A Bayesian ordinal model for heterogeneity in a multi-centre myocardial infarction clinical trial

A Bayesian methodology is developed to investigate the homogeneity of the treatment effects in a multi-centre clinical trial with an ordinal response. A hierarchical model is formulated for the ordinal response, and the marginal posterior distributions of the covariates, overall treatment and the centre effects are calculated using the Gibbs sampler. The methodology is applied to data arising from a multi-centre clinical trial of therapies for acute myocardial infarction. In this trial, the overall results show that the treatment is effective. However, there appears to be substantial differences in both the baseline risk and treatment effect across centres. Thus, the observed treatment effects may not be generalized to a broader patient population, and exploratory analyses to ascertain reasons for the treatment-by-centre interaction and its possible effect on the study conclusions would be useful.     

Glut-1 glucose transporter expression in esophageal squamous cell carcinoma is associated with tumor aggressiveness

BACKGROUND: Glucose transporter (Glut) proteins, which are membrane proteins responsible for the transport of glucose across cellular membranes, have six forms. To further elucidate the role of Glut-1 expression in esophageal squamous cell carcinoma, we examined the expression of Glut-1 protein immunohistochemically. MATERIALS AND METHODS: Immunohistochemical expression of Glut-1 was examined in surgically resected tissues from 95 patients with esophageal squamous cell carcinoma. RESULTS: Of the 95 esophageal carcinomas, 91 (95.8%) had some Glut-1 immunostaining in the membranes of the cancer cells. Positive staining (> 30% of cancer cells showing Glut-1 expression) was observed in 49 (51.6%) of the cases. Comparison of Glut-1 expression and clinicopathological characteristics in the 95 patients with esophageal cancer revealed significant associations between Glut-1 expression and tumor status (p < 0.001), lymph node status (p < 0.05), metastatic status (p < 0.01), and pathological stage (p < 0.001). The survival rates of patients with Glut-1-positive tumors were significantly lower than those of patients with Glut-1-negative tumors (log-rank p < 0.05). CONCLUSION: In conclusion, the level of Glut-1 expression may be a useful marker that can provide information on tumor aggressiveness and prognosis in patients with esophageal squamous cell carcinoma.     

Important role of serotonin in the antitumor effects of recombinant human tumor necrosis factor-alpha in mice

The possible involvement of chemical mediator(s) in the induction of the antitumor effects of recombinant human tumor necrosis factor-alpha (rTNF-alpha) on Meth A fibrosarcoma (Meth A) in mice was studied. On day 7 after intradermal implantation of Meth A in mice, rTNF-alpha caused tumor necrosis and inhibited the tumor growth. Ketanserin, cyproheptadine, and spiperone [serotonin (5-HT) receptor blockers] inhibited or attenuated the antitumor effects of rTNF-alpha, but the other types of receptor blockers tested (histamine H1 and H2, adrenaline alpha and beta, dopamine, and acetylcholine receptor blockers) did not. The large i.v. doses of 5-HT caused tumor necrosis and inhibited tumor growth in mice when given i.v. on day 7 but not when given on day 3 after Meth A implantation, which effects closely resemble those of rTNF-alpha. Its anti-tumor effects were completely inhibited by the 5-HT receptor blockers. 5-HT, like rTNF-alpha, showed no cytotoxicity against in vitro cultured Meth A cells. The results suggest that 5-HT is, at least in part, important for the induction of antitumor effects of rTNF-alpha on Meth A in mice.     

Detecting small-area similarities in the epidemiology of childhood acute lymphoblastic leukemia and diabetes mellitus, type 1: a Bayesian approach

Childhood acute lymphoblastic leukemia and diabetes mellitus, type 1, have common epidemiologic and etiologic features, including correlated international incidence and associations with infections. The authors examined whether the diseases' similar large-scale distributions are reflected in small geographic areas while also examining the influence of sociodemographic characteristics. Details of 299 children (0-14 years) with acute lymphoblastic leukemia and 1,551 children with diabetes diagnosed between 1986 and 1998 were extracted from two registers in Yorkshire, United Kingdom. Standardized incidence ratios across 532 electoral wards were compared using Poisson regression, confirming significant associations between population mixing and the geographic heterogeneity of both conditions. Bayesian methods analysis of spatial correlation between diseases by modeling a bivariate outcome based on their standardized incidence ratios was applied; spatial and heterogeneity components were included within a hierarchical random effects model. A positive correlation between diseases of 0.33 (95% credible interval: -0.20, 0.74) was observed, and this was reduced after control for population mixing (r = 0.18), population density (r = 0.14), and deprivation (r = 0.06). The Bayesian approach showed a modest but nonsignificant joint spatial correlation between diseases, only partially suggesting that the risk of both was associated within some electoral wards. With Bayesian methodology, population mixing remained significantly associated with both diseases. The links between diabetes and acute lymphoblastic leukemia observed for large regions are weaker for small areas. More powerful replications are needed for confirmation of these findings.     

The effectiveness of planned esophagectomy after neoadjuvant chemoradiotherapy for advanced esophageal carcinomas

BACKGROUND: The best treatment option for patients with locally advanced esophageal carcinoma has not yet been determined, especially because the benefits of esophagectomy after neoadjuvant chemoradiotherapy are still controversial. We report the results of a retrospective cohort comparison of definitive chemoradiotherapy without surgery (CRT) versus neoadjuvant chemoradiotherapy followed by planned surgery (CRTS) in patients with advanced esophageal squamous cell carcinoma (SCC). MATERIALS AND METHODS: Between January 1991 and December 2002, 67 patients were enrolled in this study. Fifty of the 67 patients were considered to have inoperable tumors due to distant organ metastasis, distant lymph node metastasis, severe organ dysfunction or rejection of surgery by the patient and received CRT, while the remaining 17 patients were treated with CRTS. The clinical responses of the primary tumors were evaluated. RESULTS: In the 50 CRT patients, the one- and 2-year survival rates were 33.8% and 20.2%, respectively, and the median survival time (MST) was 13.5 months. In the 17 CRTS patients, the response rate (CR + PR) was 76.5%, and the pathological complete response (pCR) rate was 29.4%. Their one- and 2-year survival rates were 61.6% and 35.9%, respectively, and the MST was 24.4 months. The survival rates of the CRT patients were lower than those of the CRTS patients (p = 0.1288). When the 12 patients with distant organ metastases were removed from the CRT group, the one- and 2-year survival rates of the remaining 38 patients were 36.5% and 24.1%, respectively, and the MST was 14.7 months. The survival rates of these 38 CRT patients without distant organ metastases were similar to those of the 12 CRTS patients in the pathological partial response (pPR) group (p = 0.6279). CONCLUSION: This retrospective cohort comparison of CRT versus CRTS demonstrated that there may not be any survival benefit from the addition of surgery in the pPR group for advanced esophageal carcinomas. For patients with a poor response to neoadjuvant chemoradiotherapy, we suggest that the addition of chemoradiotherapy, instead of planned esophagectomy, may show a similar survival rate to definitive CRT. Thus, a large series of a randomized control study will be required to confirm the benefit of surgery after chemoradiotherapy.     

Serum interleukin-12 and interleukin-18 levels as a tumor marker in patients with esophageal carcinoma

Interleukin (IL)-12 and IL-18 participate in tumor immunology. Serum IL-12 and IL-18 levels were determined in patients with esophageal carcinoma, and the relationship between clinicopathologic factors and prognosis was investigated. Peripheral blood samples were obtained from 15 healthy volunteers and from 70 patients with esophageal carcinoma before curative surgery. IL-12 and IL-18 levels were determined in each serum sample by enzyme-linked immunosorbent assay. Mean serum IL-12 and IL-18 levels were significantly higher in patients with esophageal carcinoma compared with healthy volunteers (P < 0.05) and mean serum IL-12 and IL-18 levels increased in patients as the pathologic stage progressed. A positive correlation was observed between serum IL-12 and IL-18 levels (P < 0.01). In patients with esophageal carcinoma, increasing serum IL-12 and IL-18 levels correlated with tumor growth and progression. The function of these two interleukin in the host immune response remains unclear. However, this part of the host immune response did not appear to contribute to the postoperative prognosis. Serum IL-12 and IL-18 levels might correlate with a certain depth of invasion and might be useful tumor markers in patients with esophageal carcinoma.     

The contribution of expectations to motion sickness symptoms and gastric activity

OBJECTIVE: The goal of this investigation was to determine in healthy adults the effect of expectation manipulations on the development of motion sickness, as indicated by abnormal gastric myoelectric activity and subjective reports of symptoms of motion sickness. METHOD: Eighty participants, moderately susceptible to motion sickness, experienced one of four conditions created from a two-variable (Expectation, Drum), two-factor model (High/Low expectation for sickness; Rotating/Stable Drum). The electrogastrogram (EGG) was recorded 6 min prior to the expectation manipulation; 6 min following the expectation manipulation; 6 min before drum activation; and 16 min during drum activation. Self-report questionnaires indicating expectation for sickness (MSEx) and motion sickness symptoms (Nausea Profile [NP]) were obtained following the expectation manipulation and exposure to the drum, respectively. RESULTS: No significant differences were observed among expectation groups for retrospective reports of motion sickness (NP); however, significant differences in EGG responses to drum rotation were obtained. The unexpected results of a univariate analysis of variance (ANOVA) revealed significantly greater gastric tachyarrhythmia and less normal activity, an indication of motion sickness, in the low expectation for sickness conditions. CONCLUSION: These results suggest that inducing a high expectation for sickness in healthy individuals about to be exposed to provocative motion results in a protective effect from motion sickness following exposure to the stimulus, while low expectations may induce abnormal gastric activity.     

Safety of therapeutic beta-blockade in patients with coexisting bronchospastic airway disease and coronary artery disease

Atherosclerotic coronary artery disease and bronchospastic airway disease frequently coexist in older patients. There are substantial data suggesting reduced mortality with the use of beta-adrenergic blocking drugs in patients with symptomatic coronary artery disease, especially patients who have postmyocardial infarction and/or severe coronary artery disease associated with left ventricular dysfunction. Conversely, the use of beta-adrenergic blocking drugs (even selective beta(1)-adrenergic blocking drugs) has the potential of exacerbating bronchospasm. This prospective registry evaluates the safety of use of selective beta(1)-adrenergic blocking drugs in patients with symptomatic coronary artery disease and bronchospastic airway disease. A total of 835 consecutive patients with symptomatic coronary artery disease were prospectively evaluated for coexisting coronary and bronchospastic airway disease. Of these, 30 patients (mean age: 61 +/- 14 years) met the qualifying inclusion criteria. All these study patients except 1 (29/30 [96%]) reached therapeutic beta-blockade (resting heart rate <70 beats per minute). The 1 patient who discontinued use of beta-adrenergic blocking drugs as a result of lifestyle-limiting bronchospasm had no serious adverse outcome. No hospitalizations were required because of worsening bronchospasm. Ten percent of patients reported increased requirement of inhaled beta(2)-agonist use. The patients were followed for 15 +/- 9 months. One patient died of stroke at 22 weeks of follow-up. In conclusion, use of selective beta(1)-adrenergic blocking drugs at a therapeutic dose is safe (as long as careful clinical follow-up is available) and should be considered in all patients with coexisting symptomatic coronary artery disease and bronchospastic airway disease.