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December 22, 2011

In This Issue:

arrowStudy confirms clinical validity of Pathwork tissue-of-origin test

arrowAmino acid variation in immune response gene linked with ulcerative colitis

arrowPediatric cancer drugs may be linked to later heart problems

arrowVentana and Advanced Cell Diagnostics join to market ISH assay systems

arrowWithout autopsies, hospitals bury their mistakes

arrowResearchers discover second-oldest gene mutation

arrowLack of labs hinder healthcare in Ghana

arrowHot Clips: Diagnostics

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Study confirms clinical validity of Pathwork tissue-of-origin test

A study conducted at Virginia Commonwealth University and published online in the American Journal of Clinical Pathology (AJCP) has confirmed the clinical validity of Pathwork Diagnostics’ new Pathwork Tissue of Origin Test. The test is the only FDA-cleared, Medicare-covered molecular diagnostic for identifying tissue of origin. It uses a tumor's own genomic information to help pathologists and oncologists diagnose challenging cancer cases such as those that are metastatic or that have a complex clinical history. It measures gene expression levels of 2,000 genes and uses proprietary algorithms to compare the tumor’s gene expression pattern to that of 15 tumor types, representing 58 morphologies and 90% of all solid tumors.

In the study, the analytic and clinical performance of the test was examined in 43 poorly differentiated and undifferentiated tumor samples. Results showed 97% (95% confidence interval, 80.4%-99.8%) agreement between the test result and the reference diagnosis, which was determined on the basis of clinical correlations and immunohistochemical findings and was among the 15 tumor tissue types covered by the test. This finding correlates well with the validated performance of the test, 88.5% agreement with available diagnosis in 462 specimens (95% confidence interval, 85.3%-91.3%). The test has also been evaluated in multiple independent studies involving more than 1,100 patient specimens, including large validation studies published in the Journal of Clinical Oncology and the Journal of Molecular Diagnostics. Read an abstract of the AJCP-published study.

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Amino acid variation in immune response gene linked with ulcerative colitis

The association between the inflammatory bowel disease ulcerative colitis and a gene that makes certain cell surface proteins has been pinpointed to a variant amino acid in a crucial binding site that profoundly influences immune response to antigens, including gut bacteria. So reports a team of researchers at the University of Pittsburgh, Cleveland Clinic, Carnegie Mellon University and Harvard Medical School. They published the findings December 15 in the online version of Genes & Immunity.

According to corresponding study author Richard H. Duerr, MD, variations in genes that regulate immune responses in a region of chromosome 6 have long been linked with susceptibility for many infectious and chronic inflammatory conditions, including ulcerative colitis."We tested more than 10,000 points, called single nucleotide polymorphisms, (SNPs), in the gene sequence in this chromosomal region, and we also tested amino acid variations in human leukocyte antigen (HLA) proteins that were deduced from the SNPs to identify those most important for ulcerative colitis," Dr. Duerr says. Using sophisticated association techniques, the authors confirmed that an HLA gene called DRB1, which codes for a protein involved in the immune response and is routinely tested in tissue matching for organ transplantation, was uniquely related to ulcerative colitis. Variation in that gene altered which amino acid was selected for the 11th position in the DRB1 protein—a key location in a pocket of the so-called binding cleft where other proteins, such as antigens or markers of foreign cells, attach. The study abstract provides more information.

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Pediatric cancer drugs may be linked to later heart problems

A University of Buffalo professor of pharmaceutical sciences is voicing concerns that drugs used to treat childhood leukemia and other pediatric cancers may lead to congestive heart failure or other cardiomyopathy (disease of the heart muscle) for patients later in life. In a study recently published in the Journal of Clinical Oncology, Javier G. Blanco, PhD, and colleagues link anthracylines, a class of drugs that also is used to treat breast and other cancers in adults, with cardiac toxicity. The heart problems can arise, says Blanco, anywhere from one year to 15 years after the chemotherapy. Blanco’s study compared the DNA genotypes of 170 survivors of childhood cancer with cardiomyopathy to those of a control group. His team reports that by concentrating on carbonyl reductases (CBR1 and CBR3), enzymes that break down anthracyclines into cardiotoxic alcohol metabolites, they identified a gene variant that is associated with the risk of cardiac toxicity. “We pinpointed the genetic difference or polymorphism that makes an enzyme work faster or slower in patients,” Blanco says. “Slower is better.”

Blanco acknowledges that his research shows an association, not a cause-and-effect relationship, and that further studies are needed. He also adds that the conclusion should not be drawn that oncologists should stop using anthracyclines, which routinely save the lives of children with acute lymphoblastic leukemia. The clinical key, he stresses, is the lesson that molecular diagnostics is teaching every day: the need to adjust dosage based on an understanding of how an individual is genetically coded to respond to a given drug. Read a full article describing the research.

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Ventana and Advanced Cell Diagnostics join to market ISH assay systems

Ventana Medical Systems Inc., a member of the Roche Group, and Advanced Cell Diagnostics Inc. have entered a worldwide co-promotion agreement for the first commercially available, fully automated RNA in situ hybridization (ISH) assay system capable of robust detection and visualization of virtually any expressed gene in routine clinical specimens at single-molecule sensitivity. The companies have partnered to automate this assay system on the VENTANA DISCOVERY series slide staining platforms. The product offerings are expected to become commercially available in first quarter 2012 and will initially be offered only for research-use applications.

RNA in situ hybridization is an indispensable method to analyze gene expression in the context of tissue architecture in oncology, virology, and neuroscience research. RNAscope allows researchers to interrogate the function and disease relevance of any expressed genes in situ, especially for the approximately 5,000 genes and 15,000 non-coding RNAs in the human genome where no other technologies can adequately address. It also enables researchers to tap into the estimated 400 million clinically-annotated, archived formalin-fixed paraffin-embedded (FFPE) tissue specimens for retrospective clinical studies in translational research.

The DISCOVERY XT and DISCOVERY ULTRA systems provide scientists and research professionals who require more than conventional IHC and ISH research methods with an array of fully automated applications. Learn more details including an image of mouse brain tissue mRNA detected by automated RNA scope XT assay.

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Without autopsies, hospitals bury their mistakes

A half-century ago, autopsies were routine. Autopsies, sometimes called the ultimate medical audit, were an integral part of American healthcare, 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.

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. healthcare 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 to learn about the effectiveness of medical treatments and the progression of diseases are lost. Inaccurate information winds up on death certificates, undermining the reliability of crucial health statistics.

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

“Much of what we know about medicine comes from the autopsy,” says 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.”

Dr. Elizabeth Burton, deputy director of the pathology department at Johns Hopkins University School of Medicine, says 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. Visit ProPublica for the article.

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Researchers discover second-oldest gene mutation

A new study has identified a gene mutation that researchers estimate dates back to 11,600 B.C., making it the second oldest human disease mutation yet discovered. Researchers with the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute believe the mutation arose in the Middle East some 13,600 years ago. Only a mutation seen in cystic fibrosis is believed to be older. The findings were published recently in the Orphanet Journal of Rare Diseases.

The mutation causes a rare, inherited vitamin B12 deficiency called Imerslund-Gräsbeck Syndrome (IGS). Researchers described the mutation in people of Arabic, Turkish and Jewish ancestry. They examined 20 patients, 24 parents, 8 unaffected siblings, and 4 grandparents from 16 IGS families Their findings will enable genetic diagnosis of IGS, which occurs in children born with two mutated copies of either the amnionless (AMN) or the cubilin (CUBN) gene. When a genetic mistake is present in both copies of either of these two genes, the person cannot absorb vitamin B12 in the small intestine.

Children with IGS experience a high risk of infections, fatigue, attention deficit, paralysis and, ultimately, a form of anemia that can be fatal if untreated. Four hundred to 500 cases of IGS have been described worldwide thus far. The syndrome is treatable with life-long injections of vitamin B12. View an abstract of the study to learn more.

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Lack of labs hinder healthcare in Ghana

Heathcare officials in Ghana used the first-ever scientific conference of the Eastern Regional branch of the Ghana Association of Biomedical Laboratory Scientists (GABMLS) to highlight the problems facing healthcare delivery in the West African nation—problems due in part to the scarcity of effective clinical labs. George Danquah, Acting Eastern Regional Biomedical Scientist, noted that in the Eastern Region, besides the Regional and District hospitals, some 60 other medical facilities do not have laboratory services. Danquah linked the lack of labs to the high rate—two percent—of sickle cell disease births in the country. He asked organizations within Africa and from abroad to help the Eastern Region to obtain a refrigerated centrifuge to facilitate preparation of frozen plasma, platelet concentrate, and packed cells. This would particularly benefit pregnant women, who die in significant numbers because of a lack of safe blood.

Francis Abeku Ussher, Eastern Regional Chairman of GABMLS, drew attention to the challenges posed to effective diagnostics by a lack of a continuous supply of reagents and a shortage of biomedical engineers to repair broken equipment. Dr. George Bonsu, Deputy Eastern Regional Director of Public Health, stressed the need for improving the health surveillance chain to aid in identifying possible outbreaks of disease. Ebenezer Terlabi, Deputy Eastern Regional Minister, promised the government would put its weight behind legislation to regulate biomedical science and ensure that it is practiced only by qualified personnel. The determination of the scientists and government notwithstanding, the conference underscored the obstacles that face laboratory medicine in the developing world. Learn more about the objectives and programs of GABMLS by visiting its website.

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HOT CLIPS: Diagnostics - Top Picks

Click on the highlighted links below to discover the top MLO archival properties concerning diagnostics, a topic that is now at the forefront of healthcare discussions.

  1. The global goal for TB diagnostics
  2. Diabetes cases on the rise: current diagnosis guidelines and research efforts for a cure
  3. Outbreak: the changing epidemiology of HAIs and CAIs
  4. Permissive hypercapnia’s impact on labs’ blood-gas analysis

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