AVAiL shows longer survival on Avastin for NSCLC patients


The final analysis of the Avastin in lung study (AVAiL) in patients with advanced lung cancer has shown that not only did the drug significantly slow down the disease progression, it also enabled some patients to survive for over 1 year, the longest survival ever reported in patients with this advanced disease. The results were presented 15 September 2008 at the 33rd Congress of the European Society for Medical Oncology (ESMO) in Stockholm.

The phase III Roche-sponsored AVAiL study in patients with previously untreated, advanced non-small cell lung cancer (NSCLC), has confirmed that Avastin (bevacizumab) combined with gemcitabine-cisplatin chemotherapy offers a significant improvement in the time that patients live without their disease progressing (progression- free survival; PFS).

Furthermore, although the study was not designed to demonstrate an overall survival (OS) benefit, it was analysed as a secondary endpoint. The analysis showed that while the increase in overall survival was not statistically significant, the median overall survival for patients in all arms of the study exceeded 13 months – the longest survival reported in a study of patients with advanced NSCLC.

AVAiL is the second phase III trial to demonstrate the significant clinical benefits of Avastin in NSCLC. Previously, the E4599 study, conducted in the US, showed that adding Avastin to a different platinum based chemotherapy (carboplatinpaclitaxel) resulted in a significant improvement in overall survival (its primary endpoint) compared to chemotherapy alone.



Results published for ivabradine BEAUTIFUL trial

The results of the much awaited BEAUTIFUL (mor- Bidity-mortality EvAlUaTion of the IF inhibitor ivabradine in patients with CAD and left ventricular dysfunction) trial have shown that coronary artery disease (CAD) patients with left ventricular dysfunction (LVD) and a heart rate more than 70 bpm have a significantly higher risk of cardiovascular death and other cardiovascular events and in these patients (heart rate above 70 bpm) treatment with ivabradine further reduces the risk of the most important coronary events such as fatal and non-fatal myocardial infarction and coronary revascularisation by one third, even when these patients are already receiving optimal therapy.

Commenting after the results presentation, the Chairman of the BEAUTIFUL Executive Committee, Prof Kim Fox said, “Ivabradine was always known to relieve ischemia. With the BEAUTIFUL results, ivabradine is the first antianginal treatment shown to reduce myocardial infarction and revascularisation and to have a good tolerability profile even when used with other drugs. This is the gold standard for any antianginal, anti-ischemic drug.”

The BEAUTIFUL trial was initiated in December 2004, under the guidance of an independent Executive Committee with the first patient being enrolled in early 2005. For the study 10,917 CAD patients with LVD wer recruited in 781 centres in 33 countries across 4 continents. The mean heart rate in these patients was 71 bpm and half of the patients had a heart rate more than 70 bpm. The results of the BEAUTIFUL study have shown that these patients with heart rate greater than or equal to 70 bpm are more likely to die or suffer from another cardiovascular event. The increase in risk is 34% for cardiovascular death, 46% for myocardial infarction, 56% for heart failure and 38% for coronary revascularisation.

In the overall study population, treatment with ivabradine did not result in a significant reduction of the primary composite end point (Cardiovascular death, admission to hospital for acute MI and admission to hospital for heart failure). However in patients with baseline heart rate more than 70 bpm, ivabradine significantly reduced the risk of hospitalisation for fatal and non-fatal myocardial infarction by 36% (p=0.001) and the risk of coronary revascularisation by 30% (p=0.016). What is important to note is that most of these patients were already receiving the guidelines-recommended cardiovascular therapy: antiplatelet agents (94%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (91%), betablockers (87%), as well as lipid-lowering agents (76%).

Hence the results of BEAUTIFUL constitute a step further in the management of these coronary patients with heart rate above 70 bpm because, for the first time it has been shown that pure heart rate reduction with ivabradine further reduces coronary events even in patients receiving the current optimal cardiovascular therapy. This study also confirms that ivabradine is safe and well tolerated and can be used with all routinely prescribed cardiovascular drugs.



Robot’s biological brain helps study of memory

A multidisciplinary team at the University of Reading in the UK has developed a robot which is controlled by a biological brain formed from cultured neurons. This cutting edge research is the first step to examine how memories manifest themselves in the brain, and how a brain stores specific pieces of data. The key aim is that eventually this will lead to a better understanding of development and of diseases and disorders which affect the brain such as Alzheimer's disease, Parkinson’s disease, stroke and brain injury.

The robot’s biological brain is made up of cultured neurons which are placed onto a multi electrode array (MEA). The MEA is a dish with approximately 60 electrodes which pick up the electrical signals generated by the cells. This is then used to drive the movement of the robot. Every time the robot nears an object, signals are directed to stimulate the brain by means of the electrodes. In response, the brain's output is used to drive the wheels of the robot, left and right, so that it moves around in an attempt to avoid hitting objects. The robot has no additional control from a human or a computer, its sole means of control is from its own brain.

Dr Ben Whalley, from the School of Pharmacy, said: “One of the fundamental questions that scientists are facing today is how we link the activity of individual neurons with the complex behaviours that we see in whole organisms. This project gives us a really unique opportunity to look at something which may exhibit complex behaviours, but still remain closely tied to the activity of individual neurons. Hopefully we can use that to go some of the way to answer some of these very fundamental questions.”

The researchers are now working towards getting the robot to learn by applying different signals as it moves into predefined positions. It is hoped that as the learning progresses, it will be possible to witness how memories manifest themselves in the brain when the robot revisits familiar territory.

Professor Kevin Warwick, from the School of Systems Engineering, said: “This new research is tremendously exciting as firstly the biological brain controls its own moving robot body, and secondly it will enable us to investigate how the brain learns and memorises its experiences. This research will move our understanding forward of how brains work, and could have a profound effect on many areas of science and medicine.”



Stopping smoking reduces postoperative complications

Patients who stop smoking four weeks before an operation reduce the risk of complications, according to a doctoral thesis from the Swedish medical university Karolinska Institutet. Moreover, many of those who receive help with this ahead of operations remain non-smokers for a long time afterwards.

Smokers who undergo surgery suffer complications, such as wound infections and poorly healing wounds, more often than non-smokers. Research has shown that the risk of complications is reduced if the patient stops smoking ahead of the operation, but it is unclear how long beforehand it has to happen.

Dr David Lindström works as a surgeon at the Stockholm South General Hospital (Södersjukhuset). He shows in his doctoral thesis that quitting tobacco use as late as four weeks prior to an operation is effective. His study involved 117 patients, half of whom were offered a chance to take part in a stop smoking programme four weeks before surgery. The patients in the control group went on to have roughly twice the number of complications as the programme patients.

“The complications are unpleasant for the patients and expensive for the health services,” says Dr Lindström. “Since help with quitting tobacco use is both effective and cheap compared with other preventative measures, it should always be offered as an option before an operation.”

Dr Lindström’s thesis shows that relatively many of the patients who took part in the stop smoking programme managed to quit their habit, both in the short and long terms. Approximately 58% of the patients who received help stopped smoking before their operations, and 33% were still non-smokers one year later.

“This is a very good result when you compare with other quit smoking programmes,” says Dr Lindström. “It seems as if surgery is a motivation-boosting factor for people who are already trying to kick the habit.”

Thesis: The impact of tobacco use on postoperative complications, David Lindström, Karolinska Institutet, Department of Clinical Research and Education at Södersjukhuset (KI SÖS).

Read the thesis online; http://diss.kib.ki.se/2008/978-91-7409-071-0/



Dronedarone good for patients with permanent AF

The ERATO study published 1 September 2008 in the American Heart Journal demonstrated, for the first time in patients with permanent atrial fibrillation, that dronedarone (Multaq(R)) significantly reduces mean 24 hour ventricular rate, on top of other rate control agents. The mean heart rate reduction was 11.7 beats per minute (p< 0, 0001) with dronedarone compared to placebo, which is clinically relevant and highly statistically significant.

ERATO (The Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation), a randomised, double blind, placebo-controlled, parallel group study, was conducted in 174 adult patients with symptomatic, permanent AF of at least six months’ duration, recruited from 38 centres in nine European countries.

This rate-controlling effect of dronedarone was sustained throughout the six-month trial and was additive to the effect of other rate control therapies. Dronedarone also significantly reduced maximal exercise heart rate by 24.5 beats per minute (p<0,0001) without impairing exercise capacity.

Dronedarone was well tolerated with no evidence of organ toxicity or proarrhythmia over six months.

“Effective control of ventricular rate in patients with permanent AF is associated with significant improvements in both symptom control and clinical outcomes,” explained principal investigator Jean-Marc Davy of Departement de Cardiologie, CHU Montpellier, France.

AF is the most frequent cardiac rhythm disorder and can be classified into three types: paroxysmal (selflimiting), persistent (responsive to cardioversion) or permanent (continuous atrial fibrillation with cardioversion proven or deemed ineffective). In patients with permanent AF (a substantial subset of the AF population), the only available therapeutic option is to control the ventricular response rate to prevent deterioration of the ventricular function and to minimise the symptoms (rate control strategy). Existing rate control agents (beta blockers, calcium channel blockers and cardiac glycosides) do not always achieve targeted heart rate, mainly due to the poor tolerability of high doses. In that regard, adequate rate control was only achieved in 64% of patients in the AFFIRM trial. Therefore additional therapeutic options to achieve appropriate ventricular rate are needed.

“ERATO demonstrates that dronedarone is well tolerated and demonstrates sustained ratecontrol efficacy in addition to standard agents, in patients who are only eligible for this therapeutic strategy” said Professor Davy. “In the landmark ATHENA trial, dronedarone has significantly reduced CV hospitalisation and death and has been proven to be effective and safe in paroxysmal and persistent AF patients.

ERATO provides the additive piece to complement earlier dronedarone clinical trial result findings and now confirms its efficacy and safety across the entire spectrum of AF patients,” he added.

In ERATO, the incidence of adverse events in the dronedarone arm was not statistically different although marginally higher compared to the placebo group. Gastrointestinal disturbances and mild increases in mean serum creatinine levels were observed more frequently in the dronedarone group, in accordance with previous studies. Creatinine increase occurred early after treatment initiation and reached a plateau after seven days. Values returned to baseline within one week after treatment discontinuation with no impact on renal function. No evidence of thyroid or pulmonary fibrosis was observed with dronedarone and no Torsade de Pointes was reported during the six-month follow-up.



Gene causes resistance to anti-cancer drug cisplatin

Researchers have shown that increased expression of a gene called SIRT1 in cancer cells plays a significant role in the development of resistance to the chemotherapy drug cisplatin. The SIRT1 gene, which regulates several important cellular processes including nutrient use and metabolism, appears to contribute to the development of cisplatin resistance by reducing the uptake and use of glucose by cells and by altering the function of their mitochondria.

These findings were published in the 15 September 2008 issue of Molecular Cancer Research.

Cisplatin, a chemotherapy drug that contains the metallic element platinum, is widely used in the treatment of many types of cancer, including bladder, lung, ovarian, and testicular cancer. It slows or stops the growth of cancer cells by binding to DNA. Tumors that recur after an initially positive response to treatment with cisplatin are frequently resistant to it. Knowing more about how cells become resistant to cisplatin will enable researchers to devise strategies to circumvent resistance and increase the effectiveness of this important anticancer drug.



Natural childbirth helps mothers recognise baby-cry

A new study has found that mothers who delivered vaginally compared to caesarean section delivery (CSD) were significantly more responsive to the cry of their own baby, identified through MRI brain scans two to four weeks after delivery. The results of the study, to be published today in The Journal of Child Psychology and Psychiatry, suggest that vaginal delivery (VD) mothers are more sensitive to own baby-cry in the regions of the brain that are believed to regulate emotions, motivation and habitual behaviours.

In the US the occurrence of CSD has increased steeply from 4.5% of all deliveries in 1965 to a recent high in 2006 of 29.1%. The critical capacity of adults to develop the thoughts and behaviours needed for parents to care successfully for their newborn infants is supported by specific brain circuits and a range of hormones. The experience of childbirth by VD compared with CSD uniquely involves the pulsatile release of oxytocin from the posterior pituitary, uterine contractions and vagino-cervical stimulation. Oxytocin is a key mediator of maternal behaviour in animals.

“We wondered which brain areas would be less active in parents who delivered by caesarean section, given that this mode of delivery has been associated with decreased maternal behaviours in animal models, and a trend for increased postpartum depression in humans,” said lead author Dr James Swain, Child Study Centre, Yale University. “Our results support the theory that variations in delivery conditions such as with caesarean section, which alters the neurohormonal experiences of childbirth, might decrease the responsiveness of the human maternal brain in the early postpartum.”

The researchers also looked into the brain areas affected by delivery conditions and found relationships between brain activity and measures of mood suggesting that some of the same brain regions may help regulate postpartum mood.

‘Maternal Brain Response to Own Baby Cry is Affected by Cesarean Section Delivery’; Swain JE, Tasgin E, Mayes LC, Feldman R, Constable RT, Leckman JF; The Journal of Child Psychology and Psychiatry; 49(10); DOI:10.1111/j.1469-7610.2008.01963.x



New light-sensitive pathway in the eye discovered

A set of nerve cells in the eye control our levels of sleepiness according to the brightness of our surroundings, Oxford University researchers have discovered. The cells directly regulate the activity of sleep centres in the brain, providing a new target for the development of drugs to control sleep and alertness.

Immune systems, cognitive performance, and mental health are all affected by the body’s sleep-wake cycle. Sleep disruption is known to be associated with a range of problems, including depression, immune impairment and a greater risk of cancer. Many drugs have been developed to modify sleep-wake cycles but these are crude, affecting many chemical pathways and different parts of the brain at the same time, and have side-effects.

“Sleep and the disruption of sleep patterns is a huge problem in the 21st century,” says Professor Russell G. Foster of Oxford’s Nuffield Laboratory of Ophthalmology, who led the work. “Our working culture of long hours and shift work, with the 24/7 availability of almost everything, have conspired to demote sleep in our priorities.”

The presence and absence of light can affect levels of sleepiness and alertness. It’s why dimly lit rooms lead us to feel drowsy, while bright lights stimulate wakefulness.

“We have discovered a new pathway that modulates sleep and arousal,” Prof Foster explains. “If we can mimic the effect of light pharmacologically, we could turn sleep on and off.”

Prof Foster and colleagues have previously shown that the eye contains a subset of retinal nerve cells that are sensitive to light. Working on mouse models in which these retinal ganglion cells have been turned off genetically, the research team found that the effects of light on sleep and alertness were completely abolished. The work was supported by the Wellcome Trust and a European Commission grant.

Mice are nocturnal animals, so show the opposite light response to humans. They are alert and active in the dark, but go to sleep in the light. The Oxford team videoed mice and monitored their muscle and brain activity for four hours in the dark. The lights were then switched on for an hour and after 15–20 minutes the mice went to sleep. Turning off the light-sensitive retinal ganglion cells abolished this behaviour. The mice stayed awake when the lights were on.

“There was absolutely no effect on the mice. This was a very clear and very surprising result,” comments Prof Foster. The researchers were able to track this sleep pathway to the brain. They showed that two sleep-inducing centres in the brain are directly activated by the cells, turning on or turning off sleep. By defining the whole light-responsive system that regulates sleep and alertness, the researchers have found a new pathway that could provide a new therapeutic target for manipulation of sleep and arousal in humans.

‘The acute light-induction of sleep is mediated by OPN4-based photoreception’ by Daniela Lupi, Henrik Oster, Stewart Thompson and Russell G. Foster, is published online 17 August 2008 in Nature Neuroscience.



Olive leaf extract shown to reduce hypertension

Taking 1000mg of a specific olive leaf extract (EFLA 943) can lower cholesterol and lower blood pressure in patients with mild hypertension (high blood pressure), according to findings from a ‘Twins’ trial, in which different treatments were given to identical twins. A twins trial helps researchers avoid the possibility of genetic variation interfering with the results.

The research is published in the August issue of Phytotherapy Research. Experiments in rats had previously indicated that olive leaf extract could be one way of reducing blood pressure.

To test this in humans, researchers from Switzerland and Germany conducted a pilot trial with 20 identical (monozygotic) twin pairs who had an increased blood pressure. Individuals were either given placebo capsules or capsules containing doses of 500mg or 1000mg of olive leaf extract EFLA 943. Pairs of twins were assigned to different treatments. After the subjects had taken the extract for eight weeks researchers measured blood pressures as well as collecting data about aspects of life-style.

The study confirmed that olive leaf extract EFLA 943 has antihypertensive properties in humans. EFLA is a registered product of Swiss company Frutarom.



Adipose stem cells good for cardiac regeneration

Amman-based medical research centre, Bioheart, has shown that human Adipose-Derived Stem Cells (hADSC) can be used in the regeneration of cardiac tissue following myocardial infarction.

The pre-clinical trial, spearheaded by Bioheart, was completed at the Philadelphia Biological and Medical Technology Product Development Centre in Amman, Jordan, in September this year.

The study was led by Dr Mahmoud Abu-Abeeleh, Assistant Professor of Cardiac Surgery at the University of Jordan, School of Medicine. He explained that the study data suggest that hADSCs contribute to the improvement in cardiac histological appearance after a heart attack by having cells within the infarction areas expressing structures of functional (myocardial) cells.

“This study reveals significant results which add to the growing body of investigational evidence supporting the use of hADSCs for the treatment of heart failure,” he said.

Howard J. Leonhardt, Bioheart CEO and Chief Technology Officer, said that these “preclinical studies should allow us to obtain an IND approval for the start of a human clinical trial whereby these cells are put to use in patients soon after they have a heart attack”.

 


C-section babies have 20% higher risk of diabetes

Babies delivered by Caesarean section have a 20% higher risk than normal deliveries of developing the most common type of diabetes in childhood, according to a study led by Queen’s University Belfast, Ireland.

The team, led by Dr Chris Cardwell and Dr Chris Patterson, examined 20 published studies from 16 countries including around 10,000 children with type 1 diabetes and more than a million control children.

They found a 20% increase in the risk of children born by Caesarean section developing the disease. The increase could not be explained by factors such as birth weight, the age of the mother, order of birth, gestational diabetes and whether the baby was breastfed or not, all factors associated with childhood diabetes in previous studies.

Dr Cardwell, from the School of Medicine, Dentistry and Biomedical Sciences, said: “This study revealed a consistent 20% increase in the risk of type 1 diabetes. It is important to stress that the reason for this is still not understood. It is possible that children born by Caesarean section differ from other children with respect to some unknown characteristic which consequently increases their risk of diabetes, but it is also possible that Caesarean section itself is responsible.

“Type 1 diabetes occurs when the immune system destroys the insulin producing cells in the pancreas, and one theory suggests that being born by Caesarean section may affect the development of the immune system because babies are first exposed to bacteria originating from the hospital environment rather than to maternal bacteria.”

Dr Chris Patterson said: “The study findings are interesting, but unless a biological mechanism is established it would be unwise to read too much into this association between Caesarean section delivery and diabetes.”

Fat in obese patients is “sick” compared to fat in lean patients

A study published in the September 2008 issue of Diabetes finds that the same could be said for fat tissue found in obese patients can be classified “sick”. The cells in their fat tissue don’t work properly and as a result, are sicker than cells found in lean patients’ fat tissue.

Lead author Guenther Boden, MD theorises that “sick fat” could more fully explain the link between obesity and higher risk of diabetes, heart disease and stroke.

Researchers from the departments of endocrinology, biochemistry and surgery at the Temple University School of Medicine, Philadelphia, US, took fat biopsies from the upper thighs of six lean and six obese patients and found significant differences at the cellular level.

“The fat cells we found in our obese patients were deficient in several areas,” said Dr Boden, Laura H. Carnell Professor of Medicine and chief of endocrinology. “They showed significant stress on the endoplasmic reticulum and the tissue itself was more inflamed than in our lean patients.”

The endoplasmic reticulum (ER) helps synthesize proteins and monitor how they’re folded. The stress that Dr Boden describes causes the ER in fat cells to produce several proteins that ultimately lead to insulin resistance, which has been found to play a major role in the development and progression of obesity-related conditions.

The US National Institutes of Health recently reported that each time a body mass index (BMI) over 25 is raised by one point, the risk for diabetes increases 25% and the risk for heart disease increases 10%. Currently Dr Boden and his team are looking at whether free fatty acids are a potential cause for this ER stress.

Food diary doubles weight loss

A study from Kaiser Permanente’s Center for Health Research found that keeping a food diary can double a person’s weight loss. The findings, from one of the largest and longest running weight loss maintenance trials ever conducted, were published in the August 2008 issue of the American Journal of Preventive Medicine.

“The more food records people kept, the more weight they lost,” said lead author Jack Hollis PhD, a researcher at Kaiser Permanente’s Center for Health Research. “Those who kept daily food records lost twice as much weight as those who kept no records. It seems that the simple act of writing down what you eat encourages people to consume fewer calories.”

“Keeping a food diary doesn’t have to be a formal thing. Just the act of scribbling down what you eat on a Post-It note, sending yourself e-mails tallying each meal, or sending yourself a text message will suffice. It’s the process of reflecting on what you eat that helps us become aware of our habits, and hopefully change our behaviour,” says Keith Bachman, MD, a Weight Management Initiative member. “Every day I hear patients say they can’t lose weight. This study shows that most people can lose weight if they have the right tools and support. And food journaling in conjunction with a weight management programme or class is the ideal combination of tools and support.”

Critical window of opportunity following type II diabetes diagnosis

People who lose weight soon after a diagnosis of type 2 diabetes have better control of their blood pressure and blood sugar, and are more likely to maintain that control even if they regain their weight, according to a Kaiser Permanente study – The Weight Change in Diabetes and Glycemic and Blood Pressure Control study – published online in Diabetes Care, the American Diabetes Association journal.

This is the first clinical study to show that benefits remain even if patients regain their weight. The study followed more than 2,500 adults with type 2 diabetes for four years. Those who lost weight within an average of 18 months after diagnosis were up to twice as likely to achieve their blood pressure and blood sugar targets as those who didn’t lose weight. Those benefits can prevent diabetes-related heart disease, blindness, nerve and kidney damage, and death.

“Our study shows that early weight loss can reduce the risk factors that so often lead to diabetes complications and death,” says Adrianne Feldstein, MD, MS, the study’s lead author, a practicing physician and an investigator at Kaiser Permanente’s Center for Health Research in Portland, Oregon, US. “We’ve known for a long time that weight loss is an important component in diabetes treatment and prevention. Now it appears there may be a critical window of opportunity following diagnosis in which some lasting gains can be achieved if people are willing to take immediate steps toward lifestyle changes.”

The four-year study followed 2,574 patients with type 2 diabetes between 1997 and 2002. Scientists followed the weight gain and loss patterns of these patients for three years, and then in the fourth year compared glucose control tests and blood pressure readings.

Most patients remained at about the same weight during the first three years of the study, but a small group of 314 patients lost an average of 23 pounds. This group was more likely to meet blood pressure and glucose targets during the fourth year even though, by that time, most of them had regained their weight.

“We don’t know if the initial weight loss increased the body’s sensitivity to insulin, or if the sustained lifestyle changes were the reason for the long-term health benefits,” said Gregory A. Nichols, PhD, a study coauthor at Kaiser Permanente’s Center for Health Research. “But we do know that losing weight reduces the risk factors that often lead to heart disease, blindness, nerve and kidney damage, amputations, and death in type 2 diabetes patients.”

Type-2 young diabetic men suffer low testosterone levels

Young men with type 2 diabetes have significantly low levels of testosterone, endocrinologists at the University at Buffalo, New York, have found – a condition that could have a critical effect on their quality of life and on their ability to father children.

This study follows research published earlier by these scientists reporting that one-third of middle-aged men with type 2 diabetes have low testosterone levels, requiring treatment for erectile dysfunction.

“These new findings have several clinical implications besides the impairment of sexual function in these young men,” said Paresh Dandona, PhD, UB Distinguished Professor in the Department of Medicine and senior author on both studies.

“The lack of testosterone during these critical years may lead to diminished bone mass and the lack of development or loss of skeletal muscle. In addition, these patients may gain more weight (with an average body mass index of 38 they already were obese) and become more insulin resistant.

“Also, patients with low testosterone and type 2 diabetes have been shown to have very high concentrations of C reactive protein,” he added, “which increases their risk of developing atherosclerosis and heart disease above and beyond the risk associated with diabetes.”

Results of the new study appear in the online edition of Diabetes Care.

                                  
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