Archive for the ‘Diagnostic’ Category

Taking a Leap in Cancer Diagnostics: Clarient Enters New Era in Molecular Tumor Testing, Drug Discovery Research

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Posted 13 Mar 2012 — by James Street
Category ALK, Biomarkers, BRAF, Diagnostic, EGFR, genetic research, Kras, Molecular, PI3K
Anita T. Shaffer
Published Online: Friday, March 9th, 2012

When Kenneth J. Bloom, MD, began his career in pathology more than 25 years ago, the field of genomic and molecular diagnostics in cancer therapeutics was virtually nonexistent. Today, the sector is exploding and Bloom is at the forefront of efforts to develop new oncologic tools and bring them to clinical practice.

Bloom is the chief medical officer of Clarient, Inc, a once-fledgling company that GE Healthcare acquired in December 2010 for $425 million.

Clarient provides more than 350 diagnostic tests to assess and characterize tumors, including tests for BRAF, KRAS, and EGFR gene mutations, as well as the recently launched Clarient InsightDx Mammostrat test for breast cancer recurrence. The company also offers PATHSITE, an Internet-based service where physicians can view and manage digital images, patient case histories, and test results.

In December, Clarient announced a partnership with ACORN Research, LLC, a network of community oncology practices and hospitals, through which tumor-specific biomarker data for each new patient will be collected and analyzed under standardized protocols. The data will be used to personalize treatment for individual patients, as well as to build a databank of information about particular tumor types that can be used in clinical trials and other research.

Such developments are likely to mean a big jump forward not only for the Aliso Viejo, California-based company, but also for patients, according to Bloom.

“This is the perfect storm,” Bloom said in an interview. “All of the things that are necessary are coming together as one. We can really start bringing the highest level of care to every patient anywhere within the United States, and then eventually anywhere in the world. It is incredibly exciting.”

“It’s something that five years ago nobody could have contemplated,” he added. “If you were sick in rural Georgia, you would have to go to Atlanta. But those days are changing. You’re going to be able to get access to the same level of care no matter where you are.”

Bloom said GE ownership will boost Clarient’s ability to expand internationally, while the ACORN partnership will enable the company to compare outcomes with clinical trial results and conduct drug discovery research.

“To me, when we talk about personalized healthcare, it means giving healthcare locally,” he added. “It means you don’t pick up and travel 200 miles to some other institution where your family and friends can’t visit you and you undergo therapy in isolation. If that care could be given locally with your family and friends around you, that would be hugely advantageous. I think that’s what we’ve really been striving for all along, and it’s achievable.”

To me, when we talk about personalized healthcare, it means giving healthcare locally. It means you don’t pick up and travel 200 miles to some other institution where your family and friends can’t visit you and you undergo therapy in isolation. ”
–Kenneth J. Bloom, MD

Growing With Community Oncologists in Mind

The trends now shaping the cancer diagnostics field in some ways mirror the trajectories of both Bloom’s career and Clarient’s corporate evolution.

Now, as a result of the sequencing of the human genome and advances such as polymerase chain reaction and microarray technology, the options in genomic and molecular testing in cancer diagnostics are expanding dramatically.

“When I went through medical school, molecular pathology didn’t exist,” Bloom said. “So I got zero molecular pathology in medical school, zero molecular pathology in residency. It’s really only the last 10 or 15 years of my practice that molecular pathology has come to the forefront.”

Bloom, who became a member of the College of American Pathologists in 1987, held a number of positions related to oncology at Rush-Presbyterian- St. Luke’s Medical Center, now Rush University Medical Center, in Chicago, Illinois, for more than 20 years before joining US Labs as senior medical director in 2002.

Within a few years, the Irvine, California, cancer diagnostics company was purchased by industry giant LabCorp. Bloom, who moved on to Clarient in August 2004, said he shared Clarient’s philosophy of partnering with local pathologists rather than supplanting them with a centralized lab.

Clarient itself has grown from a small company launched in the early 1990s to develop medical imaging technologies into a 400-employee business focused on diagnostics.

General Electric Company, which operates GE Healthcare, said in its 2010 annual report that Clarient was a “leading player” in a rapidly growing market, and that its purchase of the company would accelerate GE’s presence in the field. The demand for cancer diagnostics is expected to grow from $15 billion in 2010 to $47 billion by 2015, GE said.

Although the acquisition is an example of the consolidation in the industry, Bloom believes Clarient maintains a business model that preserves both local pathologists, and helps the community oncologists and hematologists with whom they work.

“We really had a passion of bringing cancer testing directly to local pathologists and hence local oncologists,” Bloom said. “The idea was that we would never compete with the local pathologists. The things that a local pathologist knew how to do, and do well, they should do.

“But all of the advanced things that they should be doing but didn’t have access to, either because they didn’t have the space, the resources, the training, or the technicians, we would not only provide that test to them, but we also would engage them in the process, and we would educate them along the way,” he said. “And that’s been an incredibly successful model.”

The GE Healthcare acquisition gives Clarient the resources to expand its model worldwide and to pursue original research, Bloom said. “Now we can lead the charge and develop the next generation of tests that will lead the way to personalized healthcare,” he said.

The Clarient InsightDx Mammostrat

The Clarient InsightDx Mammostrat

Emphasizing Role of Pathologists Amid Change

As the options in cancer diagnostics grow in number and complexity, Bloom believes oncologists will be bombarded with choices they might not be equipped to evaluate. That is why he feels pathologists are vital members of the treatment team.

“Probably the biggest question for oncologists is, ‘How do I deal with all these new tests that are coming on the market?’” he said.

“To me, it’s not obvious that just because there’s a new test, that everybody should instantly understand how that test works and how to apply it,” Bloom said. “There’s going to have to be experts that understand how to do that.”

In Bloom’s view, local pathologists should supply that expertise by working with oncologists and with labs such as Clarient that offer advanced testing.

“The pathologist can be your biggest tool, because they are charged with understanding all of the tests, monitoring the performance of those tests, and discovering why laboratory A might be better than laboratory B for a more consistent and a more robust test result,” Bloom said.

“That would be the single biggest thing that I would tell oncologists to do,” he noted. “You need to become partners with a local pathologist, even if your local pathology lab doesn’t perform the test.”

Top Tests Available at Clarient

Combining innovative diagnostic technologies with world-class pathology expertise, Clarient’s state-of-the-art laboratories provide advanced oncology testing and diagnostic services to assess and characterize cancer. Using a wide range of methodologies, including flow cytometry, IHC, ISH, FISH, cytogenic karotyping, immunofluorescence, microarray, and molecular testing, these are the 7 leading tests Clarient performs:

Mammostrat Breast Recurrence Assay

Methodology: Immunohistochemistry
Highlights:

  • Mammostrat is a novel test for estimating the risk for recurrence in hormonereceptor positive, early-stage breast cancer.
  • Mammostrat stratifies breast cancer patients into low risk (patients have a 7.6% chance of distant recurrence over a 10-year period); moderate risk (patients have a 16.3% chance of distant recurrence over a 10-year period), and high risk (patients have a 20.9% chance of distant recurrence over a 10-year period).

ALK Rearrangement

Methodology: FISH
Highlights:

  • ALK mutations have been identified in 3% to 7% of patients with non-small cell lung cancer (NSCLC).
  • The presence of ALK gene rearrangements may help treating physicians select more effective therapies for patients with NSCLC.
  • ALK gene rearrangements define a distinct molecular subset of NSCLC that is mutually exclusive from EGFR and KRAS mutations.
  • The FISH test results should be used in conjunction with other clinical information.

BRAF

Methodology: Real-time polymerase chain reaction
Highlights:

  • BRAF mutations account for approximately 12% to 15% of colorectal cancer cases.
  • BRAF mutations are biomarkers of nonresponse to anti-EGFR therapies.
  • BRAF mutations are highly predictive of nonresponse to therapy with cetuximab or panitumumab in combination with chemotherapy and as monotherapy.

BRAF V600 Mutation

Methodology: Real-time polymerase chain reaction
Highlights:

  • Approximately 60% of melanomas harbor activating mutations in BRAF V600E as identified by the cobas 4800 test.
  • The cobas 4800 test is the first FDA-approved diagnostic test to help identify patients with the BRAF V600E mutation.
  • Patients with BRAF V600 mutation-positive melanoma as detected by the cobas 4800 test showed dramatic results with vemurafenib.

EGFR Mutation Analysis

Methodology: Molecular polymerase chain reaction
Highlights:

  • EGFR mutations can be seen in approximately 10% to 15% of patients.
  • The development of selective tyrosine kinase inhibitors is an important area of drug discovery for the treatment of a variety of solid tumors such as breast, ovarian, and colorectal cancers, NSCLC, and carcinoma of the head and neck.
  • Patients with EGFR mutations respond more favorably to EGFR tyrosine kinase inhibitors than non-mutation carriers.

KRAS Mutation Analysis

Methodology: Real-time polymerase chain reaction
Highlights:

  • KRAS mutations can be detected in approximately 30% to 40% of patients with colon cancer.
  • Patients with wild-type KRAS have shown much greater benefit to anti-EGFR therapies.
  • Identification of mutations along the KRAS gene suggests that anti-EGFR therapies will not be efficacious in most patients.

PI3K

Methodology: Molecular polymerase chain reaction
Highlights:

  • The PI3K pathway plays an important role in many cancers, including colorectal, breast, and lung cancers.
  • The presence of activating mutations in the PIK3CA gene, which encodes PI3K, can occur in 20% to 30% of cases.
Source: Clarient Inc’s website www.clarient.com.

Personalized cancer treatment: Genetic differences abound in tumors

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Posted 11 Mar 2012 — by James Street
Category Biomarkers, Diagnostic, Epigenetics, Gene sequencing, genetic research
By Eryn Brown, Los Angeles Times / for the Booster Shots blogMarch 8, 2012, 5:16 p.m.

Patients are holding out hope that someday — soon, they hope — physicians will be able to personalize medical treatment more precisely than they’ve been able to in the past.  For people with cancer, this might mean taking a quick biopsy, studying the genetic profile of a tumor and then tailoring interventions  to target the cancer effectively, with as few side effects as possible.

But a study published in the New England Journal of Medicine on Wednesday underscores why the vision remains a challenge.  Cancer researchers in England showed that individual kidney tumors and their metastases had different mutations in different locations — and that those mutations, in turn, affect the biology of those tumors in varying ways in different locations.

“A single tumor-biopsy-specimen reveals a minority of genetic aberrations … that are present in an entire tumor,” wrote Dr. Marco Gerlinger of the Cancer Research UK London Research Institute and co-authors.

For example, the scientists found that one region of a renal carcinoma could display gene expression signatures associated with a good prognosis, while signatures in another region of the same tumor could be associated with a poor prognosis.

The basic insight that a single cancer can contain a number of mutations isn’t entirely new, but the team’s genetic analysis helps demonstrate why it probably won’t be possible to devise targeted, patient-specific treatment strategies by looking at minimally invasive biopsies collected from a single site, wrote Dr. Dan Longo of the National Institute on Aging in an editorial accompanying the study.

“A new world has been anticipated in which patients will undergo a needle biopsy of a tumor in the outpatient clinic, and a little while later, an active treatment will be devised for each patient on the basis of the distinctive genetic characteristics of the tumor,” he wrote.  “But a serious flaw in the imagined future of oncology is its underestimation of tumor heterogeneity.”

The Los Angeles Times has reported on tumor genetics in the past.  In April 2011, writer Amber Dance described efforts to catalog the mutations that cause cancer.  Earlier that year, Thomas H. Maugh II explained how researchers sequenced the genomes of prostate cancers in seven different men.

Local biotech company hopes save lives by focusing on microscopic cancer cells

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Posted 21 Feb 2012 — by James Street
Category Circulating Tumor Cells, Diagnostic

Health care is dying for innovation and IVDiagnostics has no shortage of game–changing ideas to transform medicine and save lives.

“My wife has survived for 22 years with three bouts of cancer, and she is my personal inspiration,” says Valparaiso resident and IVDiagnostics CEO Frank Szczepanski.

“If you believe in the current paradigm of using an imaging test to determine if you have a solid tumor, in our opinion, that’s too late. Wouldn’t you rather find the cancer when it’s microscopic?”

IVDiagnostics was formed to develop, test and market more effective diagnostic tools for rare circulating tumor cells (CTC), which find their way to a distant organ to start new cancer growth. CTCs are considered among the major causes for mortality among cancer patients, Szczepanski says.

With this company’s technology, doctors will be able to perform a real–time diagnosis of a patient’s CTCs without drawing blood.

The company’s cofounders are Frank’s brother, Tom, of East Chicago, and Wei He, who is a doctor of analytical chemistry and the team’s lead scientist. “Our No. 1 goal is to save lives,” Frank Szczepanski says.

What’s inside

IVDiagnostics is Szczepanski’s ninth start–up company. Several years ago, he met Wei He who suggested a tactic of “in vivo,” or monitoring blood inside the body. Cells of two to 10 microns can be detected.

About 25 percent of the body’s blood can be optically scanned in 30 minutes. The absence of needles is a benefit cancer patients are enthusiastic about, Szczepanski said.

The test, referred to as a liquid biopsy, also is more accurate and sensitive than surgical biopsies. “Once this gets to market there won’t be a single doctor who won’t want this for a patient,” Szczepanski said.

Repeated needle sticks common in intravenous disease treatment causes problems such as hardening of the arteries, bruising and even missed chemotherapy if clinicians can’t draw blood on any given day.

The test also doesn’t require administering toxic substances into the body such as radioactive materials used in some forms of images. “They have to light you up so they can diagnose and those isotopes stay in the body,” he said.

Innovation in medicine

The company also is developing a molecular test for pancreatic cancer, one of the hardest for early detection, which identifies mutations in DNA or deficiencies in certain proteins.

That test could be available in one year and also could be used as a susceptibility test. “Steve Jobs’ family should have this test because they are undoubted carrying the mutation,” he says. “It’s just a matter of who has it. It’s scary because mutations can skip generations. If it skips you, good for you, but your children may end up getting it.”

Szczepanski says in the future both testing devices will handheld and wireless. “You can imagine the possibilities,” he says.

Patients could take the device with them so they could be monitored at home and wouldn’t have to wait for routine consultations or follow–up visits.

IVDiagnostics’ general target is metastatic cancer such as breast, lung, prostate, melanoma and ovarian. The company is doing live tissue sample testing now and with proper funding the entire portfolio of tests could be available within three years.

Slow burn sustainability

It takes awhile for many young firms to generate cash and survival depends on having an adequate supply of cash on hand to meet expenses.

The company was originally self–funded and in a three–year period received more than $1.5 million in seed capital from two rounds of friends and family funding. It also received $400,000 in federal funding from the National Institutes of Health and the National Cancer Institute.

IVDiagnostics was recently named The Revolutionary Technology Company of the Year by the Indiana Small Business Development Center. “The time it takes to do the research and development before a product can be marketed is hugely important,” says Bill Gregory, of the Northwest Indiana SBDC.

“You have to be able to raise all sorts of additional revenue and capital and find skilled people. They’ve had to do a lot to get where they’ve gotten. It takes passion, experience, innovation and patience to do work in biomedicine.”

In Indiana, fund investments steadily fell from $14.6 million in 2007–08 to just $6.6 million in 2009–10. “That is the legacy of this recession – not one or two missed companies, but a changed capital market,” said David Johnson, president and CEO of BioCrossroads, a statewide life sciences organization.

Private venture capital invested in life sciences within Indiana, from 2002–10 was $277 million.

Some of the partners are not taking a salary, but Szczepanski said the company is good at managing its burn rate.

Burn rate refers to the rate at which a company uses up its supply of cash over time and tells investors whether a company is self-sustaining. Companies with high cash burn rates can turn an investment into ashes.

Many other biotechnology firms have a burn rate of about $2 million per year, he said. IVDiagnostics’ rate is 25 percent of that or roughly $500,000 annually.

“We have many people on our team that are sacrificing and taking equity instead of cash,” said Szczepanski. “But we can do that for only so long.”

Looking for angels

The next major round of financing hopes to secure $3 million to $5 million from angel group or venture capitalists to cover the cost of clinical trials and additional research and development.

IVDiagnostics is poised for exponential growth because of the known demand for its testing. A single community hospital has anywhere from 500 to 1,000 new cancer patients yearly and each patient could need monitoring up to five times annually.

Within five years, the company could generate $100 million in revenues. The anticipated cost to patients for the test would be $400 to $800 compared to $5,000 to $8,000 for a CAT scan.

Monitoring patients five times a year with IVDiagnostics technology compared to twice a year for an imaging test would result in annual savings of $12,000 to $15,000 per patient annually.

Worldwide, $300 billion is spent on cancer diagnosis and the United States market alone spends $124 billion. “If we can save half that amount because of better molecular medicine, the savings to the health care industry are huge,” Szczepanski says.

Restructuring Indiana’s economy

Szczepanski is a leading entrepreneur who has been involved in nine startups in the last 20 years. He looks to the future and considers himself a successful technologist.

“Unless you have the vision, inspiration and perseverance to do something new, you’re not an entrepreneur,” he said. “Everyone in our company shares a commonality that this is a noble cause.”

Indiana’s position as a life science leader is clear and has long been thought of as the one of the state’s bright economic spots.

It has weathered the recession well but tighter capital markets threaten to starve the risky process of medical innovation. That challenge is predicted to be permanently harder although the industry is still producing jobs.

The Indiana Business Research Center reported life science industry employment grew 2.9 percent between 2001 and 2007 compared to 0.2 percent for total employment and a loss of 1.9 percent for manufacturing.

According to BioCrossroads, total employment in life sciences in Indiana has held steady at around 50,000 jobs since 2007. In 2010, there were 854 establishments generating $4.3 billion in wages. The average Indiana life sciences wage was $86,537 which is more than twice the state’s average wage.

The value of Indiana’s life science exports totaled $9.0 billion in 2010, up from $5.0 billion in 2006.

Szczepanski sees the life sciences as the changing face of Indiana’s economy – from a steelmaker in a hard hat and farmer on a tractor to a scientist in a white lab coat with a microscope.

The most important factors for success is an experienced and educated workforce. The Hoosier state is a major generator of life science graduates, so it has labor pool and an industry that can fight the brain drain of college graduates.

Szczepanski’s vision for Northwest Indiana is for the university and medical communities to collaborate and form a center for advanced cancer research to accelerate molecular medicine.

“We’re looking at a new form of manufacturing,” he says. “The footprint for Northwest Indiana can change its focus on steelmaking and agriculture to nano particle production and biomedical equipment which brings a higher level of jobs. It can be a motivator in our state for a different economic force to switch from raw materials processing to biotech.”

Introducing ATCC Tumor Cell Panels: Powerful New Tools for Cancer Research

PRWeb

Tuesday, February 7, 2012

ATCC launches valuable and gentically-diverse tumor cell panels for drug discovery, pathway analysis and functional genomics

Manassas, VA (PRWEB) February 07, 2012

Searching for appropriate tumor cell models often entails a time-intensive review of the literature and genomic databases. To enable cancer researchers, ATCC (American Type Culture Collection) has introduced a collection of Tissue-Specific Tumor Cell Panels. These powerful new tools combine well-characterized adherent cell lines that were selected for their genomic mutations as found in the Sanger COSMIC database, greatly reducing the time and effort scientists devote to finding these cells. Working closely with customers, ATCC scientists have identified cell lines that that are easy to grow using standard media formulations and possess critical genetic abnormalities found in tumors.

Each Tissue-Specific Tumor Cell Panel is comprised of different cell lines that have been grouped by tissue of tumor origin. In developing the panels, ATCC scientists evaluated 20 different genes associated with tumorigenesis, including TP53, CDKN2A, BRAF, and KRAS. Descriptive information for each cell line has been annotated with details regarding known mutations in these selected oncogenes or receptors. Cell panels, as research models, are as valuable as the depth of understanding and data supporting them. There are currently 10 Tissue-Specific Tumor Cell Panels in the collection, including panels for breast cancer, triple-negative breast cancer, lung cancer, ovarian cancer, colon cancer, liver cancer and pancreatic cancer.

As part of its mission, ATCC will continue to augment the available information on the Tumor Cell Panel cell lines from other databases, and will perform further characterization on the panels. When combined with the size and scope of the ATCC tumor cell line collection, this growing knowledge base enables scientists to make smarter choices when selecting cell-based research models for cancer research, drug discovery, compound screening, biomarker selection, pathway analysis and functional genomics.

“Scientists are requiring more genomic and proteomic data on the cell lines they use in their studies to understand the roles that genetic defects have in the pathobiology of cancer,” said Dr. Richard Kolodner, Member, Ludwig Institute for Cancer Research, UC San Diego School of Medicine Branch. “ATCC is helping scientists by consulting with researchers and going through the gigabytes of data and stacks of literature to find relevant cell lines with sufficient genetic diversity to create a representative panel,” he added.

ATCC Tissue-Specific Tumor Cell panels offer economy over individual lines, are supplied with comprehensive genetic profile information, and are accompanied by expert support if needed.

For more information, please go to www.atcc.org/tcp. To speak with an expert or place an order, call toll free 1-800-638-6597 (option 2) in the U.S. and Puerto Rico, or international callers can dial +1-703-365-2700, or e-mail ATCC Customer Service at sales(at)atcc(dot)org.

ABOUT ATCC
ATCC maintains the largest and most diverse biorepository in the world. The innovative, not-for-profit organization develops and provides products for life science research, services to support biotechnology development, and standards that are consistent with its mission – to acquire, authenticate, preserve, develop, and distribute standard reference microorganisms, cell lines, and related materials for research in the life sciences. With distribution to more than 140 countries and a working relationship with 12 distribution partners, ATCC has the experience, knowledge, rigorous methodologies, standards, longevity and the global reach to serve academic institutions, government agencies, biotech, biopharma, and research organizations around the world.

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For the original version on PRWeb visit: www.prweb.com/releases/prweb2012/2/prweb9174250.htm

http://sfgate.com/cgi-bin/article.cgi?f=/g/a/2012/02/07/prweb9174250.DTL

December 19, 2011 Monday – 11:50 am EST inShare 1 Text Size Smaller Normal Larger E-mail Print ‘Fantastic Potential’: Researchers Keep Cells Alive Away From Body

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Posted 20 Dec 2011 — by James Street
Category Diagnostic, Personalized, Stem Cell Research, Targeted Cancer Therapy

December 19, 2011 Monday – 11:50 am EST

By Adam Daley

Georgetown researchers say they have just significantly changed biomedical research.

Researchers know that normal cells don’t last long once removed from a human, dividing only a few times in a laboratory setting. Common cancers won’t grow in a lab.

That’s about to change.

Senior investigator, Richard Schlegel, M.D., Ph.D., and chairman of the department of pathology at Georgetown Lombardi Comprehensive Cancer Center, has discovered a way to keep normal cells as well as tumor cells taken from an individual cancer patient alive in the laboratory. The technique could be a critical advance, ushering in a new era of personalized cancer medicine, and has potential application in regenerative medicine.

“Because every tumor is unique, this advance will make it possible for an oncologist to find the right therapies that both kills a patient’s cancer and spares normal cells from toxicity,” said Dr. Schlegel. “We can test resistance as well chemosensitivity to single or combination therapies directly on the cancer cell itself.”

The research team found that inserting a Rho kinase (ROCK) inhibitor and fibroblast feeder cells to cancer and normal cells in a laboratory pushes them to morph into stem-like cells. The cells visibly changed their shape as they reverted to a stem-like state.

“In short, we discovered we can grow normal and tumor cells from the same patient forever, and nobody has been able to do that,” said Dr. Schlegel. “Normal cell cultures for most organ systems can’t be established in the lab, so it wasn’t possible previously to compare normal and tumor cells directly.”

“Today, pathologists don’t work with living tissue. They make a diagnosis from biopsies that are either frozen or fixed and embedded in wax,” added Dr. Schlegel. “In the future, pathologists will be able to establish live cultures of normal and cancerous cells from patients, and use this to diagnose tumors and screen treatments. That has fantastic potential.”

The study, which was funded by grants from the National Institutes of Health, Department of Defense fellowship funding, and an internal grant from Georgetown Lombardi’s Cancer Center Support Grant from the National Cancer Institute, is published online today in the American Journal of Pathology.

Without Autopsies, Hospitals Bury Their Mistakes

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Posted 19 Dec 2011 — by James Street
Category Diagnostic, Finance and Politics of cancer research and treatment, Fraud
Thursday 15 December 2011
by: Marshall Allen, ProPublica [3] | Report

When Renee Royak-Schaler unexpectedly collapsed and died on May 22, no one ordered an autopsy.

Not the doctors at Howard County General Hospital in Columbia, Md., where the 64-year-old professor and cancer researcher was pronounced dead.

Not the Maryland Office of the Chief Medical Examiner, which passed on the case because no foul play was involved.

And not Royak-Schaler’s physicians at Johns Hopkins University School of Medicine who had diagnosed cancer in her hip two days beforehand but acknowledged they didn’t know what had caused her unforeseen death.

A half-century ago, an autopsy would have been routine. Autopsies, sometimes called the ultimate medical audit, were an integral part of American health care, performed on roughly half of all patients who died in hospitals. Today, data from the Centers for Disease Control and Prevention show, they are conducted on about 5 percent of such patients.

As Royak-Schaler’s husband, Jeffrey Schaler, discovered, even sudden unexpected deaths do not trigger postmortem reviews. Hospitals are not required to offer or perform autopsies. Insurers don’t pay for them. Some facilities and doctors shy away from them, fearing they may reveal malpractice. The downward trend is well-known — it’s been studied for years.

What has not been appreciated, pathologists and public health officials say, are the far-reaching consequences for U.S. health care of minuscule autopsy rates.

Diagnostic errors, which studies show are common, go undiscovered, allowing physicians to practice on other patients with a false sense of security. Opportunities are lost to learn about the effectiveness of medical treatments and the progression of diseases. Inaccurate information winds up on death certificates, undermining the reliability of crucial health statistics.

It was only because of Royak-Schaler’s connections that her case ended differently. Her colleagues at the University of Maryland School of Medicine urged her husband to authorize an autopsy and volunteered to conduct it for free.

In her case, as in so many, the autopsy revealed a surprise: Royak-Schaler, the renowned cancer researcher, had cancer ravaging her body — in her lungs, kidneys, abdomen and the marrow of her bones. A blood clot, likely related to the tumors, caused her sudden death.

Jeffrey Schaler has wrestled with anger that his wife wasn’t diagnosed sooner but said knowing how she died was better than not.

“There’s a sense of peace that accompanies that knowledge,” he said.

For the last year, ProPublica, PBS “Frontline” and NPR have probed America’s deeply flawed system of death investigation [4], focusing primarily on forensic autopsies, which are conducted by coroners’ offices and medical examiners when there is suspicion of an unnatural death. State laws vary, but the preponderance of deaths that occur in hospitals are considered natural. When deaths are unexplained, unobserved or within 24 hours of admission, hospitals may be required to report them to local coroners or medical examiners, but such  agencies rarely take hospital cases.

Hospital physicians, with consent from patients’ next of kin, may order a clinical autopsy to explore the disease process in the body and determine the cause of death. That was the norm 50 years ago, when the value of the autopsy was considered self-evident.

Fight corporate influence by keeping independent media strong! Click here to make a tax-deductible contribution to Truthout. [5]

“Much of what we know about medicine comes from the autopsy,” said Dr. Stephen Cina, chairman of the forensic pathology committee for the College of American Pathologists. “You really can’t say for sure what went on or didn’t go on without the autopsy as a quality assurance tool.”

Yet, autopsy rates at teaching hospitals, which are typically run on a nonprofit basis and have an educational mission, hover around 20 percent today. At private and community hospitals, which constitute 80 percent of facilities nationwide, rates can be close to zero.

“I know new hospitals are being built these days without a place to do an autopsy,” said Dr. Dean Havlik, the Mesa County, Colo., coroner, who estimated that the overall hospital autopsy rate in his area is less than 1 percent.

Hospitals have powerful financial incentives to avoid autopsies. An autopsy costs about $1,275, according to a survey of hospitals in eight states. But Medicare and private insurers don’t pay for them directly, typically limiting reimbursement to procedures used to diagnose and treat the living. Medicare bundles payments for autopsies into overall payments to hospitals for quality assurance, increasing the incentive to skip them, said Dr. John Sinard, director of autopsy service for the Yale University School of Medicine.

“The hospital is going to get the money whether they do the autopsy or not, so the autopsy just becomes an expense,” Sinard said.

Since a 1971 decision by The Joint Commission, which accredits health-care facilities, hospitals haven’t had to conduct autopsies to remain in good standing. The commission had mandated autopsy rates of 20 percent for community hospitals and 25 percent for teaching facilities, but dropped the requirement. Many hospitals were performing autopsies “simply to meet the numbers” and not to improve quality, said Dr. Paul Schyve, the commission’s senior adviser of health-care improvement.

Doctors, too, have gravitated away from autopsies because of growing confidence in modern diagnostic tools such as CT scans and MRIs, which can identify ailments while patients are still alive.

Still, in study after study, autopsies have revealed that doctors make a high rate of diagnostic errors even with increasingly sophisticated imaging equipment.

A 2002 review of academic studies by the federal Agency for Healthcare Research and Quality found [6] that when patients were autopsied, major errors related to the principle diagnosis or underlying cause of death were found in one of four cases. In one of 10 cases, the error appeared severe enough to have led to the patient’s death.

“Clinicians have compelling reasons to request autopsies far more often than currently occurs,” the agency concluded.

Schyve called the findings of such studies flawed because cases in which autopsies are performed are typically the most complex, making diagnostic errors more likely. The overall error rate is far lower, he said.

But Sinard said so few autopsies are being conducted — one survey found that 63 percent of hospitals in Louisiana performed none in a given year — that doctors and hospitals can’t say for certain how patients are dying. “They’ve never checked,” the Yale pathologist said.

Pathologists interviewed by ProPublica said they often find diagnostic errors. “We often identify things that the imaging study could not,” said Dr. Debra Kearney, director of autopsy pathology at Texas Children’s Hospital.

Autopsies can also be a crucial tool for evaluating and improving medical care.

Dr. Elizabeth Burton, deputy director of the pathology department at Johns Hopkins University School of Medicine, said performing autopsies on patients who have died of hospital-acquired infections helps save others. Infection clusters “go in waves” in hospitals, she said. Physicians have used her findings to change antibiotic regimens, snuffing out the bacterium.

Dr. Renu Virmani, president and medical director of the nonprofit CVPath Institute, has used postmortem examinations to help reform the treatment of heart disease. Virmani and her team have collected about 250 specimens of metal stents removed at autopsy from patients who had procedures to clear blockages from their arteries.

Their work showed that, in certain patients, a type of stent designed to reduce the risk of blood clots was causing delayed healing, inflammation and reactions that could be fatal. As a result, patients who receive these stents are now required to take blood-thinning medication for a year after the procedure.

Sitting in her lab in Gaithersburg, Md., Virmani peers through a microscope at a specimen slide taken from a 61-year-old man who died suddenly in 2004, about four months after receiving a clot-resistant stent. She points out signs of inflammation in the cross-section of his stented artery, describing the swirls and grains, stained pink and purple so they stand out on the slide. The autopsy showed that the stent had led to the patient’s fatal blood clot.

Autopsies should be used to evaluate the effectiveness of other therapies, Virmani said, from chemotherapy to heart-valve replacements. “The only way to learn is through autopsies.”

Hospital autopsies are even rarer when patients older than 60 die in hospitals, representing a lost opportunity to learn about age-related diseases, Burton said. More than 684,000 such patients died in hospitals in 2008 — more than one-quarter of the total deaths in the country — and just 2.3 percent were autopsied, CDC data show.

Without autopsies to confirm patients’ precise causes of death, public health officials say, the health-care system overall suffers. Erroneous information sometimes ends up on death certificates. Broad categories of disease such as cancer are probably accurate, but specifics such as the type of cancer may not be, said Robert Anderson, chief of the mortality statistics branch of the CDC’s National Center for Health Statistics.

“These data are used to set public health priorities, to develop public health programs and allocate resources,” Anderson said. “We do the best that we can given the information we have, but if you put bad information into the system, you’re going to get bad information out.”

In 1999, the Medicare Payment Advisory Commission, or MedPAC, which advises Congress about Medicare, issued a report stating that increasing the rate of clinical autopsies could improve health care and reduce errors.

The report recommended paying pathologists directly for autopsies and giving hospitals bonuses or penalties for hitting or missing target autopsy rates. The advisory group also suggested that Medicare change its hospital regulations to encourage more autopsies and use them as a standard of performance.

But Medicare has not acted upon these recommendations. An official from the Centers for Medicare & Medicaid Services declined ProPublica’s request for an interview, saying the use of autopsies in hospitals “is not within [Medicare’s] bailiwick at all.”

Other organizations that advocate for better medicine, such as the Institute for Healthcare Improvement, National Quality Forum and The Joint Commission, have not pushed for higher levels of autopsies, either, despite the widely held belief  that this could produce improved care.

Raising the rate “is not one of our priorities by any means,” The Joint Commission’s Schyve said.

Dr. George Lundberg, a pathologist and one of the country’s most vocal advocates for increasing the autopsy rate, shakes his head when discussing the medical industry’s apathy about low autopsy rates.  Lundberg, the editor of the journal MedPage Today, said The Joint Commission should re-establish mandatory autopsy rates “like they used to have back in the good old days of quality when we weren’t running away from trying to find the truth [about] our sickest patients.”

One way to shake the complacency, various experts told ProPublica, would be for insurance companies and the government to pay for autopsies. But an official from UnitedHealth Group, the largest health-insurance company in the country, said the autopsy is not reimbursed because it “isn’t a procedure that would prevent or treat a sickness or injury” in a patient.

Virmani called this shortsighted. The cost of an autopsy is small relative to the money spent on drugs, treatment and diagnostic imaging, she said, and the payoff could save lives and money.

“We are letting go of something which we could really use tomorrow to improve the health care of patients,” she said.

‘Cancer’ or ‘Weird Cells’: Which Sounds Deadlier?

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Posted 22 Nov 2011 — by James Street
Category Diagnostic
By
Published: November 21, 2011

My friend’s mother got terrifying news after she had a mammogram. She had Stage 0 breast cancer. Cancer. That dreadful word. Of course she had to have surgery to get it out of her breast, followed by hormonal therapy.

Or did she?

Though it is impossible to say whether the treatment was necessary in this case, one thing is growing increasingly clear to many researchers: The word “cancer” is out of date, and all too often it can be unnecessarily frightening.

“Cancer” is used, these experts say, for far too many conditions that are very different in their prognoses — from “Stage 0 breast cancer,” which may be harmless if left alone, to glioblastomas, brain tumors with a dismal prognosis no matter what treatment is tried.

It is like saying a person has “mental illness” when he or she might have schizophrenia or mild depression or an eating disorder.

Now, some medical experts have recommended getting rid of the word “cancer” altogether for certain conditions that may or may not be potentially fatal.

The idea of cancer as a progressive disease that will kill if the cells are not destroyed dates to the 19th century, said Dr. Otis Brawley, chief scientific and medical officer at the American Cancer Society. A German pathologist, Rudolph Virchow, examined tissue taken at autopsy from people who had died of their cancers, looking at the cells under a light microscope and drawing pictures of what he saw.

Virchow was a spectacular artist, and he ended up being the first to describe a variety of cancers — leukemia, breast cancer, colon cancer, lung cancer.

Of course, his patients were dead. So when he noted that aberrant-looking cells will kill, it made sense. The deranged cells were cancers, and cancers were fatal.

Now, Dr. Brawley said, the situation is very different. Instead of taking tissue from someone who died, a doctor takes tissue from a living patient, threading a thin needle into a woman’s breast or a man’s prostate, for example. Then a pathologist looks for abnormal cells.

Yet “how it looks under a microscope,” Dr. Brawley said, “does not always predict.” That is especially true for things like Stage 0 breast cancer or similar conditions in other areas of the body — conditions detected by screening and not by symptoms or by feel.

Researchers have come to appreciate this conundrum.

“The definition of cancer has changed,” said Dr. Robert Aronowitz, a professor of history and sociology of medicine at the University of Pennsylvania.

Many medical investigators now speak in terms of the probability that a tumor is deadly. And they talk of a newly recognized risk of cancer screening — overdiagnosis. Screening can find what are actually harmless, if abnormal-looking, clusters of cells.

But since it is not known for sure whether they will develop into fatal cancers, doctors tend to treat them with the same methods that they use to treat clearly invasive cancers. Screening is finding “cancers” that did not need to be found. So maybe “cancer” is not always the right word for them.

That happened recently with Stage 0 breast cancer, also known as ductal carcinoma in situ, or D.C.I.S. It is a small accumulation of abnormal-looking cells inside the milk ducts of the breast. There’s no lump, nothing to be felt. In fact, Stage 0 was almost never detected before the advent of mammography screening.

Now, with widespread screening, this particular diagnosis accounts for about 20 percent of all breast cancers. That is, if it actually is cancer. After all, it is confined to a milk duct, has not spread into the rest of the breast, and may never spread if left alone — it might even go away.

It could also break free and enter the breast tissue. But for now, it is hard to know in many cases whether it makes any difference to treat D.C.I.S. right away or to wait to see if it spreads, treating it then.

Two years ago, an expert panel at the National Institutes of Health said the condition should be renamed. Get rid of the loaded word “carcinoma,” the panel said. A carcinoma is invasive; D.C.I.S. has not invaded the breast. If those cells do invade, they are no longer D.C.I.S. Then they are cancer. So call the condition something else, perhaps “high-grade dysplasia.”

The word “cancer” is so powerful it overwhelms any conversation about what Stage 0 breast cancer actually is, said Cynthia Pearson, executive director of the National Women’s Health Network. When women contact her group to ask about cancer treatments, “sometimes we’re well into the conversation with them before it comes out that they don’t actually have an invasive cancer.”

The same situation arises with prostate cancer screening.

The pathologist Donald Gleason, who invented Gleason scoring for prostate tumors, wanted to rename a very common tumor — the so-called Gleason 3 + 3 — “adenosis” instead of cancer, Dr. Brawley said. His idea was that by calling a 3 + 3 “cancer,” men and their doctors would feel they had to get rid of it right away.

Despite Dr. Gleason’s wishes, 3 + 3 cells are still called cancer. And despite the panel’s advice about D.C.I.S., that name has not changed either.

Cervical cancer specialists had better luck. In 1988, they changed the name of a sort of Stage 0 of the cervix. It had been called cervical carcinoma in situ. They renamed it cervical intraepithelial neoplasia, Grades 1 to 3, taking away the cancer connotation.

But Dr. Brawley, for one, has not given up on educating doctors and patients about the general inadequacy of the word “cancer.” As he put it, “The movement is not quite dead.”

New model establishes guidelines for earlier cancer detection November 16, 2011

Tumors can grow for 10 years or longer before currently available blood tests will detect them, a new mathematical model developed by Stanford University School of Medicine scientists indicates. The analysis, which was restricted to ovarian tumors but is broadly applicable across all solid tumor types, will be published online Nov. 16 in Science Translational Medicine.

“The study’s results can be viewed as both bad and good news,” said Sanjiv “Sam” Gambhir, MD, PhD, professor and chair of radiology and the study’s senior author. (Sharon Hori, PhD, a postdoctoral scholar in Gambhir’s laboratory, is the lead author.)

The bad news, Gambhir said, is that by the time a reaches a detectable size using today’s available blood tests, it is likely to have metastasized to other areas of the body, making it much more deadly than if it had been caught early on. “The good news is that we have, potentially, 10 or even 20 years to find the tumor before it reaches this size, if only we can improve our blood-based methods of detecting tumors,” he said. “We think our will help guide attempts to do that.”

The study advances previous research about the limits of current detection methods. For instance, it is strikingly consistent with a finding reported two years ago by Stanford biochemistry professor Patrick Brown, MD, PhD, that current tests could not detect tumors early enough to make a significant dent in the mortality rate. There is a push to develop more-sensitive diagnostic tests and find better , and Gambhir’s new model could be an essential tool in this effort. It for the first time connects the size of a tumor with blood biomarker levels being shed by that tumor.

To create their model, Gambhir and Hori used mathematical models originally developed to predict the concentration of drugs injected into the blood as they move in and out of the bloodstream. The investigators linked these to additional models of tumor cell growth.

Tumors don’t secrete drugs, but they can shed telltale molecules into surrounding tissue, from which those substances, known as biomarkers, diffuse into the blood. Some biomarkers may be made predominantly by tumor cells, while others exclusively by them. Either way, these substances can be measured in the blood as proxies for a tumor.

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Some biomarkers are in wide use today. One is the well-known PSA, for prostate cancer. Another is CA125, for ovarian cancer. But these and other currently used blood tests for cancer biomarkers weren’t specifically developed for early detection, and are generally more effective for relatively noninvasive monitoring of the progress of late-stage tumors or their response to treatment. (Rising blood levels of the substance indicate that the tumor is growing, while declining levels denote possible shrinkage.)

Both CA125 and PSA are also produced, albeit in smaller amounts, by healthy tissue, complicating efforts to detect cancer at an early stage when the tumor’s output of the biomarker is relatively low.

The new mathematical model employs separate equations, each governing the movement of a biomarker from one compartment into the next. Into these equations, one can plug known values — such as how fast a particular type of tumor grows, how much of the biomarker a tumor cell of this type sheds per hour and the minimum levels of the biomarker that must be present in the blood for a currently available assay to detect it.

As a test case, Gambhir and Hori chose CA125, a well-studied biomarker shed into blood by ovarian tumors. Ovarian cancer is a notorious example of a condition for which early detection would make a huge difference in survival outcomes.

CA125 is a protein made almost exclusively by ovarian tumor cells. The pharmacokinetics, metabolic fates, typical amounts secreted by an ovarian cell and other properties of CA125 are all well-known, as are ovarian tumors’ typical growth rates, making it excellent for “road testing” with Gambhir and Hori’s model. CA125 is by no means the ideal biomarker, said Gambhir, just one that can be used to help better understand ideal properties of biomarkers for early ovarian cancer detection.

Applying their equations to CA125, Gambhir and Hori showed that before the currently best available test for CA125 could reliably detect an ovarian tumor, the tumor would need to reach a size of about 1.7 billion cells, or the volume of a cube with about a 2-cm edge. That would take about 10.1 to 12.6 years of development, at typical tumor-growth rates, from the first, single cancer cell.

The model further calculated that a biomarker otherwise equivalent to CA125 but shed only by ovarian tumor cells would allow reliable detection within 7.7 years, when a tumor’s size would be that of a tiny cube about one-sixth of an inch high.

In the last decade, many potential new biomarkers for different cancers have been identified. There’s no shortage of promising candidates — six for lung cancer alone, for example. But validating a biomarker in large clinical trials is a long, expensive process. So it is imperative to determine as efficiently as possible which, among many potential tumor biomarkers, is the best prospective candidate.

“This model could take some of the guesswork out of it,” Gambhir said. “It can be applied to all kinds of solid cancers and prospective biomarkers as long as we have enough data on, for instance, how much of it a tumor cell secretes per hour, how long the biomarker can circulate before it’s degraded and how quickly tumor cells divide.

“We can tweak one or another variable — for instance, whether a biomarker is also made in healthy tissues or just the tumor, or assume we could manage to boost the sensitivity of our blood tests by 10-fold or 100-fold — and see how much it advances our ability to detect the tumor earlier on.”

There are now new detection technologies capable of detecting biomarkers at concentrations as low as a few hundred molecules per mm (cc) of blood. A couple of years ago, Gambhir and his colleagues reported on one such developing technology: so-called magneto-nanosensors that can detect biomarkers with a 100-fold greater sensitivity than current methods.

Better biomarker detection alone might shrink the time an ovarian tumor can grow before detection to about nine years, said Gambhir.

A second priority is to come up with new and better biomarkers. “It’s really important for us to find biomarkers that are made exclusively by ,” he said.

Under the right conditions (a highly sensitive assay measuring levels of a biomarker that is shed only by cancer cells), Gambhir said, the model predicts that a tiny tumor with a volume equivalent to a cube less than one-fifteenth of an inch on a side could be spotted.

Provided by Stanford University Medical Center

Lung Cancer Deaths Not Reduced by Chest X-Ray Screening

By Anna Azvolinsky, PhD | October 26, 2011
 A trial of 154,901 participants between the ages of 55 and 74 sought to address whether performing chest radiographs affects lung cancer incidence and mortality rates from lung cancer. The trial, which randomized people one to one either to annual screening or usual care for four years, found that chest x-rays did not reduce lung cancer mortality.
Both sides of the lungs are visible with a growth on the left side of the lung, which could be lung cancer.

The intervention group was offered annual posteroanterior-view chest radiographs while usual-care patients were not offered interventions. The study is published today, online in the November 2 issue of JAMA (doi:10.1001/jama.2011.1591) and will be presented at the annual meeting of the American College of Chest Physicians (CHEST 2011). The results are part of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Randomized Trial.

Martin M. Oken, MD of the University of Minnesota and Philip C. Prorok, PhD of the Division of Cancer Prevention at the NCI and colleagues analyzed participants at one of ten screening centers in the United States between 1993 and 2001. The demographics of the two groups were similar: half were women, about 45% had never smoked, 42% were former smokers, and 10% were current smokers. A total of 1,213 lung cancer deaths were observed in the x-ray screened group compared to 1230 in the usual care group over a 13-year follow up period. In total, 1,696 lung cancers were detected in the screened group and 1620 were detected in the usual care group. It was not possible to accurately detect overdiagnosis rates.

The authors conclude that “these findings provide good evidence that there is not a substantial lung cancer mortality benefit from lung cancer screening with four annual chest radiographs.” The Mayo Lung Project trial of chest radiograph and sputum cytology screenings completed in the early 1980s also did not show a mortality benefit.

In an accompanying editorial, Harold C. Sox, MD at Dartmouth Medical School highlights that this is one of two complementary lung cancer screening trial results released in the last two months The second is the National Lung Screening Study (NSLT), which found that annual low-dose computed tomography reduced lung cancer mortality by 20% relative to annual chest radiography (“NCI-Funded Study Finds Low-Dose CT Scans Better than X-Rays in Reducing Lung Cancer Mortality,” July 21, 2011, CancerNetwork).

Sox comments that the “PLCO lung cancer study provides convincing evidence that lung cancer screening with chest radiography is not effective.” He highlights that this study is important for putting the question of whether chest radiography is beneficial for decreasing the rate of mortality from lung cancer. According to Sox, “the NLST showed convincingly that early detection can lower the risk of death from lung cancer, a big step forward.” Now, he suggests that a real-world comparison between usual care and low-dose CT is warranted.

High tech detection of breast cancer using nanoprobes and SQUID

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Posted 28 Oct 2011 — by James Street
Category Breast Cancer, Diagnostic, HER2/neu, NanoTechnology, Physics and Engineering

Contact: Dr Hilary Glover
hilary.glover@biomedcentral.com
44-020-319-22370
BioMed Central

Mammography saves lives by detecting very small tumors. However, it fails to find 10-25% of tumors and is unable to distinguish between benign and malignant disease. New research published in BioMed Central’s open access journal Breast Cancer Research provides a new and potentially more sensitive method using tumor–targeted magnetic nanoprobes and superconducting quantum interference device (SQUID) sensors.

A team of researchers from University of New Mexico School of Medicine and Cancer Research and Treatment Center, Senior Scientific, LLC, and the Center for Integrated Nanotechnologies facility at Sandia National Laboratories created nanoprobes by attaching iron-oxide magnetic particles to antibodies against HER-2, a protein overexpressed in 30% of breast cancer cases. Using these tiny protein-iron particles the team was able to distinguish between cells with HER-2 and those without, and were able to find HER-2 cancer cells in biopsies from mice. In their final test the team used a synthetic breast to determine the potential sensitivity of their system.

Dr Helen Hathaway explained, “We were able to accurately pinpoint 1 million cells at a depth of 4.5 cm. This is about 1000x fewer cells than the size at which a tumor can be felt in the breast and 100x more sensitive than mammographic x-ray imaging. While we do not expect the same level of nanoparticle uptake in the clinic, our system has an advantage in that dense breast tissue, which can mask traditional mammography results, is transparent to the low-frequency magnetic fields detected by the SQUID sensors.”

Future refining of the system could allow not only tumor to be found but to be classified according to protein expression (rather than waiting for biopsy results). This in turn could be used to predict disease progression and refine treatment plans and so improve patient survival.