Independent study of Pathwork tissue of origin test confirms clinical validity; “cost-effective for increasing cancer patient survival”

Results of a study conducted at Virginia Commonwealth University of the Pathwork Diagnostics’ Pathwork tissue of origin test have been published online in the American Journal of Clinical Pathology, in a paper entitled “Clinical verification of the performance of the Pathwork tissue of origin test: utility and limitations”. The Pathwork tissue of origin test is an FDA-cleared, Medicare-covered molecular diagnostic for identifying tissue of origin. It uses a tumour’s own genomic information to help pathologists and oncologists in the diagnosis of challenging cancer cases such as those that are metastatic or that have a complex clinical history.

In the study, the analytic and clinical performance of the tissue of origin test was examined in 43 poorly differentiated and undifferentiated tumour samples. Results showed 97 per cent (95 per cent confidence interval, 80.4 to 99.8 per cent) agreement between the tissue of origin test result and the reference diagnosis, which was determined on the basis of clinical correlations and immunohistochemical findings and was among the 15 tumour tissue types covered by the tissue of origin test.

The Pathwork tissue of origin test measures gene expression levels of 2,000 genes and uses algorithms to compare the tumour’s gene expression pattern with that of 15 tumour types, representing 58 morphologies and 90 per cent of all solid tumours. The test provides objective genomic information to help the physician diagnose what type of cancer the patient has. An accurate diagnosis allows oncologists to match therapy to the cancer.

In a related development, results from a study involving the Pathwork tissue of origin test have been presented at the American Association for Cancer Research – International Association for the Study of Lung Cancer joint conference on The Molecular Origins of Lung Cancer: Biology, Therapy and Personalised Medicine in San Diego, CA. The study, “Cost-effectiveness of gene-expression profiling for tumour-site origin”, was authored by John Hornberger, Irina Degtiar, Hialy Gutierrez, Ashwini Shewade, W David Henner, Shawn Becker and Stephen Raab.

The retrospective, observational study examined treatment changes made in patients by physicians who received tissue of origin test results. Changes in planned chemotherapy, surgery, radiation therapy, blood tests, imaging and referral to hospice care before and after test results were recorded. Estimates of the effect of changes in chemotherapy on survival were based on National Comprehensive Cancer Network (NCCN) and other treatment guidelines. Costs were estimated based on data from NCCN and Centers for Medicare and Medicaid Services fee schedules. Changes in overall survival, costs and cost per quality-adjusted life year (QALY) gained were estimated. In the study, use of chemotherapy regimens consistent with guidelines for the final tumour-site diagnosis increased from 42 per cent to 65 per cent. Overall survival was projected to increase from 15.9 months to 19.5 months, a mean gain of 3.6 months. The average increase in survival adjusted for quality of life was 2.7 months and the average cost per QALY gained was US$46,858.

Article source; Diagnostics Focus, edited by Sophie Bracken, medical news editor at Espicom Business Intelligence.

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Gilead Sciences Truvada

Gilead Sciences has submitted an sNDA application for the approval of once-daily Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection among uninfected adults. Truvada was approved by the FDA in 2004 for the treatment of HIV-1 infection and is currently the most-prescribed antiretroviral treatment in the US.

If the sNDA is approved, Truvada would be the first agent indicated for uninfected individuals to reduce the risk of acquiring HIV through sex, a prevention approach called PrEP. The application is based on the results of two large placebo-controlled trials of Truvada as PrEP, sponsored by the National Institutes of Health (NIH) and the University of Washington.

The first trial providing data to support the Truvada sNDA is a Phase III, randomised, double-blind, placebo-controlled trial known as the Pre-Exposure Prophylaxis Initiative (iPrEx), which was sponsored by the NIH and conducted among 2,499 high-risk HIV-negative adult homosexuals in the US and countries in Africa, Asia and South America. Results from the trial, published in the New England Journal of Medicine in November 2010, showed that once-daily use of Truvada for PrEP reduced the risk of acquiring HIV overall by 44 per cent compared with placebo and by up to 73 per cent among men who reported taking the drug consistently (defined as at least 90 per cent of days). Among men who took the drug consistently enough to have detectable drug in their body, the risk was reduced by more than 90 per cent.

The Truvada sNDA submission is also supported by data from Partners PrEP, a Phase III, randomised, double-blind, placebo-controlled trial conducted among 4,758 heterosexual couples in Kenya and Uganda, in which one partner was infected with HIV and the other was not. The trial, sponsored by the University of Washington, showed that once-daily use of oral Truvada by the HIV-negative participants reduced their risk of acquiring HIV by 73 per cent compared with placebo.

Additional supportive data come from two studies sponsored by the Centers for Disease Control (CDC). The first trial, known as TDF2, was a Phase III, randomised, double-blind, placebo-controlled trial conducted in Botswana among 1,200 HIV-negative heterosexual men and women. Participants taking once-daily oral Truvada for PrEP had 63 per cent fewer HIV infections compared with those receiving placebo. The second trial, known as CDC 4323, was a Phase II, randomised, placebo-controlled, double-blind study of homosexual men in the US primarily designed to assess the safety, adherence and acceptability of PrEP.

Although full details are not yet available, another separate Phase III study of Truvada for PrEP known as FEM-PrEP was stopped in April 2011 based on a recommendation by the study’s Independent Data Monitoring Committee that the trial would not be able to establish the efficacy of Truvada among HIV-negative women in sub-Saharan Africa. The reason for this outcome is not yet understood and a complete detailed analysis of the data is currently under way.

In all studies, side-effects included nausea, weight loss and serum creatinine elevations. The incidence of side effects was consistent with Truvada’s safety and tolerability profile when used as HIV treatment, which is supported by more than 1.8 million years of patient use. Overall, there have been more than 4.4 million patient years of experience with tenofovir-containing regimens. Three cases of resistance to emtricitabine were reported in the iPrEx trial among participants who tested negative for HIV infection by serology at enrollment, but were later found to have been infected with HIV prior to enrolment using a different assay. Two of these cases occurred in the active drug arm, and one case occurred in the placebo arm.

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Today’s post on the Medical Technology Blog come from Medical Industry Week, Espicom’s current business publication on the medical industry, please read on…

Researchers from Loyola University Chicago Stritch School of Medicine have discovered a possible new blood test to help diagnose heart attacks.

Featured within the Journal of Molecular and Cellular Cardiology, the investigators provided details of a large protein known as cardiac myosin binding protein-C (cMyBP-C), which is released to the blood following a heart attack. Senior author, Dr Sakthivel Sadayappan, believes this could potentially become the basis for a new test, used in conjunction with other blood tests, to help diagnose heart attacks, however, additional studies will be necessary to establish cMyBP-C as a true biomarker for heart attacks.

Between 60 and 70 per cent of all patients who complain of chest pain do not have heart attacks. Many of these patients are admitted to the hospital, at considerable time and expense, until a heart attack is definitively ruled out. An electrocardiogram can diagnose major heart attacks, but not minor ones. There are also blood tests for various proteins associated with heart attacks, but most of these proteins are not specific to the heart. Elevated levels could indicate a problem other than a heart attack, such as a muscle injury. Only one protein now used in blood tests, called cardiac troponin-I, is specific to the heart, however, it takes at least four to six hours for this protein to show up in the blood following a heart attack.

 The Loyola study is the first to find that cMyBP-C is associated with heart attacks. The researchers evaluated blood samples from heart attack patients, and also evaluated rats that had experienced heart attacks. They found that in both humans and rats, cMyBP-C was significantly elevated following heart attacks. cMyBP-C is a large assembly protein that stabilises heart muscle structure and regulates cardiac function. During a heart attack, a coronary artery is blocked, and heart muscle cells begin to die due to lack of blood flow and oxygen. As heart cells die, cMyPB-C breaks into fragments and is released into the blood. Future studies would determine the time course of release, peak concentrations and half life in the circulatory system. Sadayappan holds a provisional patent to determine the risk factors associated with cMyBP-C degradation and release into human body fluid.

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This weeks artice on the Medical Technology Blog is taken fromEspicom’s business publication, Cardiovascular Device Business, please read on…

In a paper published in the September issue of the Biophysical Journal, lead author Dr Oscar Abilez, a postdoctoral scholar and PhD candidate in bioengineering, and a multidisciplinary team from Stanford University, describe how they have, for the first time, engineered human heart cells that can be paced with light using a technology called optogenetics. In the near term, the researchers say the advance will provide new insight into heart function. In the long term, however, the development could lead to an era of light-based pacemakers and genetically matched tissue patches that replace muscle damaged by a heart attack.

To create the light-responsive heart cells, the researchers first inserted DNA encoding a light-sensitive protein called channelrhodopsin-2 (ChR2), into human embryonic stem cells. ChR2 controls the flow of electrically charged ions into the cell. For heart cells, the primary ion is sodium, which initiates an electrochemical cascade that causes the cell to contract. They then transformed the optogenetically engineered stem cells into cardiomyocytes those that respond to light.

The key protein for the experiment is ChR2, which is sensitive to a very specific wavelength of blue light and regulates tiny channels in the cell surface. When ChR2 is illuminated by the right wavelength of blue light, the channels open to allow an influx of electrically-charged sodium into the cell, producing a contraction. After creating the cells in a laboratory dish, the researchers tested their new cells in a computer simulation of the human heart, injecting the light-sensitive cells in various locations in the heart and shining a virtual blue light on them to observe how the injections affected contraction as it moved across the heart.

In a real heart, the pacemaking cells are on the top of the heart and the contraction radiates down and around the heart. With these models, the researchers say they can demonstrate not only that pacing cells with light will work, but also where to best inject cells to produce the optimal contraction pattern.

The long-term goal is the development of a new class of pacemakers. At present, surgically-implanted electrical pacemakers and defibrillators are commonplace, regulating the pulses of millions of faulty hearts around the world. However, Abilez adds that neither is without problems – pacemakers fail mechanically and the electrodes can cause tissue damage. Defibrillators, on the other hand, can produce tissue damage due to the large electrical impulses that are sometimes needed to restore the heart’s normal rhythm. In the future, the researchers envision that bioengineers will use induced pluripotent stem cells fashioned from the recipient’s own body, or similar cell types that can give rise to genetically matched replacement heart cells paced with light, circumventing the drawbacks of electrical pacemakers.

Co-author, Dr Christopher Zarins, professor emeritus of surgery and director of the lab, speculates the the work could result in a pacemaker that is not in physical contact with the heart. Instead of surgically implanting a device that has electrodes poking into the heart, engineered light-sensitive cells would be injected into the faulty heart and used to pace the heart remotely with light, possibly even from outside of the heart. The leads for such a light-based pacemaker might be placed outside the heart, but inside the pericardium, the protective sack surrounding the heart. Another concept to be explored is a pacemaker placed inside the heart chambers, as with traditional pacemakers, whose light can travel through the intervening blood to pace light-sensitive heart cells implanted inside. Since the new heart cells are created from the host’s own stem cells, they would be a perfect genetic match.

The authors conclude that optogenetics could also lead to advances beyond the heart. It might lead to new insights for various neuronal, musculoskeletal, pancreatic and cardiac disorders, including depression, schizophrenia, cerebral palsy, paralysis, diabetes, pain syndromes and cardiac arrhythmias.

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Today’s article in the Medical Technology Blog is provided by Sophie Sanderson editor of Diagnostics Focus, please read on…

A team of researchers from the UK look to have come up with a ‘cheap and reliable’ diagnostic test for a rare form of cancer – hereditary leiomyomatosis and renal cell cancer (HLRCC) – which involves screening tumour samples for a particular molecular fingerprint unique to this cancer.

HLRCC is a disorder that causes the development of benign, but often painful tumours in the skin and, in females, in the uterus. Between one in six and one in ten people affected by the disorder will go on to develop an aggressive form of kidney cancer called papillary renal cell cancer. The disorder is caused by mutations, which may be inherited, in a gene responsible for the production of an enzyme known as fumarate hydratase (FH). This leads to an accumulation within cells of fumarate, which promotes the development of cancer cells. Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. HLRCC is said to follow an autosomal dominant inheritance pattern, in which a mutation happens in only one copy of the gene – meaning that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation.

Led by researchers at the Henry Wellcome Building for Molecular Physiology, University of Oxford, an international team of scientists claim to have identified a particular protein modification that is induced by FH deficiency (and hence an over-abundance of fumarate). This alteration is unique to this type of tumour and can be used as a biomarker – a biological ‘fingerprint’ to identify tumours caused by this mechanism.

For the first time, scientists are now in a position to screen for tumours caused by this rare, but often very serious condition using a test that is simple, cheap and reliable. The test for this protein modification offers great potential as it can be carried out in under two hours and will identify tumours with FH mutations. This approach is also said to be more cost-effective than genetic testing of all possible cases using DNA sequencing. When screening cases of papillary renal cell cancer using this new test, the researchers identified undiagnosed cases of HLRCC for genetic testing.

In the future, by applying this test in all cases of papillary renal cell cancer to identify people with FH mutations, families could receive advice on their own relative risks of developing the disorder and associated kidney cancer. Dr Lesley Walker, Director of cancer information at Cancer Research UK, reinforces the importance of this notion, stating that “…being able to identify other family members who are at risk so they can be monitored more closely is crucial to improving survival rates from this rare aggressive form of kidney cancer.” Tests like this could also help identify other patients with the same mutation, paving the way for the development of targeted treatments for specific groups of patients that could revolutionalise cancer treatment in the future.

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MJFF launches biomarker initiative study aimed at finding a cure for Parkinsons Disease

In its latest quest to find a cure for Parkinson’s disease (PD), the Michael J Fox Foundation for Parkinson’s Research (MJFF) has unveiled further details of its Parkinson’s Progression Markers Initiative (PPMI), the first-ever large-scale clinical study exclusively focused on identifying and validating PD biomarkers. The study forms a major part of MJFF’s goal to develop a cure for PD within the coming decade. Since it began in 2000, the foundation has spent over US$205 million in specialised research in the field, either directly or through partnerships, which has helped the foundation learn more about the disease; develop better treatments for patients; and, ultimately, move a step closer to ending PD.

The latest five-year study, expected to cost US$40 million over five years, will be funded by the foundation with a lead gift from Lily Safra, a Board member of MJFF, and through the support of industry partners that include Pfizer and GE Healthcare. The PPMI study will be led by principal investigator, Dr Kenneth L Marek, President and Senior Scientist, Institute for Neurodegenerative Disorders, New Haven, CT.

The study will be carried out at 18 sites in the US and Europe, and will track 400 people newly-diagnosed with PD and 200 who do not have the disease. The study is testing the most promising biomarker candidates at present through neuroimaging, the collection of blood, urine, and spinal fluid, and clinical and behavioural tests. Valid measures could allow scientists to predict, objectively diagnose and monitor diseases, as well as definitively determine which medications work and which will not. The goal of the collaboration is to help increase the pace of biomarker validation and clinical testing, as well as accelerate the pace of discovery.

Recruitment of study volunteers is now under way at six sites, with all sites expected to be recruiting by year-end. Sites participating in the PPMI include the University of Alabama; Arizona Parkinson’s Disease Consortium; Baylor College of Medicine; Institute for Neurodegenerative Disorders; Northwestern University; the Parkinson’s Institute and Clinical Center; Boston University; Oregon Health & Science University; and the University of Pennsylvania. Additional sites will also join the study in Atlanta, GA; Tampa, FL; Baltimore, MD; Rochester, NY; Seattle, WA; Innsbruck, Austria; Kassel/Marburg, Germany; Tuebingen, Germany; and Naples, Italy.

Described as an observational study as opposed to an interventional trial, the PPMI will not test any experimental drug. Participants will be contributing to a large body of data and biological specimens whose aim is to further biomarker research. The PPMI will make biological samples and collect clinical data from a single, large and well-characterised cohort available to qualified researchers around the world, to help spark further innovation and collaboration, in order to develop new, more effective treatments more quickly.

When considering the implications of this research for the industry, a biomarker could dramatically reduce both the cost and time of development – since to bring a new central nervous therapy to market requires an investment of over US$1 billion and takes over nine years. Current US annual sales of PD therapies are estimated at US$800 million – however, this could increase to US$2 to US$3 billion with the advent of a disease-modifying therapy.

In the past, PD biomarkers have represented a key area of R&D for MJFF, with approximately US$25 million invested to date over several years. As the foundation embarks on PPMI, it believes more strongly than ever that the discovery of PD biomarkers is a high-impact use of its resources, and that this study will pay dividends towards better treatments and a cure.

This article was taken from an issue of our Espicom’s excellent publication Diagnostics Focus which is edited by Sophie Sanderson

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Welcome back to The Medical Technology blog. My apologies for the lack of posts last week, but I  was extremely busy updating Espicom’s main website. Please read on….

Interesting news has come this week from a study funded by the FDA’s Agency for Healthcare Research and Quality (AHRQ) which gives qualified backing to the adoption of percutaneous heart valve replacement (PVR) procedures in preference to open heart surgery

The report, produced by the Duke Evidence-based Practice Center for AHRQ and published online in the Annals of Internal Medicine, found that PVR, a minimally-invasive procedure in which a replacement valve is implanted through a catheter rather than by open heart surgery, is a realistic option for some patients with heart valve disease, especially older or sicker patients.

The report concluded that this form of heart valve replacement may be a safe and effective alternative to open heart surgery, especially in the short term, for this patient group. However, the FDA body maintains that information is lacking on the potential long-term benefits and risks of this procedure, particularly compared with open heart valve replacement surgery.

In this study, approximately 92 per cent of patients who received a percutaneous valve survived the procedure, of which 86 per cent survived for at least 30 days. The authors looked at 62 published studies representing a total of 856 patients, as well as additional studies that have not yet been published. However, researchers were unable to make direct comparisons between percutaneous valves and traditional surgical replacement due to differences between patient groups receiving the treatments.

In total, seven percutaneous valves were featured in the study, namely the Sapien transcatheter heart valve (Edwards), CoreValve ReValving system, Melody heart valve (Medtronic), Paniagu heart valve (Endoluminal Technology Research), Lotus valve (Sadra Medical) and Ventor Embracer (Ventor Technologies). This particular study didn’t look at the comparative performance of the devices, leaving that to be revealed through other studies currently in progress in the US. The AHRQ argues that there are plenty of comparative “mine’s better than yours” studies but little in the way of  observational studies and decision modelling that could help inform clinical and health policy in the absence of randomised control trials.

It’s an important question since, as with most of the developed world, the US population  proportion of older adults continues to increase, bring with it higher incidences of degenerative heart valve disease. Calcific aortic stenosis (narrowing) and ischaemic and degenerative mitral regurgitation (leakage) are the most common valvular disorders in adults aged 70 years and older.

Mechanical and, more latterly, bioprosthetic heart valves, have radically transformed the way in which we treat patients with heart disease. The urgent need now is to make sure that includes policymakers, decision makers for third-party payers, clinicians, patients and investigators, get the right form of information.

Thanks for reading, and come back soon, Paul.

Hello once again to The Medical Technology Blog. A couple of weeks ago I posted an article concerning the Early Detection of Alzheimer’s Disease (AD) using Eye-Imaging, and today I have another post that also concerns the early identification of Alzheimer’s, using a different method. I apologise if I appear to be concentrating on Alzheimer’s, but as I said before, I think it a horrendous disease. An uncle of mine suffered from AD and by the time he was admitted to a specialist home for Alzheimers sufferers, he could neither recognize his wife, nor my mother, it was heartbreaking for them both. I welcome any study into this disease, please read on….

A study by researchers at the University of California Davis has found that abnormal brain images combined with examination of the composition of the fluid that surrounds the spine may offer the earliest signs identifying healthy older adults at risk of developing Alzheimer’s disease (AD), well before cognitive problems emerge. Published in the journal Neurobiology of Aging, the study analysis identified a subgroup of healthy adults who would later experience a decline in memory performance typical of early AD long before other study participants.

For the study, the scientists used data from the Alzheimer’s Disease Neuro-imaging Initiative, which provides researchers with access to brain scans, clinical data and other laboratory results from spinal fluid and blood tests from more than 800 older adults. Some study participants began with a clean slate of cognitive health, some with mild cognitive impairment, and others with mild or moderate AD.

The researchers analysed data from 220 normal older adults who had undergone structural MRI and clinical examinations, and approximately half also provided spinal fluid samples. Among the 96 participants, cluster analysis identified three distinct subgroups of individuals based solely on their baseline imaging and laboratory measures. Over the next three years, few of these healthy individuals showed any cognitive change. However, cognitive tests for people in one of the subgroups – approximately 10 per cent of the sample – declined at nearly five times the rate as healthy older adults. The researchers believe this group, which had the most extreme MRI and spinal fluid measurements, may represent the earliest stages of subclinical cognitive decline and AD.

The finding is said to be an important step towards discovering the constellation of imaging and fluid biomarkers that foreshadow cognitive decline, as well as a means of determining whether new treatments are effective. It is believed that this method could improve clinical trials for prevention and reduce the numbers of study participants necessary to speed drug discovery – and eventually change how the pharmaceutical industry and National Institutes of Health conduct AD clinical trials.

According to Laurel Beckett, a professor of public health sciences at UC Davis and the lead study author, these findings indicate that a distinctive pattern of imaging and biomarker deviations from typical adults may be an early warning sign of neurobiological pathology and an early sign of AD. By the time people are diagnosed with AD using cognitive tests, there is already a lot of brain damage. It is therefore hoped that future methods combining brain imaging and biomarker assessments can enable earlier diagnosis, while learning more about the mechanisms causing AD so that better treatments can be developed.

Thank you for reading, please check back soon, and feel free to  leave a comment and your name, with a link back to your own site or blog.

Regards, Paul

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