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Spinal Fluid Biomarkers of AD and Brain Functional Network Integrity on Imaging Studies

Both Aß and tau pathology appear to be associated with default mode network integrity before clinical onset of Alzheimer disease (AD), according to a study by Liang Wang, M.D., and colleagues at Washington University in St. Louis, Missouri.

Accumulation of Aß and tau proteins, the pathologic hallmarks of AD, starts years before clinical onset. Pathophysiological abnormalities in the preclinical phase of AD may be detected using cerebrospinal fluid (CSF) or neuroimaging biomarkers, according to the study background.

A total of 207 older adults with normal cognition participated in the cross-sectional group study. Researchers examined the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals using resting-state functional connectivity magnetic resonance imaging.

According to the study results, decreased cerebrospinal fluid Aß42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions (regions of the brain associated with memory). Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas.

Study: Cerebrospinal Fluid Aβ42, Phosphorylated Tau181, and Resting-State Functional Connectivity [JAMA Neurology]

Source: EurekAlert!

Pretesting Cervical Tumors Could Inform Treatment

Doctors at Washington University School of Medicine in St. Louis have shown that testing cervical tumors before treatment for vulnerability to chemotherapy predicts whether patients will do well or poorly with standard treatment. The study supports the future possibility of personalized medicine for cervical cancer, a tumor normally addressed with a one-size-fits-all approach.

“Even though this is a small study, its strength is that it links a lab test of the tumor’s chemotherapy response to survival outcomes for the patients,” said Julie K. Schwarz, MD, PhD, assistant professor of radiation oncology. “Very few cancers have been studied this way, and this is the first such report for cervical cancer.”

Since 1999, nearly all cervical cancer cases have been treated the same way: daily radiation therapy targeted to the tumor plus a weekly intravenous infusion of the chemotherapy drug cisplatin.

“We believe that radiation does the majority of the work with cervical cancer,” said Schwarz, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But a randomized trial published in 1999 showed that combining it with cisplatin chemotherapy improved survival outcomes.”

Even today, according to Schwarz, doctors have no way of knowing who will do well or poorly with the combined radiation and chemotherapy that every patient receives. Now, Schwarz and her colleagues have shown that the tumor’s response to chemotherapy, independent of radiation, may be a major deciding factor in whether a patient will do well with the standard treatment.

The study appears online in the journal Gynecologic Oncology.

“This is evidence that cisplatin is not just helping the radiation work better,” Schwarz said. “It is having some direct toxic effect on cancer cells that may be hiding elsewhere in the body, some place where the radiation is not hitting it, since we target the radiation so precisely to the main tumor. We think it would be beneficial for that drug to be selected appropriately for the patient’s individual tumor.”

The investigators tested tumors from 33 cervical cancer patients before their treatment began. They divided the patients’ tumors into three categories – responsive, intermediate response and nonresponsive – based on how well cisplatin killed the tumor cells growing in a dish.

For tumors categorized as responsive – those cancer cells that cisplatin killed most easily – 100 percent of the patients were alive and disease-free after two years. For those that showed an intermediate response, 83 percent of the patients were alive and disease-free after two years. And for those tumors deemed nonresponsive, only 58 percent of patients had two-year disease-free survival.

Cervical cancers can be divided into two main types based on how they look under a microscope – squamous cell carcinoma and adenocarcinoma. The nonresponsive number was even worse for patients diagnosed with the more common squamous cell carcinoma, with 46 percent disease-free survival at two years.

“Ideally, we would like to be able to design clinical trials for the nonresponsive patients,” Schwarz said. “One chemotherapy drug isn’t working for everyone, but there isn’t going to be one explanation for why the chemo doesn’t work. It’s going to be 50 different explanations, and figuring that out is the challenge.”

Schwarz is quick to point out the weaknesses of this study. In addition to the small number of patients, the lab test used was not ideal and should not be used to decide therapy for patients, she said. The investigators initially evaluated 75 tumors for chemotherapy response. And though some patients’ data was not included because they did not adhere to the treatment regimen, 31 patients were excluded from the analysis because their tumor cells did not grow well in the lab.

“This is definitely not the definitive test,” Schwarz said. “But I think our results should prompt investigators to think outside the box and start generating new ideas about how best to treat this disease. The bottom line is a one-size-fits-all treatment for each patient is going by the wayside. As we develop personalized strategies, this is the sort of testing that can guide it.”

Study: In vitro chemoresponse to cisplatin and outcomes in cervical cancer.

Source: Washington University in St. Louis

Alzheimer’s Markers Predict Start of Mental Decline

Scientists at Washington University School of Medicine in St. Louis have helped identify many of the biomarkers for Alzheimer’s disease that could potentially predict which patients will develop the disorder later in life. Now, studying spinal fluid samples and health data from 201 research participants at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, the researchers have shown the markers are accurate predictors of Alzheimer’s years before symptoms develop.

“We wanted to see if one marker was better than the other in predicting which of our participants would get cognitive impairment and when they would get it,” said Catherine Roe, PhD, research assistant professor of neurology. “We found no differences in the accuracy of the biomarkers.”

The study, supported in part by the National Institute on Aging, appears in Neurology.

The researchers evaluated markers such as the buildup of amyloid plaques in the brain, newly visible thanks to an imaging agent developed in the last decade; levels of various proteins in the cerebrospinal fluid, such as the amyloid fragments that are the principal ingredient of brain plaques; and the ratios of one protein to another in the cerebrospinal fluid, such as different forms of the brain cell structural protein tau.

The markers were studied in volunteers whose ages ranged from 45 to 88. On average, the data available on study participants spanned four years, with the longest recorded over 7.5 years.

The researchers found that all of the markers were equally good at identifying subjects who were likely to develop cognitive problems and at predicting how soon they would become noticeably impaired.

Next, the scientists paired the biomarkers data with demographic information, testing to see if sex, age, race, education and other factors could improve their predictions.

“Sex, age and race all helped to predict who would develop cognitive impairment,” Roe said. “Older participants, men and African Americans were more likely to become cognitively impaired than those who were younger, female and Caucasian.”

Roe described the findings as providing more evidence that scientists can detect Alzheimer’s disease years before memory loss and cognitive decline become apparent.

“We can better predict future cognitive impairment when we combine biomarkers with patient characteristics,” she said. “Knowing how accurate biomarkers are is important if we are going to some day be able to treat Alzheimer’s before symptoms and slow or prevent the disease.”

Clinical trials are already underway at Washington University and elsewhere to determine if treatments prior to symptoms can prevent or delay inherited forms of Alzheimer’s disease. Reliable biomarkers for Alzheimer’s should one day make it possible to test the most successful treatments in the much more common sporadic forms of Alzheimer’s.

Study: Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later

Source: EurekAlert!

Horizon Discovery Establishes Three New Centers of Excellence in Asia

Horizon Discovery (Horizon), a leading provider of research tools to support the development of personalized medicines, recently announced it has established three new Centers of Excellence (CoE’s) for gene editing in Asia. The new Centers are at Aichi Cancer Center, Japan, Seoul National University, South Korea, and the National Cancer Centre (NCC), Singapore. Horizon will support the three research centers in their application of its proprietary gene engineering technology, GENESIS™, to generate human isogenic cell lines harboring specific genes/mutations relating to cancer.

“We are delighted these three new institutes have joined our Centers of Excellence program,” said Dr Rob Howes, Principal Scientist, Horizon. “We are excited to continue expanding our rAAV genome editing network into Asia, and hope to add to this further through 2013.”

The Aichi Cancer Center is Horizon’s second CoE in Japan, and will focus on elucidation of the molecular mechanisms of viral proliferation and oncogenesis of Epstein Barr Virus, as part of the world-wide effort to combat virally-initiated cancers. The principal investigator for this program will be Dr. Takayuki Murata.

Seoul National University, Institute of Molecular Biology and Genetics, will work with Horizon to create isogenic cell lines to study the regulatory mechanisms of BubR1 spindle assembly checkpoint, in order to increase understanding of the basis of genetic instability of cancer. Associate Professor Hyunsook Lee will be leading the program for Seoul National University.

Dr Daniel SW Tan, PI at the NCC Singapore, Department of Medical Oncology, will use Horizon’s technology to study the effects on cell lines of cancer-causing EGFR mutations, which are implicated in a wide range of cancer types.

These centers become part of the larger Horizon Centers of Excellence network, which includes high profile Institutions such as Cambridge University, UCL, Yale University, Washington University in St Louis, the NCI in Bethesda, and the National Cancer Centre, Japan.

Source: Business Wire

Reducing Medical Mistakes: Two Recently Published Studies Support the Use of DNA Testing on Biopsy Samples to Prevent Misdiagnoses

Strand Diagnostics, LLC, maker of the know error® system for breast and prostate biopsies recently announced the publication of two peer-reviewed studies that examine the use of DNA testing on biopsy samples as a means of reducing common diagnostic mistakes. The first study, published in the American Journal of Clinical Pathology, found that up to 3.5 percent of patients initially diagnosed with cancer were subject to undetected specimen switches or contaminations which may have compromised the accuracy of their diagnosis. The second, published recently in Value in Health concluded that performing a simple DNA test to confirm the provenance of malignant tissue samples is a cost-effective way to improve patient safety and diagnostic accuracy.