Citations

Published literature have not discerned end-of-life palliative versus life-shortening effects of pharmacologically maintaining continuous deep sedation until death (ie, dying in deep sleep) compared with common sedation practices relieving distress in the final conscious phase of dying. Continuous deep sedation predictably suppresses brainstem vital centers and shortens life. Continuous deep sedation remains controversial as palliation for existential suffering and in elective death requests by discontinuation of chronic ventilation or circulatory support with mechanical devices. Continuous deep sedation contravenes the double-effect principle because: (1) it induces permanent coma (intent of action) for the contingency relief of suffering and for social isolation (desired outcomes) and (2) because of its predictable and proportional life-shortening effect. Continuous deep sedation should be distinguished from common sedation practices for palliation and characterized instead as physician-assisted death.

Abstract Genomics and proteomics have held out the promise of individualized medicine for the last 10 or 20 years, but clinical medicine has not yet delivered on this promise. Some cancers, such as breast cancer and some hematologic malignancies, have been at the forefront of individualized therapeutic approaches by integrating molecular biomarkers into treatment decision algorithms. Until recently, the treatment of colorectal cancer (CRC) has lagged behind these other cancers in this regard and therapeutic decisions have been solely empirical. Data from various clinical trials and translational studies have now opened the door for individualized treatment approaches by identifying patients with metastatic CRC who are most likely to benefit from antibodies against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab. Activating mutations of KRAS, a downstream mediator of EGFR signaling, has been shown to render EGFR antibodies ineffective, such that analyzing tumors for these mutations has become mandatory before the use of EGFR antibodies is considered in CRC. Beyond KRAS, several additional biomarkers are currently being investigated as potential positive or negative predictors for the efficacy of EGFR-targeted therapy. Most of these markers are alterations of molecules integrated in the EGFR pathway. This review will focus on the type and quality of evidence that has been gathered to date to predict resistance to monoclonal antibodies against EGFR in CRC. (Clin Cancer Res 2009;15(24):7492–501)

Purpose We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. Methods The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. Results Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R2 = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R2 = 0.67 for both 2- and 3-year DFS) and 7-year OS (R2 = 0.70 for both 2- and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. Conclusion Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials.

Abstract Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 × 109/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.

Purpose Statins have antilymphoma properties but have also been shown to inhibit the binding of rituximab to the CD20 antigen, resulting in reduced antitumor activity of rituximab in vitro. The clinical impact of statin use on the outcome of lymphoma patients treated with a rituximab-containing regimen is unknown. Patients and Methods Consecutive patients with newly diagnosed, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were enrolled onto a registry and observed prospectively. The impact of statin use on patients' outcomes was analyzed. Results Two hundred twenty-eight patients with DLBCL and 293 patients with FL were enrolled from September 2002 through June 2007; 21% of patients with DLBCL and 19% of patients with FL were on statins at diagnosis, and 20% and 17% remained on statins during lymphoma treatment, respectively. All patients with DLBCL and 39% of patients with FL received initial therapy containing rituximab. The median follow-up time was 47 months (range, 13 to 80 months). Statin use had no impact on the overall response rate (P = .67), overall survival (P = .76), or event-free survival (EFS) in patients with DLBCL (hazard ratio [HR] = 0.85; 95% CI, 0.43 to 1.68). Statin use at diagnosis was associated with improved EFS in patients with FL (HR = 0.45; 95% CI, 0.26 to 0.77), including subgroups treated with rituximab or a rituximab-containing regimen (HR = 0.38; 95% CI, 0.14 to 1.07) and patients who were observed only (HR = 0.38; 95% CI, 0.17 to 0.84). Conclusion The concurrent use of statins during the treatment of patients with DLBCL and FL in the rituximab era did not adversely affect outcome. The apparent benefit of statin therapy on FL outcome requires further studies.

Background: Previous studies have found positive bias and frequent outliers when central venous catheter (CVC) whole blood is used to dose glucose meters. We designed a study to determine whether positive bias and outliers with CVC whole blood glucose samples are due to exogenous glucose contamination of CVC samples, inherent bias and imprecision of glucose meters, or properties of CVC whole blood that interfere with the function of some glucose meters. Methods: We studied the relationship between venous whole blood and venous plasma glucose drawn by venipuncture to CVC whole blood and CVC plasma glucose in 50 hospitalized patients. In 27 patients whole blood glucose was measured on both the Accu-Chek ® Inform (Roche Diagnostics, Indianapolis, IN) and StatStrip™ (Nova Biomedical, Waltham, MA). Results: By comparing CVC plasma to venous plasma glucose, we determined that contamination of CVC samples with exogenous glucose was uncommon. On the Inform meter outliers were approximately twice as common with CVC whole blood compared to venous whole blood. In 27 patients who had CVC whole blood analyzed by both Inform and StatStrip, outliers occurred approximately twice as often on the Inform compared to the StatStrip. Accounting for CVC samples contaminated with exogenous glucose, outliers on the StatStrip did not occur significantly more often using CVC whole blood compared to venous whole blood. Conclusions: Properties unique to CVC whole blood differentially affect glucose meter bias and imprecision. Device selection is critical in practices that wish to use CVC whole blood to monitor glucose concentration in hospitalized patients.

AbstractThe objective of this case-control study was to compare the efficacy and toxicity of lenalidomide plus dexamethasone (len/dex) versus thalidomide plus dexamethasone (thal/dex) as initial therapy for newly diagnosed myeloma. We retrospectively studied 411 newly diagnosed patients treated with len/dex (228) or thal/dex (183) at the Mayo Clinic. The differences were similar in a matched-pair analysis that adjusted for age, sex, transplantation status, and dexamethasone dose. The proportions of patients achieving at least a partial response to len/dex and thal/dex were 80.3% versus 61.2%, respectively (P < .001); very good partial response rates were 34.2% and 12.0%, respectively (P < .001). Patients receiving len/dex had longer time to progression (median, 27.4 vs 17.2 months; P = .019), progression-free survival (median, 26.7 vs 17.1 months; P = .036), and overall survival (median not reached vs 57.2 months; P = .018). A similar proportion of patients in the 2 groups experienced at least one grade 3 or 4 adverse event (57.5% vs 54.6%, P = .568). Main grade 3 or 4 toxicities of len/dex were hematologic, mainly neutropenia (14.6% vs 0.6%, P < .001); the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, P = .058) and peripheral neuropathy (10.4% vs 0.9%, P < .001). Len/dex appears well-tolerated and more effective than thal/dex. Randomized trials are needed to confirm these results.

The sensitivity of baroreflex control of sympathetic nerve activity (SNA) represents the responsiveness of SNA to changes in blood pressure. In a slightly different analysis, the baroreflex threshold measures the probability of whether a sympathetic burst will occur at a given diastolic blood pressure. We hypothesized that baroreflex threshold analysis could be used to estimate the sensitivity of the sympathetic baroreflex measured by the pharmacological modified Oxford test. We compared four measures of sympathetic baroreflex sensitivity in 25 young healthy participants: the “gold standard” modified Oxford analysis (nitroprusside and phenylephrine), nonbinned spontaneous baroreflex analysis, binned spontaneous baroreflex analysis, and threshold analysis. The latter three were performed during a quiet baseline period before pharmacological intervention. The modified Oxford baroreflex sensitivity was significantly related to the threshold slope ( r = 0.71, P < 0.05) but not to the binned (1 mmHg bins) and the nonbinned spontaneous baroreflex sensitivity ( r = 0.22 and 0.36, respectively, P > 0.05), which included burst area. The threshold analysis was also performed during the modified Oxford manipulation. Interestingly, we found that the threshold analysis results were not altered by the vasoactive drugs infused for the modified Oxford. We conclude that the noninvasive threshold analysis technique can be used as an indicator of muscle SNA baroreflex sensitivity as assessed by the modified Oxford technique. Furthermore, the modified Oxford method does not appear to alter the properties of the baroreflex.