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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY



Quinta-feira, 20.08.15

Molecular Profiles Early Detection for Prostate Cancer

 

In a first-ever study, findings identified five gene sets that can predict clinical outcome in independent patient cohorts with prostate cancer, according to researchers in England.1  

Combining gene copy number and gene expression data has yielded a new 100-gene risk-stratification signature for prostate cancer that appears to outperform prostate specific antigen (PSA) and Gleason scores, and might allow early detection of the most aggressive cases.

Whereas previous studies had used either gene expression or copy number data to develop molecular risk-stratification signatures for prostate cancer, this study's authors assessed each approach and then tried something new: they combined gene copy-number and expression data.

“Combining these data provides a more powerful tool to predict outcome following surgery,” lead study author Helen Ross-Adams, PhD, told Cancer Therapy Advisor. Dr. Ross-Adams is at the Cancer Research UK Cambridge Institute at the University of Cambridge, in Cambridge, United Kingdom.

The study “is one of the most comprehensive looks at the integration of copy number and transcriptomic data in a large cohort of patients with localized prostate cancer,” noted Sumanta Kumar Pal, an ASCO Expert and an assistant professor at the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer, in Duarte, CA.

Using healthy blood and tissue samples and prostate tumor tissue samples from discovery and validation cohorts of 125 and 103 men, respectively, the researchers searched tumor-genetics data predictive of biochemical relapse. The study confirmed prostate tumor development associations for MYC amplification, PCA3, and AMACR overexpression, and the loss of MSMB expression, and for six genes already known to be involved in prostate cancer: MAP3K7, MELK, RCBTB2, ELAC2, TPD52, and ZBTB4.

But surprisingly, the combined-data analysis also discovered new prostate cancer associations for 94 other genes—genes whose associations with prostate cancer progression “would not have been detected using either transcript or copy number data alone,” the study authors noted.

The METABRIC study2 used the same integrative method to show that breast cancer represents at least 10 distinct molecular malignancies, Dr. Ross-Adams noted.

Gene expression and copy number alterations for a total of 100 prostate cancer-associated genes allowed differentiation of five separate prognostic subgroups that consistently predicted biochemical relapse.1

The resulting genetic assay “outperforms established clinical predictors of poor prognosis like PSA and Gleason score” and the authors report that they found in the validation cohort that the 100-gene signature showed significant power to separate out a poor prognosis patient group with quicker time to recurrence, from the low-risk cohorts, with much lower chance for recurrence and slower disease progression.

The signature involved different molecular processes (such as nucleic acid processing and protein phosphorylation) than previously published gene signatures that are based on cell-cycle and lipid-metabolism genes, the researchers noted.

They next compared the 100-gene signature's prognostic performance with that of previously published prostate cancer gene signatures and the OncoType Dx Prostate Cancer assay.

“Our 100-gene signature outperformed all other gene sets in identifying patients with early time to biochemical relapse” (P=0.0001), they reported.

“We've developed a tool that will help clinicians identify the most aggressive prostate cancers, with the highest risk of relapsing after surgery,” Dr. Ross-Adams explained.

That suggests their gene signature might indeed emerge “as an effective tool to outperform previously published gene signatures, or the conventional PSA or histology risk markers,” as noted by Joseph Ragaz, MD, FRCP, MRCS-LRCP, senior medical oncologist and clinical professor at the University of British Columbia's School of Population and Public Health, in Vancouver, Canada, and an expert on cancer outcome research including cancer risk stratification.

The new study is “just a first step,” Dr. Ross-Adams is quick to acknowledge. “We're quite a way away from this being offered routinely in clinics. The temptation is to run before we can walk, but these findings need to be confirmed in larger clinical trials.”

 

RELATED: Prostate Cancer May Impact Relationship Satisfaction Among Couples

Using more genes “certainly may improve the performance of a classifier, but it is also possible that it could add more ‘noise' to the signal,” cautioned Dr. Pal.

But the study was based on biochemical relapse – elevation in blood PSA – rather than documented metastasis, Drs. Pal and Ragaz each warned.

“Other platforms have also shown the ability to predict clinical metastases, arguably a more important endpoint in patients with prostate cancer,” Dr. Pal said.

“Biochemical recurrence, the resurgence of PSA after definitive treatment, can be a long and indolent disease state. Furthermore, if you look carefully at the Kaplan-Meier curves [in the new study], you can see that there is considerable overlap in clinical outcome between the risk groups defined by this algorithm.”

Because her team's patient cohorts had no deaths attributable to prostate cancer and few metastases, however, that was not possible for this study, Dr. Ross-Adams noted.

“Our primary cohort is maturing and our data are publically available, so this could certainly be revisited in the future,” she added.

“We have also made matched tissue microarrays (TMAs) for these patients, with the idea being that we can offer this as a resource for further translational research to address these sorts of questions.”

But her team's results represent a promising advance with potentially important clinical implications, Dr. Ross-Adams said.

“At the moment, treatment decisions for prostate cancer are made on the basis of tumor histology, PSA, and tumor staging, which are relatively ‘blunt' instruments—it's not uncommon for patients to respond differently than expected, based on these parameters.”

Better predicting which tumors will progress aggressively would allow life-saving, early interventions, and Dr. Ross-Adams and her colleagues hope their proposed 100-gene signature may help do just that, as an additional tool used alongside tumor stage, histology, and PSA, to better determine prognosis, identify the most dangerous cases, and to plan treatments accordingly.

If this signature proves itself in larger clinical trials, it will join OncotypeDx and other gene signature tests. But using these tools in guidelines is still a matter of contention, or at least considered premature or “experimental.”

“There is no shortage of molecular predictors for clinical outcome in prostate cancer,” Dr. Pal noted. “The real question is what to do with them. Patients often face a difficult decision between surgery, radiation, or active surveillance when they are diagnosed with prostate cancer. To my knowledge, none of the genomic tools that have been introduced to date definitely help arbitrate this decision.”

Ragaz said that the “real problem is a long-term validation, and also lack of studies testing their predictive worth”—the ability of the test to associate a genetic signature with response to a therapy, be it surgery, chemotherapy, radiation or hormones.

 

RELATED: A Decade of Dramatic Change in the Treatment of Prostate Cancer

The study used surgically-excised tumor tissue. “The next step is to see whether these findings would be as useful in identifying aggressive cases using tissue from diagnostic biopsies,” Dr. Ross-Adams noted.

One concern is that such biopsies will not prove to be representative of all cancer cells in a tumor, because of tumors' genetic heterogeneity. But template biopsies that use MRI to identify the best target regions, might help, she said.

References

  1. Ross-Adams H, Lamb AD, Dunning MJ, et al. Integration of copy number and transcriptomics provides risk stratification in prostate cancer: a discovery and validation cohort study. EBioMedicine. 2015. [epub ahead of print]. doi: 10.1016/j.ebiom.2015.07.017.
  2. Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346-352. 

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por cyto às 12:05

Quarta-feira, 19.08.15

link between smaller hippocampal brain volume and marijuana use

Scientists reveal link between smaller hippocampal brain volume and marijuana use

Published on August 19, 2015 at 6:15 AM ·

How scientists study the effects of marijuana on the brain is changing. Until recently marijuana research largely excluded tobacco users from its participant pool, but scientists at the Center for BrainHealth at The University of Texas at Dallas have found reason to abandon this practice, uncovering significant differences in the brains of individuals who use both tobacco and marijuana and the brains of those who only use marijuana.

In a study that appears online in the journal Behavioural Brain Research, scientists report an association between smaller hippocampal brain volume and marijuana use. Although the size of the hippocampus, an area of the brain associated with memory and learning, is significantly smaller in both the marijuana group and marijuana plus tobacco group compared to non-using controls and individuals who use tobacco exclusively, the relationship to memory performance is unique.

Hippocampal size of nonusers reflects a direct relationship to memory function; the smaller the hippocampus, the poorer the memory function. Individuals who use marijuana and tobacco show an inverse relationship, i.e., the smaller the hippocampus size, the greater memory the function. Furthermore the number of nicotine cigarettes smoked per day in the marijuana and nicotine using group appears to be related to the severity of hippocampal shrinkage. The greater the number of cigarettes smoked per day, the smaller the hippocampal volume and the greater the memory performance. There were no significant associations between hippocampal size and memory performance in individuals who only use tobacco or only use marijuana.

"Approximately 70% of individuals who use marijuana also use tobacco," explained Francesca Filbey, Ph.D., the study's principal investigator and Director of Cognitive Neuroscience of Addictive Behaviors at the Center for BrainHealth. "Our findings exemplify why the effects of marijuana on the brain may not generalize to the vast majority of the marijuana using population, because most studies do not account for tobacco use. This study is one of the first to tease apart the unique effects of each substance on the brain as well as their combined effects."

Dr. Filbey's research team used magnetic resonance imaging (MRI) to examine the hippocampus; an area of the brain that is know to have altered size and shape in association with chronic marijuana use. Participants completed a substance use history assessment and neuropsychological tests three days prior to an MRI head scan. The team compared four groups: nonusers (individuals who have not had any marijuana or tobacco in the past three months), chronic marijuana users (individuals who use marijuana at least four times per week), frequent nicotine users (10 or more times daily) and chronic marijuana plus frequent nicotine users (at least four marijuana uses per week and 10 or more nicotine uses per day).

"We have always known that each substance is associated with effects on the brain and hypothesized that their interaction may not simply be a linear relationship. Our findings confirm that the interaction between marijuana and nicotine is indeed much more complicated due to the different mechanisms at play," said Filbey. "Future studies need to address these compounding effects of substances."

She continued, "The combined use of marijuana and tobacco is highly prevalent. For instance, a 'blunt' is wrapped in tobacco leaf. A 'spliff' is a joint rolled with tobacco. We really need to understand how the combined use changes the brain to really understand its effects on memory function and behavior."

Source:

Center for BrainHealth

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por cyto às 12:15

Quarta-feira, 19.08.15

Oncolytic virotherapy lends benefits to melanoma patients

Oncolytic virotherapy lends benefits to melanoma patients

Published on August 19, 2015 at 6:12 AM

Recent study published online by Melanoma Research journal indicates that melanoma patients would significantly benefit from prolonging the survival with oncolytic viroherapy treatment (http://journals.lww.com/melanomaresearch/toc/publishahead).

The study  revealed that the early stage  melanoma patients treated with oncolytic medicine Rigvir were 4 to 6 times more likely to survive than those who following the current guidelines for the treatment of melanoma were only observed.

Oncolytic virotherapy

Melanoma is one of the fastest-growing cancers and has the highest mortality rate of skin cancers. More than half of melanoma patients experience progression of disease within next 3 years after diagnosis. Unfortunately, current clinical practice guidelines for early stage melanoma patients provide few, if any, recommendations for treatment after surgery.

Rigvir is a live nonpathogenic enterovirus, adapted and selected for melanoma that has not been genetically modified. Rigvir has oncotropic and oncolytic properties. Rigvir finds and infects tumour cells, a process called oncotropism. Then, Rigvir replicates in tumour cells and destroys them. This process is called oncolysis.

Both of these processes, oncotropism and oncolysis, are selective for tumour cells and normal healthy cells are minimally, if at all, affected. Moreover, Rigvir demonstrated an outstanding safety profile because there was no record of any untoward side effect from Rigvir treatment or its discontinuation.

Melanoma treatment using oncolytic virus is a cancer treatment option that has been observed for over a century and is presently being studied intensively. The effect of viruses on cancers, including melanoma, has been tested in clinical trials, however the effectivness of an approved and marketed virus has not yet  been shown in a clinical setting.

Rigvir is the first oncolytic virus in the world with anticancer and immunomodulating effects, which is registered for cancer virotherapy and introduced in medical practice. Rigvir was approved in 2004 in Latvia for melanoma therapy and since 2011 is fully reimbursed by government for skin melanoma patients here. Since 2015 Rigvir is included in the national guidelines for the skin cancer and melanoma treatment.

Source:

International Virotherapy Center

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por cyto às 12:10

Quarta-feira, 19.08.15

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Unituxin (dinutuximab) granted EC Marketing Authorisation for treatment of childhood neuroblastoma

Published on August 17, 2015 at 7:21 AM ·

United Therapeutics Corporation (NASDAQ: UTHR) announced today that the European Commission (EC) has granted Marketing Authorisation for Unituxin™ (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT). Unituxin is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the European Union of approximately 1500 patients, of whom 50% are diagnosed as having high-risk disease.

The European approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) sponsored by the US National Cancer Institute under a Cooperative Research and Development Agreement with United Therapeutics and conducted by the Children's Oncology Group (COG).

Trial design and results

The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm. Patients in each arm received six cycles of treatment. The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age (median age 3.8 years).

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death. The primary intent-to-treat analysis found an improvement in EFS associated with dinutuximab immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66% among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48% in subjects receiving isotretinoin alone (log-rank test p = 0.033) although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses. In addition, OS was evaluated with 3 years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive dinutuximab immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80% compared with 67% among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165). Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received dinutuximab immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74% for dinutuximab immunotherapy compared to 57% for isotretinoin alone (log-rank test p = 0.030).

Frequently occurring adverse reactions

The most frequently occurring (more than 30% of patients) adverse reactions reported during the neuroblastoma studies were hypotension (67%), pain (66%), hypersensitivity (56%), pyrexia (53%), urticaria (49%), capillary leak syndrome (45%), anaemia (45%), hypokalaemia (41%), platelet count decreased (40%), hyponatraemia (37%), alanine aminotransferase increased (35%), decreased lymphocyte count (34%) and decreased neutrophil count (31%). Additional adverse reactions characteristic of an allergic response were also reported – including anaphylactic reaction (18%) and bronchospasm (4%).

Posology and method of administration

Unituxin is to be administered by intravenous infusion over five courses at a daily dose of 17.5 mg/m2. It is administered on days 4-7 during courses 1, 3 and 5 (each course lasting approximately 24 days) and on days 8-11 during courses 2 and 4 (each course lasting approximately 28 days).

The treatment regimen consists of Unituxin, GM-CSF, IL-2, and isotretinoin, administered over six consecutive courses.

Source:

United Therapeutics Corporation

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por cyto às 12:08

Quarta-feira, 19.08.15

Inflammation from diets deficient in nutrients contribute to weight despite intake of macronutrients

 

Inflammation from diets deficient in nutrients contribute to weight despite intake of macronutrients

Published on August 6, 2015 at 8:41 AM ·

If you are watching what you eat, working out, and still not seeing improvements in your cholesterol, blood pressure, blood sugar, etc., here's some hope. A new report appearing in the August 2015 issue of The FASEB Journal suggests that inflammation induced by deficiencies in vitamins and minerals might be the culprit. In this report, researchers show that - in some people - improvement results in many of the major markers of health when nutritional deficiencies are corrected. Some even lost weight without a change in their diet or levels of activity.

"It is well known that habitual consumption of poor diets means increased risk of future disease, but clearly this is not a compelling enough reason for many to improve their eating habits," said Bruce Ames, Ph.D., a senior scientist at Children's Hospital Oakland Research Institute, director of their Nutrition and Metabolism Center, and a professor emeritus of Biochemistry and Molecular Biology at the University of California, Berkeley. "However, a relatively easy intervention with something like the nutrient bar used in this study may help people to realize the positive impact that a diet with adequate nutrition can have in their daily lives, which may be a stronger incentive for change."

To make their Ames and colleagues undertook three clinical trials in which adults ate two nutrient bars each day for two months. Participants acted as their own controls, meaning that changes in a wide variety of biochemical (e.g., HDL-c, LDL-c, insulin) and physical (e.g., blood pressure, weight) measurements were recorded in each individual over the two-month period. People who were overweight/obese moved in a healthier metabolic direction (e.g., improved HDL, LDL, insulin, glucose, etc.), and some lost weight by just eating small, low-calorie, nutrient bars each day for two months, without any additional requirements.

"If being healthy was as simple as 'losing weight' or 'keeping thin,' our ancient ancestors who lived in times of extreme food scarcity might still be with us today," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "This report shows that what you eat is as important, if not more, than how much you eat and how many calories you burn in the gym."

Source:

Federation of American Societies for Experimental Biology

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por cyto às 11:56

Quarta-feira, 19.08.15

Low-fat diets better than low-carb diets for weight loss, NIH study finds

Low-fat diets better than low-carb diets for weight loss, NIH study finds

Published on August 14, 2015 at 7:30 AM ·

In a recent study, restricting dietary fat led to body fat loss at a rate 68 percent higher than cutting the same number of carbohydrate calories when adults with obesity ate strictly controlled diets. Carb restriction lowered production of the fat-regulating hormone insulin and increased fat burning as expected, whereas fat restriction had no observed changes in insulin production or fat burning. The research was conducted at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. Results were published August 13 in Cell Metabolism.

"Compared to the reduced-fat diet, the reduced-carb diet was particularly effective at lowering insulin secretion and increasing fat burning, resulting in significant body fat loss," said Kevin Hall, Ph.D., NIDDK senior investigator and lead study author. "But interestingly, study participants lost even more body fat during the fat-restricted diet, as it resulted in a greater imbalance between the fat eaten and fat burned. These findings counter the theory that body fat loss necessarily requires decreasing insulin, thereby increasing the release of stored fat from fat tissue and increasing the amount of fat burned by the body."

The researchers studied 19 non-diabetic men and women with obesity in the Metabolic Clinical Research Unit at the NIH Clinical Center in Bethesda, Maryland. Participants stayed in the unit 24 hours per day for two extended visits, eating the same food and doing the same activities. For the first five days of each visit they ate a baseline balanced diet. Then for six days, they were fed diets containing 30 percent fewer calories, achieved by cutting either only total carbs or total fat from the baseline diet, while eating the same amount of protein. They switched diets during the second visit.

The researchers had previously simulated the study with a math model of human metabolism, whose body fat predictions matched the data later collected in the study. When simulating what might happen over longer periods, the model predicted relatively small differences in body fat loss with widely varying ratios of carbs to fat. Those results suggest the body may eventually minimize differences in body fat loss when diets have the same number of calories. More research is needed to assess the physiological effects of fat and carb reduction in the long term.

"This NIH study provides invaluable evidence on how different types of calories affect metabolism and body composition," said NIDDK Director Griffin P. Rodgers, M.D. "The more we learn about the complicated topic of weight loss, the better we can find ways to help people manage their health."

More than two-thirds of American adults are overweight or obese. Maintaining a healthy weight can help prevent complications related to overweight and obesity such as heart disease, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death.

"Our data tell us that when it comes to body fat loss, not all diet calories are exactly equal," Hall said. "But the real world is more complicated than a research lab, and if you have obesity and want to lose weight, it may be more important to consider which type of diet you'll be most likely to stick to over time."

Source:

NIH/National Institute of Diabetes and Digestive and Kidney Diseases

 

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por cyto às 11:47

Quarta-feira, 19.08.15

special brain mechanism that can retrieve unconscious memories

 

Scientists discover special brain mechanism that can retrieve unconscious memories

Published on August 18, 2015 at 8:46 AM ·

Some stressful experiences - such as chronic childhood abuse - are so overwhelming and traumatic, the memories hide like a shadow in the brain.

At first, hidden memories that can't be consciously accessed may protect the individual from the emotional pain of recalling the event. But eventually those suppressed memories can cause debilitating psychological problems, such as anxiety, depression, post-traumatic stress disorder or dissociative disorders.

A process known as state-dependent learning is believed to contribute to the formation of memories that are inaccessible to normal consciousness. Thus, memories formed in a particular mood, arousal or drug-induced state can best be retrieved when the brain is back in that state.

In a new study with mice, Northwestern Medicine scientists have discovered for the first time the mechanism by which state-dependent learning renders stressful fear-related memories consciously inaccessible.

"The findings show there are multiple pathways to storage of fear-inducing memories, and we identified an important one for fear-related memories," said principal investigator Dr. Jelena Radulovic, the Dunbar Professor in Bipolar Disease at Northwestern University Feinberg School of Medicine. "This could eventually lead to new treatments for patients with psychiatric disorders for whom conscious access to their traumatic memories is needed if they are to recover."

It's difficult for therapists to help these patients, Radulovic said, because the patients themselves can't remember their traumatic experiences that are the root cause of their symptoms.

The best way to access the memories in this system is to return the brain to the same state of consciousness as when the memory was encoded, the study showed.

The study will be published August 17 in Nature Neuroscience.

Changing the Brain's Radio Frequencies

Two amino acids, glutamate and GABA, are the yin and yang of the brain, directing its emotional tides and controlling whether nerve cells are excited or inhibited (calm). Under normal conditions the system is balanced. But when we are hyper-aroused and vigilant, glutamate surges. Glutamate is also the primary chemical that helps store memories in our neuronal networks in a way that they are easy to remember.

GABA, on the other hand, calms us and helps us sleep, blocking the action of the excitable glutamate. The most commonly used tranquilizing drug, benzodiazepine, activates GABA receptors in our brains.

There are two kinds of GABA receptors. One kind, synaptic GABA receptors, works in tandem with glutamate receptors to balance the excitation of the brain in response to external events such as stress.

The other population, extra-synaptic GABA receptors, are independent agents. They ignore the peppy glutamate. Instead, their job is internally focused, adjusting brain waves and mental states according to the levels of internal chemicals, such as GABA, sex hormones and micro RNAs. Extra-synaptic GABA receptors change the brain's state to make us aroused, sleepy, alert, sedated, inebriated or even psychotic. However, Northwestern scientists discovered another critical role; these receptors also help encode memories of a fear-inducing event and then store them away, hidden from consciousness.

"The brain functions in different states, much like a radio operates at AM and FM frequency bands," Radulovic said. "It's as if the brain is normally tuned to FM stations to access memories, but needs to be tuned to AM stations to access subconscious memories. If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again, essentially tuning the brain into the AM stations."

Retrieving Stressful Memories in Mice

In the experiment, scientists infused the hippocampus of mice with gaboxadol, a drug that stimulates extra-synaptic GABA receptors. "It's like we got them a little inebriated, just enough to change their brain state," Radulovic said.

Then the mice were put in a box and given a brief, mild electric shock. When the mice were returned to the same box the next day, they moved about freely and weren't afraid, indicating they didn't recall the earlier shock in the space. However, when scientists put the mice back on the drug and returned them to the box, they froze, fearfully anticipating another shock.

"This establishes when the mice were returned to the same brain state created by the drug, they remembered the stressful experience of the shock," Radulovic said.

The experiment showed when the extra-synaptic GABA receptors were activated with the drug, they changed the way the stressful event was encoded. In the drug-induced state, the brain used completely different molecular pathways and neuronal circuits to store the memory.

"It's an entirely different system even at the genetic and molecular level than the one that encodes normal memories," said lead study author Vladimir Jovasevic, who worked on the study when he was a postdoctoral fellow in Radulovic's lab.

This different system is regulated by a small microRNA, miR-33, and may be the brain's protective mechanism when an experience is overwhelmingly stressful.

The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.

Traumatic Memories Rerouted and Hidden Away

Memories are usually stored in distributed brain networks including the cortex, and can thus be readily accessed to consciously remember an event. But when the mice were in a different brain state induced by gaboxadol, the stressful event primarily activated subcortical memory regions of the brain. The drug rerouted the processing of stress-related memories within the brain circuits so that they couldn't be consciously accessed.

Source:

Northwestern University

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por cyto às 11:42

Quarta-feira, 19.08.15

ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107

GLIOBASTOMA GBM

ImmunoCellular signs agreement with FDA for phase 3 registrational trial of cancer immunotherapy ICT-107

Published on August 13, 2015 at 8:32 AM ·

ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT: IMUC) announced today that it has reached agreement with the US Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) for the phase 3 registrational trial of its cancer immunotherapy ICT-107 to treat patients with newly diagnosed glioblastoma.

The phase 3 trial is designed as a randomized, double-blind, placebo-controlled study of about 400 HLA-A2 positive subjects, which will be conducted at about 120 sites in the US, Canada and the EU. The primary endpoint in the trial is overall survival, which the FDA and EU regulators have stated is the appropriate endpoint for registrational clinical studies in glioblastoma. Secondary endpoints include progression-free survival and safety, as well as overall survival in the two pre-specified MGMT subgroups. Patient enrollment is anticipated to begin in the late third quarter or early fourth quarter of 2015.

A Special Protocol Assessment is a written agreement between the sponsor company and the FDA on the design, clinical endpoints, size and statistical design of a clinical trial intended to form the primary basis of an efficacy claim in the marketing application, such as a biologic licensing application (BLA) or a new drug application (NDA). Final marketing approval depends upon the safety and efficacy results demonstrated in the phase 3 clinical program.

Andrew Gengos, ImmunoCellular's Chief Executive Officer Commented: "We are pleased to have achieved this important milestone, and think that successful completion of the SPA process adds meaningful validation to the ICT-107 phase 3 program and design, especially the use of the gold standard primary endpoint of overall survival. With this SPA in place, we think that ICT-107 is uniquely positioned in the field of immuno-oncology approaches being tested in glioblastoma. We are making significant progress toward establishing our clinical site network and obtaining the necessary institutional review board approvals. We are confident that we are on track to begin patient enrollment in the late third quarter or early fourth quarter of this year."

Source:

ImmunoCellular Therapeutics, Ltd.

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por cyto às 11:37

Domingo, 16.08.15

For First-line Treatment of Colorectal Cancer, Nintedanib Plus mFOLFOX6 Appears Efficacious

For First-line Treatment of Colorectal Cancer, Nintedanib Plus mFOLFOX6 Appears Efficacious

Nintedanib in combination with oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) showed efficacy in metastatic colorectal cancer.
Nintedanib in combination with oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) showed efficacy in metastatic colorectal cancer.

Nintedanib in combination with oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) showed efficacy as first-line therapy in patients with metastatic colorectal cancer (mCRC) and a manageable safety profile, a new study published online ahead of print in the journal Annals of Oncology has shown.

For the open-label, phase 1/2 study, researchers sought to evaluate the safety and efficacy of nintedanib in combination with chemotherapy compared with bevacizumab plus chemotherapy as first-line treatment in patients with mCRC.

Researchers enrolled 128 patients with histologically confirmed mCRC and randomly assigned them 2:1 to receive nintedanib 200 mg twice daily plus mFOLFOX6 or bevacizumab combined with mFOLFOX6.

Results showed that 9-month progression-free survival was 62.1% with nintedanib vs 70.2% with bevacizumab. Confirmed objective responses were observed in 63.5% and 56.1% of patients, respectively.

In regard to safety, 37.6% of patients in the nintedanib arm experienced serious adverse events compared with 53.7% of patients in the bevacizumab arm.

 

RELATED: No Definite Link Between Yoga, Quality of Life in Patients with Colorectal Cancer

Pharmacokinetic analyses demonstrated no interaction between nintedanib and the components of mFOLFOX6.

The findings suggest that further studies are warranted to evaluate the efficacy and safety of nintedanib 200 mg twice daily combined with mFOLFOX6 as first-line treatment for this patient population.

Nintedanib is already approved by the U.S. Food and Drug Administration (FDA) for the treatment of idiopathic pulmonary fibrosis and is being studied in various solid tumors.

Reference

  1. van Cutsem E, Prenen H, D'Haens G, et al. A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients. Ann Oncol. 2015. [epub ahead of print]. doi: 10.1093/annonc/mdv286.

 

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por cyto às 14:22

Domingo, 16.08.15

Stem cell transplantation improves outcomes for children with rare form of leukemia

 

Stem cell transplantation improves outcomes for children with rare form of leukemia

Improved outcomes have seen treating JMML with stem cell transplantation.
Improved outcomes have seen treating JMML with stem cell transplantation.

Researchers have shown greatly improved outcomes in using stem cell transplantation to treat patients with juvenile myelomonocytic leukemia (JMML), a very rare form of chronic blood cancer. Their findings were published in a letter to Blood (2015; doi:10.1182/blood-2015-05-644161).

Allogeneic hematopoietic stem cell transplantation (HSCT) involves the transplantation of stem cells from a donor, which may be derived from bone marrow, peripheral blood, or umbilical cord blood. The recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation.

Allogeneic HSCT is the only reported cure for JMML; however, best outcomes of the therapy have shown that cure is achieved in only half of patients with the disease. According to the researchers, there is currently no standard conditioning regimen for children with JMML undergoing HSCT.

This study, conducted by researchers in the Division of Hematology, Oncology and Blood & Marrow Transplantation at Children's Hospital Los Angeles (CHLA) in California and led by Hisham Abdel-Azim, MD, looked at children with JMML who underwent HSCT at Children's Hospital Los Angeles. All of the seven patients were alive and in clinical remission at a median follow-up of 25.3 months. Their average age was 2.6 years.

"The lack of transplant-related mortality in the group of children we studied at the Children's Center for Cancer and Blood Diseases at CHLA suggests that BUMEL [intravenous busulfan and melphalan] may represent a successful HSCT high-dose chemotherapy regimen," said Abdel-Azim. "It is also possible that administering conventional dose chemotherapy, before HSCT, to patients with more progressive disease may have contributed to the improved outcomes."

He added that a follow up clinical trial is warranted to confirm these promising findings.

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por cyto às 14:15

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