Anthracyclines play a critical role in the treatment of a variety of childhood cancers. However, the cumulative cardiotoxic effects of anthracyclines limit the use of these agents in many treatment regimens. Dexrazoxane is a cardioprotectant that significantly reduces the incidence of adverse cardiac events in women with advanced breast cancer treated with doxorubicin-containing regimens. Clinical evidence for the efficacy of dexrazoxane as a cardioprotectant in children, especially from randomized clinical trials, is limited, but the available data support a short-term cardioprotective effect. Long-term follow-up in children treated with dexrazoxane has not been reported. Dexrazoxane’s impact on the antitumor effect and toxicity profile of the anthracyclines and the role of dexrazoxane in the development of secondary malignant neoplasms in patients who received dexrazoxane are reviewed. Based on the available data, dexrazoxane appears to be a safe and effective cardioprotectant in children, and it does not appear to alter overall survival times in children with cancer. Continued follow-up from previous trials is needed to determine the long-term effect of dexrazoxane on cardiac outcomes and quality of life. 
Month: November 2010
Opioid Rotation in the Management of Chronic Pain: Where Is the Evidence?
The management of chronic pain remains a challenge because of its complexity and unpredictable response to pharmacological treatment. In addition, accurate pain management may be hindered by the prejudice of physicians and patients that strong opioids, classified as step 3 medications in the World Health Organization ladder for cancer pain management, are reserved for the end stage of life. Recent information indicates the potential value of strong opioids in the treatment of chronic nonmalignant pain. There are, up until now, insufficient data to provide indications about which opioid to use to initiate treatment or the dose to be used for any specific pain syndrome. The strong inter-patient variability in opioid receptor response and in the pharmacokinetic and pharmacodynamic behavior of strong opioids justifies an individual selection of the appropriate opioid and stepwise dose titration. Clinical experience shows that switching from one opioid to another may optimize pain control while maintaining an acceptable side effect profile or even improving the side effects. This treatment strategy, described as opioid rotation or switch, requires a dose calculation for the newly started opioid. Currently, conversion tables and equianalgesic doses are available. However, those recommendations are often based on data derived from studies designed to evaluate acute pain relief, and sometimes on single dose studies, which reduces this information to the level of an indication. In daily practice, the clinician needs to titrate the optimal dose during the opioid rotation from a reduced calculated dose, based on the clinical response of the patient. Further research and studies are needed to optimize the equianalgesic dosing tables.
source: Wiley library
Vascular Pathophysiology in Response to Increased Heart Rate
This review summarizes the current literature and the open questions regarding the physiology and pathophysiology of the mechanical effects of heart rate on the vessel wall and the associated molecular signaling that may have implications for patient care. Epidemiological evidence shows that resting heart rate is associated with cardiovascular morbidity and mortality in the general population and in patients with cardiovascular disease. As a consequence, increased resting heart rate has emerged as an independent risk factor both in primary prevention and in patients with hypertension, coronary artery disease, and myocardial infarction. Experimental and clinical data suggest that sustained elevation of heart rate—independent of the underlying trigger—contributes to the pathogenesis of vascular disease. In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis. The underlying mechanisms are only partially understood and appear to involve alterations of mechanic properties such as reduction of vascular compliance. Clinical studies reported a positive correlation between increased resting heart rate and circulating markers of inflammation. In patients with coronary heart disease, increased resting heart rate may influence the clinical course of atherosclerotic disease by facilitation of plaque disruption and progression of coronary atherosclerosis. While a benefit of pharmacological or interventional heart rate reduction on different vascular outcomes was observed in experimental studies, prospective clinical data are limited, and prospective evidence determining whether modulation of heart rate can reduce cardiovascular events in different patient populations is needed.
source: americal journal of cardiology
Percutaneous endoscopic gastrostomy versus nasogastric tube feeding for adults with swallowing disturbances.
A number of conditions compromise the passage of food along the digestive tract. Nasogastric tube (NGT) feeding is a classic, time-proven technique, although its prolonged use can lead to complications such as lesions to the nasal wing, chronic sinusitis, gastro-oesophageal reflux, and aspiration pneumonia. Another method of infusion, percutaneous endoscopy gastrostomy (PEG), is generally used when there is a need for enteral nutrition for a longer time period. There is a high demand for PEG in patients with swallowing disorders, although there is no consistent evidence about its effectiveness and safety as compared to NGT.
OBJECTIVES: To evaluate the effectiveness and safety of PEG as compared to NGT for adults with swallowing disturbances.
SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, and LILACS from inception to August 2009, as well as contacting main authors in the subject area. There was no language restriction in the search.
SELECTION CRITERIA: We planned to include randomised controlled trials comparing PEG versus NGT for adults with swallowing disturbances or dysphagia and indications for nutritional support, with any underlying diseases. The primary outcome was intervention failures (feeding interruption, blocking or leakage of the tube, no adherence to treatment).
DATA COLLECTION AND ANALYSIS: Review authors performed selection, data extraction and evaluation of methodological quality of studies. For dichotomous and continuous variables, we used risk ratio (RR) and mean difference (MD), respectively with the random-effects statistical model and 95% confidence interval (CI). We assumed statistical heterogeneity when I(2) > 50%.
MAIN RESULTS: We included nine randomised controlled studies. Intervention failure occurred in 19/156 patients in the PEG group and 63/158 patients in the NGT group (RR 0.24 (95%CI 0.08 to 0.76, P = 0.01)) in favour of PEG. There was no statistically significant difference between comparison groups in complications (RR 1.00, 95%CI 0.91 to 1.11, P = 0.93).
AUTHORS’ CONCLUSIONS: PEG was associated to a lower probability of intervention failure, suggesting the endoscopic procedure is more effective and safe as compared to NGT. There is no significant difference of mortality rates between comparison groups, and pneumonia irrespective of underlying disease (medical diagnosis). Future studies should include previously planned and executed follow-up periods, the gastrostomy technique, and the experience of the professionals to allow more detailed subgroup analysis.
source: cochrane library
ARBs plus ACE Inhibitors, Used in Combination, Seem to Heighten Cancer Risk
Researchers, investigating the reported association between antihypertensive drugs and cancer, examined data from 70 randomized trials encompassing over 300,000 participants with a mean follow-up of 3.5 years. Their analysis found no added risk for cancer from ARBs, beta-blockers, ACE inhibitors, calcium-channel blockers, or diuretics, when compared with placebo. However, the combination of ACE inhibitors and ARBs posed a 14% relative risk increase.
Commentators say the finding of no increased risk with most antihypertensives is “hardly surprising,” given the short follow-up period. They also point out that the ACE inhibitor/ARB combination is often used in patients with severe heart failure, who have lower life expectancies.
Treatment of Intermediate/Advanced Hepatocellular Carcinoma in the Clinic: How Can Outcomes Be Improved?
Hepatocellular carcinoma (HCC) is a complex condition associated with a poor prognosis. Treatment outcomes are affected by multiple variables, including liver function, performance status of the patient, and tumor stage, making a multidisciplinary approach to treatment essential for optimal patient management. Only 
30% of patients are eligible for curative therapies (surgery or ablation); palliative treatments include transcatheter arterial chemoembolization (TACE) and sorafenib. Treatment choice is guided by staging systems and treatment guidelines, although numerous systems exist and treatment guidelines vary by region. The current standard of care for patients unsuitable for potentially curative therapy is locoregional therapy with TACE. This treatment is associated with survival benefits, but there is no consensus regarding the optimum treatment/retreatment strategy. For patients with more advanced disease or who have failed locoregional therapy, sorafenib is the standard of care. Sorafenib is a targeted agent with proven survival benefits as monotherapy in these patients, and ongoing studies will clarify its role in combination with other agents and in patients with impaired liver function. Although other novel agents and therapeutic approaches are emerging, such as radioembolization and various targeted agents, further suitably designed randomized clinical trials (RCTs) comparing these agents with the standard of care are needed. In addition to RCTs, the collection of real-life data will also be important to allow physicians to make fully informed treatment decisions. The Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study is a global, noninterventional study of patients with unresectable HCC receiving sorafenib. The aim of that study is to compile a large robust database to evaluate local, regional, and global factors influencing the management of patients with HCC. It is hoped that findings from the GIDEON study along with phase III RCT data will lead to better outcomes for patients with intermediate–advanced HCC
source: the oncolologist
PPIs in First Trimester Not Associated with Birth Defects
Proton-pump inhibitors taken by expectant mothers during the first trimester are not associated with major birth defects in the offspring, according to a New England Journal of Medicine study.
Researchers used Danish registries to identify roughly 5000 women who filled prescriptions for PPIs in the 4 weeks before conception through the first trimester of pregnancy. Omeprazole was the most commonly prescribed PPI.
PPI exposure during the first trimester was not associated with increased risk for major birth defects, compared with no exposure. However, PPI use in the 4 weeks before conception was associated with higher risk for major birth defects (adjusted odds ratio, 1.39). The authors and an editorialist say unmeasured confounding likely explains the latter result.
Given that the pre-conception risk was lowest with omeprazole, the editorialist suggests it may be “the PPI of choice” for women of childbearing potential.
source: NEJM
Daily Dialysis
The frequency of dialysis was established at three times a week in 1965,1 and this frequency has been used in most centers around the world. Soon after the establishment of this dialysis schedule, an analogue simulation concluded that daily (also known as quotidian) short dialysis sessions would be more effective than thrice-weekly longer dialysis sessions in lowering the average concentration of various markers, such as urea, which rapidly equilibrate among body-fluid compartments.2 With thrice-weekly hemodialysis, the relatively long interval between dialysis sessions results in a “peak-and-valley” effect characterized by fluctuations in the levels of toxins and body-fluid volume, affecting the ability of patients to tolerate dialysis sessions.3 Shorter but more frequent dialysis sessions appeared to be a potential solution to this problem.
Early research (from March 1969 through May 1973) on frequent hemodialysis in patients with end-stage renal disease, in which the before-and-after methods of study were used, showed that more frequent dialysis improved clinical and laboratory variables.4 The results were sufficiently impressive that it was predicted that daily dialysis would soon be the standard of care.4,5 The number of patients undergoing dialysis daily has since increased, but not at the predicted pace.
One reason for a slow pace may be the cost of daily dialysis. A request for an increase in reimbursement from Medicare by proponents of daily dialysis led to a National Institutes of Health Task Force on Daily Dialysis, in April 2001 (Order #342, Conference ID 108).6 That body reached a consensus that observational studies provided insufficient evidence to change the standard of care and that a randomized, controlled trial was indicated. The practitioners involved in delivering daily dialysis were already convinced of its substantial clinical advantage. In contrast, others still thought that a randomized, controlled trial would be required to prove the superiority of one method over another.
In this issue of the Journal, Chertow et al. report the results of a randomized trial that compared outcomes with different frequencies of dialysis.7 The investigators anticipated challenges in enrollment. Such difficulty in patient recruitment is not uncommon when randomized, controlled trials compare different treatment methods. Chertow et al. enrolled 378 patients and randomly assigned 245; it is unclear how many potential candidates were screened and how many declined to undergo randomization. Whether any patients undergoing peritoneal dialysis were approached is not stated. The patients in the study were in better health than are those in the general U.S. population who are undergoing hemodialysis, as shown by the fact that the rate of death in the control (thrice-weekly) group at 1 year was only 7.5%, whereas the rate of death in the wider U.S. population undergoing hemodialysis is more than 18.5%.
In this randomized, controlled trial, a similar technique was used for dialysis six times per week and for thrice-weekly dialysis, although many would argue that both the required dialysis machines and vascular-access techniques should be different. For patients undergoing daily dialysis, it is particularly important to use the buttonhole method of needle insertion into the fistula with a single puncture, since there are fewer complications with this method, despite more frequent cannulations.8 (When this method is used, with repeated cannulation into the exact same puncture site, a scar-tissue tunnel tract develops that allows the needle to follow the same path to the blood vessel on each cannulation.) The authors did not provide information about whether this technique was used in one or both groups; if this method of fistula puncture was not used, that fact could explain the adverse results regarding vascular access in frequent-dialysis group.
This randomized, controlled trial, which took a decade to complete, did show that frequent dialysis was better with respect to control of hypertension and control of hyperphosphatemia. Furthermore, it was associated with favorable changes in the coprimary composite outcomes of death or change (from baseline to 12 months) in left ventricular mass, as assessed by cardiac magnetic resonance imaging, and death or change in the physical-health composite score of the RAND 36-item health survey. Whether more frequent dialysis will become the standard of care is not yet evident. However, despite issues with suboptimal reimbursement, the number of patients undergoing daily hemodialysis has been slowly increasing.
This study confirms that more frequent hemodialysis confers certain advantages. Whether the more frequent vascular-access and clotting issues would be increasingly problematic over time is not known. Whether patients would do even better at home is also unclear.
source: NEJM
lantus insulin and malignancy
Several articles published online in Diabetologia by the European Association for the Study of Diabetes investigated the possible relationship between use of insulin glargine (Lantus, sanofi-aventis) and the development of certain malignancies. The authors themselves, and the accompanying editorial, cautioned against over-interpretation of their limited data and analyses, which precluded them from drawing any firm conclusions. For example, there were contradictory findings among the studies, patient populations were not always comparable, and the duration of observation was short. Nonetheless, since the relationship of type 2 diabetes to cancer is of critical importance, further study is warranted.
The American Association of Clinical Endocrinologists (AACE) does not recommend that the use of any insulin be changed. AACE supports further research into the effectiveness and safety of all diabetes therapies and will continue to update recommendations as further data becomes available. Individual patient concerns should be discussed with their physicians.
On June 26, 2009 several articles published online in Diabetologia by the European Association for the Study of Diabetes investigated the possible relationship between use of insulin glargine (Lantus, sanofi-aventis) and the development of certain malignancies. The authors themselves, and the accompanying editorial, cautioned against over-interpretation of their limited data and analyses, which precluded them from drawing any firm conclusions. For example, there were contradictory findings among the studies, patient populations were not always comparable, and the duration of observation was short. Nonetheless, since the relationship of type 2 diabetes to cancer is of critical importance, further study is warranted.
The American Association of Clinical Endocrinologists (AACE) does not recommend that the use of any insulin be changed. AACE supports further research into the effectiveness and safety of all diabetes therapies and will continue to update recommendations as further data becomes available. Individual patient concerns should be discussed with their physicians.
Surgical Management of Brain Metastases
In the past 20 years, surgical resection has found an established role in the management of metastatic brain tumors. Several factors, however, make strong evidence-based medicine impossible to provide for all possible patient presentations. These important factors, such as patient variables (eg, age, medical comorbidities, preoperative performance), tumor variables (eg, number, size, location, histology), and primary disease status must be taken into account on a case-by-case basis to guide patient selection and treatment strategy. Although progress has been made to answer some of the major questions in the management of metastatic brain tumors, several important questions remain. Future studies comparing surgery with stereotactic radiosurgery, for example, are needed to delineate patient selection, complications, and outcome for both of these important modalities.
ARYAN'S BLOG 