Everolimus may be the new hope for resistant breast cancer

A new study led by researchers from France and presented at the 5th IMPAKT Breast Cancer Conference in Brussels, Belgium, shows that everolimus can overcome transtuzumab resistant breast cancer. The study however showed no statistically significant difference in clinical response rates in some patients with breast cancer when everolimus was added to trastuzumab. This means that the benefit of the everolimus is due to independent molecular mechanisms other than the researchers thought.

Prof Mario Campona, Principal Investigator at the Institute Cancerologie de l’Ouest in Nantes, France, said that as new targeted drugs are discovered, the challenge is to identify patients who will benefit from these individual agents. Prof Campona added that one of the aims of the study was to discover molecular biomarkers that predict whether a cancer patient will respond to combination treatment everolimus-transtuzumab compared to transtuzumab alone.

Transtuzumab, a monoclonal antibody directed against HER2/ neu receptor, is used to treat primary breast cancer, but there are ongoing studies to verify the effectiveness of this drug in the treatment of other cancers. Clinical trials conducted so far have shown that transtuzumab prolongs survival of patients with advanced breast cancer; in early stages it appears to decrease the risk of tumor recurrence after surgery. Although treatment response is good at first, many patients go on to develop resistance.

However, preclinical studies have shown that everolimus can overcome resistance to trastuzumab, which is a major benefit. Everolimus is an oral inhibitor of mTOR, that is mammalian target of rapamycin. The way everolimus overcomes resistance to transtuzumab is not yet fully understood. Prof Campona explained that resistance can occur due to molecular alterations that appear at different levels in the PI3K/Akt pathway. mTOR inhibits a major effector in this pathway, therefore it can restore sensitivity to transtuzumab. In preclinical trials it was demonstrated that everolimus  can overcome resistance to transtuzumab caused by upregulation of IGF-1R expression, an alternative pathway that leads to tumor growth and proliferation. The clinical response rate was 35% in patients who received only transtuzumab and 45% in patients who received transtuzumab and everolimus.

Researchers also wanted to find biomarkers that predict which patients respond to combined treatment transtuzumab-everolimus. But of the 7 biomarkers identified, none was able to predict which patients will benefit from the combination of the two drugs. “It appears the combination of everolimus and trastuzumab is effective independently of the activation of the PI3K/AKT/mTOR pathway and without any anti-proliferative and pro-apoptotic effect”, Porf Campona explained.

Risk of autism linked with birth weight

A study led by researchers from the University of Manchester, reveals new findings on autism. There seems to be a connection between autism and baby’s weight, in other words babies who grow above average in the womb or babies with poor fetal growth have a higher risk of developing this condition. This is the first large study conducted on 40,000 child health records showing that there is a clear connection between the risk of Autism Spectrum Disorder and baby weight. The study also comes to confirm the results of other research that has shown that premature babies and those with low birth weight are more likely to develop autism.

Autism is disease that affects behavior and interactions with others. Statistics show that in the UK 1 in 100 children has autism. Although there is no cure for autism, there are therapies that improve the manifestations of this disorder. Nobody knows exactly what causes autism, but it is believed that both genetic factors and environmental factors contribute to autism onset.

Professor Kathryn Abel, from the University’s Centre for Women’s Mental Health and Institute of Brain, Behaviour and Mental Health, said that the processes that cause ASD probably start during fetal life and that the signs announcing this disease occur in the first 3 years of life. She explained that fetal growth is influenced by both genetic and non-genetic factors. She added that it is important to understand in detail the factors that modulate fetal growth in order to find the cure for ASD.

babies

The data necessary for the study were taken from the Youth Cohort Stockholm in Sweden (repeated measurements of weight baby during pregnancy). Birth, motor, social, cognitive and language skills of the children were clinically evaluated. Of the cohort which contained records of 589,114 children aged 0-17 in Sweden (between 2001 and 2007), it was found that 4,283 young people had autism.

Researchers have found that children who had more than 4.5 kg at birth had a higher risk of developing autism, as well as those with low birth weight (less than 2.5 kg). It seems that, compared with babies normally grown babies, babies with poor fetal growth have a  63% higher risk of developing autism. Also, babies who grow above average  have a 60% risk of developing autism compared to those with normal weight at birth. “We now need more research into fetal growth, how it is controlled by the placenta and how this affects how the brain develops. One of the key areas to research is maternal condition and healthy growth,” said Professor Abel.

Flexible endoscopy for Zenker’s diverticulum is safe

According to researchers, flexible endoscopic treatment of Zencker’s diverticulum is effective and safe in the long-term. Zencker’s diverticulum is a disorder that occurs mostly in older patients and is manifested by difficulty in swallowing. The results of the study conducted by researchers from Belgium are published in Gastrointestinal Endoscopy journal (of the American Society for Gastrointestinal Endoscopy). Zencker’s diverticulum is an abnormal mucosal pouch located on the posterior wall of the pharyngo-esophageal junction. It is believed that what causes esophageal diverticula are related to esophageal motility, such as incomplete muscle relaxation or increased pressure inside the esophagus. This condition can be asymptomatic or can cause symptoms like regurgitation, difficulty in swallowing or chronic coughing. It is often accompanied by gastroesophageal reflux disease. Untreated, Zencker’s diverticulum can cause a number of complications such as bleeding, ulceration, diverticular perforation, infection, aspiration, pneumonia, and others.

Zenker’s diverticulum

Treatment of  Zencker’s  diverticulum consists of myotomy, that is muscle incision to release the constriction, which can be performed either by open surgery or by endoscopic approach. Obviously endoscopic treatment is preferably to open surgery due to a lower risk of complications and because of a shorter hospitalization stay. It must be mentioned that endoscopic therapy has evolved greatly in the last 20 years, and that there have been many studies showing the benefits of using flexible compared to the rigid endoscope.

A previous study showed that diverticulotomy with flexible endoscope and soft diverticuloscope is a safe and effective treatment for treating Zencker’s diverticulum. Lead author Jacques Devi, MD, PhD, Hôpital Erasme, Brussels, Belgium, said that this first study led them to improve the technique and add endoclips in order to reduce the risk of perforation and bleeding.

Researchers performed a retrospective study that included 150 patients who were treated between 2002 and 2011 in the Hôpital Erasme, Brussels, Belgium. Patients with Zencker’s diverticulum were treated by endoscopic approach and after the treatment, patients were re-evaluated at one month and at the end of follow-up. Study results showed that all patients had successful endoscopic treatment and a median hospital stay of one day. There were only 4 cases of adverse reactions and all these were treated conservatively.

Dysphagia score decreased from 1.88 to 0.29 and 0.34 at the end of follow-up (0 means no dysphagia and 4 means complete dysphagia). Chronic cough and regurgitation decreased significantly from 73% and 27% to 11% and 2% at the end of follow-up, respectively. The conclusion of the investigators was that flexible endoscopy has become the new standard for the treatment Zencker’s diverticulum.

Dopamine regulates our motivation to act

Latest studies conducted by researchers in Spain show that dopamine may be involved in the regulation of motivation, which means that previous beliefs according to which this neurotransmitter is involved in the generation of pleasure can be of the past. Now researchers have shown that dopamine underlies motivation and cause individuals to act or to persevere to get what they want. Discoveries made by researchers at the Universitat Jaume I of Castellón, have implications in many neurological diseases such as Parkinson’s, multiple sclerosis, fibromyalgia, and in addiction.

Mercè Correa explained that a long time it was thought that dopamine is associated with pleasure because it is released when we get something we want. In fact, recent studies show that dopamine acts before, in other words make us act. He added that dopamine is released to get something good or to avoid something bad. Studies so far have shown that dopamine is released not only in terms of pleasure but also under stress, pain or loss. However, according to Correa, this research has been done to highlight only the positive influence of dopamine. The new article is actually a review of several investigations on the role of dopamine in motivated behavior in animals.

Depression

Dopamine level is different for each man separately, some are more motivated to take action to achieve their purpose while others are more lax. Correa explained that dopamine is involved in maintaining the level of activity required to achieve a goal. He added that although it is generally positive, it largely depends on the stimuli. Increased levels of dopamine could explain the behavior of some individuals with various addictions. Understanding the biological parameters underlying human motivation has applications not only in medicine but also in other areas such as education or work.

Because of this these latest findings, dopamine is now seen as a neurotransmitter that can compensate for the lack of energy and motivation that occur in certain diseases such as depression. Correa explained that depressed people are not motivated to act and this is due to low levels of dopamine. Lack of energy and motivation are also found in other diseases such as multiple sclerosis, fibromyalgia, Parkinson’s and others.

On the other hand, dopamine is involved in addictive behavior because high levels can cause a compulsive attitude. Correa suggests that dopamine antagonist therapy that have been applied so far had no effect perhaps because of inadequate treatment which was based on a misunderstanding of the mechanism by which dopamine function.

GLUT inhibitors

Researchers at Karolinska Institutet in Sweden have made further progress in the fight against cancer. The study conducted by them was published in the scientific magazine Nature Structural & Molecular Biology and reveals interesting findings about new ways to fight cancer. The study is based on the mechanism by which glucose enters the cell. It is known that glucose, the main energy source for cells, enters the cells with a protein named GLUT. Now researchers from Karolinska Institutet have managed to get more information about how GLUT protein transports glucose into cells.

Because tumors are fast growing, they need the proteins that carry nutrients into the cells to function at full capacity. Therefore, researchers have thought that an important strategy for cancer treatment would be to block these proteins. In this way would be blocked all cell metabolism (which means that cells would starve). GLUT family is one of the major group of membrane transport proteins that transport glucose and other substances into cells. Because glucose is one of the most important nutrients of cell, GLUT transporters play an essential role in cancer growth.

Cancer cell

To learn more about the transport of glucose into cells, researchers at Karolinska Institutet have done experiments on Escherichia coli bacterium. They studied how glucose transport is performed by protein XylE (from Escherichia coli bacterium) and found details about the mechanism by which this protein transport sugars within the cell. It seems that when it carries sugar molecules, the protein structure changes and adopts two different conformations.
Pär Nordlund at the Department of Medical Biochemistry and Biophysics, one of the researchers behind the study, said that by showing the details of the molecular structure of the region where it binds glucose, their study opens new opportunities to discover new inhibitors of GLUT. He added that information on protein structure facilitates the development of new drugs more rapidly. GLUT inhibitors may underlie new anticancer therapies.

Furthermore, the study results are important not only in cancer, but also diabetes. GLUT plays an important role in diabetes because insulin cause blood glucose uptake by these proteins. In addition, the protein XylE and GLUT are part of the Major Facilitator Superfamily (MFS), a large group of transporters that are involved in many diseases. “Many aspects concerning molecular mechanisms for the function of GLUT transporters are probably common to many members of the MFS family, which are involved in a broad spectrum of diseases in addition to cancer and diabetes”, Pär Nordlund explained.

Exercise may prevent liver cancer

Researchers have demonstrated in studies conducted on rats that regular exercise reduces the risk of developing hepatocellular carcinoma. The study results were presented at the International Liver Congress 2013. Although it is a study made on laboratory animals, this research opens the way to other studies conducted on humans to prove that regular exercise reduces the risk of liver cancer.

The relationship between liver cancer, obesity and type 2 diabetes has already been questioned in previous studies. It seems that patients with type 2 diabetes and poor control of circulating insulin are up to seven times more likely to develop liver cancer than the non-diabetics.

The researchers wanted to see if exercise is a protective factor for liver cancer and therefore conducted an experiment involving two groups of rats: one group was fed with the control diet and the other was fed with a high fat diet. Then the rats were divided into  two groups: the exercise group ( 60 minutes a day, 5 days a week ) and the sedentary group. After 32 weeks of exercise, only 71% of rats in the controlled diet group developed tumors larger than 10 mm compared to those in the sedentary group, where all rats developed tumors. In addition, it was seen that the average number and tumor volume were lower in the exercise group compared to the sedentary group.

Cardio

EASL’s Education Council Prof. Jean-Francois Dufour, said that exercise brings a significant benefit in preventing liver cancer. It was also found that exercise resulted in decreased levels of non-alcoholic fatty liver disease in rats that were fed with high fat diet. Prof. Jean-Francois Dufour also said that modern unhealthy lifestyles predispose people to non-alcoholic fatty liver disease which increases the risk of liver cancer. Statistics show that liver cancer is about 5% of all tumor types; it is the fifth most common cause of liver cancer in men and the eighth most common cause of cancer in women. 90% of liver cancers are hepatocellular carcinomas and the most common cause incriminated so far is cirrhosis. Cirrhosis is most often caused by chronic alcohol consumption and chronic infection with hepatitis C.

Liver cancer prognosis is low because often the tumor cannot be completely resected. In addition, symptoms related to liver cancer are nonspecific and patients see the doctor in advanced stages. This is one of the reasons that cirrhotic patients are monitored closely by a doctor (abdominal ultrasound every 6 months and measurement of serum levels of alpha fetoprotein).

Melanoma

According to recent studies, the survival rate of patients with metastatic melanoma can now be predicted by computed tomography and serum LDH levels. Among all types of skin cancer, melanoma is the most aggressive form of skin cancer and has a very poor prognosis, especially if discovered in advanced stages.

There is a genetic predisposition for melanoma. There have been discovered several genes involved in the onset of this type of cancer, such as CDKN2A, MC1R, p53 and others. In terms of environmental factors, it is believed that sun exposure is the most important risk factor for the occurrence of melanoma. In addition, it is believed that the presence of melanocytic nevi (more than 50 nevi on the skin) and skin type (people with sensitive skin who burn easily in the sun) contributes to the development of this type of skin cancer.

Signs of malignancy of a nevus can be systematized using the well-known formula: ABCDE, which refers to asymmetry, irregular borders, changes in color, diameter greater than one inch and elevation. Other signs such as itching, bleeding or ulceration must determine the patient to consult a dermatologist.

Tan

Researchers at the University of Mississippi Medical Center in Jackson and at the Ohio State University Comprehensive Cancer Center in Columbus, wanted to determine the survival rate in patients with metastatic melanoma treated with anti-angiogenic therapy. Therefore, clinical and laboratory data were collected (imaging investigations) in 46 patients and it seems that the results were similar to those found in patients with kidney tumors, other type of cancers that are highly vascular and also treated with anti -angiogenic therapy.

Dr. Smith said that patients with increased LDH tend to have a worse prognosis than patients with low serum LDH. He added that the level of LDH is used for staging metastatic melanoma but is weakly associated with survival rate when used alone. However, when the level of LDH and MASS Criteria findings are combined, the accuracy to predict progression-free and overall survival increases significantly.

Dr Smith said that this is an exploratory study and the next step is to verify these findings in a prospective clinical trial. The study indicates that patients with low LDH and tumor devascularization (assessed using CT) are more likely to have a favorable response to CT. Dr. Smith said they want to identify those patients who best respond to anti-angiogenic therapy to improve their quality of life and survival. Patients who do not respond to treatment should follow alternative therapies so as to avoid unnecessary drug toxicity.

Alcohol Abuse

Researchers at Indiana University School of Medicine have made new discoveries about alcohol abuse. It seems that the release of dopamine, a neurotransmitter in the brain, is related to the taste of beer, without the intoxicating effect of alcohol, as previously thought. The study was published in the journal Neuropsychopharmacology and demonstrates that alcohol abuse could be caused by some inherited risk factors.

Neuroscientists conducted a study that assessed the level of dopamine in the brain to certain substances. The study included 49 participants who were evaluated twice using positron emission tomography (PET). First they tracked dopamine levels after participants have tasted beer and then they evaluated the dopamine levels after participants have tasted Gatorade. Participants received a low dose of beer (15 mg each of their favorite beer) that tasted over 15 minutes so that no traces of detectable blood alcohol result. Dopamine is a neurotransmitter that has many roles in the brain and is released after ingestion of alcohol or drugs. Dopamine levels in the brain was detected using PET scanning, which is a medical imaging technique that uses a tracer (positron-emitting radionuclide).

Beer

It has been shown that dopamine levels are much higher after ingestion of beer than after ingestion of Gatorade. Also, it seems that the level of this neurotransmitter is much higher in subjects with a family history of alcoholism.
David A. Kareken, Ph.D., professor of neurology at the IU School of Medicine and the deputy director of the Indiana Alcohol Research Center, said this is the first experiment that demonstrates that the taste of beer, without the intoxicating effect of alcohol, may cause the release of increased amounts of dopamine. The fact that dopamine was released in higher amounts in participants with a family history of alcoholism shows that there is a genetic risk factor for this kind of abuse. “We believe this is the first experiment in humans to show that the taste of an alcoholic drink alone, without any intoxicating effect from the alcohol, can elicit this dopamine activity in the brain’s reward centers,” he added.

However this is not the first study to show that dopamine is linked to drug abuse. Mechanism of dopamine release and its role in certain brain regions underlies therapies for recovering alcoholics. The researchers mentioned that the participants had higher craving after tasting beer. But not the same thing happened after they tasted the sport drink, even though many were believed that Gatorade actually tasted better than beer.

Enlarged Prostate Patients Can Now Benefit From Novel Nonsurgical Minimal Invasive Treatment

Patients with enlarged prostate now benefit from minimally invasive treatment: prostatic artery embolization or PAE, which involves reducing blood flow to the prostate gland. Benign prostatic hypertrophy is one of the most common diseases that occur in older men and is manifested by pollakiuria, which means frequent urination.
The prostate is a gland located around the urethra and an increased gland has many consequences on urinary system . First, the patient begins to urinate with difficulty because the increased gland compresses the urethra and thus appears pollakiuria (first at night and then becomes permanent). Because of pollakiuria, urinary bladder begins to stop properly evacuate which leads to urinary retention. This residual urine increases gradually and can lead to false incontinence. Other complications that can occur are complete retention of urine, stones, infections. Also, other consequences of benign prostatic hypertrophy is hydronefrosis and kidney failure.

BHP

Patients with benign prostatic hyperplasia are treated with drugs or surgery. Drug treatment is chosen depending on the patient’s symptoms and includes various types of drugs such as alpha blockers, 5-alpha reductase inhibitors, phytotherapy. When drug therapy brings no benefit, patients may choose surgery that can be done in several ways: there is transurethral resection of the prostate ( TURP), transurethral incision of the prostate ( TUIP). Others methods of treatment involve transurethral needle ablation of the prostate ( TUNA), transurethral microwave therapy ( TUMP) etc.

This treatment should be chosen depending on the patient’s condition and preferences, etc.. Now researchers have come up with a minimally invasive treatment option. Prostatic artery embolization or PAE can be an alternative for those who do not want surgical intervention or health condition does not indicate this type of treatment. Sandeep Bagle, MD, the study’s lead author and year interventional radiologist in the department of cardiovascular and interventional radiology at Inova Alexandria Hospital in Alexandria, said that surgery can be risky for some patients and involves several side effects. He added that PAE is a minimally invasive technique with low risk and that reduces symptoms in most patients.

PAE effectiveness has been tested so far in only 14 patients but of these 13 had a significant reduction in symptoms after just one month. None of the participants have suffered major complications such as impotence, incontinence or urethral infection. Now researchers want to conduct a prospective study showing long-term results of the PAE. “Patients who have not been helped by surgery or laser treatments have benefited. Since the treatment does not involve placing a catheter or device into the penis, there is no risk of narrowing of the urethra, incontinence or bleeding,” Bagle said.