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Anderson G.G.,Pathwork Diagnostics | Weiss L.M.,City of Hope National Medical Center
Applied Immunohistochemistry and Molecular Morphology

BACKGROUND: Pathologists use various panels of immunohistochemical (IHC) stains to identify the site of tissue of origin for metastatic tumors, particularly poorly or undifferentiated cancers of unknown or uncertain origin. Although clinicians believe that immunostains contribute greatly to determining the probable primary site among 3 or more possibilities, objective evidence has not been convincingly presented. This meta-analysis reviews the objective evidence supporting this practice and summarizes the performance reported in 5 studies published between 1993 and 2007. METHODS: A literature search was conducted to identify IHC performance studies published since 1990 that were masked, included more than 3 tissues types, and used more than 50 specimens. The 5 studies found in this search were separated into 2 subgroups for analysis: those, which included only metastatic tumors (n=368 specimens) and the blended studies, which combined primary tumors and metastases (n=289 specimens). RESULTS: The meta-analysis found that IHCs provided the correct tissue identification for 82.3% (95% confidence interval=77.4%-86.3%) of the blended primary and metastatic samples and 65.6% (95% confidence interval=60.1%-70.7%) of metastatic cancers. This difference is both clinically and statistically significant. CONCLUSIONS: This literature review confirms that there is still an unmet medical need in identification of the primary site of metastatic tumors. It establishes minimum performance requirements for any new diagnostic test intended to aid the pathologist and oncologist in tissue of origin determination. Copyright © 2009 by Lippincott Williams & Wilkins. Source

Monzon F.A.,University of Pittsburgh | Medeiros F.,Mayo Medical School | Lyons-Weiler M.,University of Pittsburgh | Henner W.D.,Pathwork Diagnostics
Diagnostic Pathology

Background. Carcinomas of unknown primary (CUP) represent approximately 3%-5% of malignant neoplasms. Identifying the tissue of origin (TOO) in these tumors allows for more specific treatment and improves outcomes. However, primary classification remains a challenge in many cases. We evaluated the ability of a microarray-based gene expression test to identify the TOO in tumor specimens from 21 patients with a diagnosis of CUP. Methods. The Pathwork® TOO Test was used to measure gene expression patterns for 1550 genes; these were compared for similarity to patterns from 15 known tissue types. Results. The TOO Test yielded a clear single positive call for the primary site in 16 of 21 (76%) specimens and was indeterminate in 5 (24%). The positive results were consistent with clinicopathologic suggestions in 10 of the 16 cases (62%). In the remaining six cases the positive results were considered plausible based on clinical information. Positive calls included colorectal (5), breast (4), ovarian (3), lung (2), and pancreas (2). The TOO Test ruled out an average of 11 primary tissues in each CUP specimen. Conclusion. The Pathwork TOO Test reduced diagnostic uncertainty in all CUP cases and could be a valuable addition or alternative to current diagnostic methods for classifying uncertain primary cancers. © 2010 Monzon et al. Source

Baia G.S.,Johns Hopkins University | Caballero O.L.,Johns Hopkins University | Orr B.A.,Johns Hopkins University | Lal A.,Pathwork Diagnostics | And 5 more authors.
Molecular Cancer Research

The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals, and its proposed function is to control tissue homeostasis by regulating cell proliferation and apoptosis. The core components are composed of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4, and functions as a transcriptional factor promoting the expression of key target genes. Components of the Hippo pathway are mutated in human cancers, and deregulation of this pathway plays a role in tumorigenesis. Loss of the NF2 tumor suppressor gene is the most common genetic alteration in meningiomas, and the NF2 gene product, Merlin, acts upstream of the Hippo pathway. Here, we show that primary meningioma tumors have high nuclear expression of YAP1. In meningioma cells, Merlin expression is associated with phosphorylation of YAP1. Using an siRNA transient knockdown of YAP1 in NF2-mutant meningioma cells, we show that suppression of YAP1 impaired cell proliferation and migration. Conversely, YAP1 overexpression led to a strong augment of cell proliferation and anchorage-independent growth and restriction of cisplatin-induced apoptosis. In addition, expression of YAP1 in nontransformed arachnoidal cells led to the development of tumors in nude mice. Together, these findings suggest that in meningiomas, deregulation of the Hippo pathway is largely observed in primary tumors and that YAP1 functions as an oncogene promoting meningioma tumorigenesis. ©2012 AACR. Source

Grenert J.P.,University of California at San Francisco | Smith A.,University of California at San Francisco | Ruan W.,University of California at San Francisco | Pillai R.,Pathwork Diagnostics | Wu A.H.B.,University of California at San Francisco
Clinica Chimica Acta

Background: Molecular profiling assays have emerged as a promising tool in tumor diagnosis. Recent advances have allowed the use of formalin-fixed, paraffin-embedded (FFPE) tissues in such assays involving the use of microarrays. The Pathwork Tissue of Origin (TOO) Test was developed for use with FFPE tissue to aid tumor diagnosis. We sought to determine the performance of the TOO test on routine specimens from an independent laboratory. Methods: Forty-five blinded, archived clinical specimens from the UCSF Department of Pathology were tested. Total RNA was processed to prepare labeled cDNA for hybridization to Pathchip microarrays. Hybridization data was analyzed with a 2000-gene classification model to quantify similarity between RNA expression of the study specimens and the 15 tissues on the test panel. Results: 44/45 (98%) specimens were successfully processed. 37 cases met study inclusion criteria. Of these, 35 (95%) gave results which were in agreement with the reference diagnosis. In no case was the reference diagnosis ruled out. Conclusions: The Tissue of Origin Test gave a high agreement with the reference diagnosis when archived clinical specimens from UCSF were assessed. Molecular profiling assays are highly accurate, and can be a useful tool in cancer diagnosis. © 2011 Elsevier B.V. Source

Crawled News Article
Site: www.zdnet.com

As someone who has been covering cloud computing since the dawn of Amazon’s Elastic Compute Cloud (EC2) I’m constantly in education mode about what is and isn’t cloud computing. To borrow an analogy from my Forrester colleague Ted Schadler’s keynote at last year’s IT Forum, the challenge is a lot like helping blind men discern an elephant through just the parts of the animal they can reach. One feels the trunk and declares it a cylindrical, yet hairy and warm snake. The other calls it a strong, tough and deeply rooted tree upon feeling its hind leg. Each examiner brings their own experience and context to the challenge as well as their own judgments, then leaps to the conclusion that best fits their desires. Many IT ops pros see the cloud as competition and quickly race to its flaws, declaring it unsafe and immature while they scheme for how to duplicate its benefits – rapid provisioning, shared infrastructure – within their own data center. Others quickly conclude that it is nothing more than virtualization and thus relabel their VMware environment “private cloud.” Each vendor looks at cloud from within its own context declaring it either “something we’ve been offering to the market for years” or a natural outgrowth of their core value – even if the value of cloud is clearly tangential or even well beyond what they offer. The result: all are making dangerous leaps of logic that skip over the true change cloud computing represents and put all at risk of disruption. Cloud computing, especially in the form of Infrastructure as a Service (IaaS) and Platform as a Service (PaaS) are evolutionary steps in hosting that change both the deployment model and the business value of IT in profound ways. Those that acknowledge this and accept what truly is different about it stand to gain the most from it. But let’s be clear, cloud computing isn’t your future – it’s a new part of your overall IT portfolio. There are lots of definitions out there purporting the scope and architecture of cloud but what’s important is to focus on what makes cloud computing a new and unique value. Simply painting pre-existing services with a wash of cloud helps no one. The fundamentals of cloud computing are more important to understand than the basic words of a definition, as they are clearly open to interpretation in the same way the elephant becomes a snake or a tree. First off, let’s get one thing straight. Cloud might be another word for the Internet, but cloud computing isn’t another word for services delivered over the Internet. We already have plenty of words for those – Internet services and web services for starters. It’s combining cloud with computing that draws out the distinction, as cloud computing is about cloud-enabling your business services via abstracted components deployed at virtual scale. Read here how Pathwork Diagnostics is creating new market value via cloud computing. There are three core fundamentals to cloud computing which distinguish it from traditional IT and other Internet services that bring forth its different business value: I know a lot of you will argue with these fundamentals and I encourage that discussion here, via Twitter and through your own blogs. I will be defending these fundamentals in my keynote address at next week’s IT Forum by showing how your peers – enterprises, innovative startup companies and leading vendors – are leveraging cloud computing to differentiate themselves and maximize profitability. They aren’t cloudwashing, they’re cloud enabling their businesses. I’ll show you how you can follow in their footsteps. And on Friday during the Forum (and at our IT Forum EMEA in Lisbon in June), I’ll walk you through the ROI of cloud computing so you can sell the value up the chain. I’ll also help you understand how cloud isn’t the sole future of IT and why you shouldn’t try to move everything to the cloud. Or you can choose to ignore what’s different about true cloud computing. Keep your head in the sand, cloud wash your existing services and fight for relevancy. But know that doing so exposes you and your company to the risk of being passed by those who are truly harnessing this innovation. We hope to see you at Forrester’s IT Forum next week.

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