Chemo Regimens Selected by MDs: SNP Test to Predict Side Effects

October 16, 2012 by 2012pharmaceutical

Reporter: Aviva Lev-Ari, PhD, RN

Inform Genomics Developing SNP Test to Predict Side Effects, Help MDs Choose among Chemo Regimens

October 10, 2012

Inform Genomics, a Boston-based diagnostics company, said its “Oncology Preferences and Risk of Toxicity,” or OnPART, test showed greater than 90 percent accuracy in predicting which cancer patients are at risk of experiencing serious side effects to various chemotherapy regimens in an early-stage study.

The company is developing the test to predict a patient’s risk for six common adverse events to combination chemotherapy regimens for colorectal, breast, lung, or ovarian cancer.

Inform Genomics’ president and CEO, Ed Rubenstein, told PGx Reporter that the company is narrowing down a set of SNP signatures that can predict six common moderate to serious side effects linked to different, but equally effective chemotherapy regimens, including dose-dense doxorubicin, cyclophosphamide and paclitaxel for breast cancer; oxaliplatin-based regimens for colorectal cancer; and carboplatin plus paclitaxel-based regimens for lung and ovarian cancer.

Rubenstein said that results from the discovery study, performed at the West Clinic in Memphis, Tenn., showed the signatures for all six side effects — nausea and vomiting, mouth sores, diarrhea, fatigue, cognitive dysfunction, and peripheral neuropathy — had greater than 90 percent predictive accuracy.

“What’s unique about [OnPART],” he said, “is that [it analyzes] not only genomic risk of six common side effects of combination chemotherapy regimens the way they are actually used in clinical practice, but it also includes a way to quantify patients’ concerns for how they view these side effects,” through a copyrighted patient questionnaire the company calls “Preference Assessment Inventory.”

He explained that Inform Genomics intends the test to display for oncologists the risk of these six side effects across different chemotherapy regimens that are considered “relatively equivalent” from an efficacy standpoint “but have wide variation in their toxicity profile.”

The company hopes this will allow patients to discuss with doctors, before beginning therapy, what their real risks are “as opposed to theoretical risks from population-based studies,” Rubenstein said.

He cited the example of a cancer patient who is a professional musician with a high genetic risk for neuropathy, according to OnPART. This patient’s quality of life would be greatly impacted if the chemotherapy regimen he or she was on caused debilitating nerve damage. “When they fill out their concerns and say neuropathy is a concern for them, that allows the doctor to help them understand their risk, and switch their chemotherapy regimen to another that is equally effective but does not put the patient at risk for neuropathy,” Rubenstein explained.

In the company’s discovery study, researchers tested saliva from 384 patients at the West Clinic who had been followed for a minimum of two cycles of chemotherapy and who had reported symptoms of the six side effects using a validated questionnaire.

Using Illumina microarrays, the group profiled 2.5 million potential SNPs to find those that correlated with particular side effects and regimens. Then the team used Inform Genomics’ proprietary Bayesian analysis algorithms to look at interactions between these SNPs.

“We have list of SNPs, and then from that we look at location on genes or outside genes and look at functional pathways and biology to make sure that what we are looking at makes sense,” Rubenstein explained.

Though the exact number of SNPs to be used for each side effect-predictor in OnPART has not yet been determined, Rubenstein said the marketed panel would likely include about 400 SNPs.

“[Our] commercial product is likely to be a custom chip because we don’t need 2.5 million once we’ve narrowed down the predictive SNPs,” he said. “So, let’s say we have six symptoms and each have 80 to 100 SNPs; maybe the chip would be 400 SNPs.”

The company plans to release a more detailed picture of the study and its results at future oncology meetings.

Rubenstein said the next step will be to raise additional capital and then design prospective validation studies for both OnPART and another test the company is developing to predict oral and gastrointestinal mucositis: side effects of high-dose chemotherapy administered before autologous stem cell transplant for multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphoma.

He said Inform Genomics is currently “in dialogue” with large practices and oncology networks who may be part of these future validation efforts.

“Our current plan is that we would launch the [OnPART] product by the third quarter of 2014,” he said. According to the company’s website, the transplant test would follow in 2015.

Molika Ashford is a GenomeWeb contributing editor and covers personalized medicine and molecular diagnostics. E-mail her here.

Personalized Pancreatic Cancer Treatment Option

October 16, 2012 by 2012pharmaceutical

Personalized Pancreatic Cancer Treatment Option

Reporter: Aviva Lev-Ari, PhD, RN

Clovis on Track to Unveil Data on New Personalized Pancreatic Cancer Treatment Option by Year End

October 10, 2012

By Turna Ray

Drug developer Clovis Oncology is planning to report data from a clinical trial later this year that may yield a new treatment option for pancreatic cancer patients who are poor responders to gemcitabine.

Clovis is conducting a study, called LEAP, of 360 chemotherapy-naïve metastatic pancreatic cancer patients who are randomized to receive the current standard of care gemcitabine, or the investigational CO-101, a gemcitabine-lipid conjugate. The study investigators are hypothesizing that unlike gemcitabine, CO-101 won’t depend on the expression levels of the protein cellular transporter hENT1 to enter and destroy tumor cells.

Gemcitabine, currently the first-line standard chemotherapy treatment for metastatic pancreatic cancer patients, requires a transport mechanism to help it enter tumor cells. Previously published data suggest that patients with high hENT1 expression respond well to gemcitabine, while those with low expression — about two-thirds of pancreatic cancer patients — respond poorly to the chemotherapeutic.

LEAP researchers have prospectively collected biopsy samples and have enrolled both high- and low-hENT1 expressers. Study investigators will be blind to the hENT1 expression status of patients until the end of the trial. Clovis is working with Roche subsidiary Ventana Medical Systems to simultaneously develop and validate a companion diagnostic that can gauge low and high hENT1 expression. The primary outcome that study investigators are measuring in LEAP is overall survival in the hENT1-low population.

“The question really is whether the lipid, which facilitates entry into the cell through passive diffusion, is going to be able to deliver gemcitabine as efficiently as when a nucleoside transporter is present,” Clovis CEO Patrick Mahaffy told PGx Reporter. “The answer is we don’t know, but we’ll find out in the study.”

The study may reveal that since CO-101 doesn’t depend on hENT1 to enter tumor cells, all metastatic pancreatic cancer patients, regardless of low or high expression of this protein, derive a level of benefit from the new treatment. Still, Clovis is using a companion test to stratify patients after factoring in reimbursement and cost-effectiveness considerations, which currently are perhaps the biggest barriers to the adoption of personalized treatments.

“Nothing we know suggests that we would be better than gemcitabine … in the hENT1 high population. Given the evolving reimbursement environment and the fact that gemcitabine is generic and is priced as such, pending a successful outcome we anticipate that [CO-101] would be used primarily, if not solely, in the hENT1 low population where we anticipate poor outcomes for gemcitabine,” Mahaffy said. “We anticipate that gemcitabine would continue to be the favored product on price alone even if we were to show equivalence to CO-101 in the hENT1 high population.”

Clovis Oncology will commercialize CO-101 globally. The company is currently setting up commercialization infrastructure in the US for the drug, anticipating a launch as early as next year. Clovis won’t necessarily co-promote CO-101 and the companion test with Ventana. The test developer will be in charge of commercializing the test, and Clovis will market the drug with its sales representatives, who will also be educating oncologists about the need for a companion test.

Ventana will submit its premarket approval application for the hENT1 expression test at the same time that Clovis submits its new drug application for CO-101. The test will be marketed as not just a companion diagnostic to assess whether pancreatic cancer patients have low levels of hENT1 and would therefore respond to CO-101, but Ventana will also be able to market the diagnostic as a tool to determine which high-hENT1 expressing patients should be given gemcitabine.

“The [LEAP] trial will clinically validate the diagnostic both for determining response to both gemcitabine and CO-101,” Mahaffy said.

There are around 120,000 cases of pancreatic cancer each year in the US, EU, and Japan, and around 24 percent of patients survive for one year. Around 80 percent of pancreatic cancer patients receive gemcitabine as monotherapy or in combination with other cytotoxic agents. Based on the low incidence of metastatic pancreatic cancer, Clovis has garnered Orphan Drug status for CO-101 from US and European regulatory authorities.

Although a number of retrospective trials have demonstrated that hENT1 expression levels impact outcomes in pancreatic cancer patients in the metastatic and adjuvant setting, LEAP will be the first prospective validation of this observation. “That’s why this trial is so important to the pancreatic cancer community,” Mahaffy said. “Because not only are we going to learn about CO-101, but we’re going to learn prospectively about the role hENT1 plays in determining the outcome for patients’ treatment with gemcitabine alone.”

Testing for hENT1 expression status is not widely conducted by doctors in the care of pancreatic patients. “In fact, it’s not even widely known in the broader community setting,” noted Mahaffy, adding that academic oncologists are increasingly aware of the association between hENT1 expression and gemcitabine efficacy. After LEAP concludes and if the trial is successful, Clovis plans to initiate discussions with treatment guideline-setting bodies.

In addition to looking at CO-101 as a first-line metastatic pancreatic cancer treatment in hENT1-low patients, Clovis is also studying the drug-conjugate as a second-line treatment in metastatic pancreatic cancer (Phase II), as well as in non-small cell lung cancer (Phase I).

Personalized NSCLC Drug

In addition to CO-101, Clovis has a number of investigational agents in its pipeline that it is developing in molecularly defined patient subsets. For example, CO-1686 is a selective covalent inhibitor of EGFR mutations that the firm is exploring in patients with NSCLC. Currently Clovis is conducting a dose-finding Phase I/II trial involving CO-1686 in NSCLC patients with T790M mutations. Patients with these “gatekeeper” mutations become resistant to treatment to widely prescribed EGFR-inhibiting NSCLC drugs, Roche/Genentech’s Tarceva and AstraZeneca’s Iressa.

CO-1686 “is a very potent inhibitor of T790M … [mutations in] which occur in 50 percent of lung cancer patients, after treatment with Tarceva,” Mahaffy said. After the dose-finding portion of the Phase I/II trial, Clovis plans to initiate an expansion cohort looking at T790M mutation-positive patients who are resistant to Tarceva. “If we see the kind of results we hope to in that expansion cohort, we would initiate a registration study beginning in 2014 in Tarceva-failed patients with T790M mutations,” he said.

While CO-1686 is an inhibitor of T790M mutations and other activating mutations of EGFR, the drug doesn’t inhibit wild-type EGFR like Tarceva and Iressa do, which can make NSCLC patients prone to serious side effects. “What is interesting about [CO-1686] is it is a very potent inhibitor of activating mutations of EGFR, the same targets that Tarceva or Iressa address, but unlike those drugs, [CO-1686] does not inhibit wild-type EGFR,” Mahaffy said. With CO-1686, “we should see very limited rash and diarrhea side effects associated with Tarceva and Iressa.”

First, Clovis will study CO-1686 as a second-line treatment in NSCLC patients with T790M mutations. Eventually, Clovis plans to study the drug head-to-head against Tarceva in the first-line setting. “Given the activity of our drug in animal models so far, we think we may have the ability to demonstrate superiority in terms of efficacy and from the side effects of Tarceva,” Mahaffy said. “We would hope to demonstrate in addition to a cleaner safety profile, a longer duration of benefit, because we would prevent that primary resistance mechanism in T790M from emerging.”

Roche Molecular Systems has partnered with Clovis to develop a companion diagnostic for CO-1686.

Meanwhile, last year, the European Commission approved the use of Roche/Genentech’s Tarceva as a first-line treatment for NSCLC in patients with EGFR mutations (PGx Reporter 9/7/2012). Last month, UK’s National Institute for Health and Clinical Excellence issued a draft guidance recommending that the country’s National Health Service pay for Tarceva as an option for this patient population. The company is in discussions with the US Food and Drug Administration about launching Tarceva in this population (PGx Reporter 06/08/2011).

Additionally, Boehringer Ingelheim is developing afatinib, a drug intended for advanced NSCLC patients with EGFR mutation-positive tumors (PGx Reporter 6/6/2012). Boehringer is working with Qiagen to advance a companion test for its drug.

An NGS-Based Companion Dx?

Another drug in Clovis’ pipeline is an inhibitor of PARP 1 and PARP 2, called rucaparib, which the company licensed from Pfizer. Rucaparib is currently undergoing Phase I/II trials in breast and ovarian cancer. The company is investigating the efficacy and safety of the drug in patients who lack the ability to repair damaged DNA that cancer cells need to thrive.

Mahaffy highlighted that Clovis is currently continuing a dose-finding Phase I study initiated by Pfizer combining rucaparib with carboplatin, and is conducting a Phase I trial investigating the drug as a monotherapy. This latter study will include an extension cohort of ovarian cancer patients with germline BRCA mutations.

Clovis is among a handful of drug developers, including Abbott and AstraZeneca, that are advancing PARP inhibitors with a personalized medicine strategy, betting that patients with BRCA 1/2 mutations will respond better to this class of drugs than those without these mutations. Previous studies have demonstrated that the PARP 1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer tumors. Patients with BRCA mutations can’t repair DNA damage in this way, so then PARP inhibitors can be more effective in stopping cancer growth.

Abbott and AstraZeneca are using a companion test developed by Myriad Genetics to study their PARP inhibitors in BRCA-mutated patients with these diseases. Myriad markets BRACAnalysis, a test that gauges germline BRCA mutations associated with hereditary breast and ovarian cancer. However, gene alternations other than germline BRCA 1/2 mutations are linked to faulty DNA repair and PARP inhibitor response. For example, Clovis estimates that around 15 percent of women with ovarian cancer harbor germline BRCA 1/2 mutations, but another 8 percent of patients have somatic mutations in BRCA. Meanwhile, germline BRCA 1/2 mutations comprise only 5 percent of breast cancers.

When Pfizer was developing rucaparib, it was working with MDxHealth to explore methylation-specific markers associated with DNA damage repair and response to PARP inhibiters (PGx Reporter 2/2/2011). According to MDxHealth both methylation and mutation testing can characterize BRCA gene activity. The company previously estimated that BRCA methylation appears in about 40 percent to 50 percent of triple-negative breast cancer patients, and in about 10 percent to 30 percent in sporadic breast cancers.

Clovis has an open contract with MDxHealth looking at methylation profiles in breast and ovarian cancer, and will continue to explore this approach, specifically for methylated BRCA in triple-negative breast cancer. Additionally, Clovis is “considering the opportunity to look at both germline and somatic mutations of BRCA, based on a tissue-based assay,” Mahaffy said.

Beyond this, in August, Clovis and Foundation Medicine announced they are working together to investigate other genetic defects related to DNA repair deficiency.

“We went with Foundation Medicine … because it will allow us to reach a broader population,” Mahaffy said. For example, in ovarian cancer, Foundation Medicine’s next-generation sequencing platform could identify other mechanisms of DNA repair deficiencies that could potentially increase the intent-to-treat population for rucaparib from 15 percent of ovarian cancer patients with germline BRCA mutations to as much as 50 percent of the population that has somatic mutations in 28 additional genes that have been described as conferring “BRCA-ness” or as having a BRCA-like effect on DNA repair.

Clovis plans to develop a companion test for rucaparib on Foundation Medicine’s Foundation One targeted NGS platform. However, one challenge for Clovis is that the FDA hasn’t yet elucidated how it plans to regulate NGS-based tests. “Clearly, there is a seismic shift underway, and we may be one of the first to have plans to go forward on a premarket approval path with next-gen sequencing,” Mahaffy said. “But clearly the FDA and everyone else knows this tidal wave is coming.”

Clovis hopes to initiate a registration trial in the second half of next year looking at rucaparib as a maintenance therapy in ovarian cancer patients sensitive to platinum-based chemotherapy who have alterations in BRCA and deficiencies in other DNA repair genes. Foundation Medicine and Clovis have separately initiated discussions with the FDA about getting taking NGS-based tests through regulatory approval, Mahaffy said.

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

Country’s Genetic Diversity can predict the success of its Economy: On Economics and Genetics

October 16, 2012 by 2012pharmaceutical

Reporter: Aviva Lev-Ari, PhD, RN

Economics and genetics meet in uneasy union

Use of population-genetic data to predict economic success sparks war of words.

Ewen Callaway

10 October 2012 Corrected:

12 October 2012

The United States has the right amount of genetic diversity to buoy its economy, claim economists.

picture: D. ACKER/BLOOMBERG VIA GETTY

“The invalid assumption that correlation implies cause is probably among the two or three most serious and common errors of human reasoning.” Evolutionary biologist Stephen Jay Gould was referring to purported links between genetics and an individual’s intelligence when he made this familiar complaint in his 1981 book The Mismeasure of Man.

Fast-forward three decades, and leading geneticists and anthropologists are levelling a similar charge at economics researchers who claim that a country’s genetic diversity can predict the success of its economy. To critics, the economists’ paper seems to suggest that a country’s poverty could be the result of its citizens’ genetic make-up, and the paper is attracting charges of genetic determinism, and even racism. But the economists say that they have been misunderstood, and are merely using genetics as a proxy for other factors that can drive an economy, such as history and culture. The debate holds cautionary lessons for a nascent field that blends genetics with economics, sometimes called genoeconomics. The work could have real-world pay-offs, such as helping policy-makers to “reduce barriers to the flows of ideas and innovations across populations”, says Enrico Spolaore, an economist at Tufts University near Boston, Massachusetts, who has also used global genetic-diversity data in his research.

But the economists at the forefront of this field clearly need to be prepared for harsh scrutiny of their techniques and conclusions. At the centre of the storm is a 107-page paper by Oded Galor of Brown University in Providence, Rhode Island, and Quamrul Ashraf of Williams College in Williamstown, Massachusetts¹. It has been peer-reviewed by economists and biologists, and will soon appear in American Economic Review, one of the most prestigious economics journals.

Corrected:

In the original text, we wrongly attributed to Enrico Spolaore the opinion that using genetic data in economics could help policy-makers to set immigration levels. He actually suggested that the work could reduce barriers to the flows of ideas and innovations across populations. The text has been amended to reflect that.

References

Ashraf, Q. & Galor, O. Am. Econ. Rev. (in the press).
Show context
Spolaore, E. & Wacziarg, W. Q. J. Econ. 124, 469–529 (2009).
Show context
Benjamin, D. J. et al. Annu. Rev. Econ. 4, 627–662 (2012).

Posted in Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical | Tagged Genetic diversity, Harvard Medical School, Harvard University, Stephen Jay Gould, Tufts University | Leave a Comment »

Sustained Cardiac Atrial Fibrillation: Management Strategies by Director of the Arrhythmia Service and Electrophysiology Lab at The Johns Hopkins Hospital

October 16, 2012 by 2012pharmaceutical

Atrial Fibrillation: The Latest Management Strategies

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 8/5/2013

Ischemic strokes are the most common type of AFib-related stroke⁵ and can be extremely debilitating.^6,7 It’s important to help your patients understand the risk of ischemic stroke and how you can help lower that risk.

Nearly 9 out of 10 AFib-related strokes are ischemic, and most are cardioembolic^5,8,9

Cardioembolic strokes are most commonly caused by AFib^9,10
Hemorrhagic strokes account for approximately 10% of AFib-related strokes⁵
AFib-related ischemic strokes are primarily caused by an embolus formed in the left atrial appendage of the heart¹¹

Ischemic strokes can be devastating, often resulting in irreversible brain damage²

Debilitating effects of a stroke include paralysis, slurred speech, and memory loss¹²
- Every second, ≈32,000 brain cells can die due to hypoxia from lack of blood flow⁴
- In 1 minute, nearly 2 million brain cells can die—increasing the risk of disability or death^2-4
Severely disabling stroke is frequently rated by patients as equivalent to or worse than death¹³

Strokes are a leading cause of disability in the US¹⁴

The good news is you can significantly reduce your AFib patients’ risk of ischemic stroke with anticoagulation therapy.^11,15,16 By keeping them appropriately anticoagulated, you can help your patients avoid the devastation of ischemic stroke.¹¹

AFib=atrial fibrillation.

References

Types of stroke. Johns Hopkins Medicine Web site. http://www.hopkinsmedicine.org/healthlibrary/printv.aspx?d=85,P00813. Accessed August 9, 2012.
Maas MB, Safdieh JE. Ischemic stroke: pathophysiology and principles of localization. Hospital Physician Neurology Board Review Manual. 2009;13:1-16.http://www.turner-white.com/pdf/brm_Neur_V13P1.pdf. Accessed February 1, 2013.
Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke. 1999;30:736-743.
Saver JL. Time is brain—quantified. Stroke. 2006;37:263-266.
Mercaldi CJ, Ciarametaro M, Hahn B, et al. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation. Stroke. 2011;42:112-118.
Vemmos KN, Tsivgoulis G, Spengos K, et al. Anticoagulation influences long-term outcome in patients with nonvalvular atrial fibrillation and severe ischemic stroke. Am J Geriatr Pharmacother. 2004;2:265-273.
Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27:1760-1764.
Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German Stroke Data Bank. Stroke. 2001;32:2559-2566.
Bogousslavsky J, Van Melle G, Regli F, Kappenberger L. Pathogenesis of anterior circulation stroke in patients with nonvalvular atrial fibrillation: the Lausanne Stroke Registry. Neurology. 1990;40:1046-1050.
Freeman WD, Aguilar MI. Prevention of cardioembolic stroke. Neurotherapeutics. 2011;8:488-502.
Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:700-752.
Effects of stroke. American Stroke Association Web site. http://www.strokeassociation.org/STROKEORG/AboutStroke/EffectsofStroke/Effects-of-Stroke_UCM_308534_SubHomePage.jsp. Accessed December 8, 2012.
Gage BF, Cardinalli AB, Owens DK. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life. Arch Intern Med. 1996;156:1829-1836.
Centers for Disease Control and Prevention (CDC). Prevalence of Stroke—United States, 2006-2010. MMWR Morb Mortal Wkly Rep. 2012;61:379-382.
Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151:297-305.
Lip GYH, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace. 2011;13:723-746.

SOURCE

http://www.medscape.com/infosite/afib/public/

Straightforward, informed answers to your most important questions about living

with atrial fibrillation – the most common sustained cardiac arrhythmia.

Written by

Hugh G. Calkins, M.D., Director of the Arrhythmia Service

and Electrophysiology Lab at The Johns Hopkins Hospital,

and Ronald Berger, M.D.,

If you’ve ever run up a flight of stairs, chased a tennis ball across the court, or reacted in fright at a scary movie, you know what a pounding heart feels like…

But for the 2.3 million Americans who suffer from atrial fibrillation (AF or AFib), a racing heart is a way of life. Simple tasks like getting out of bed in the morning or rising from a chair can cause dizziness, weakness, shortness of breath, or heart palpitations. For these people, AF severely impairs quality of life – and even when symptoms stemming from AF are mild, the disorder can seriously impact health, increasing the risk of stroke and heart failure.

AF can be a debilitating even deadly condition. Fortunately, it can be successfully managed – but there are various approaches for treating AF or preventing a recurrence. How do you and your doctor choose which approach is right for you?

If you or a loved one has AF, there are so many questions: Do I need an anticoagulant… should I be taking medication to control my heart rate… will my symptoms respond to cardioversion… if I need an antiarrhythmic drug to control AF episodes, which one should I take… when is an ablation procedure appropriate… and more.

It’s critically important to learn everything you can now — so you can partner with your doctor effectively, ask the right questions, and understand the answers.

To help you, we asked two eminent experts at Johns Hopkins to share their expertise and hands-on experience with arrhythmia patients in an important new report, Atrial Fibrillation: The Latest Management Strategies.

Dr. Hugh Calkins and Dr. Ronald Berger are ideally positioned to help you understand and manage your AF. Together with their colleagues at Johns Hopkins, they perform approximately 2,000 electrophysiology procedures and 200 pulmonary vein isolation procedures for atrial fibrillation each year.

Hugh Calkins, M.D. is the Nicholas J. Fortuin, M.D. Professor of Cardiology, Professor of Pediatrics, and Director of the Arrhythmia Service, the Electrophysiology Lab, and the Tilt Table Diagnostic Lab at The Johns Hopkins Hospital. He has clinical and research interests in the treatment of cardiac arrhythmias with catheter ablation, the role of device therapy for treating ventricular arrhythmias, the evaluation and management of syncope, and the study of arrhythmogenic right ventricular dysplasia.

Ronald Berger, M.D., Ph.D., a Professor of Medicine and Biomedical Engineering at Johns Hopkins, is Director of the Electrophysiology Fellowship Program at The Johns Hopkins Hospital. He serves on the editorial board for two major journals in the cardiovascular field and has written and coauthored more than 100 articles and book chapters.

Atrial Fibrillation: The Latest Management Strategies is now available to you in a digital PDF download and print version.

“I feel like my heart is going to jump out of my chest…”

An arrhythmia is an abnormality in the timing or pattern of the heartbeat, causing the heart to beat too rapidly, too slowly, or irregularly. Sounds pretty straightforward, but there’s a lot we don’t know about why the heart rhythm goes awry… or the best way to treat it.

In Atrial Fibrillation: The Latest Management Strategies, we focus on what we DO know. In page after page of this comprehensive report, we address your most serious concerns about living with AF, such as:

I don’t have any symptoms. Is my problem definitely AF?
Can drinking alcohol trigger or worsen AF?
Is every person who has AF at risk for a stroke?
If my doctor suspects AF, will I have to wear an implantable or event monitor to be sure?
Why does AF often show up later in life?
What would you recommend to the older patient – 75 and older – who has AF but no bothersome symptoms?
What do you recommend for the person with longstanding persistent AF?
Is the AF experienced by an otherwise healthy person different from that of a person with underlying heart disease or other health issues?
What are the differences among: paroxysmal AF, persistent AF, and longstanding persistent AF?
What is the “pill-in-the-pocket” approach to AF?

Anticoagulation Therapy: What You Should Know

While AF is generally not life threatening, for some patients it can increase the likelihood of blood clots forming in the heart. And if a clot travels to the brain, a stroke will result. Anticoagulation therapy is used to prevent blood clot formation in people with AF…

Why is anticoagulation therapy with warfarin (Coumadin) needed for some people with AF?
How is the use of warfarin monitored?
How does a doctor determine if a patient with AF needs to take warfarin?
What’s the CHADS2 score and how is it used?
If a patient’s CHADS2 score is 1, how do you decide between aspirin and warfarin, or nothing at all?
Why is it so difficult to keep within therapeutic range with warfarin?
Can I test my INR (a test measuring how long it takes blood to clot) at home?
What happens if my INR is too high?
What options are available if a patient cannot take warfarin?
What are the benefits of dabigatran, a new blood-thinning alternative to warfarin therapy?

Symptom Control: The Art of Rate and Rhythm Control

For many patients and their doctors, it’s difficult to achieve and maintain heart rhythm. Two key management strategies are used: heart rate and heart rhythm control. In Atrial Fibrillation: The Latest Management Strategies, you’ll read an in-depth discussion of the benefits of rate versus rhythm control for AF:

What have we learned from the AFFIRM study, and how has this knowledge affected the management of AF?
What is catheter ablation of the AV (atrioventricular) node?
Why is cardioversion needed?
Are there different types of cardioversion?
What is chemical cardioversion? What is electrical cardioversion?
Can medication be used to convert the heart back to normal sinus rhythm?
Which antiarrhythimic drugs are used to treat AF?
How is catheter ablation for AF performed?
What is pulmonary vein antrum isolation (PVAI) and how is it performed?
Who are the best candidates for PVAI?

There’s more to Atrial Fibrillation: The Latest Management Strategies, much more.

We explain surgical ablation of AF, a procedure performed through small incisions in the chest wall… discuss when it’s appropriate to seek a second opinion… take a close look at strokes and explain the warning signs and differences among ischemic, thrombotic, embolic, and hemorrhagic strokes… and provide an arrhythmia glossary of key AF terms used by electrophysiologists and cardiologists.

Direct to You From Johns Hopkins

Atrial Fibrillation: The Latest Management Strategies is designed to give you unprecedented access to the expertise of the hospital ranked #1 of America’s Best Hospitals for 21 consecutive years 1991-2011 by U.S. News & World Report. You simply won’t find a more knowledgeable and trustworthy source of the medical information you require. A tradition of discovery and medical innovation is the hallmark of Johns Hopkins research. Since its founding in 1889, The Johns Hopkins Hospital has led the way transferring the discoveries made in the laboratory to the administration of effective patient care. No one institution has done more to earn the trust of the men and women diagnosed with AF and other cardiovascular conditions.

http://www.johnshopkinshealthalerts.com/eletter/profile/8975/92954.html?ET=johnshopkins:p92954:1366266a:&st=pmail&s=PFH_121008_A10

Posted in Bio Instrumentation in Experimental Life Sciences Research, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Medical Devices R&D Investment, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Technology Transfer: Biotech and Pharmaceutical | Tagged Atrial fibrillation, Biomedical Engineering, Cardiovascular Disorders, CHADS2 score, Conditions and Diseases, Heart disease, Heart Rhythm Society, Hugh Calkins, Johns Hopkins, Johns Hopkins Hospital, Ronald Berger, Stroke | 2 Comments »

Centers for Medicare and Medicaid (CMS) Targets Hospital Readmissions – Update on Practices and Policy

October 16, 2012 by Alan F. Kaul, PharmD., MS, MBA, FCCP

Reporter: Alan F. Kaul, Pharm.D., M.S., M.B.A., FCCP

Centers for Medicare and Medicaid (CMS) Targets Hospital Readmissions – Update on Practices and Policy

An earlier post on June 8, 2012 in Pharmaceutical Intelligence presented an overview of the Hospital Readmissions Reduction Program (HRRP) and its requirement to reduce payments under the Inpatient Prospective Payment System (IPPS) to hospitals reporting excess readmissions commencing with discharges on October 1, 2012. As CMS moved forward with HRRP, hospitals readiness for population based accountable care seemed questionable based on a 34 percent survey response or 1,672 hospitals.

http://pharmaceuticalintelligence.com/2012/06/12/centers-for-medicare-and-medicaid-cms-targets-hospital-readmissions-a-disconnect-among-the-hospitals-or-poor-education/

According to Medicare Payment Advisory Commission (MedPAC) report, approximately two-thirds of hospitals will be penalized (capped at 1 percent) for above average readmissions commencing October 1, 2012. This penalty will escalate to 2% in 2014 and 3 percent in 2015. Looking at the hospital readmission measures for Acute Myocardial Infarction (AMI), Heart Failure (HF), and Pneumonia (PN), this penalty will average $125,000 per hospital. Overall, the CMS payment to all hospitals will be reduced by 0.24 percent. A preliminary analysis indicated little variation by hospital type (i.e., urban, rural, teaching, non-teaching, profit, non-profit).

MedPAC pointed out several long-term issues with the readmission reduction program including:

Computing the penalty multiple – Penalty increases as readmission rate decreases and the penalty multiplier differs for each condition. Solutions could include using a fixed multiplier, using all-condition readmissions, and eliminating the multiplier and setting a lower target readmission rate to maintain budget neutrality
Random variation and small number of observations – Solutions could include using all-condition readmissions, using more than the 3 years of data currently used, and allowing hospitals to aggregate performance within a system for penalty purposed while continuing to report individual hospital performance
Unrelated and planned readmissions – Solutions could include switching to a-condition measures that have exceptions for planned and unrelated readmissions such as the Yale all condition model or the 3M all-condition model.
Socio-economic status and risk-reduction- Possible situations may include allow current incentives to close the gap, comparing hospitals against similar hospitals to compute the penalty, and providing financial assistance to hospitals with a disproportionate share of low-income patients

Moving forward in refining the policy several objectives were noted: maintaining or increasing average hospitals’ incentive to reduce readmissions; increasing the share of hospitals with an incentive to reduce readmissions; making any penalty a consistent multiple of the cost of readmissions; being at least budget neutral to current policy, with a preference for lower readmission rates rather than higher penalties. Any policy refinements will require a change in law and must proceed carefully.

http://www.medpac.gov/transcripts/readmissions Sept 12 presentation.pdf

On October 3, 2012, CMS issues a notice indicating that errors were discovered in its initial calculation for readmissions penalties under the Inpatient Prospective Payment Systems (IPPS) that went into effect the beginning of October. The revisions were in part to implement capital and operating related costs to acute care hospitals arising from CMS’s continued experience with the systems. Also updated were payment policies and rate of increase limits for certain hospitals excluded from IPPS and paid under Medicare’s Prospective Payment System such as Long Term Acute Care Hospitals (LTACHs).

Based on a Kaiser analysis of the miscalculation, 1,422 hospitals will lose more and 55 hospitals will lose less than originally projected. The changes were tiny averaging 0.002 percent of a hospital’s regular Medicare reimbursement. A total of 2,217 hospitals are being punished in the first year of the program which began on October 1, 2012. Of those punished, 307 (14%) will be penalized the maximum 1% of their regular Medicare reimbursement.

http://cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/FY-2013-IPPS-Final-Rule-Home-Page-Items/CMS-1588-F-Text-Version.html

http://www.kaiserhealthnews.org/Stories/2012/October/03/medicare-revises-hospitals-readmissions-penalties.aspx

As reported in the Napa Valley Register on October 14, 2012, variations in local practices patterns are already being noticed. For example in Napa Valley, Queen of Valley Medical Center has a 18 percent readmission rate, St. Helena Hospital a 13 percent readmission rate, and Kaiser Permanente Vallejo Medical Center a 7 percent readmission rate. Local hospital officials are claiming that reduced readmissions incorrectly assumes better care and that not making exceptions for unavoidable readmissions are policy flaws. While officials at Kaiser Permanente of Northern California indicated that they had no concerns about the policy change because “it promotes co-ordianation of care, individuals at Queen of Valley Medical Center and St Helena’s Hospital expressed a variety of concerns from the fragile natur of patients in certain of the included diagnoses and the 30-day time fram to evaluate readmissions. Moving forward to lower readmission rates at Queen and St. Helena indicated that they will pay more attention as patients are discharged from the hospitals during transitions of care, Professionals will coach patients in self-management through home visits and phone-calls after they have been discharged from the hospital.

http://napavalleyregister.com/news/local/local-hospitals-challenged-to-cut-medicare-readmissions/article_1827ecfc-159c-11e2-8ad2-001a4bcf887a.html?comment_form=true

Posted in Health Economics and Outcomes Research, Health Law & Patient Safety, Population Health Management, Genetics & Pharmaceutical, Statistical Methods for Research Evaluation | Tagged aca, ACO, CMS, popualtion health | Leave a Comment »

Why is Dysthymia, a chronic form of Depression, serious, requiring Medical Intervention

October 16, 2012 by 2012pharmaceutical

Reporter: Aviva Lev-Ari, PhD, RN

Dysthymia: Often Chronic, Always Serious

Johns Hopkins Health Alert

Dysthymia is a chronic form of depression that is characterized by the presence of a depressed mood for most of the day, for more days than not, over a period of at least two years. Dysthymia may be intermittent and interspersed with periods of feeling normal, but these periods of improvement last for no more than two months.

Dysthymia often goes unnoticed. And because of its chronic nature, the person may come to believe, “I’ve always been this way.” In addition to depressed mood, symptoms of dysthymia include two or more of the following:

poor appetite or overeating
insomnia or hypersomnia (excessive sleeping)
low energy or fatigue
low self-esteem
poor concentration or difficulty making decisions
feelings of hopelessness

It is far better to treat dysthymia than to think of it as a minor condition. Bypassing treatment places people at increased risk for subsequently developing major depression. In fact, about 10 percent of people with dysthymia also have recurrent episodes of major depression, a condition known as double depression.

What causes of dysthymia? Some medical conditions, including neurological disorders (such as multiple sclerosis and stroke), hypothyroidism, fibromyalgia and chronic fatigue syndrome, are associated with dysthymia. Investigators believe that, in these cases, developing dysthymia is not a psychological reaction to being ill but rather is a biological effect of these disorders.

There are many reasons for this connection. It may be that these medical conditions interfere with the action of neurotransmitters, or that medications (such as corticosteroids or beta-blockers) taken for a medical illness may trigger the dysthymia or that both dysthymia and the medical illness are related in some other way, reinforcing each other in a complicated manner.

Dysthymia can also follow severe psychological stress, such as losing a spouse or caring for a chronically ill loved one. Older people who have never had psychiatric disorders are particularly susceptible to developing dysthymia after significant life stresses.

Posted in Depression and Anxiety on October 16, 2012

Medical Disclaimer: This information is not intended to substitute for the advice of a physician. Click here for additional information: Johns Hopkins Health Alerts Disclaimer

http://www.johnshopkinshealthalerts.com/alerts/depression_anxiety/Dysthymia-Symptoms_6339-1.html?ET=johnshopkins:e92813:1366266a:&st=email&s=EDH_121016_001

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Innovations in Neurophysiology & Neuropsychology, Pain: Etiology, Genetics & Innovations in Treatment, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry | Tagged depression, Dysthymia, Johns Hopkins, Major depressive disorder, Mental health, Self-esteem | Leave a Comment »

Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?

October 16, 2012 by Dror Nir

Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?

Author: Dror Nir, PhD

Advances in techniques for cancer lesions’ detection and localisation [1-6] opened the road to methods of localised (“focused”) cancer treatment [7-10]. An obvious challenge on the road is reassuring that the imaging-guided treatment device indeed treats the region of interest and preferably, only it.

A step in that direction was taken by a group of investigators from Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada who evaluate the feasibility and safety of magnetic resonance (MR) imaging–controlled transurethral ultrasound therapy for prostate cancer in humans [7]. Their study’s objective was to prove that using real-time MRI guidance of HIFU treatment is possible and it guarantees that the location of ablated tissue indeed corresponds to the locations planned for treatment. Eight eligible patients were recruited.

The setup

Treatment protocol

The result

“There was excellent agreement between the zone targeted for treatment and the zone of thermal injury, with a targeting accuracy of ±2.6 mm. In addition, the temporal evolution of heating was very consistent across all patients, in part because of the ability of the system to adapt to changes in perfusion or absorption properties according to the temperature measurements along the target boundary.”

Technological problems to be resolved in the future:

“Future device designs could incorporate urinary drainage during the procedure, given the accumulation of urine in the bladder during treatment.”

“Sufficient temperature resolution could be achieved only by using 10-mm-thick sections. Our numeric studies suggest that 5-mm-thick sections are necessary for optimal three-dimensional conformal heating and are achievable by using endorectal imaging coils or by performing the treatment with a 3.0-T platform.”

Major limitation: “One of the limitations of the study was the inability to evaluate the efficacy of this treatment; however, because this represents, to our knowledge, the first use of this technology in human prostate, feasibility and safety were emphasized. In addition, the ability to target the entire prostate gland was not assessed, again for safety considerations. We have not attempted to evaluate the effectiveness of this treatment for eradicating cancer or achieving durable biochemical non-evidence of disease status.”

References

SIMMONS (L.A.M.), AUTIER (P.), ZATURA (F.), BRAECKMAN (J.G.), PELTIER (A.), ROMICS (I.), STENZL (A.), TREURNICHT (K.), WALKER (T.), NIR (D.), MOORE (C.M.), EMBERTON (M.). Detection, localisation and characterisation of prostate cancer by Prostate HistoScanning.. British Journal of Urology International (BJUI). Issue 1 (July). Vol. 110, Page(s): 28-35
WILKINSON (L.S.), COLEMAN (C.), SKIPPAGE (P.), GIVEN-WILSON (R.), THOMAS (V.). Breast HistoScanning: The development of a novel technique to improve tissue characterization during breast ultrasound. European Congress of Radiology (ECR), A.4030, C-0596, 03-07/03/2011.
Hebert Alberto Vargas, MD, Tobias Franiel, MD,Yousef Mazaheri, PhD, Junting Zheng, MS, Chaya Moskowitz, PhD, Kazuma Udo, MD, James Eastham, MD and Hedvig Hricak, MD, PhD, Dr(hc) Diffusion-weighted Endorectal MR Imaging at 3 T for Prostate Cancer: Tumor Detection and Assessment of Aggressiveness. June 2011 Radiology, 259,775-784.
Wendie A. Berg, Kathleen S. Madsen, Kathy Schilling, Marie Tartar, Etta D. Pisano, Linda Hovanessian Larsen, Deepa Narayanan, Al Ozonoff, Joel P. Miller, and Judith E. Kalinyak Breast Cancer: Comparative Effectiveness of Positron Emission Mammography and MR Imaging in Presurgical Planning for the Ipsilateral Breast Radiology January 2011 258:1 59-72.
Anwar R. Padhani, Dow-Mu Koh, and David J. Collins Reviews and Commentary – State of the Art: Whole-Body Diffusion-weighted MR Imaging in Cancer: Current Status and Research Directions Radiology December 2011 261:3 700-718
Eggener S, Salomon G, Scardino PT, De la Rosette J, Polascik TJ, Brewster S. Focal therapy for prostate cancer: possibilities and limitations. Eur Urol 2010;58(1):57–64).
Rajiv Chopra, PhD, Alexandra Colquhoun, MD, Mathieu Burtnyk, PhD, William A. N’djin, PhD, Ilya Kobelevskiy, MSc, Aaron Boyes, BSc, Kashif Siddiqui, MD, Harry Foster, MD, Linda Sugar, MD, Masoom A. Haider, MD, Michael Bronskill, PhD and Laurence Klotz, MD. MR Imaging–controlled Transurethral Ultrasound Therapy for Conformal Treatment of Prostate Tissue: Initial Feasibility in Humans. October 2012 Radiology, 265,303-313.
Black, Peter McL. M.D., Ph.D.; Alexander, Eben III M.D.; Martin, Claudia M.D.; Moriarty, Thomas M.D., Ph.D.; Nabavi, Arya M.D.; Wong, Terence Z. M.D., Ph.D.; Schwartz, Richard B. M.D., Ph.D.; Jolesz, Ferenc M.D. Craniotomy for Tumor Treatment in an Intraoperative Magnetic Resonance Imaging Unit. Neurosurgery: September 1999 – Volume 45 – Issue 3 – p 423
Medel, Ricky MD, Monteith, Stephen J. MD, Elias, W. Jeffrey MD, Eames, Matthew PhD, Snell, John PhD, Sheehan, Jason P. MD, PhD, Wintermark, Max MD, MAS, Jolesz, Ferenc A. MD, Kassell, Neal F. MD. Neurosurgery: Magnetic Resonance–Guided Focused Ultrasound Surgery: Part 2: A Review of Current and Future Applications. October 2012 – Volume 71 – Issue 4 – p 755–763
Bruno Quesson PhD, Jacco A. de Zwart PhD, Chrit T.W. Moonen PhD. Magnetic resonance temperature imaging for guidance of thermotherapy. Journal of Magnetic Resonance Imaging, Special Issue: Interventional MRI, Part 1, Volume 12, Issue 4, pages 525–533, October 2000

Writer: Dror Nir, PhD

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Imaging-based Cancer Patient Management | Tagged biopsies, brain lesion, breast biopsies, breast biopsy, breast cancer, breast cancer mortality, breast cancer screening, breast screening, Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, cancer patient management, Clinical trial, cost efficient cancer diagnosis, cost efficient cancer treatment, cost efficient solution, CT scans, directed biopsies, DW MRI, efficient business, european congress of radiology, evidence based medicine, free hand biopsies, guided biopsies, hands on appoach, health, healthcare, healthcare business, imaging guided biopsies, imaging in cancer, Imaging-based Cancer Patient Management, Imaging-based Cancer Patient Management | Tagged biopsies, innovation in health, innovation in healthcare, Magnetic resonance imaging, magnetic resonance imaging mri, magnetic tracking, mammography, Medical Devices R&D Investment, medicine, MRI, MRI imaging, multi-functional MRI, mutation, open mri systems, personalised medicine, prostat cancer screening, Prostate, Prostate biopsy, Prostate cancer, prostate guided biopsies, prostate hisoscanning, Prostate-specific antigen, radiographically dense breasts, research, science, tagged biopsy needles, tracking, Transrectal ultrasonography, Triple-negative breast cancer, TRUS, ultrasound guided breast biopsy breast biopsy, ultrasound imaging, ultrasound imaging Bio Instrumentation in Experimental Life Sciences Research | 23 Comments »

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

October 15, 2012 by anamikasarkar

Author and Reporter: Anamika Sarkar, Ph.D.

Targeted therapies are proven approaches in Cancer and other complicated diseases. Degrees of activation of measured EGFR and ERB2/HER2 in cancer cells are thought of one of the ways to identify the scale of aggressiveness of cancer in tissues. There are drugs, mostly for breast cancer, which targets inhibition of these receptors. Lapatinib (Tykerb, GSK – see Source for other targeted drugs) is the first drug which inhibits both EGFR and ERB2/HER2 gave hope to cancer patients, especially advanced ERB2-postive or metastatic breast cancer patients. Despite of proven high efficacy, Lapatinib didn’t show promising results in clinical responses due to acquired resistance.

Komurov et. al. (Mol. Systems.Biol., 2012) used network analysis along with experimental findings on cultured human breast cancer cell lines (SKBR3) and showed that a large part of acquired resistance to Lapatinib is due to increased levels of activated states of glucose deprivation signaling network. The authors cultured ERB2-positive SKBR3 cells with increasing doses of Lapatinib, to make the control cell lines for analyzing their experimental results in comparison with (SKBR3- R),SKBR3-Resistant cells. Their Western Blot analysis showed that Lapatinib was successful to inhibit down signaling pathways to ERB2 and EGFR in both control and resistant cells however fails to induce apoptotic pathways in resistant cells when compared with the controlled cells.

To identify other factors which can influence the differential effects of Lapatinib on controlled and resistant cell lines, Komurov et. al. used a data biased random walk network analysis method called Netwalk (Komurov et. al. PLOS Comp Biol., 2010). Their method is data driven and based on comparative network analysis of gene expressions at different conditions rather than network analysis at one gene level. Their network analysis identified presence of high levels of genes which act as compensatory mechanisms for glucose deprivation (as shown in Figure 2 of the paper Komurov et. al. (2012) Figure 2). They showed validation of their network analysis findings using Western Blot analysis (as shown in Figure 3 of the paper Komurov et.al. (2012) Figure 3).

The authors’ results not only show a nice elegant way of finding new information using network analysis and experimental techniques together, but also points out an important concept which can be future of cancer therapy. Their results show that along with targeting mutated Oncogenes eg., EGFR and ERB2/HER2 as in case of Lapatinib, additional way of controlling the pathway of deprivation of glucose, can achieve better clinical responses for cancer patients with aggressive levels of cancer. Targeting glucose or pathways of glucose can be tricky, because of its ubiquitous links to many physiological functions, including metabolism. However, the levels at which these pathways need to be targeted to achieve certain positive responses at in-vitro, supported by systems biology methods, and then in-vivo studies can be informative. Moreover, targeting many parts in the network in smaller amounts, along with targeted cancer drugs, may produce interesting results.

Sources:

Komurov et.al. (2012) : http://www.ncbi.nlm.nih.gov/pubmed/22864381

A News and Views on Lapatinib (2005) : http://www.emilywaltz.com/Herceptin.pdf

Komurov et.al. (2010) – Article published on methods of Netwalk : http://www.ncbi.nlm.nih.gov/pubmed/20808879

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Pharmaceutical R&D Investment, Uncategorized | Tagged Cancer - General, Cell Biology, Clinical trial, Conditions and Diseases, ERB2, genome, GlaxoSmithKline, HER2, Lapatinib, medicine, network analysis, systems biology, targeted therapies. EGFR | 4 Comments »

Mediterranean Diet is BEST for patients with established Heart Disorders

October 15, 2012 by 2012pharmaceutical

Reporter: Aviva Lev-Ari, PhD, RN

What’s Up with the Mediterranean Diet?

Why Heart Doctors Love It

Most of us have heard about the Mediterranean diet, which has generated interest from both the media and the medical community as the gold standard in healthy eating. But what’s all the fuss about – is this diet really worth all the attention?

The answer is yes, according toMurray Mittleman, MD, DrPH, a physician in the CardioVascular Institute at Beth Israel Deaconess Medical Center, Director of the Master’s in Public Health program at Harvard Medical School, and Director of cardiovascular epidemiological research at BIDMC.

“The Mediterranean diet is a very healthy eating style that has been shown to improve cardiovascular risk factors – even for patients with established heart disorders,” Mittleman says.

What is the Mediterranean Diet?

While most healthy diets include produce, whole grains, and fish, the Mediterranean diet and lifestyle offer subtle differences that may reduce the risk for heart disease, while making it easier to stick to healthy eating habits.

According to the American Heart Association, traditional Mediterranean diets have the following characteristics in common:

High consumption of fruits, vegetables, beans, nuts and grains
Use of olive oil rather than saturated fats like butter, lard, and cottonseed, palm and coconut oils
Low to moderate consumption of dairy, eggs, fish and poultry
Very little red meat
Wine in low-to-moderate amounts

The Diet’s “Discovery”

Originating from the culture and traditional foods found in the area bordering the Mediterranean Sea, this diet first drew the attention of the American scientist Ancel Keys, who was stationed in Italy during World War II. Keys became convinced that middle-aged American men were experiencing heart attacks due to their diets and lifestyles. After conducting studies in the U.S., he began to work with researchers overseas in the first cross-cultural comparison of males and heart attack risk in what is known as the Seven Countries Study.

Starting in 1958, the Seven Countries Study followed 11,579 men, 40 to 59 years of age, in four regions of the world (United States, Northern Europe, Southern Europe and Japan). This study found that men in Southern Europe were far less likely to experience coronary deaths than those in the U.S. and Northern Europe. The study also began to identify the eating pattern known as the Mediterranean diet and its protective benefits.

Since then, “additional research has continued to show the beneficial effects of the diet,” says Mittleman. “The Lyon Diet Heart Study, conducted in the 1990s in France, showed that those who followed the Mediterranean Diet for three years had significantly fewer additional heart attacks and a 76 percent reduction in cardiovascular deaths compared to the control group.”

How Does it Work?

Murray A. Mittleman, MD, DrPH

The Mediterranean diet is a combination of many healthy choices that work together to promote good health, according to Mittleman.

“There is a low intake of refined carbs and very little processed food, which is an important distinction that also lowers fat and salt content,” he explains. “There is more variety in fruit and vegetable consumption, and portions are smaller than those commonly found in the U.S.”

Understanding how and why the Mediterranean diet works involves looking at each of the components that make up this particular style of eating.

Healthy Fats

The Mediterranean diet does not focus on limiting total fat consumption, but it does avoid the use of saturated fats and hydrogenated oils (trans fats), which both contribute to heart disease.

Most of the fat calories in a Mediterranean diet come from “good” or monounsaturated fats, mainly from olive oil and also from nuts.

“These plant-based fats don’t raise blood cholesterol levels the way saturated fat does,” says Mittleman. “In fact, monounsaturated fats actually help reduce LDL cholesterol levels when used in place of saturated or trans fats.”

Monounsaturated fats such as olive, canola, sesame, sunflower and corn oils contain alpha-linolenic acid, a type of omega-3 fatty acid from plant sources. Omega-3 fatty acids lower triglycerides, moderate blood pressure, decrease blood clotting and improve the health of your blood vessels.

Light Protein Sources

Fish is frequently on the menu of the Mediterranean diet, and red meat is rarely served. Light in calories, fish is a beneficial substitute for meat-heavy Western cuisine, which is higher in unhealthy saturated fat. In addition, fish such as mackerel, lake trout, herring, sardines, albacore tuna and salmon are rich sources of omega-3 fatty acids.

Other plant-based protein sources, such as beans and nuts, also predominate in this style of eating. These vegetable protein sources are also light on saturated fat, helping to keep cholesterol and blood pressure in check.

Plenty of Produce

A wide variety of fruits and vegetables play an important role in the Mediterranean diet, and include fresh salads, greens sautéed in garlic and olive oil, soups, and vegetarian pasta dishes.

Fruits, such as melon, often serve as dessert, rather than the sweetened, high-fat concoctions that Western-style dining offers. Baked sweets are generally reserved for holidays or special occasions. Fresh produce provides phytonutrients that prevent and repair damage to cells and protect blood vessels. In addition, the added fiber in the diet slows the release of glucose in the blood stream, which is an important way to help prevent or control diabetes.

A Little Wine

Kenneth J. Mukamal, MD, MPH

The Mediterranean diet typically includes a small amount of wine. While red wine has antioxidant properties, the amount, frequency and style of enjoying wine is what makes this an important part of Mediterranean dining, according toDr. Kenneth J. Mukamal, an internist and cardiovascular researcher at BIDMC.

Mukamel served as lead researcher in a BIDMC study that linked the heart benefits of alcohol to the frequency of drinking. The study, which investigated 38,000 men over a 12-year period, was published in the New England Journal of Medicine in January 2003.

“The study confirmed that people who have one drink a day have the lowest rate of heart disease compared with non-drinkers or heavy drinkers,” says Mukamal. “It doesn’t seem to be the type of alcohol that matters; it’s the frequency. Individuals who drink a little bit three to-seven days a week are at lowest risk. There’s also evidence that alcohol consumed with meals — which is typical in the Mediterranean diet — is safest, providing a more gradual increase in blood alcohol levels.”

How much alcohol is appropriate? The American Heart Association recommends up to one drink a day for women and one to two drinks a day for men. Examples of one drink include 4 ounces of wine, 12 ounces of beer, or 1.5 ounces of distilled spirits (80 proof).

Mukamal cautions that for some people, such as those who have or are at risk for breast cancer or hepatitis C, regular consumption of alcohol may not be advisable.

“It’s a complex mixture of potential risks and benefits, so it’s always worth a discussion with your doctor to be sure that drinking small amounts of alcohol is right for your situation,” he says.

Taking the Mediterranean Route

The incidence of heart disease and deaths in Mediterranean countries is lower than in the United States, but such statistics may not be entirely dependent upon diet. The Mediterranean diet is part of a lifestyle in which exercise, such as walking, is frequent. Families and friends gather to enjoy meals and each other’s company. And the pace of living seems less frenetic than elsewhere.

But you don’t have to go to Rome to live as the Romans do. With some planning and attention to diet and lifestyle, you can bring the flavor and health benefits of the Mediterranean into your own life.

The changes aren’t as severe as you might think. Here are some steps that can get you moving in the right direction:

Take a half-hour walk each day.
Use olive oil instead of butter or margarine.
Increase servings of fresh veggies and fruits – aim for at least seven per day.
Eat fish and poultry and minimize or eliminate red meat.
Aim for several meatless meals each week, incorporating legumes as a protein source when possible.
Use fresh herbs and spices to flavor food instead of salt.
Avoid foods that are processed, high in fat, or contain trans or saturated fat.
Have a small glass of wine with dinner, if your doctor agrees.
Invite your family and friends to join you!

“The Mediterranean diet is very sustainable and livable,” says Mittleman. “There’s a lot of variety for your palate and it’s easy to maintain. The heart-health benefits will pay you back for a lifetime.”

Above content provided by the CardioVascular Institute at Beth Israel Deaconess Medical Center. For advice about your medical care, consult your doctor.

Posted October 2012

http://bidmc.org/CentersandDepartments/Departments/CardiovascularInstitute/CVINewsletter/MediterraneanDiet.aspx

Posted in Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, Metabolomics, Nutrigenomics, Nutrition, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Nutrition and Phytochemistry | Tagged Beth Israel Deaconess Medical Center, Mediterranean, Mediterranean Diet, Monounsaturated fat, Murray Mittleman, Seven Countries Study | 1 Comment »

Facial Nerve, Intracanalicular Meningiomas, Vestibular Schwannomas: Surgical Planning

October 15, 2012 by 2012pharmaceutical

Reporter: Aviva Lev-Ari, PhD, RN

Just learned about that diagnosis given to a long time professional colleague. Started to research this topic and found an excellent clinical paper which I found appropriate for our Scientific Web Site – an Open Journal edifying the public on health related issues, BioMedical, Pharmaceutical and the Life Sciences.

HEAD AND NECK

Intracanalicular Meningioma Mimicking Vestibular Schwannoma

+Author Affiliations

^athe Carolina Neuroscience Institute for Skull Base Surgery, Raleigh
^bthe Carolina Ear Research Institute, Raleigh
^cthe Division of Neurosurgery, Duke University Medical Center, Durham, NC
^dthe Division of Otolaryngology, Duke University Medical Center, Durham, NC

Address reprint requests to Katsuyuki Asaoka, MD, PhD, Carolina Neuroscience Institute for Skull Base Surgery, 4030 Wake Forest Road, Suite 115, Raleigh, NC 27609

Abstract

Summary: Three cases of intracanalicular meningioma mimicking vestibular schwannoma are presented. In each case, a contrast-enhancing mass filling the internal auditory canal was identified on MR images and was originally diagnosed as a vestibular schwannoma. Although it is difficult to differentiate definitively between these lesions preoperatively, imaging findings inconsistent with a diagnosis of vestibular schwannoma can be identified. Preoperative identification of intracanalicular meningiomas permits alterations in surgical planning that allow for the more complete resection of these rare tumors.

Meningiomas that occupy the cerebellopontine angle usually arise from the posterior surface of the petrous bone or the petrotentorial junction. Although, in some instances, a large cerebellopontine angle meningioma secondarily involves the internal auditory canal (IAC), meningiomas primarily arising from and mainly confined to the IAC are rare (1–10). We herein present three cases of intracanalicular meningioma, each with a different type of extracanalicular extension, that were initially suspected to be cases of vestibular schwannoma, and we discuss the diagnostic and therapeutic issues related to this disease entity.

Case Reports

Case 1

A 66-year-old man had a 3-month history of decreased hearing and high-pitched tinnitus in the left ear. He was seen by the local otologic service and the diagnosis of a vestibular schwannoma in the left IAC was made on the basis of MR imaging findings (Fig 1). He was referred to our institute for tumor resection. The preoperative audiologic examination showed that hearing on the left side was decreased to 50 dB pure tone average (500–3000 Hz), with a word recognition score of 56%. Because the patient’s hearing was still serviceable, we decided to use the middle fossa approach to attempt tumor eradication with hearing preservation. In the IAC, a tan, multilobulated, soft tumor with abundant vascularity was seen displacing the facial nerve posteriorly. The tumor did not appear to be a vestibular schwannoma and on frozen section was confirmed to be a meningioma. The tumor was meticulously dissected, with preservation of the facial and vestibulocochlear nerves. The origin of the tumor was the anterior wall of the IAC. The tumor, including the dural attachment, was totally removed. Postoperatively, the patient’s hearing worsened to a word recognition score of 20%, but the facial nerve function was normal. The final histologic examination revealed a meningioma with numerous psammoma bodies.

FIG 1.

Case 1: 66-year-old man with an entirely intracanalicular meningioma. Contrast-enhanced axial T1-weighted MR image (450/14 [TR/TE]) reveals a homogeneously enhancing mass filling the IAC.

Case 2

A 39-year-old man noted a 1-year history of progressive decrease in hearing in his left ear, which had been of relatively sudden onset. He did not have tinnitus or dizziness. His MR images showed an enhancing mass occupying the left IAC and extending toward the petrous apex (Fig 2A and B). The preoperative audiogram showed a complete hearing loss in his left ear at 106 dB pure tone average. With a preoperative diagnosis of vestibular schwannoma, the tumor was removed by means of a translabyrinthine approach. Because of the anterior extension of the tumor, the facial nerve was completely skeletonized from the descending segment in the mastoid to the IAC. After incising the IAC dura, a friable, hypervascular tumor was exposed. The tumor entirely engulfed and was severely adherent to the facial nerve, with invasion into the anterior petrosal bone. A frozen histologic section showed a meningioma. The facial nerve was sharply dissected from the tumor and was rerouted inferiorly after cutting the greater superficial petrosal nerve. The invaded petrosal bone, including the cochlea, was extensively drilled away toward the petrous apex to totally remove the tumor. After surgery, mild left facial weakness (House-Brackmann grade III) was observed, which gradually returned to normal. The permanent pathologic specimen revealed a meningioma with tumor invasion into bone (Fig 2C). Immunohistochemistry showed that the tumor cells stained strongly for vimentin and did not stain for S-100 protein, features consistent with meningioma.

FIG 2.

Case 2: 39-year-old man with an intracanalicular meningioma.

A, Contrast-enhanced axial T1-weighted MR image (540/12) shows an enhancing mass in the IAC extending toward the petrous apex and the cerebellopontine angle.

B, Contrast-enhanced coronal T1-weighted MR image (540/12) shows dural enhancement (arrow) in the IAC, which was noticed retrospectively.

C, Photomicrograph of specimen shows meningioma infiltrating into bone. (hematoxylin and eosin, original magnification ×100).

Case 3

A 67-year-old woman who had left hearing loss approximately 20 years previously gradually developed left facial weakness over a 2- to 3-year period. As a result, she underwent MR imaging that revealed an enhancing mass occupying the IAC and extending out to the porus acoustics (Fig 3) and was then referred to our institute with a diagnosis of vestibular schwannoma. Neurologic examination showed left facial weakness (House-Brackmann grade III) and left deafness. On the basis of our experience with the former two cases, we suspected a possibility of meningioma as a differential diagnosis because of the broad-based extension pattern of the tumor, which is unusual for vestibular schwannoma, and the association of facial weakness with a small intracanalicular tumor. The patient underwent surgery by means of translabyrinthine approach. The tumor was hypervascular and showed the typical appearance of meningioma under the operating microscope with numerous small calcifications. The frozen histologic section also revealed a meningioma. The origin of the tumor was the dura near the porus acoustics in the IAC. Because the tumor severely adhered to the facial nerve in the IAC, we had to leave a small amount of the tumor tissue on the nerve to avoid its damage. The histologic diagnosis was meningioma.

FIG 3.

Case 3: 67-year-old woman with an intracanalicular meningioma. Contrast-enhanced axial T1-weighted MR image (600/9) shows an enhancing mass occupying the IAC and extending out to the cerebellopontine angle.

Discussion

The development of high-spatial-resolution MR imaging has facilitated detection of small intracanalicular lesions. Although vestibular schwannomas account for most intracanalicular lesions, other, less common pathologic abnormalities including meningioma should always be considered, because they have implications for management strategy (1, 11–13). Intracanalicular meningioma, which originates from and mainly occupies the IAC, is a rare entity. To the best of our knowledge, 14 cases have been reported in the literature before our three cases. Eleven of 17 cases, including ours, were diagnosed by using contrast-enhanced MR imaging.

Origin of the Tumor

It is known that the origin of meningiomas is the arachnoid villi that are primarily found along major venous sinuses, especially around the superior sagittal sinus. Meticulous histologic study has shown that these arachnoid villi can also be within the IAC and could serve as a site of origin for intracanalicular meningiomas. Nager and Masica (14) found that arachnoid villi were distributed not only along the dural sinuses and in the gasserian envelopes but also along the greater superficial petrosal nerve, within the IAC, around the geniculate ganglion of the facial nerve, and within the jugular foramen. Guzowski et al (15) histologically examined 200 randomly selected temporal bones and confirmed the presence of arachnoid granulations around the petrous apex, near the trigeminal impression, and in the sulcus for the greater superficial petrosal nerve. Although they could not find true arachnoid granulations in the IAC, there were small clusters of arachnoid epithelium that could also serve as an origin of meningioma.

Diagnostic Considerations

It is difficult to differentiate small intracanalicular meningiomas from vestibular schwannomas preoperatively. The clinical symptoms caused by intracanalicular meningiomas are mostly identical to those caused by vestibular schwannomas and other lesions that occupy the IAC. Most of the cases initially manifest a hearing problem. The subtle difference is that facial nerve symptoms are more likely to occur with meningiomas than with vestibular schwannomas when the size is small. Four of 17 cases presented facial nerve symptoms, three with facial paralysis and one with hemifacial spasm, yet vestibular schwannomas of a similar size rarely cause facial paresis. Needless to say, the facial nerve schwannoma should also be considered when the patient presents with facial nerve symptoms.

Signal intensity of these masses on MR images will not contribute to the accurate radiographic diagnosis of the intracanalicular meningioma. Both lesions are isointense to hypointense on T1-weighted MR images and are of variable signal intensity on T2-weighted MR images. They will also both brightly enhance after administration of contrast medium. Vestibular schwannomas that originate from the IAC comprise approximately 90% of cerebellopontine angle tumors (16). In this context, when a patient is found to have an enhancing mass in the IAC, it is usually assumed to be a vestibular schwannoma. Most of the reported cases of intracanalicular meningiomas, including our three cases, were initially suspected to be vestibular schwannomas (3,5–10).

Nonetheless, there are some radiographic findings that should raise the suspicion of intracanalicular meningioma. Calcification and a “dural tail” may be helpful, although these findings are also nonspecific (1, 17). In our second case, we retrospectively discovered intracanalicular dural enhancement in the coronal section of contrast-enhanced MR images. Another key is the extension pattern of the tumor. On the basis of the reported 17 cases, we categorized the extension patterns into following four types: 1) entirely intracanalicular (seven cases); 2) intracanalicular with cerebellopontine angle extension (five cases); 3) intracanalicular with both cerebellopontine angle extension and invasion into surrounding bone (three cases); and 4) intracanalicular with bone invasion but no cerebellopontine angle extension (two cases). Although it is very difficult to differentiate a meningioma from a vestibular schwannoma if an entirely intracanalicular type is encountered, other extension patterns may provide some information leading to the correct diagnosis. When the tumor extends out to the cerebellopontine angle, as in our third case, the growing pattern outside the IAC deserves attention. We think that broad-based extension into the petrous bone and a rugged medial tumor surface are valuable clues to the diagnosis of meningiomas, whereas vestibular schwannomas usually have a more spherical shape and have a smoother surface. Meningiomas in the IAC also have a tendency to involve adjacent nerve tissues or bones, (1, 2, 7, 9) as presented in our second case. Nager and Masica (14) showed, by histologic examination, that meningiomas located in the IAC can invade the labyrinth and cochlea by following their individual nerve fibers to their ends. Meningiomas can also infiltrate widely into surrounding petrous bone marrow spaces and air cells. Conversely, dilatation of the IAC due to bone erosion is a more common radiologic finding with vestibular schwannomas and extensive bone invasion is unusual. Thus, the presence of bone invasion around the IAC is suggestive the diagnosis of meningioma.

Therapeutic Issues

Preservation of facial nerve function is one of the most important issues in the surgery of intracanalicular lesions. It is important to note that the anatomic relationship between the tumor and the facial nerve in cases of intracanalicular meningioma is different from that in cases of vestibular schwannoma. With vestibular schwannoma, the facial nerve is compressed and classically displaced rostrally and medially by the tumor mass in the IAC. However, in our experience with these three cases of intracanalicular meningiomas, the tumor did not just compress the facial nerve but intimately involved it. Both in our second and third cases, the facial nerve was totally engulfed in the tumor. The adhesions between meningiomas and the facial nerve are also much more difficult to separate, even for smaller tumors, than those found in cases of vestibular schwannoma. Meticulous sharp dissection is very important to avoid damage to the facial nerve, even in cases of small intracanalicular meningiomas.

Conclusion

Complete resection of these tumors is important, because meningiomas are also more likely to recur than vestibular schwannomas. One of the reasons for this characteristic is considered to come from invasiveness into the adjacent structures, as mentioned above. Surgery of an intracanalicular meningioma, therefore, should be more extensive, resecting the tumor mass along with the attached dura and the invaded petrous bone. Because the preoperative differential diagnosis of intracanalicular lesions is usually difficult to make, intraoperative histologic diagnosis is essential. If meningioma is found, a more radical resection is accomplished to attempt to prevent recurrence. Preoperative suspicion of intracanalicular meningioma will assist the surgeon by allowing alterations in surgical planning that permit better exposure and more extensive resection of these difficult lesions.

References

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Received February 5, 2002.
Accepted after revision April 2, 2002.

Articles citing this article

Intralabyrinthine Meningioma Am. J. Neuroradiol. 2003 24: 1642-1645
Intracanalicular Aneurysm of the Anterior Inferior Cerebellar Artery Revealed by Multi-Detector CT Angiography Am. J. Neuroradiol. 2003 24: 1338-1340

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Posted in Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Imaging-based Cancer Patient Management | Tagged Facial Nerve, Meningioma, Sheryl Crow, Vestibular schwannoma | 2 Comments »

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Intracanalicular Meningioma Mimicking Vestibular Schwannoma

Abstract

Case Reports

Case 1

Case 2

Case 3

Discussion

Origin of the Tumor

Diagnostic Considerations

Therapeutic Issues

Conclusion

References

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Ischemic strokes choke the brain by inhibiting the transport of oxygen,¹ often leading to permanent neurologic injury or death in just a matter of minutes^2-4

Nearly 9 out of 10 AFib-related strokes are ischemic, and most are cardioembolic^5,8,9

Ischemic strokes can be devastating, often resulting in irreversible brain damage²

Strokes are a leading cause of disability in the US¹⁴