 7-day latency period. The fixator was removed after total bone healing. Plate fixation or bone transplantation was not used. The average rate of lengthening was 6.2 cm (4.5-10.5 cm), and the achieved lengthening was 27% (range: 16-44%). The average healing index was 32 day/cm. One patient who suffered from temporary radial paresis, and temporary flexion contracture of the elbow was regarded as a complication following placement of the fixator. Based on our results, humeral shortening can effectively be treated with the unilateral Wagner fixator. The main difference between the original Wagner method and our approach is that we were able to leave the fixator in the humerus until total bony reconstruction so there was no need for plate fixation or bone transplantation.     

Selective NR1/2B N-methyl-D-aspartate receptor antagonists among indole-2-carboxamides and benzimidazole-2-carboxamides

(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.     

Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture

Administration of subanesthetic concentrations of ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) type of glutamate receptors, is a widely accepted therapeutic modality in perioperative and chronic pain management. Although extensive clinical use has demonstrated its safety, recent human histopathological observations as well as laboratory data suggest that ketamine can exert adverse effects on central nervous system neurons. To further investigate this issue, the present study was designed to evaluate the effects of ketamine on the survival and dendritic arbor architecture of differentiated gamma-aminobutyric acidergic (GABAergic) interneurons in vitro. We show that short-term exposure of cultures to ketamine at concentrations of > or =20 microg/ml leads to a significant cell loss of differentiated cells and that non-cell death-inducing concentrations of ketamine (10 microg/ml) can still initiate long-term alterations of dendritic arbor in differentiated neurons, including dendritic retraction and branching point elimination. Most importantly, we also demonstrate that chronic (>24 h) administration of ketamine at concentrations as low as 0.01 microg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal morphology and thus might lead to dysfunctions of neural networks.     

Potentially toxic effects of anaesthetics on the developing central nervous system

A growing body of experimental evidence suggests that anaesthetics, by influencing GABAergic and glutaminergic neural signalling, can have adverse effects on the developing central nervous system. The biological foundation for this is that gamma-aminobutyric acid and glutamate could act non-synaptically, in addition to their role in neurotransmission in the adult brain, in the regulation of neuronal development in the central nervous system. These neurotransmitters and their receptors are expressed from very early stages of central nervous system development and appear to influence neural progenitor proliferation, cell migration and neuronal differentiation. During the synaptogenetic period, pharmacological blockade of N-methyl-d-aspartate (NMDA)-type glutamate receptors as well as stimulation of GABAA receptors has been reported to be associated with increased apoptosis in the developing brain. Importantly, recent data suggest that even low, non-apoptogenic concentrations of anaesthetics can perturb neuronal dendritic development and thus could potentially lead to impairment of developing neuronal networks. The extrapolation of these experimental observations to clinical practice is of course very difficult and requires extreme caution as differences in drug concentrations and exposure times as well as interspecies variations are all important confounding variables. While clinicians should clearly not withhold anaesthesia based on current animal studies, these observations should urge more laboratory and clinical research to further elucidate this issue.     

Multidimensional Social Support and the Health of Homeless Individuals

Homeless individuals often suffer from serious health problems. It has been argued that the homeless are socially isolated, with low levels of social support and social functioning, and that this lack of social resources contributes to their ill health. These observations suggest the need to further explore the relationship between social networks, social support, and health among persons who are homeless. The purpose of this study was to examine the association between multidimensional (cognitive/perceived and behavioral/received) social support and health outcomes, including physical health status, mental health status, and recent victimization, among a representative sample of homeless individuals in Toronto, Canada. Multivariate regression analyses were performed on social support and health outcome data from a subsample of 544 homeless adults, recruited from shelters and meal programs through multistage cluster sampling procedures. Results indicated that participants perceived moderately high levels of access to financial, emotional, and instrumental social support in their social networks. These types of perceived social supports were related to better physical and mental health status and lower likelihood of victimization. These findings highlight a need for more services that encourage the integration of homeless individuals into social networks and the building of specific types of social support within networks, in addition to more research into social support and other social contextual factors (e.g., social capital) and their influence on the health of homeless individuals.     

Psychometric test of the Team Climate Inventory-short version investigated in Dutch quality improvement teams

Background  

Although some studies have used the Team Climate Inventory within teams working in health care settings, none of these included quality improvement teams. The aim of our study is to investigate the psychometric properties of the 14-item version of the Team Climate Inventory in healthcare quality improvement teams participating in a Dutch quality collaborative.