Does Serum CA19-9 Play a Practical Role in the Management of Patients With Colorectal Cancer?

PURPOSE: CA19-9 is often used in combination with carcinoembryonic antigen to manage patients with colorectal cancer, even though there is insufficient evidence to support this use of CA19-9. Carcinoembryonic antigen, by contrast, has been regarded as a better indicator of poor prognosis and recurrence. The purpose of this study is to clarify whether CA19-9 is, in fact, a useful marker in the management of colorectal cancer patients by comparing it with carcinoembryonic antigen. METHODS: A retrospective investigation was done for a consecutive series of 155 patients with colorectal adenocarcinoma who underwent potentially curative surgery between 1995 and 1999. Excluded were patients with postoperative assays performed less than three times for either carcinoembryonic antigen or CA19-9 and those who had developed secondary cancers. Data from 118 patients were analyzed in terms of prediction of prognosis and detection of recurrences. RESULTS: The sensitivities of preoperative CA19-9 and carcinoembryonic antigen were 29.8 percent and 45.3 percent, respectively. In the univariate analysis of preoperative carcinoembryonic antigen and CA19-9 assays in 114 patients, high carcinoembryonic antigen level was significantly associated with poor prognosis (P = 0.0090 by log-rank test). We could not find a significant association between preoperative CA19-9 abnormality and survival (P = 0.12). Multivariate analysis of preoperative factors indicated significance in TNM stage (P = 0.0094) and tumor location (P = 0.036) but in neither carcinoembryonic antigen (P = 0.061) nor CA19-9 (P = 0.22). Among 40 patients with recurrences, postoperative elevations of tumor markers were seen in 19 cases for CA19-9 and in 37 for carcinoembryonic antigen throughout the follow-up periods. Sensitivity, specificity, positive predictive value, and negative predictive value were 0.48, 0.88, 0.68, and 0.77, respectively, for CA19-9, and 0.93, 0.88, 0.80, and 0.96, respectively, for carcinoembryonic antigen. In patients with recurrences, the initial postoperative elevation of tumor markers was seen earlier than the detection of recurrence in 68.4 percent of those with CA19-9 elevation and in 67.6 percent of those with carcinoembryonic antigen elevation. There was only one patient with recurrence who had CA19-9 elevation without carcinoembryonic antigen elevation, while 19 recurrent patients had carcinoembryonic antigen elevation without CA19-9 elevation. Multivariate analysis showed a significant risk of carcinoembryonic antigen elevation against recurrence with an odds ratio of 32.0 (P < 0.0001), in contrast to an insignificant association of CA19-9 elevation (P = 0.23). CONCLUSION: We could not find clinical significance to support the use of CA19-9 to predict the prognosis and detect recurrence of colorectal cancer. Because of this, we do not recommend routine use of CA19-9 in staging and surveillance of colorectal cancer patients.     

Does Mechanical Injury of the Peripheral Airways Play a Role in the Genesis of COPD in Smokers?

In the present account it is proposed that in smokers the transition from peripheral airway disease to COPD is characterized by three sequential stages: Stage I, during which the closing volume eventually exceeds the functional residual capacity; Stage II, during which tidal expiratory flow limitation (EFL) is eventually exhibited; and Stage III, during which dynamic hyperinflation progressively increases leading to dyspnea and exercise limitation, which may be considered as markers of overt disease. Presence of airway closure (Stage I) and EFL (Stage II) in the tidal volume range may promote peripheral airway injury and accelerate the abnormalities of lung function. It is such injury that may determine which smoker is destined to develop COPD.     

Interleukin-33 in Asthma: How Big of a Role Does It Play?

In complex disorders such as asthma and allergic disease, the goal for developing disease-modifying biotherapeutics is to find a target that is a central instigator of immunologic activity. Interleukin (IL)-33 seems to be such a molecule, as it is one of the earliest-released signaling molecules following epithelial damage and can orchestrate the recruitment and activation of the cells responsible for disease. Unregulated IL-33 activity leads to activation of T-helper type 2 cells, mast cells, dendritic cells, eosinophils, and basophils, ultimately leading to increased expression of cytokines and chemokines that define the disease. As such, IL-33 is an attractive candidate for therapeutic intervention with the goal of ameliorating disease. This review focuses on the role of IL-33 in promoting and maintaining the asthma phenotype.     

What Role Does Measuring Medication Compliance Play in Evaluating the Efficacy of Naltrexone?

BACKGROUND: Compliance with medication in pharmacotherapy trials of alcoholism has been shown to be equal to, or more, important than in other areas of medicine. Research has suggested that naltrexone's effectiveness can be greatly influenced by the compliance of participants in clinical trials. Presently, we compare 2 compliance measurement methods [urine riboflavin and medication event monitoring system (MEMS)] used simultaneously to evaluate naltrexone's efficacy and the impact of compliance on the size of observable treatment effects. METHODS: One hundred and thirty-seven of 160 randomized alcoholic patients completed 12-weeks (84 days) of naltrexone or placebo and cognitive behavioral therapy (CBT) or motivational enhancement therapy (MET). Urine riboflavin was determined during study weeks 2, 6, and 12. The MEMS provided a detailed computerized record of when a participant opened their medication bottle throughout the trial. Baseline predictors of MEMS (80% openings) and urine riboflavin (>or=1,500 ng/mL by fluorimetry) compliance were examined. The effects of the treatments in the compliant participants defined by one, the other, or both methods were compared and contrasted with a previously reported intent-to-treat analysis where compliance was not taken into account. RESULTS: Age was predictive of compliance. 105 participants were deemed compliant via urine riboflavin criteria, 87 via MEMS, and 77 when both criteria were met, with no significant differences between treatment groups. The most compliant participants showed a significant medication by therapy interaction. Those treated with naltrexone/CBT showed more abstinence days (p<0.03), less heavy drinking days (p<0.03) and less total drinks (p<0.03) than the other groups. The effect size of this interaction increased from about 0.2 in the intent-to-treat analysis, to about 0.4 to 0.5 in the compliant group analyses, with little difference between compliance measurement methods. CONCLUSIONS: Compliance measurement does appear to influence the evaluation of the efficacy of naltrexone within the context of CBT. Treatment effect sizes approximately doubled in the most compliant individuals. Measuring compliance by either of 2 distinct methods provides approximately similar results. As compliance with naltrexone within the context of CBT has such a large impact of treatment outcome, methods of enhancing compliance during treatment should be given the utmost attention.     

Does Endothelin Play a Role in Chemoreception During Acute Hypoxia in Normal Men?

BACKGROUND: The peripheral chemoreceptors are the dominant reflex mechanism responsible for the rise in ventilation and muscle sympathetic nerve activity (MSNA) in response to hypoxia. Animal studies have suggested that endothelin (ET) plays an important role in chemosensitivity. Moreover, several human clinical conditions in which circulating ET levels are increased are accompanied by enhanced chemoreflex sensitivity. Whether ET plays a role in normal human chemosensitivity is unknown. METHODS: We determined whether bosentan, a nonspecific ET receptor antagonist, would decrease chemoreflex sensitivity in 14 healthy subjects. We assessed the effects of bosentan on the response to isocapnic hypoxia, using a randomized, crossover, double-blinded study design. RESULTS: Bosentan increased mean (+/- SEM) plasma ET levels from 1.97 +/- 0.28 to 2.53 +/- 0.23 pg/mL (p = 0.01). Hypoxia increased mean minute ventilation from 6.7 +/- 0.3 to 8+/0.4 L/min (p < 0.01), mean MSNA from 100 to 111 +/- 5% (p < 0.01), mean heart rate from 67 +/- 3 to 86 +/- 3 beats/min (p < 0.01), and mean systolic BP from 116 +/- 3 to 122 +/- 3 mm Hg (p < 0.01). However, none of these responses differed between therapy with bosentan and therapy with placebo (p = 0.26). Bosentan did not affect the mean MSNA responses to the apneas, during normoxia (change from baseline: placebo, 259 +/- 58%; bosentan, 201 +/- 28%; p = 0.17) or during hypoxia (change from baseline: placebo, 469 +/- 139%; bosentan, 329 +/- 46%; p = 0.24). The durations of the voluntary end-expiratory apneas in normoxia and hypoxia, and the subsequent reductions in oxygen saturation, were also similar with therapy using bosentan and placebo (p = 0.42). CONCLUSION: In healthy men, ET does not play an important role in peripheral chemoreceptor activation by acute hypoxia.     

HCC: Where Does HCV Therapy Play a Role?

Viral infections have the potential to induce carcinogenesis through chronic inflammation. Hepatitis B and hepatitis C (HCV) are two major risk factors for the development of hepatocellular carcinoma (HCC) and are responsible for 70–80 % of cases seen worldwide. The incidence of HCC has been rising in the USA over the last several decades, largely in part to the prevalence of HCV-induced cirrhosis. Curative therapies with resection and orthotopic liver transplantation are only available for individuals with early-stage HCC, and disease recurrence is still common after treatment, highlighting the need for both primary and secondary preventative measures. Despite the low rates of viral eradication with interferon-based regimens, many studies have shown a chemo-protective effect in patients who do achieve a sustained virologic response. The emergence of new direct-acting antiviral agents with cure rates above 95 % has the potential to change the landscape of HCV-induced HCC. This article discusses the current data for HCV therapy as a chemo-preventive agent and HCV treatment strategies for patients with various stages of hepatocellular carcinoma.     

Does Apoptosis Play a Role in Varicella Zoster Virus Latency and Reactivation?

Varicella zoster virus (VZV) is an exclusively human highly neurotropic alphaherpesvirus. To date, VZV has been shown to induce apoptosis, primarily through the intrinsic pathway in different cell types, except for neurons in which the virus becomes latent. This review summarizes current studies of varicella-induced apoptosis in non‑neuronal cells. Future studies are proposed to determine whether apoptosis is terminated prematurely or even begins in neurons that are non-productively infected with VZV.     

Does Contractility Modulation Have a Role in the Treatment of Heart Failure?

Cardiac resynchronization therapy (CRT) is an established therapy for patients with systolic dysfunction, QRS duration greater than 120 ms, and New York Heart Association (NYHA) class III or IV symptoms. However, most patients with heart failure have QRS duration below 120 ms and 30% or more of CRT recipients are nonresponders. Cardiac contractility modulation (CCM) signals are nonexcitatory electrical impulses applied during the absolute refractory period that are intended to enhance contractile strength independent of QRS duration. Myocardial biopsy studies suggest that modulation of protein phosphorylation and gene expression underlie the mechanisms by which CCM exerts its effects. Two prospective randomized studies have investigated the impact of CCM on exercise tolerance and quality of life in patients with chronic heart failure. These studies have included predominantly patients with NYHA class III heart failure with QRS duration below 130 ms. This review summarizes results of these clinical studies and outlines additional studies underway to further clarify the role of CCM in the treatment of heart failure.     

Does Orthostatic Testing Have Any Role in the Evaluation of the Young Subject With Mild Hypertension?: An Insight From the HARVEST Study

The aim of the study was to assess the clinical significance of the blood pressure (BP) reaction to standing in 1029 stage I hypertensives. Office BP was measured six times in the supine position and six times after 2 min of standing. All subjects underwent 24-h ambulatory BP monitoring, and measurements of 24-h urinary epinephrine and norepinephrine excretion. Echocardiography was performed in 636 patients. With use of mixture analysis we could single out a population with abnormal diastolic BP response to standing (hyperreactors, n = 95). These subjects had a diastolic BP increase from lying to standing of >11 mm Hg. The other subjects were defined as normoreactors (n = 934). Office systolic BP was similar in the two groups. Diastolic BP was lower (91 ± 6 mm Hg v 95 ± 5 mm Hg, P < .0001) and heart rate was higher in the hyperreactors (77 ± 10 beats/min v 75 ± 9 beats/min, P = .004). After adjusting for age, gender, and smoking habits the statistical significance did not change. Adjusted 24-h systolic BP (P = .02) and diastolic BP (P = .02) were higher in the hyperreactors than in the normoreactors. Hyperreactors were characterized by higher cardiac index (3.2 ± 0.8 L/min/m² v 3.0 ± 0.7 L/min/m², P = .008 for adjusted values), lower total peripheral resistance (1420 ± 330 dyne/sec/cm⁻⁵ v 1600 ± 380 dyne/sec/cm⁻⁵, P = .003), and higher urinary norepinephrine output (114.9 ± 80.3 μg/24 h v 90.6 ± 78.5 μg/24 h, P = .03). Dimensional echocardiographic data and albumin excretion rate did not differ between the two groups. In conclusion, mixture analysis allowed us to identify a population of young mild hypertensives with exaggerated BP response to standing. Hyperreactors were characterized by higher whole-day BP and by a hyperkinetic hemodynamic pattern as a result of increased sympathetic tone.     

Does Self-Reported Physical Activity Underestimate the Importance of Activity in Cardiovascular Disease Prevention?

Engagement in regular exercise or physical activity (PA) is known to protect against cardiovascular disease. Evidence for this strong association comes from both epidemiologic studies in which individuals self-report their level of PA and randomized controlled trials in which individuals increase their level of PA to a pre-defined level for a specific duration. Misclassification biases associated with self-reported PA may underestimate the true reduction in cardiovascular disease (CVD) risk obtained through regular engagement in PA, particularly at high levels. Given the strong dose–response relationship observed between objectively measured PA and changes in CVD risk factors in randomized controlled trials, the estimated risk reduction associated with high levels of PA (> 2,000 kcal/wk) would be predicted to be larger than current estimates (30% risk reduction) derived from epidemiologic studies. Self-reported PA may underestimate the true risk reduction in CVD produced through engagement in high levels of PA, although definitive evidence is not available.