Posts Tagged ‘companion diagnostics’

New Risk Stratification for Breast Cancer

Larry H. Bernstein, MD, FCAP, Curator


Updated 01/26/2021

Invasive Lobular Breast Cancer May Have Worse Prognosis than Ductal Cancer

— Analysis highlights need for further research, says Megan Kruse, MD

Source: https://www.medpagetoday.com/meetingcoverage/sabcsvideopearls/90531

An analysis of the largest recorded cohort of patients with invasive lobular breast cancer (ILBC) demonstrates that outcomes are significantly worse when compared with invasive ductal breast cancer, highlighting a significant need for more research and clinical trials on patients with ILBC. The findings were presented at the virtual 2020 San Antonio Breast Cancer Symposium.

In this exclusive MedPage Today video, Megan Kruse, MD, of the Cleveland Clinic, explains the multi-institutional study and the insights in provides for future prognostic research.

This work was spearheaded by clinicians who are interested in lobular breast cancer, and trying to figure out how lobular breast cancer is different than ductal breast cancer in a way that would be meaningful for patient care. And so since lobular breast cancer is about 10-15% of all the breast cancers we see, we knew that this work would have to be done on a multi-institution basis.
What we ultimately found was that for lobular cancer patients, those tumors were often diagnosed at a higher stage — meaning larger tumor size and greater lymph node involvement. These were also diagnosed in patients who were of older age compared to the ductal cancer patients, and the patients in the lobular cancer group were less likely to be HER2-positive and less likely to receive chemotherapy.

MD Anderson Researchers Develop New Breast Cancer Staging System


NEW YORK (GenomeWeb) – Researchers at the University of Texas MD Anderson Cancer Center have developed a new breast cancer staging system that incorporates tumor biology as a critical prognostic indicator for women who undergo neoadjuvant therapy.

Published this week in JAMA Oncology, the Neo-Bioscore staging system incorporates HER2/ERBB2 status, which allows for more precise prognostic stratification of all breast cancer subtypes.

To date, breast cancer patient staging involved considering the size of the primary tumor, metastasis, or disease in the lymph nodes at the time of presentation as the primary factors.However, this fails to take into account the biology of the tumor, which has shown to be critically important, Elizabeth Mittendorf, associate professor of Breast Surgical Oncology at MD Anderson and corresponding author on the study, said in a statement.

The new system builds on the development of an earlier breast cancer staging system developed by MD Anderson, CPS+EG, that incorporates preclinical stage, estrogen receptor status, grade, and post-treatment pathologic stage. While it was an improvement from previous methods, it is no longer a sufficient staging system because it predates the routine use of trastuzumab in the neoadjuvant setting and therefore had a limited ability to provide prognostic information for HER2/ERBB2-positive patients, Mittendorf said.

To develop the staging system, the researchers conducted a retrospective study that evaluated 2,377 MD Anderson breast cancer patients who all had non-metastatic invasive breast cancer and were treated with neoadjuvant chemotherapy.

Each patient’s clinicopathologic data were recorded, including age, clinical and pathological stage, ER status, HER2/ERBB2 status, and nuclear grade. Patients’ ER status was recorded as a percentage of cells staining positive under immunohistochemical analysis. Their ERBB2 status was defined as positive at a reading of 3+ on immunohistochemical analysis or when gene amplification was shown on fluorescence in situ hybridization.

All patients received an anthracycline and/or taxane-based neoadjuvant chemotherapy regimen. Patients with HER2/ERBB2-positive disease routinely completed one year of trastuzumab therapy. After completing chemotherapy, patients underwent either breast-conserving therapy or mastectomy with axillary evaluation with or without post-mastectomy irradiation.

Patients’ CPS+EG score was determined according to the previously published staging system and was calculated twice (once using 1 percent or higher as the cutoff for ER positivity and again using 10 percent or higher as the cutoff).

Their disease-specific survival (DSS) was also calculated using multiple staging systems: AJCC clinical stage, AJCC pathologic stage, CPS+EG (1 percent cutoff), and CPS+EG (10 percent cutoff). Within each staging system, DSS among subgroups was compared using the log-rank test.

After the researchers determined a CPS+EG score for each patient, they added the patient’s respective HER2/ERBB2 status to the model. They then constructed the novel staging system by adding a point to the CPS+EG score for HER2-negative tumors. In the study cohort, 591 patients were HER2/ERBB2 positive.

The researchers found that in addition to validating previous findings that CPS+EG score improved prognostication of patients, the Neo-Bioscore created a more refined stratification in approximately 75 percent of the study cohort. This shift reflects the number of HER2/ERBB2-negative tumors in the study and demonstrated that adding HER2/ERBB2 standards created a highly significant improvement.

“With this tool, I can give my patients the precise information they are looking for: a more refined prognosis. Also, with this data, we will know which patients are in greatest need of additional therapy,” Mittendorf said. “Hopefully these findings will result in more informed conversations between doctor and patient.”

The Neo-Bioscore Update for Staging Breast Cancer Treated With Neoadjuvant ChemotherapyIncorporation of Prognostic Biologic Factors Into Staging After Treatment 

Elizabeth A. Mittendorf, MD, PhD1; Jose Vila, MD1; Susan L. Tucker, PhD2; ….; W. Fraser Symmans, MD6; Aysegul A. Sahin, MD6; Gabriel N. Hortobagyi, MD3; Kelly K. Hunt, MD
JAMA Oncol. Published online March 17, 2016.              http://dx.doi.org:/10.1001/jamaoncol.2015.6478

Importance  We previously described and validated a breast cancer staging system (CPS+EG, clinical-pathologic scoring system incorporating estrogen receptor–negative disease and nuclear grade 3 tumor pathology) for assessing prognosis after neoadjuvant chemotherapy using pretreatment clinical stage, posttreatment pathologic stage, estrogen receptor (ER) status, and grade. Development of the CPS+EG staging system predated routine administration of trastuzumab in patients with ERBB2-positive disease (formerly HER2 or HER2/neu).

Objective  To validate the CPS+EG staging system using the new definition of ER positivity (≥1%) and to develop an updated staging system (Neo-Bioscore) that incorporates ERBB2 status into the previously developed CPS+EG.

Design, Setting, and Participants  Retrospective review of data collected prospectively from January 2005 through December 2012 on patients with breast cancer treated with neoadjuvant chemotherapy at The University of Texas MD Anderson Cancer Center.

Main Outcomes and Measure  Prognostic scores were computed using 2 versions of the CPS+EG staging system, one with ER considered positive if it measured 10% or higher, the other with ER considered positive if it measured 1% or higher. Fits of the Cox proportional hazards model for the 2 sets of prognostic scores were compared using the Akaike Information Criterion (AIC). Status of ERBB2 was added to the model, and the likelihood ratio test was used to determine improvement in fit.

Results  A total of 2377 patients were included; all were women (median age, 50 years [range, 21-87 years]); ER status was less than 1% in 28.9%, 1% to 9% in 8.3%, and 10% or higher in 62.8%; 591 patients were ERBB2 positive. Median follow-up was 4.2 years (range, 0.5-11.7 years). Five-year disease-specific survival was 89% (95% CI, 87%-90%). Using 1% or higher as the cutoff for ER positivity, 5-year disease-specific survival estimates determined using the CPS+EG stage ranged from 52% to 98%, thereby validating our previous finding that the CPS+EG score facilitates more refined categorization into prognostic subgroups than clinical or final pathologic stage alone. The AIC value for this model was 3333.06, while for a model using 10% or higher as the cutoff for ER positivity, it was 3333.38, indicating that the model fits were nearly identical. The improvement in fit of the model when ERBB2 status was added was highly significant, with 5-year disease-specific survival estimates ranging from 48% to 99% (P < .001). Incorporating ERBB2 into the staging system defined the Neo-Bioscore, which provided improved stratification of patients with respect to prognosis.

Conclusions and Relevance  The Neo-Bioscore improves our previously validated staging system and allows its application in ERBB2-positive patients. We recommend that treatment response and biologic markers be incorporated into the American Joint Committee on Cancer staging system.

Transforming Breast Cancer Treatment

Landmark preclinical study cured lung metastases in 50 percent of breast cancers by making nanoparticles inside the tumor.


A team of investigators from Houston Methodist Research Institute may have transformed the treatment of metastatic triple negative breast cancer by creating the first drug to successfully eliminate lung metastases in mice.

The majority of cancer deaths are due to metastases to the lung and liver, yet there is no cure. Existing cancer drugs provide limited benefit due to their inability to overcome biological barriers in the body and reach the cancer cells in sufficient concentrations. Houston Methodist nanotechnology and cancer researchers have solved this problem by developing a drug that generates nanoparticles inside the lung metastases in mice.

In this study, 50 percent of the mice treated with the drug had no trace of metastatic disease after eight months. That’s equivalent to about 24 years of long-term survival following metastatic disease for humans.

Due to the body’s own defense mechanisms, most cancer drugs are absorbed into healthy tissue causing negative side effects, and only a fraction of the administered drug actually reaches the tumor, making it less effective, said Mauro Ferrari, Ph.D, president and CEO of the Houston Methodist Research Institute. This new treatment strategy enables sequential passage of the biological barriers to transport the killing agent into the heart of the cancer. The active drug is only released inside the nucleus of the metastatic disease cell, avoiding the multidrug resistance mechanism of the cancer cells. This strategy effectively kills the tumor and provides significant therapeutic benefit in all mice, including long-term survival in half of the animals.

This finding comes 20 years after Ferrari started his work in nanomedicine. Ferrari and Haifa Shen, M.D., Ph.D., are co-senior authors on the paper, which describes the action of the injectable nanoparticle generator (iNPG), and how a complex method of transporting a nano-version of a standard chemotherapy drug led to never before seen results in mice models with triple negative breast cancer that had metastasized to the lungs.

“This may sound like science fiction, like we’ve penetrated and destroyed the Death Star, but what we discovered is transformational. We invented a method that actually makes the nanoparticles inside the cancer and releases the drug particles at the site of the cellular nucleus. With this injectable nanoparticle generator, we were able to do what standard chemotherapy drugs, vaccines, radiation, and other nanoparticles have all failed to do,” said Ferrari.

Houston Methodist has developed good manufacturing practices (GMP) for this drug and plans to fast-track the research to obtain FDA-approval and begin safety and efficacy studies in humans in 2017.

“I would never want to overpromise to the thousands of cancer patients looking for a cure, but the data is astounding,” said Ferrari, senior associate dean and professor of medicine, Weill Cornell Medicine. “We’re talking about changing the landscape of curing metastatic disease, so it’s no longer a death sentence.”

The Houston Methodist team used doxorubicin, a cancer therapeutic that has been used for decades but has adverse side effects to the heart and is not an effective treatment against metastatic disease. In this study, doxorubicin was packaged within the injectable nanoparticle generator that is made up of many components.

Shen, a senior member of the department of nanomedicine at Houston Methodist Research Institute, explains that each component has a specific and essential role in the drug delivery process. The first component is the nanoporous silicon material that naturally degrades in the body. The second component is a polymer made up of multiple strands that contain doxorubicin. Once inside the tumor, the silicon material degrades, releasing the strands. Due to natural thermodynamic forces, these strands curl-up to form nanoparticles that are taken up by the cancer cells. Once inside the cancer cells, the acidic pH close to the nucleus causes the drug to be released from the nanoparticles. Inside the nucleus, the active drug acts to kill the cell.

“If this research bears out in humans and we see even a fraction of this survival time, we are still talking about dramatically extending life for many years. That’s essentially providing a cure in a patient population that is now being told there is none,” said Ferrari, who holds the Ernest Cockrell Jr. Presidential Distinguished Chair and is considered one of the founders of nanomedicine and oncophysics (physics of mass transport within a cancer lesion).

The Houston Methodist team is hopeful that this new drug could help cancer physicians cure lung metastases from other origins, and possibly primary lung cancers as well.

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Cancer Companion Diagnostics

Curator: Larry H. Bernstein, MD, FCAP


Companion Diagnostics for Cancer: Will NGS Play a Role?

Patricia Fitzpatrick Dimond, Ph.D.


Companion diagnostics (CDx), in vitro diagnostic devices or imaging tools that provide information essential to the safe and effective use of a corresponding therapeutic product, have become indispensable tools for oncologists.  As a result, analysts expect the global CDx market to reach $8.73 billion by 2019, up from from $3.14 billion in 2014.

Use of CDx during a clinical trial to guide therapy can improve treatment responses and patient outcomes by identifying and predicting patient subpopulations most likely to respond to a given treatment.

These tests not only indicate the presence of a molecular target, but can also reveal the off-target effects of a therapeutic, predicting toxicities and adverse effects associated with a drug.

For pharma manufacturers, using CDx during drug development improves the success rate of drugs being tested in clinical trials. In a study estimating the risk of clinical trial failure during non-small cell lung cancer drug development in the period between 1998 and 2012 investigators analyzed trial data from 676 clinical trials with 199 unique drug compounds.

The data showed that Phase III trial failure proved the biggest obstacle to drug approval, with an overall success rate of only 28%. But in biomarker-guided trials, the success rate reached 62%. The investigators concluded from their data analysis that the use of a CDx assay during Phase III drug development substantially improves a drug’s chances of clinical success.

The Regulatory Perspective

According to Patricia Keegen, M.D., supervisory medical officer in the FDA’s Division of Oncology Products II, the agency requires a companion diagnostic test if a new drug works on a specific genetic or biological target that is present in some, but not all, patients with a certain cancer or disease. The test identifies individuals who would benefit from the treatment, and may identify patients who would not benefit but could also be harmed by use of a certain drug for treatment of their disease. The agency classifies companion diagnosis as Class III devices, a class of devices requiring the most stringent approval for medical devices by the FDA, a Premarket Approval Application (PMA).

On August 6, 2014, the FDA finalized its long-awaited “Guidance for Industry and FDA Staff: In Vitro Companion Diagnostic Devices,” originally issued in July 2011. The final guidance stipulates that FDA generally will not approve any therapeutic product that requires an IVD companion diagnostic device for its safe and effective use before the IVD companion diagnostic device is approved or cleared for that indication.

Close collaboration between drug developers and diagnostics companies has been a key driver in recent simultaneous pharmaceutical-CDx FDA approvals, and partnerships between in vitro diagnostics (IVD) companies have proliferated as a result.  Major test developers include Roche Diagnostics, Abbott Laboratories, Agilent Technologies, QIAGEN), Thermo Fisher Scientific, and Myriad Genetics.

But an NGS-based test has yet to make it to market as a CDx for cancer.  All approved tests include PCR–based tests, immunohistochemistry, and in situ hybridization technology.  And despite the very recent decision by the FDA to grant marketing authorization for Illumina’s MiSeqDx instrument platform for screening and diagnosis of cystic fibrosis, “There still seems to be a number of challenges that must be overcome before we see NGS for targeted cancer drugs,” commented Jan Trøst Jørgensen, a consultant to DAKO, commenting on presentations at the European Symposium of Biopathology in June 2013.

Illumina received premarket clearance from the FDA for its MiSeqDx system, two cystic fibrosis assays, and a library prep kit that enables laboratories to develop their own diagnostic test. The designation marked the first time a next-generation sequencing system received FDA premarket clearance. The FDA reviewed the Illumina MiSeqDx instrument platform through its de novo classification process, a regulatory pathway for some novel low-to-moderate risk medical devices that are not substantially equivalent to an already legally marketed device.

Dr. Jørgensen further noted that “We are slowly moving away from the ‘one biomarker: one drug’ scenario, which has characterized the first decades of targeted cancer drug development, toward a more integrated approach with multiple biomarkers and drugs. This ‘new paradigm’ will likely pave the way for the introduction of multiplexing strategies in the clinic using gene expression arrays and next-generation sequencing.”

The future of CDxs therefore may be heading in the same direction as cancer therapy, aimed at staying ahead of the tumor drug resistance curve, and acknowledging the reality of the shifting genomic landscape of individual tumors. In some cases, NGS will be applied to diseases for which a non-sequencing CDx has already been approved.

Illumina believes that NGS presents an ideal solution to transforming the tumor profiling paradigm from a series of single gene tests to a multi-analyte approach to delivering precision oncology. Mya Thomae, Illumina’s vice president, regulatory affairs, said in a statement that Illumina has formed partnerships with several drug companies to develop a universal next-generation sequencing-based oncology test system. The collaborations with AstraZeneca, Janssen, Sanofi, and Merck-Serono, announced in 2014 and 2015 respectively, seek to  “redefine companion diagnostics for oncology  focused on developing a system for use in targeted therapy clinical trials with a goal of developing and commercializing a multigene panel for therapeutic selection.”

On January 16, 2014 Illumina and Amgen announced that they would collaborate on the development of a next-generation sequencing-based companion diagnostic for colorectal cancer antibody Vectibix (panitumumab). Illumina will develop the companion test on its MiSeqDx instrument.

In 2012, the agency approved Qiagen’s Therascreen KRAS RGQ PCR Kit to identify best responders to Erbitux (cetuximab), another antibody drug in the same class as Vectibix. The label for Vectibix, an EGFR-inhibiting monoclonal antibody, restricts the use of the drug for those metastatic colorectal cancer patients who harbor KRAS mutations or whose KRAS status is unknown.

The U.S. FDA, Illumina said, hasn’t yet approved a companion diagnostic that gauges KRAS mutation status specifically in those considering treatment with Vectibix.  Illumina plans to gain regulatory approval in the U.S. and in Europe for an NGS-based companion test that can identify patients’ RAS mutation status. Illumina and Amgen will validate the test platform and Illumina will commercialize the test.

Treatment Options

Foundation Medicine says its approach to cancer genomic characterization will help physicians reveal the alterations driving the growth of a patient’s cancer and identify targeted treatment options that may not have been otherwise considered.

FoundationOne, the first clinical product from Foundation Medicine, interrogates the entire coding sequence of 315 cancer-related genes plus select introns from 28 genes often rearranged or altered in solid tumor cancers.  Based on current scientific and clinical literature, these genes are known to be somatically altered in solid cancers.

These genes, the company says, are sequenced at great depth to identify the relevant, actionable somatic alterations, including single base pair change, insertions, deletions, copy number alterations, and selected fusions. The resultant fully informative genomic profile complements traditional cancer treatment decision tools and often expands treatment options by matching each patient with targeted therapies and clinical trials relevant to the molecular changes in their tumors.

As Foundation Medicine’ s NGS analyses are increasingly applied, recent clinical reports describe instances in which comprehensive genomic profiling with the FoundationOne NGS-based assay result in diagnostic reclassification that can lead to targeted drug therapy with a resulting dramatic clinical response. In several reported instances, NGS found, among the spectrum of aberrations that occur in tumors, changes unlikely to have been discovered by other means, and clearly outside the range of a conventional CDx that matches one drug to a specific genetic change.

TRK Fusion Cancer

In July 2015, the University of Colorado Cancer Center and Loxo Oncology published a research brief in the online edition of Cancer Discovery describing the first patient with a tropomyosin receptor kinase (TRK) fusion cancer enrolled in a LOXO-101 Phase I trial. LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors.

While the authors say TRK fusions occur rarely, they occur in a diverse spectrum of tumor histologies. The research brief described a patient with advanced soft tissue sarcoma widely metastatic to the lungs. The patient’s physician submitted a tumor specimen to Foundation Medicine for comprehensive genomic profiling with FoundationOne Heme, where her cancer was demonstrated to harbor a TRK gene fusion.

Following multiple unsuccessful courses of treatment, the patient was enrolled in the Phase I trial of LOXO-101 in March 2015. After four months of treatment, CT scans demonstrated almost complete tumor disappearance of the largest tumors.

The FDA’s Elizabeth Mansfield, Ph.D., director, personalized medicine staff, Office of In Vitro Diagnostics and Radiological Health, said in a recent article,  “FDA Perspective on Companion Diagnostics: An Evolving Paradigm” that “even as it seems that many questions about co-development have been resolved, the rapid accumulation of new knowledge about tumor biology and the rapid evolution of diagnostic technology are challenging FDA to continually redefine its thinking on companion diagnostics.” It seems almost inevitable that a consolidation of diagnostic testing should take place, to enable a single test or a few tests to garner all the necessary information for therapeutic decision making.”

Whether this means CDx testing will begin to incorporate NGS sequencing remains to be seen.

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Targeted immunotherapy

Larry H. Bernstein, MD, FCAP, Curator



Fighting cancer with targeted drugs “Cancer” is a collective term that describes numerous different and malignant new tissue formations. Malignant tumors emerge from changes in DNA fragments when the body can no longer counteract these mutations, which is often associated with increased age. Yet the risk of developing cancer also depends on genetic factors, lifestyle habits and different environmental influences. Chemotherapy – an optimized base The classic triad of medical treatment, radiation therapy and surgery is a proven procedure.

While radiation therapy uses ionizing radiation to completely inactivate or at least push back the tumor, cytostatic drugs are applied in chemotherapy to inhibit cell growth. The treatment planning depends on specific tumor characteristics, the patient’s overall health condition, as well as the stage of the disease. New, individual therapeutic approaches promise more effective cancer treatment.

Chemotherapy is almost always applied – mainly by infusion, while certain cytostatic drugs are also suited for oral administration. Since researchers have tested and re-combined proven active ingredients in different doses, as well as introduced new substances, good results are now often achieved at higher tolerance. While emerging countries focus on chemotherapy, the standard treatment in the industrial world is more and more often combined with new, targeted therapeutic approaches.

Revolution in cancer treatment The cell division of healthy people is strictly regulated. A cell is only reproduced when it receives an according signal. If this procedure is thrown out of balance, the result is uncontrolled cell growth. Unlike cytostatic drugs, which act as cellular toxin, modern therapies draw on the molecular bases of tumor development. A type of enzymes known as kinases plays an important role in transmitting the signals. Kinase inhibitors act as low-molecular agents and block their function. For instance, the treatment of chronic myeloid leukemia with the active ingredient Imatinib1 has proven successful and spurred research. Most kinase inhibitors are administered orally and are partly based on highly complex formulations. Angiogenesis inhibitors are another example of targeted therapeutics. They block the development of blood vessels, which are indispensable for the growth of tumor cells. Immunotherapy against cancer In immunotherapy, the patient’s own immune system is stimulated to take independent action against tumor cells. This way, monoclonal antibodies can be developed, which attach themselves to the characteristic structures of the tumor surface. They inhibit cell proliferation (uncontrolled cell growth) or induce cell death. The targeted effect of monoclonal antibodies can also be combined with cell poison such as cytostatic agents or toxins.

Like in a Trojan Optimal operator protection at the highest product quality – sterile filling lines combined with barrier systems 1

Vasella, Daniel (2003): Magic Cancer Bullet: How a Tiny Orange Pill May Rewrite Medical History 6


Checkpoint inhibitors block the control points and are thus able to direct the immune system against the cancer. Since antibodies are complex protein structures that are “digested” by the gastrointestinal tract, this therapy is administered via infusion.

Therapeutic differentiation The trend is toward individually tailored therapies. Companion diagnostics are consequently becoming the focus of active ingredient development to verify the effectiveness for each patient before treatment initiation. Conversely, this implies an even closer cooperation between pharmaceutical companies and manufacturers of laboratory diagnostics as well as medical devices. Ever more specific therapies reduce the number of patients available for clinical studies, increasingly blurring the line between drug development and treatment. This medicine, which is described as “translational”, offers great opportunities to fight tumors formerly known as difficult to treat. More targeted tumor therapies will hence change the image of cancer – from death sentence to a severe, yet manageable chronic condition.

For further information, please contact: Dr Johannes Rauschnabel Phone: +49 7951 402 452 E-mail: johannes.rauschnabel@bosch.com

So-called antibody-drug conjugates transport the cell poison directly into the cancer cells. In the context of “checkpoint inhibition”, particular attention has recently been paid to monoclonal antibodies. The immune system is equipped with control points that protect the organism against autoimmune reactions. Tumors use these mechanisms to thwart a counter-reaction of the immune system.

Fighting cancer with Bosch technologies

The portfolio from Bosch Packaging Technology is suited for nearly all forms of oncological drug development, production and filling. For instance, sterile filling lines can be combined with barrier systems to protect operators from highly potent active agents such as cytostatic drugs, while ensuring the highest possible quality. Oral cytostatic drugs such as the active ingredient Imatinib can be processed on capsule filling machines and tablet presses from Bosch, which in conjunction with containment systems protect the operators from product dust. Bosch also offers machines for all laboratory process steps for both liquid and solid pharmaceuticals. Devices for the biopharmaceutical production of monoclonal antibodies and antibody-drug conjugates are among the core process competencies of the Bosch subsidiary Pharmatec. The production of antibodies requires a multi-stage process. First, the cells are cultivated in increasing scaling steps and harvested (upstream process). The active ingredients are then separated and purified using different technologies, followed by the formulation of the final injection solution (downstream process).

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Cancer Biomarkers []

Writer and Curator: Larry H. Bernstein, MD, FCAP

Cancer Biomarkers

This discussion is extracted from the Special Section – Cancer Biomarker Update – in May Arch Pathology and Lab Med.  It is not intended to be complete, but it has quite timely content.  There are three articles I shall cover. Cancer Biomarkers Cancer Biomarkers in Structured Data Reporting Cancer Biomarkers in Myeloid Malignancies National Comprehensive Cancer Network Consensus on Use of Cancer Biomarkers

Cancer Biomarkers – The Role of Structured Data Reporting
Simpson,  RW; Berman, MA; Foulis PR, et al.
Arch Pathol Lab Med. 2015;139:587–593

The College of American Pathologists has been producing cancer protocols since 1986 to aid pathologists in the diagnosis and reporting of cancer cases. Many pathologists use the included cancer case summaries as templates for dictation/data entry into the final pathology report. These summaries are now available in a computer-readable format with structured data elements for interoperability, packaged as ‘‘electronic cancer checklists.’’ Most major vendors of anatomic pathology reporting software support this model. Objectives.—To outline the development and advantages of structured electronic cancer reporting using the electronic cancer checklist model, and to describe its extension to cancer biomarkers and other aspects of cancer reporting. Data Sources.—Peer-reviewed literature and internal records of the College of American Pathologists. Conclusions.—Accurate and usable cancer biomarker data reporting will increasingly depend on initial capture of this information as structured data. This process will support the standardization of data elements and biomarker terminology, enabling the meaningful use of these datasets by pathologists, clinicians, tumor registries, and patients.

Narrative Versus Structured Data Reporting Clinical laboratory reports typically consist of discrete data elements with structured qualitative or quantitative information, often using standardized laboratory methods, data elements, and units. When discrete data elements are electronically transmitted to external clinical information systems, the transmitted information may be annotated with one or more terminologies such as Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT)4 and Logical Observation Identifiers Names and Codes (LOINC),5 although the consistent application of such codes to structured laboratory data is not yet an interoperable standard. Because the structure of clinical laboratory data tends to be fixed and standardized before the point of data entry, reporting these data elements in a tabular synoptic format is a relatively simple process. The report output may not include all data collected (eg, methodologic details), but clinically relevant data can be easily extracted by computer algorithm and automatically reported in easily readable format (including custom text, result explanations, and test value trends).

Anatomic pathology reports, by contrast, have traditionally been narrative and recorded as unstructured or partially structured fields of text. Unfortunately, narrative reporting often lacks consistency in organization, content, units, terminology, and completeness.6–8 These structural inconsistencies create difficulties in finding and understanding clinically important data and increase the chance of omitting key data elements and misinterpreting information present in the narrative. This is particularly problematic when clinicians encounter reports from multiple pathology laboratories or when patients receive care at multiple institutions. Narrative reporting has equally negative effects on computer readability; the ability of computers to correctly parse and classify information contained in a narrative report is imperfect even when using advanced natural language processing software designed specifically for anatomic pathology.9,10 Natural language processing–parsed text must always undergo human review, editing, and signoff before release for patient care or research.

Ensuring consistency and readability of cancer and biomarker reports requires a reporting solution integrated into the pathologist workflow that supports entry of standardized data directly into a laboratory information system and/or electronic health record system. These systems can produce highly readable synoptic reports and can include computer-based report validation of standardized data elements to reduce or eliminate the chance of omitting required data elements. With the transition from narrative to synoptic reporting for cancer cases, many laboratories have been using modified CCPs or locally developed templates or macros, which may or may not contain all required data elements. This common mode of data entry fits well into the pathologist workflow and can result in organized, highly readable synoptic reports, but generally results in information stored as text in a single large data field. Even when results are entered as discrete data elements, subsequent storage mechanisms usually result in nonstructured text or nonstandard custom data fields in a local computer system. Unfortunately, narrative and nonstandardized data sets are very difficult to reliably aggregate and analyze for laboratory quality assurance, research, or cancer registry surveillance. Such aggregated data also remain relatively unreliable because of changes in information systems. Many of these issues can be eliminated by entering and reporting structured data with standardized electronic templates.

CAP eCC History, Development, and Adoption Efforts to bring structure to cancer pathology reporting began in the late 1980s and early 1990s1,11,12 with publication of templates that were the precursors of the current CCPs (Table). The primary goal was to improve the care of cancer patients by improving the reporting rate of clinically important data elements. The checklist approach was adopted to help standardize terminology and ensure all relevant data elements are reported. The 66 current CCPs, 3 new cancer biomarker templates,13–16 and 85 eCC templates represent the evolution of the original 1986 CCP model. The CCPs and templates are created and maintained through the ongoing work of the CAP Cancer and Cancer Biomarker Reporting Committees. The CCPs are widely adopted by laboratories and used for accreditation purposes by the American College of Surgeons–Commission on Cancer17 and CAP Laboratory Accreditation Program.18

During the past several years, the CAP has worked to create standardized pathology reporting templates that enable individual pathologists and software vendors to capture, store, retrieve, transmit, and analyze diagnostic cancer pathology information. Electronic versions of these templates, the eCCs, are based on consistent structured data representation, which enables simple yet robust computerization of cancer pathology data elements suitable for patient care, cancer registry transmission, and research. Synoptic reports are not the same as ‘‘structured data.’’ Although synoptic reports are formatted for optimum human readability and understanding, they consist of textbased questions and answers (ideally one pair per line) that present problems for computer readability and interoperability. Structured data, by contrast, refers to representation of data elements in a computer-readable data exchange format such as XML. The structured data model used by eCC XML templates assigns a unique identifier (a composite key) to every question and answer choice, template, section, and note listed in the template. Composite keys are used throughout the entire eCC life cycle to transmit the precise identity of each data element and its origin in a specific version of an eCC template.

The CAP eCC model has been implemented province wide by Cancer Care Ontario through their multiyear synoptic pathology reporting and change-management project.19–21 The Canadian Partnership Against Cancer is also currently working with several other Canadian provinces to implement population-level electronic synoptic reporting based on the CAP eCC. The Cancer Care Ontario project has shown that there is high acceptability among pathologists and clinicians22 and that data are usable for the secondary needs of tumor registries,20 but there remains room for improvement. For instance, both the Reporting Pathology Protocols project reports23–25 and the Cancer Care Ontario implementation reports22 suggest that pathologists require more time to complete the reporting task.

While this may meet quality and data reporting needs, it remains a potential barrier to acceptance. Automated human-readable report generation also could be improved, especially in terms of creating best practice guidelines for report output. Both data entry and report generation have traditionally been supported by laboratory information systems vendors, but the success of implementation has varied, and often significant effort is required to modify the resultant human readable report to satisfy local clinical needs. Because the final report remains most important for patient care, the CAP Diagnostic Intelligence in Health Information Technology and Pathology Electronic Reporting committees have initiated work on creating and promoting a standardized data structure within cancer pathology reports.

Abbreviated CAP eCC History and Milestones

2010–2012 CCO successfully implements population level electronic synoptic reporting in nearly all disease sites based on 2010 CAP eCC standards, which include AJCC 7th edition TNM staging; 97% of labs report using structured data from eCC.20

2010 CAP Laboratory Accreditation Program begins to survey institutions for inclusion of required CCP data elements in AP reports.38

2010 NAACCR Pathology Data Workgroup develops implementation guide to assist with CAP eCC-based transmissions of cancer data to central cancer registries.39

2011 CCO user acceptability data demonstrate high level of acceptance for eCC-derived synoptic reports among clinicians and pathologists.22

2012 CAP forms the multi-organizational Cancer Biomarker Reporting Workgroup, tasked to produce standardized reporting templates for breast, colorectal, and lung cancer biomarkers.40

2013 eCC-based reporting in Ontario is used to improve quality and practice performance.20

2013 The first cancer biomarker templates are produced for breast, colorectal, and lung cancer.13–16 They are available on the http://www.cap.org/cancerprotocols Web site in Word and PDF format (accessed April 28, 2014). The eCC versions are available through CAP.

2013 Launch of CAP eFRM, a software product to aid vendor integration of eCCs into AP-LIS systems or for use as a standalone product.

2014 By December 2013, CAP is maintaining current versions of 66 CCPs, 3 cancer biomarker templates, and 85 corresponding eCC templates.


13. Cagle PT, Sholl LM, Lindeman NI, et al. Template for reporting results of biomarker testing of specimens from patients with non–small cell carcinoma of the lung. Arch Pathol Lab Med. 2014; 138(2):171–174. http://dx.doi.org:/10.5858/arpa.2013-0232-CP

14. Cagle PT, Allen TC, Olsen RJ. Lung cancer biomarkers: present status and future developments. Arch Pathol Lab Med. 2013; 137(9):1191–1198.

15. Bartley AN, Hamilton SR, Alsabeh R, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum. Arch Pathol Lab Med. 2014; 138(2):166–170.

16. Fitzgibbons PL, Dillon DA, Alsabeh R, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. Arch Pathol Lab Med. 2014; 138(5):595–601.

20. Srigley J, Lankshear S, Brierley J, et al. Closing the quality loop: facilitating improvement in oncology practice through timely access to clinical performance indicators. J Oncol Pract. 2013; 9(5):e255–e261. http://dx.doi.org:/10.1200/JOP.2012.000818

22. Lankshear S, Srigley J, McGowan T, Yurcan M, Sawka C. Standardized synoptic cancer pathology reports—so what and who cares?: a population-based satisfaction survey of 970 pathologists, surgeons, and oncologists. Arch Pathol Lab Med. 2013; 137(11):1599–1602.

38. College of American Pathologists. CAP cancer protocols frequently asked questions. http://www.cap.org/apps//cap.portal
39. Klein WT, Havener LA, eds. Standards for Cancer Registries Volume V: Pathology Laboratory Electronic Reporting, Version 4.0. Springfield, IL: North American Association of Central Cancer Registries; 2011:1–310.
40. Fitzgibbons PL, Lazar AJ, Spencer S. Introducing new College of American Pathologists reporting templates for cancer biomarkers. Arch Pathol Lab Med. 2014; 138(2):157–158. http://dx.doi.org:/10.5858/arpa.2013-0233-ED

41. Amin MB. The 2009 version of the cancer protocols of the College of American Pathologists. Arch Pathol Lab Med. 2010; 134(3):326–330.
http://dx.doi.org:/10. 1043/1543-2165-134.3.326.

Figure 1. (not shown) Narrative versus synoptic versus structured reporting of breast biomarker testing (excerpts). The narrative row shows a portion of a dictated biomarker report. The synoptic row satisfies the College of American Pathologists (CAP) synoptic reporting requirements, but is not computer readable.



Figure 2. (not shown) The College of American Pathologists (CAP) Cancer Protocols (CCPs) are developed by the CAP Cancer Committee. Each CCP is reformulated as question/answer structures, entered into the CAP electronic Cancer Checklist (eCC) Template Editor (not shown), and stored in the eCC template database. The eCC files in XML format are produced from this database and delivered to vendors of anatomic pathology/laboratory information system (LIS) software systems. Vendors convert the eCC files into data entry form implementations using their local technologies. In addition, most vendors create eCC-based templates for creating synoptic reports. When pathologists enter data into the eCC-based data-entry forms, the vendor software is able to run validation checks such as assessing whether all CCP-required data elements are recorded. Synoptic reports are developed from the eCC-derived data and delivered to health care providers for patient care. The eCC-structured data is stored in the vendor database, where it can be transmitted in interoperable format to other computer systems. Secondary uses of eCC-based data include cancer registry reporting, quality assurance, biospecimen annotation, research, decision support, and financial reporting. The horizontal arrows involve the exchange of eCC composite keys, preserving the fidelity of the data as part of an eCC template, providing the foundation for interoperable data transmission formats, and enabling the regeneration of eCC datasets in the exact format in which they were recorded. Activity columns that directly impact health care activities are shaded in light blue. Abbreviation: EHR, electronic health record.

Future The use of standardized, structured data elements is foundational for the development of improved reporting and clinical decision support for biomarker results. Clinicians are currently faced with synthesizing data from multiple narrative reports to decide on treatment options. Often these narrative reports are from different laboratories with very different report formats and include variable methodologic details, all of which hinders understanding of important results. For biomarkers that determine a patient’s eligibility for specific drugs, a computer-generated report that presents test results in a tabular form, similar to antibiotic susceptibility testing, may be desirable. This reporting method would allow for display of biomarker test results over time and could also link to other databases.

Structured data allows for clinical decision support such that the report displays only eligible drugs, or the report displays a note stating that a test result suggests a patient is not eligible for a specific drug. Using standardized terminology allows these rules to be the same between institutions, even if electronic health record system vendors use different means of implementation.

Figure 3. (not shown) College of American Pathologists electronic Cancer Checklist lung cancer biomarker template—anaplastic lymphoma kinase (ALK). Abbreviations: EML4, echinoderm microtubule-associated protein-like 4; KIF5B, kinesin family member 5B; KLC1, kinesin light chain 1; TFG, tropomyosin receptor kinase–fused gene.

Figure 4. (not shown) Examples of tumor biomarker dashboards. Abbreviations: ALK, anaplastic lymphoma kinase; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

This system would allow for more efficient, more accurate, and safer methods of providing data for optimizing patient care, with all of the discrete data transmitted electronically and linked to the original tumor report. In Ontario, Canada, this vision is rapidly advancing, as demonstrated by the Cancer Care Ontario successes with eCC implementation and current plans to implement the eCC biomarker templates across the province. Future challenges include the identity and tracking of related tumor samples over time and integration of testing from different laboratories. Because testing on a given specimen can be performed at different times and in different laboratories, a future standard must address the annotation of results with tumor source, procurement dates, and other biospecimen-specific data.30 The relationship of test results from multiple specimens from the same patient needs to be recorded in a standard format so that this parent-child hierarchical relationship can be analyzed over time.

Pathologists are increasingly asked to provide biomarker information for patient care, tumor registries, epidemiologic studies, translational research, and quality improvement activities.20 The eCC model provides a pathway to meet these demands, with efficient and error-free data entry, reporting, and transmission of data elements, and with the ability to produce output that is human readable, efficient to use, and easy to interpret. As the CCPs and eCCs have matured, Ontario pathologists and cancer registries have demonstrated success with large-scale implementations. However, continued improvements are needed. As the field of pathology grows, particularly in the area of biomarkers, structured electronic reporting will become critical to helping physicians provide optimal patient care and will facilitate secondary uses of pathology data.

  1. Robb JA, Gulley ML, Fitzgibbons PL, et al. A call to standardize preanalytic data elements for biospecimens. Arch Pathol Lab Med. 2014; 138(4):526–537.

Molecular Genetic Biomarkers in Myeloid Malignancies
Matynia AP, Szankasi P, Shen W, Kelley TW.
Arch Pathol Lab Med. 2015;139:594–601

Recent studies using massively parallel sequencing technologies, so-called next-generation sequencing, have uncovered numerous recurrent, single-gene variants or mutations across the spectrum of myeloid malignancies. Objectives.—To review the recent advances in the understanding of the molecular basis of myeloid neoplasms, including their significance for diagnostic and prognostic purposes and the possible implications for the development of novel therapeutic strategies. Data Sources.—Literature review. Conclusions.—The recurrent mutations found in myeloid malignancies fall into distinct functional categories.

These include (1) cell signaling factors, (2) transcription factors, (3) regulators of the cell cycle, (4) regulators of DNA methylation, (5) regulators of histone modification, (6) RNA-splicing factors, and (7) components of the cohesin complex. As the clinical significance of these mutations and mutation combinations is established, testing for their presence is likely to become a routine part of the diagnostic workup. This review will attempt to establish a framework for understanding these mutations in the context of myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia.

Pathways Affected by Recurrent Mutations in Myeloid Malignancies

Cell Signaling The ability of a cell to respond to diverse physiologic stimuli, including cytokines, chemokines, growth factors, and hormones, or to the presence of bacteria and other microorganisms is mediated via the interaction of specific ligands and their corresponding cell surface receptors. Ligand binding usually results in receptor dimerization and activation of a tyrosine kinase, either intrinsically present in the cytoplasmic domain or as an associated polypeptide. Further propagation of the signal from the cell surface to the nucleus involves the formation of macromolecular complexes and the activation or inactivation of various enzymes. The final outcome of the signal transduction is modulation of the expression of certain genes and their products, which ultimately produces a cellular response. In normal cells, this process is tightly regulated owing to the involvement of negative or inhibitory signals. In tumor cells these processes may be perturbed owing to mutations that impart inappropriate activation or deactivation of enzymatic function. Genes for receptor protein tyrosine kinases, such as FLT3 and KIT, or receptor-associated kinases, such as JAK2, are the most commonly mutated cell-signaling factors in myeloid malignancies. Activating mutations in these proteins occur in narrowly defined hotspots, resulting in ligand-independent dimerization or constitutive kinase activation. An example is the protein tyrosine kinase JAK2, which transduces signals from ligand-bound cell surface receptors for thrombopoietin (TPOR/MPL) and erythropoietin (EPOR).

Activating mutations in JAK2 are commonly found in the myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These disorders appear to be driven, in large part, by the inappropriate activation of growth factor– signaling pathways, and JAK2 is central to signaling from EPOR and TPOR/MPL via STAT5, STAT3, the RAS-MAP kinase pathway, and the PI-3 kinase–AKT pathway. Many negative regulators of cytokine signaling, such as SH2B adaptor protein 3 (SH2B3, also known as LNK)1,2 and cytokine-inducible SH2-containing protein (CISH, also known as SOCS)3 keep the pathway in balance. Downstream RAS signaling is counteracted by NF1, a protein that stimulates the intrinsic RAS guanosine triphosphatase activity. An effect similar to JAK2 mutations may be achieved through mutations in other proteins involved in these pathways, including activating mutations of a surface receptor (MPL) or loss-of-function mutations in negative regulators (SH2B3, CISH), all of which promote survival, proliferation, and differentiation of committed myeloid progenitors.4 Example genes included in this group: JAK2, MPL, KIT, FLT3, CSF3R, PTPN11, KRAS, NRAS, and NF1.

Transcription Transcription is a tightly regulated process that depends on the formation and assembly of protein and protein-DNA complexes. These complexes, called transcription factors, bind to specific DNA sequences adjacent to the genes they regulate and promote (in the case of an activator) or block (in the case of a repressor) the recruitment of RNA polymerases to those genes. This regulatory activity controls the formation of messenger RNA (mRNA) transcripts. Mutations that block the activity of transcriptional activators may, in certain circumstances, lead to a block in cellular differentiation due to the lack of the necessary gene products. Many of the transcription factors that are recurrently mutated in myeloid malignancies, such as RUNX1, GATA1, GATA2, and CEBPA, are involved in fundamental aspects of myelopoiesis and it is believed that these mutations lead to a block in myeloid differentiation.  Example genes included in this group: RUNX1, CEBPA, GATA1, GATA2, ETV6, and PHF6.

Epigenetic Modifiers: Regulation of DNA Methylation DNA methylation involves the addition of a methyl group to cytosine bases in the context of cytosine-guanine sequences (so-called CpG sites), leading to the creation of 5-methylcytosine. CpG islands are usually located in or near promoter regions. Their methylation is an important epigenetic mechanism for regulating gene expression and, in the context of heritable methylation patterns, underlies the process of genomic imprinting. Additionally, it has been hypothesized that aberrant DNA methylation may contribute to the pathogenesis of cancers,5–8 including myeloid neoplasms. Although cancer genomes tend to be globally hypomethylated, in comparison with normal tissues, hypermethylation of specific CpG islands at tumor suppressor genes, resulting in their inactivation, is common in many tumors.9

ormation of compact, inactive heterochromatin.10 Several factors regulate the process of DNA methylation. Mutations in some of these factors have been found recurrently in myeloid neoplasms.11–13 DNA methyltransferases catalyze the methylation at the 50 position of cytosine. DNMT3A and DNMT3B are involved in de novo methylation, whereas DNMT1 maintains hemimethylated DNA during replication. Once created, 5-methylcytosine can be further modified by a group of methylcytosine dioxygenases (Ten Eleven Translocation dioxygenases: TET1, TET2, and TET3) to 50-hydroxymethylcytosine, a presumed short-lived intermediary that may lead to demethylation of cytosine.

Mutations in both DNMT3A and TET2 likely lead to loss of function of the respective enzyme activities. Recently, mutations in IDH1 and IDH2 have been identified in myeloid neoplasms and other cancers. Interestingly, recurring mutations of an arginine residue in the active site (R132 in IDH1 and R140 in IDH2) prevent the normal catalytic function of the enzyme (conversion of isocitrate to aketoglutarate) and appear to induce a neomorphic enzyme activity resulting in the formation of the rare oncometabolite 2-hydroxyglutarate.14 TET2 belongs to a family of dioxygenases that requires a-ketoglutarate as a cofactor.15,16 It has been shown that 2-hyroxyglutarate acts as a competitive inhibitor of a-ketoglutarate–dependent dioxygenases, which include TET2 and members of the KDM family of histone demethylases, thereby inducing epigenetic changes at both the level of DNA methylation and histone modification.14,17

Therapeutic inhibitors of mutant forms of IDH proteins and the resulting 2-hydroxyglutarate are also under investigation.18 Example genes included in this group: DNMT3A, TET2, IDH1, and IDH2.

Epigenetic Modifiers: Mutations Affecting Histone Function  Histone proteins are involved in the dynamic organization of DNA into zones of active euchromatin and inactive heterochromatin in a process that is regulated, in part, by a complex series of posttranslational modifications to histone tails, including acetylation and methylation. These modifications affect the recruitment of regulatory proteins such as transcription factors, corepressors, and coactivators, as well as histone-modifying enzymes themselves. Trimethylation of the lysine at position 27 in histone H3 (H3K27), one of the more common modifications, generally leads to reduced gene expression and it would be expected that mutations that reduce methylation at H3K27 would activate transcription. Recently, recurrent mutations in several genes encoding histone regulators, including ASXL1, EZH2, SUZ12, and KDM6A (also known as UTX), have been identified.

Perturbations in epigenetic pathways result in global, genome-wide effects and it is often difficult to identify which altered cellular function eventually leads to neoplasia. The same also holds true for perturbations in the RNA splicing machinery and the cohesion complex (see below). Example genes included in this group: ASXL1, EZH2, SUZ12, and KDM6A.

Cohesin Complex Genes  The cohesin complex is a conserved multimeric protein complex that regulates cohesion of sister chromatids during cell division,21 postreplicative DNA repair,22,23 and global gene expression.24–28
Example genes included in this group: STAG2, RAD21, SMC1A, and SMC3.

RNA-Splicing Factors  RNA splicing results in the formation of mature mRNA transcripts derived from exons, the protein coding portion of the genome. Splicing occurs in a macromolecular complex of small nuclear RNAs and proteins assembled de novo on each pre-mRNA strand in a multistep process. This complex is known as the spliceosome. Transcripts may undergo alternative splicing in a tissue, or context-specific manner and the protein products of alternatively spliced transcripts may have altered function.
Example genes included in this group: SF3B1, SRSF2, ZRSR2, and U2AF1.

Cell Cycle Regulators  Example genes included in this group: TP53 and NPM1.

Genetic Biomarkers in Myeloid Malignancies

Myeloproliferative Neoplasms  Myeloproliferative neoplasms encompass a group of clonal stem cell disorders characterized by expansion of 1 or more of the myeloid lineages resulting in bone marrow hypercellularity and increased peripheral blood myeloid cell counts. The MPN category includes chronic myelogenous leukemia, PV, ET, PMF, chronic neutrophilic leukemia, mastocytosis, and others. The underlying genetic landscape of some of these disorders is very well understood, as in the case of chronic myelogenous leukemia with t(9;22), but is much less well understood in many other entities.

The discovery of a recurrent codon 617 activating mutation (V617F) in exon 14 of the tyrosine kinase JAK237–40 and additional mutations in JAK2 exon 1241 provided the first genetic evidence of the importance of dysregulated growth factor signaling in these disorders. The prevalence of JAK2 mutations in classical MPNs varies from 95% to 99% in PV, 50% to 70% in ET, 40% to 50% in PMF,37–41,43 and molecular tests for their detection are available and widely used in clinical practice. Similarly, activating mutations in the MPL gene, encoding the thrombopoietin receptor, are present in approximately 4% of ET cases and approximately 11% of PMF cases.44–47 Recently, calreticulin (CALR), encoding an endoplasmic reticulum chaperone, has also been shown to be important. Somatic CALR mutations are found in 70% to 84% of patients with ET or PMF with wild-type JAK2 and MPL, 8% of MDS cases, and occasionally in other myeloid neoplasms.48 Clonal analyses suggest CALR mutations act as an initiating mutation in some patients.48 In ET and PMF, CALR mutations and JAK2 and MPL mutations are mutually exclusive,49 and CALR mutations appear to be absent in PV.49 CALR mutations appear to be primarily insertion or deletion mutations that result in a frameshift and the subsequent generation of a novel C-terminal peptide.48,49

Many other genes involved in intracellular signaling, such as negative regulators of the JAK2 signaling pathway, are mutated in MPNs. Among these is SH2B3, which negatively regulates JAK2 activation through its SH2 domain. Mutations in SH2B3 during the chronic phase are uncommon, fewer than 5% in ET and PMF50; however, their frequency increases during leukemic transformation, suggesting a role in disease progression.51 Another negative regulator found mutated in MPNs is the Cbl proto-oncogene, E3 ubiquitin protein ligase gene (CBL). CBL acts as a multifunctional adapter with ubiquitin ligase activity and by competitive blockade of signaling.

A shift from a simple, chronic myelogenous leukemia–like model for MPN pathophysiology to a more complex model occurred with the emergence of evidence of a ‘‘pre-JAK2’’ genetic event. This concept is based on the observation that mutations in signaling molecules are not sufficient for disease development and that several cooperating genetic hits appear to be required.4 Mutations in genes involved in epigenetic regulation, including EZH2, ASXL1, and TET2 (also found in many other myeloid neoplasms), are postulated to act as those initialing events, preceding JAK2V617F mutations.55 EZH2 mutations do not occur in ET, but are present in 3% of PVs and 13% of MFs.56 ASXL1 mutations are found in only approximately 7% of patients with ET and PV but more frequently in PMF cases (from 19%–40%).57,58 TET2 mutations occur in approximately 14% of MPNs, ranging from 11% in ETs to 19% in PMFs.59,60 Finally, there are mutations that are rarely found during the chronic phase but which may be present at transformation, and are therefore thought to play a role in disease progression. IDH1 and IDH2 mutations, for example, have a low frequency in the chronic phase (0.8% in ET, 1.9% in PV, and 4.2% in MF) but a much higher frequency in blast phase.61

Myelodysplastic Syndromes and MDS/MPN Overlap Disorders 

The myelodysplastic syndromes are a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, morphologic evidence of dysplasia in at least 1 of the myeloid lineages, peripheral cytopenias, bone marrow hypercellularity, and an increased risk of development of AML.74 Clonal cytogenetic abnormalities, including large deletions and chromosome gains, as well as balanced translocations, are observed in approximately 50% of MDS cases by routine methods,74 and their identification aids in establishing the diagnosis and may provide prognostic information.

Acute Myelogenous Leukemia  Acute myeloid leukemia is a genetically heterogeneous disease resulting in the accumulation of myeloblasts in bone marrow with a concomitant reduction in normal hematopoiesis. The diagnosis and subclassification of AML depends on detecting the presence of recurrent cytogenetic abnormalities.74 In many cases, particularly those that are cytogenetically normal (CN-AML), several single-gene mutations further aid in the stratification of disease outcomes. The significance of mutations in genes such as FLT3, NPM1, and CEBPA is well established but nextgeneration sequencing has led to the discovery of numerous additional recurrent mutations, including in TET2,12,59 ASXL1,104 IDH1/IDH2,13,105,106 DNMT3A,11,107 and PHF6.108

Among the most common mutations found in de novo AML are NMP1, FLT3, and DNMT3A mutations, present in 22% to 29%, 22% to 37%, and 15% to 26% of samples, respectively.31,110,111 Other genes less commonly targeted by mutations are IDH1/IDH2 (15%– 20%), KRAS/NRAS (12% combined), RUNX1 (5%–10%),TET2 (8%–14%), TP53 (2%–8%), CEBPA (6%–14%), WT1 (6%–8%), PTPN11 (4%), and KIT (4%–6%).31,110,111

The prognostic significance of a subset of recurrent mutations is well established. In CN-AML, biallelic CEBPA mutations127,128 and NPM1 mutations without FLT3-ITD mutations129–133 are associated with a favorable prognosis. In contrast, FLT3-ITD without NPM1 mutations112,113,129–132 and MLL–partial tandem duplication mutations134–136 portend poor outcome. KIT mutations in AML with t(8;21) or inv(16)131,137 are also associated with unfavorable outcome. The European LeukemiaNet panel138 first proposed a standardized classification according to both cytogenetic and molecular genetic data to allow a better comparison of prognosis among patients with AML. However, only mutations of NPM1, CEBPA, and FLT3 were included in their recommendations. The relevance of more recently discovered mutations, including IDH1, IDH2, WT1, TET2, ASXL1, among others, remains unclear.139–142 The presence of certain mutations may also allow for more targeted therapeutic regimens; for example, FLT kinase inhibitors may be useful in cases with mutations and IDH1 inhibitors are under investigation in patients with IDH1 mutations.143,144

An enormous amount of new information illuminating the genetic complexity of myeloid neoplasms has been generated during the last few years. Much work remains to be done but it is clear that the future role of the pathologist in collecting and interpreting this information will be an essential component of the management of these patients.


The Cancer Genomics Resource List 2014
Zutter MM, Bloom KJ, Cheng L, Hagemann IS, et al.
Arch Pathol Lab Med. http://dx.doi.org:/10.5858/arpa.2014-0330-C

Optimizing the Clinical Utility of Biomarkers in Oncology: The NCCN Biomarkers Compendium
Marian L. Birkeland, Joan S. McClure
Arch Pathol Lab Med. 2015;139:608–611

The rapid development of commercial biomarker tests for oncology indications has led to confusion about which tests are clinically indicated for oncology care. By consolidating biomarker testing information recommended within National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), the NCCN Biomarkers Compendium aims to ensure that patients have access to appropriate biomarker testing based on the evaluations and recommendations of the expert NCCN panel members.
Objectives.—To present the recently launched NCCN Biomarkers Compendium. Data Sources.—Biomarker testing information recommended within NCCN Clinical Treatment Guidelines as well as published resources for genetic and biological information. Conclusions.—The NCCN Biomarkers Compendium is a continuously updated resource for clinicians who need access to relevant and succinct information about biomarker testing in oncology and is linked directly to the recommendations provided within the NCCN Clinical Practice Guidelines.

Most recommendations contained within the NCCN Guidelines are based upon lower-level evidence and uniform NCCN consensus (category 2A).1 This is not a deficiency of the guidelines, but is rather because high-level evidence is not available for most decisions across the continuum of care. A deeper look at what constitutes a ‘‘recommendation’’ might begin to clarify that issue. A recommendation can include all of the recommended workup, surgical options, options for chemotherapy, and tests recommended for ongoing surveillance. Although many of these options are routinely used as standard of care in clinical practice, there is often not the available body of high-level evidence that supports category 1 recommendations, thus most are category 2A levels of evidence and consensus. In other instances, recommendations for chemotherapy regimens for which there is high-level, randomized clinical trial evidence are listed as category 1.

Several derivative products arise from the NCCN Guidelines. The NCCN Drugs & Biologics Compendium (NCCN Compendium) is a resource outlining appropriate use of drugs and biologics as recommended in the NCCN Guidelines. To be included in the compendium, an agent must first be recommended in at least 1 of the NCCN Guidelines. The compendium is typically used by clinicians and payors to determine appropriate use and as a standard to determine coverage. The rapid development and commercialization of biomarker and companion diagnostic testing in cancer gave rise to the NCCN Biomarkers Compendium, to be used by both payors and clinicians to facilitate identification of biomarker tests recommended for use by NCCN guideline panels. The NCCN uses a broad definition of ‘‘biomarker’’ for the purposes of this compendium. All tests measuring genes or gene products, which are used for diagnosis, screening, monitoring, surveillance, or for providing predictive or prognostic information, are included in the biomarkers compendium. This compendium focuses on the biology of the biomarker itself and its clinical utility in supporting clinical decision making. Information is organized by the biomarker being measured, and not by listing of commercially available tests or test kits. Close to 1000 biomarker testing recommendations are included in the NCCN Biomarkers Compendium.

The NCCN Biomarkers Compendium is presented on the NCCN Web site as a series of drop-down menus, allowing users to pick from menus listing Guideline, Disease, Molecular Abnormality, or Gene Symbol.3 Users can retrieve all recommendations for a particular disease, or can select a gene-based search in order to show which diseases have a validated use for a particular gene test. Additional fields can be displayed by selecting from a series of boxes to the right of the drop-down menus (see Figure 1, which shows default fields for RAS testing in colon cancer). Once records are displayed, the resulting table can be sorted by the information in any of the displayed columns. If a searcher chooses, all records can be displayed and then searched with any text term or sorted by any of the columns for a more comprehensive picture of the contents of the database.

Figure 1. (not shown)  KRAS mutation testing recommendation from the National Comprehensive Cancer Network (NCCN) Biomarkers Compendium.3 Reproduced with permission from the NCCN Biomarkers Compendium [1] 2014 National Comprehensive Cancer Network, Inc. (NCCN.org; accessed February 21, 2014). To view the most recent and complete version of the NCCN Biomarkers Compendium, go online to NCCN.org. National Comprehensive Cancer Network, NCCN, NCCN Guidelines, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Disease Description Colon cancer
Specific Indication Metastatic disease
Molecular Abnormality KRAS/NKRAS mutation
Chromosome 1p13.2, 12p12.1
Gene Symbol KRAS/NKRAS
Test Detects Mutation
Category of Evidence 2A
Specimen Types FFPE tumor tissue
Recommendation …Determination of RAS mutations.
Test Purpose Predictive
Guideline Page COL 4 of 5, COL 4, COL 9
Note All patients with metastatic colorectal cancer should be genotyped for RAS mutations. At the very least …

Figure 2. (Table)  Example of PDF file generated from ‘‘print’’ command of National Comprehensive Cancer Network (NCCN) Biomarkers Compendium record. Reproduced with permission from the NCCN Biomarkers Compendium [1] 2014 National Comprehensive Cancer Network, Inc (NCCN.org; accessed February 21, 2014). To view the most recent and complete version of the NCCN Biomarkers Compendium, go online to NCCN.org. National Comprehensive Cancer Network, NCCN, NCCN Guidelines, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Table 2. (List) Summary of Testing Types Included in the National Comprehensive Cancer Network Biomarkers Compendiuma,b

Protein expression
Chromosomal defect
Gene rearrangement
Virus detection
Antigen expression
Serum proteins
Short repeated sequences
Promoter methylation
Gene expression pattern
Helicobacter pylori

Table 3. Predictive Tests Used for Treatment Decision Making, Extracted From National Comprehensive Cancer Network Guidelines and Biomarkers Compendiuma,b

Test   Disease
21-gene RT-PCR

BCR-ABL1 translocation

Breast cancer
ABL1 mutation Ph+ acute lymphoblastic leukemia, chronic myelogenous leukemia
ALK rearrangement Non–small cell lung cancer
BRAF mutation Non–small cell lung cancer, melanoma, colon cancer, rectal cancer
EGFR mutation Non–small cell lung cancer
ERBB2 amplification/overexpression Breast cancer, esophageal and esophagogastric junction cancers, gastric cancer
ESR1 expression Breast cancer
KIT mutation Soft tissue sarcoma: GIST
KRAS mutation Colon cancer, rectal cancer, non–small cell lung cancer
MGMT promoter methylation Central nervous system cancers: anaplastic glioma/glioblastoma
MLH1, MSH2, MSH6, PMS2 expression and/or mutation, MSI testing Colon cancer, rectal cancer
PDGFRA mutation Soft tissue sarcoma: GIST
PGR expression Breast cancer
ROS1 rearrangement Non–small cell lung cancer

A large number of tests were grouped for the purposes of this simplified table into the category of gross chromosomal abnormalities. Interestingly, the guidelines so far contain only a single recommendation for the use of a gene expression profiling test, and this is the 21-gene reverse transcription–polymerase chain reaction test recommended within the breast cancer treatment guideline, where the score for this test can be used as part of a decision-making process for chemotherapy recommendations in node negative, hormone receptor–positive, HER2-negative disease.

Table 3 summarizes the biomarker tests included in the NCCN Biomarkers Compendium that are predictive for either responsiveness (eg, BRAF mutation and vemurafenib sensitivity) or nonresponsiveness (eg, KRAS mutation testing and cetuximab or panitumumab insensitivity) to a particular type of therapy. As the number of companion diagnostics and targeted therapies grows, we expect this category of test to become one of the largest categories of testing contained within the Biomarkers Compendium, and it may be surprising to note that only 15 of these types of test are currently recommended within the NCCN Guidelines.

The NCCN Biomarkers Compendium generally avoids recommendations for particular methodologies or test kits to use to assess mutations and translocations. The choice of methodology and supplier for carrying out the recommended biomarker tests remains that of the treating oncologists and pathologists.

The NCCN Biomarkers Compendium may be used by payers as a reference for coverage decisions and by clinicians as a guide to which biomarkers are appropriate to test. The Biomarkers Compendium focuses on the clinical usefulness of biomarker testing rather than specific tests or test kits that identify the presence or absence of the marker. Other groups are continuing to assess clinical and analytic validity for specific biomarker test methodologies. Even the US Food and Drug Administration approval process is limited to clinical and analytic validity, and does not specifically address clinical utility. The NCCN Biomarkers Compendium is complementary to these other efforts. By providing biomarker testing information, the NCCN Biomarkers Compendium aims to ensure that patients have coverage and access to appropriate biomarker testing, based on the evaluations and recommendations of the expert NCCN panel members.

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The Union of Biomarkers and Drug Development

The Union of Biomarkers and Drug Development

Author and Curator: Larry H. Bernstein, MD, FCAP

There has been consolidation going on for over a decade in both thr pharmaceutical and in the diagnostics industry, and at the same time the page is being rewritten for health care delivery.  I shall try to work through a clear picture of these not coincidental events.

Key notables:

  1. A growing segment of the US population is reaching Medicare age
  2. There is also a large underserved population in both metropolitan and nonurban areas and a fragmentation of the middle class after a growth slowdown in the economy since the 2008 deep recession.
  3. The deep recession affecting worldwide economies was only buffered by availability of oil or natural gas.
  4. In addition, there was a self-destructive strategy to cut spending on national scales that withdrew the support that would bolster support for infrastrucrue renewl.
  5. There has been a dramatic success in the clinical diagnostics industry, with a long history of being viewed as a loss leader, and this has been recently followed by the pharmaceutical industry faced with inability to introduce new products, leading to more competition in off-patent medications.
  6. The introduction of the Accountable Care Act has opened the opportunities for improved care, despite political opposition, and has probably sustained opportunity in the healthcare market.

Let’s take a look at this three headed serpent. – Pharma, Diagnostics, New Entity
?  The patient  ?
?  Insurance    ?
?  Physician    ?

Part I.   The Concept

When Illumina Buys Roche: The Dawning Of The Era Of Diagnostics Dominance

Robert J. Easton, Alain J. Gilbert, Olivier Lesueur, Rachel Laing, and Mark Ratner
http://PharmaMedtechBI.com    | IN VIVO: The Business & Medicine Report Jul/Aug 2014; 32(7).

  • With current technology and resources, a well-funded IVD company can create and pursue a strategy of information gathering and informatics application to create medical knowledge, enabling it to assume the risk and manage certain segments of patients
  • We see the first step in the process as the emergence of new specialty therapy companies coming from an IVD legacy, most likely focused in cancer, infection, or critical care

When Illumina Inc. acquired the regulatory consulting firm Myraqa, a specialist in in vitro diagnostics (IVD), in July, the press release announcement characterized the deal as one that would bolster illumina’s in-house capabilities for clinical readiness and help prepare for its next growth phase in regulated markets. That’s not surprising given the US Food and Drug Administration’s (FDA) approval a year and a half ago of its MiSeq next-generation sequencer for clinical use. But the deal could also suggest illumina is beginning to move along the path toward taking on clinical risk – that is, eventually

  • advising physicians and patients, which would mean facing regulators directly

Such a move – by illumina, another life sciences tools firm, or an information specialist from the high-tech universe – is inevitable given

  • the emerging power of diagnostics and traditional health care players’ reluctance to themselves take on such risk.

Alternatively, we believe that a well-funded diagnostics company could establish this position. either way, such a champion would establish dominion over and earn higher valuation than less-aggressive players who

  • only supply compartmentalized drug and device solutions.

Diagnostics companies have long been dogged by a fundamental issue:

  1. they are viewed and valued more along the lines of a commodity business than as firms that deliver a unique product or service
  2. diagnostics companies are in position to do just that today because they are now advantaged by having access to more data points.
  3. if they were to cobble together the right capabilities, diagnostics companies would have the ability to turn information into true medical knowledge

Example: PathGEN PathChip

nucleic-acid-based platform detects 296 viruses, bacteria, fungi & parasites


This puts the diagnostics player in an unfamiliar realm where it can ask the question of what value they offer compared with a therapeutic. The key is that diagnostics can now offer unique information and potentially unique tools to capture that information. In order to do so, it has to create information from the data it generates, and then to supply that knowledge to users who will value and act on that knowledge. Complex genomic tests, as much as physical examination, may be the first meaningful touch point for physicians’ classification of disease.

Even if lab tests are more expensive, it is a cheaper means for deciding what to do first for a patient than the trial and error of prescribing medication without adequate information. Information is gaining in value as the amount of treatment data available on genomically characterizable subpopulations increases. In such a circumstance
it is the ability to perform that advisory function that will add tremendous value above what any test provides, the leverage of being able to apply a proprietary diagnostics platform – and importantly, the data it generates. It is the ability to perform that advisory function that will add tremendous value above what any test provides.

Integrated Diagnostics Inc. and Biodesix Inc. with mass spectrometry has the tools for unraveling disease processes, and numerous players are quite visibly in or are getting into the business of providing medical knowledge and clinical decision support in pursuit of a huge payout for those who actually solve important disease mysteries. Of course one has to ask whether MS/MS is sufficient for the assigned task, and also whether the technology is ready for the kind of workload experienced in a clinical service compared to a research vehicle.  My impression (as a reviewer) is that it is not now the time to take this seriously.

Roche has not realized its intent with Ventana: failing to deliver on the promise of boosting Roche’s pipeline, which was a significant factor in the high price Roche paid. The combined company was to be “uniquely positioned to further expand Ventana’s business globally and together develop more cost-efficient, differentiated, and targeted medicines.  On the other hand,  Biodesix decided to use Veristrat to look back and analyze important trial data to try to ascertain which patients would benefit from ficlatuzumab (subset). The predictive effect for the otherwise unimpressive trial results was observed in both progression-free survival and overall survival endpoints, and encouraged the companies to conduct a proof-of-concept study of ficlatuzumab in combination with Tarceva in advanced Non Small Cell Lung Cancer Patients (NSCLC) selected using the Veristrat test.

A second phase of IVD evolution will be far more challenging to pharma, when the most accomplished companies begin to assemble and integrate much broader data
sets, thereby gaining knowledge sufficient to actually manage patients and dictate therapy, including drug selection. No individual physician has or will have access to all of this information on thousands of patients, combined with the informatics to tease out from trillions of data points the optimal personalized medical approach. When the IVD-origin knowledge integrator amasses enough data and understanding to guide therapy decisions in large categories, particularly drug choices, it will become more valuable than any of the drug suppliers.

This is an apparent reversal of fortune. The pharmaceutical industry has been considered the valued provider, while the IVD manufacturer has been the low valued cousin. Now, it is by an ability to make kore accurate the drug administration that the IVD company can control the drug bill, to the detriment of drug developers, by finding algorithms that generate equal-to-innovative-drug outcomes using generics for most of the patients, thereby limiting the margins of drug suppliers and the upsides for new drug discovery/development.

It is here that there appears to be a misunderstanding of the whole picture of the development of the healthcare industry.  The pharmaceutical industry had a high value added only insofar it could replace market leaders for treatment before or at the time of patent expiration, which largely depended either introducing a new class of drug, or by relieving the current drug in its class of undesired toxicities or “side effects”.  Otherwise, the drug armamentarium was time limited to the expiration date. In other words, the value was dependent on a window of no competition.  In addition, as the regulation of healthcare costs were tightening under managed care, the introduction of new products that were deemed to be only marginally better, could be substitued by “off-patent” drug products.

The other misunderstanding is related to the IVD sector.  Laboratory tests in the 1950’s were manual, and they could be done by “technicians” who might not have completed a specialized training in clinical laboratory sciences.  The first sign of progress was the introduction of continuous flow chemistry, with a sampling probe, tubing to bring the reacting reagents into a photocell, and the timing of the reaction controlled by a coiled glass tubing before introducing the colored product into a uv-visible photometer.  In perhaps a decade, the Technicon SMA 12 and 6 instruments were introduced that could do up to 18 tests from a single sample.

Part 2. Emergence of an IVD Clinical Automated Diagnostics Industry

Why tests are ordered

  1. Screening
  2. Diagnosis
  3. Monitoring

Historical Perspective

Case in Point 1:  Outstanding Contributions in Clinical Chemistry. 1991. Arthur Karmen.

Dr. Karmen was born in New York City in 1930. He graduated from the Bronx High School of Science in 1946 and earned an A.B. and M.D. in 1950 and 1954, respectively, from New York University. In 1952, while a medical student working on a summer project at Memorial-Sloan Kettering, he used paper chromatography of amino acids to demonstrate the presence of glutamic-oxaloacetic and glutaniic-pyruvic ransaminases (aspartate and alanine aminotransferases) in serum and blood. In 1954, he devised the spectrophotometric method for measuring aspartate aminotransferase in serum, which, with minor modifications, is still used for diagnostic testing today. When developing this assay, he studied the reaction of NADH with serum and demonstrated the presence of lactate and malate dehydrogenases, both of which were also later used in diagnosis. Using the spectrophotometric method, he found that aspartate aminotransferase increased in the period immediately after an acute myocardial infarction and did the pilot studies that showed its diagnostic utility in heart and liver diseases.  This became as important as the EKG. It was replaced in cardiology usage by the MB isoenzyme of creatine kinase, which was driven by Burton Sobel’s work on infarct size, and later by the troponins.

Case in point 2: Arterial Blood Gases.  Van Slyke. National Academy of Sciences.

The test is used to determine the pH of the blood, the partial pressure of carbon dioxide and oxygen, and the bicarbonate level. Many blood gas analyzers will also report concentrations of lactate, hemoglobin, several electrolytes, oxyhemoglobin, carboxyhemoglobin and methemoglobin. ABG testing is mainly used in pulmonology and critical care medicine to determine gas exchange which reflect gas exchange across the alveolar-capillary membrane.

DONALD DEXTER VAN SLYKE died on May 4, 1971, after a long and productive career that spanned three generations of biochemists and physicians. He left behind not only a bibliography of 317 journal publications and 5 books, but also more than 100 persons who had worked with him and distinguished themselves in biochemistry and academic medicine. His doctoral thesis, with Gomberg at University of Michigan was published in the Journal of the American Chemical Society in 1907.  Van Slyke received an invitation from Dr. Simon Flexner, Director of the Rockefeller Institute, to come to New York for an interview. In 1911 he spent a year in Berlin with Emil Fischer, who was then the leading chemist of the scientific world. He was particularly impressed by Fischer’s performing all laboratory operations quantitatively —a procedure Van followed throughout his life. Prior to going to Berlin, he published the  classic nitrous acid method for the quantitative determination of primary aliphatic amino groups,  the first of the many gasometric procedures devised by Van Slyke, and made possible the determination of amino acids. It was the primary method used to study amino acid

composition of proteins for years before chromatography. Thus, his first seven postdoctoral years were centered around the development of better methodology for protein composition and amino acid metabolism.

With his colleague G. M. Meyer, he first demonstrated that amino acids, liberated during digestion in the intestine, are absorbed into the bloodstream, that they are removed by the tissues, and that the liver alone possesses the ability to convert the amino acid nitrogen into urea.  From the study of the kinetics of urease action, Van Slyke and Cullen developed equations that depended upon two reactions: (1) the combination of enzyme and substrate in stoichiometric proportions and (2) the reaction of the combination into the end products. Published in 1914, this formulation, involving two velocity constants, was similar to that arrived at contemporaneously by Michaelis and Menten in Germany in 1913.

He transferred to the Rockefeller Institute’s Hospital in 2013, under Dr. Rufus Cole, where “Men who were studying disease clinically had the right to go as deeply into its fundamental nature as their training allowed, and in the Rockefeller Institute’s Hospital every man who was caring for patients should also be engaged in more fundamental study”.  The study of diabetes was already under way by Dr. F. M. Allen, but patients inevitably died of acidosis.  Van Slyke reasoned that if incomplete oxidation of fatty acids in the body led to the accumulation of acetoacetic and beta-hydroxybutyric acids in the blood, then a reaction would result between these acids and the bicarbonate ions that would lead to a lower than-normal bicarbonate concentration in blood plasma. The problem thus became one of devising an analytical method that would permit the quantitative determination of bicarbonate concentration in small amounts of blood plasma.  He ingeniously devised a volumetric glass apparatus that was easy to use and required less than ten minutes for the determination of the total carbon dioxide in one cubic centimeter of plasma.  It also was soon found to be an excellent apparatus by which to determine blood oxygen concentrations, thus leading to measurements of the percentage saturation of blood hemoglobin with oxygen. This found extensive application in the study of respiratory diseases, such as pneumonia and tuberculosis. It also led to the quantitative study of cyanosis and a monograph on the subject by C. Lundsgaard and Van Slyke.

In all, Van Slyke and his colleagues published twenty-one papers under the general title “Studies of Acidosis,” beginning in 1917 and ending in 1934. They included not only chemical manifestations of acidosis, but Van Slyke, in No. 17 of the series (1921), elaborated and expanded the subject to describe in chemical terms the normal and abnormal variations in the acid-base balance of the blood. This was a landmark in understanding acid-base balance pathology.  Within seven years after Van moved to the Hospital, he had published a total of fifty-three papers, thirty-three of them coauthored with clinical colleagues.

In 1920, Van Slyke and his colleagues undertook a comprehensive investigation of gas and electrolyte equilibria in blood. McLean and Henderson at Harvard had made preliminary studies of blood as a physico-chemical system, but realized that Van Slyke and his colleagues at the Rockefeller Hospital had superior techniques and the facilities necessary for such an undertaking. A collaboration thereupon began between the two laboratories, which resulted in rapid progress toward an exact physico-chemical description of the role of hemoglobin in the transport of oxygen and carbon dioxide, of the distribution of diffusible ions and water between erythrocytes and plasma,
and of factors such as degree of oxygenation of hemoglobin and hydrogen ion concentration that modified these distributions. In this Van Slyke revised his volumetric gas analysis apparatus into a manometric method.  The manometric apparatus proved to give results that were from five to ten times more accurate.

A series of papers on the CO2 titration curves of oxy- and deoxyhemoglobin, of oxygenated and reduced whole blood, and of blood subjected to different degrees of oxygenation and on the distribution of diffusible ions in blood resulted.  These developed equations that predicted the change in distribution of water and diffusible ions between blood plasma and blood cells when there was a change in pH of the oxygenated blood. A significant contribution of Van Slyke and his colleagues was the application of the Gibbs-Donnan Law to the blood—regarded as a two-phase system, in which one phase (the erythrocytes) contained a high concentration of nondiffusible negative ions, i.e., those associated with hemoglobin, and cations, which were not freely exchaThe importance of Vanngeable between cells and plasma. By changing the pH through varying the CO2 tension, the concentration of negative hemoglobin charges changed in a predictable amount. This, in turn, changed the distribution of diffusible anions such as Cl” and HCO3″ in order to restore the Gibbs-Donnan equilibrium. Redistribution of water occurred to restore osmotic equilibrium. The experimental results confirmed the predictions of the equations.

As a spin-off from the physico-chemical study of the blood, Van undertook, in 1922, to put the concept of buffer value of weak electrolytes on a mathematically exact basis.
This proved to be useful in determining buffer values of mixed, polyvalent, and amphoteric electrolytes, and put the understanding of buffering on a quantitative basis. A
monograph in Medicine entitled “Observation on the Courses of Different Types of Bright’s Disease, and on the Resultant Changes in Renal Anatomy,” was a landmark that
related the changes occurring at different stages of renal deterioration to the quantitative changes taking place in kidney function. During this period, Van Slyke and R. M. Archibald identified glutamine as the source of urinary ammonia. During World War II, Van and his colleagues documented the effect of shock on renal function and, with R. A. Phillips, developed a simple method, based on specific gravity, suitable for use in the field.

Over 100 of Van’s 300 publications were devoted to methodology. The importance of Van Slyke’s contribution to clinical chemical methodology cannot be overestimated.
These included the blood organic constituents (carbohydrates, fats, proteins, amino acids, urea, nonprotein nitrogen, and phospholipids) and the inorganic constituents (total cations, calcium, chlorides, phosphate, and the gases carbon dioxide, carbon monoxide, and nitrogen). It was said that a Van Slyke manometric apparatus was almost all the special equipment needed to perform most of the clinical chemical analyses customarily performed prior to the introduction of photocolorimeters and spectrophotometers for such determinations.

The progress made in the medical sciences in genetics, immunology, endocrinology, and antibiotics during the second half of the twentieth century obscures at times the progress that was made in basic and necessary biochemical knowledge during the first half. Methods capable of giving accurate quantitative chemical information on biological material had to be painstakingly devised; basic questions on chemical behavior and metabolism had to be answered; and, finally, those factors that adversely modified the normal chemical reactions in the body so that abnormal conditions arise that we characterize as disease states had to be identified.

Viewed in retrospect, he combined in one scientific lifetime (1) basic contributions to the chemistry of body constituents and their chemical behavior in the body, (2) a chemical understanding of physiological functions of certain organ systems (notably the respiratory and renal), and (3) how such information could be exploited in the
understanding and treatment of disease. That outstanding additions to knowledge in all three categories were possible was in large measure due to his sound and broadly based chemical preparation, his ingenuity in devising means of accurate measurements of chemical constituents, and the opportunity given him at the Hospital of the Rockefeller Institute to study disease in company with physicians.

In addition, he found time to work collaboratively with Dr. John P. Peters of Yale on the classic, two-volume Quantitative Clinical Chemistry. In 1922, John P. Peters, who had just gone to Yale from Van Slyke’s laboratory as an Associate Professor of Medicine, was asked by a publisher to write a modest handbook for clinicians describing useful chemical methods and discussing their application to clinical problems. It was originally to be called “Quantitative Chemistry in Clinical Medicine.” He soon found that it was going to be a bigger job than he could handle alone and asked Van Slyke to join him in writing it. Van agreed, and the two men proceeded to draw up an outline and divide up the writing of the first drafts of the chapters between them. They also agreed to exchange each chapter until it met the satisfaction of both.At the time it was published in 1931, it contained practically all that could be stated with confidence about those aspects of disease that could be and had been studied by chemical means. It was widely accepted throughout the medical world as the “Bible” of quantitative clinical chemistry, and to this day some of the chapters have not become outdated.

History of Laboratory Medicine at Yale University.

The roots of the Department of Laboratory Medicine at Yale can be traced back to John Peters, the head of what he called the “Chemical Division” of the Department of Internal Medicine, subsequently known as the Section of Metabolism, who co-authored with Donald Van Slyke the landmark 1931 textbook Quantitative Clinical Chemistry (2.3); and to Pauline Hald, research collaborator of Dr. Peters who subsequently served as Director of Clinical Chemistry at Yale-New Haven Hospital for many years. In 1947, Miss Hald reported the very first flame photometric measurements of sodium and potassium in serum (4). This study helped to lay the foundation for modern studies of metabolism and their application to clinical care.

The Laboratory Medicine program at Yale had its inception in 1958 as a section of Internal Medicine under the leadership of David Seligson. In 1965, Laboratory Medicine achieved autonomous section status and in 1971, became a full-fledged academic department. Dr. Seligson, who served as the first Chair, pioneered modern automation and computerized data processing in the clinical laboratory. In particular, he demonstrated the feasibility of discrete sample handling for automation that is now the basis of virtually all automated chemistry analyzers. In addition, Seligson and Zetner demonstrated the first clinical use of atomic absorption spectrophotometry. He was one of the founding members of the major Laboratory Medicine academic society, the Academy of Clinical Laboratory Physicians and Scientists.

Davenport fig 10.jpg

Case in Point 3.  Nathan Gochman.  Developer of Automated Chemistries.

Nathan Gochman, PhD, has over 40 years of experience in the clinical diagnostics industry. This includes academic teaching and research, and 30 years in the pharmaceutical and in vitro diagnostics industry. He has managed R & D, technical marketing and technical support departments. As a leader in the industry he was President of the American Association for Clinical Chemistry (AACC) and the National Committee for Clinical Laboratory Standards (NCCLS, now CLSI). He is currently a Consultant to investment firms and IVD companies.

Nathan Gochman

Nathan Gochman

The clinical laboratory has become so productive, particularly in chemistry and immunology, and the labor, instrument and reagent costs are well determined, that today a physician’s medical decisions are 80% determined by the clinical laboratory.  Medical information systems have lagged far behind.  Why is that?  Because the decision for a MIS has historical been based on billing capture.  Moreover, the historical use of chemical profiles were quite good at validating healthy dtatus in an outpatient population, but the profiles became restricted under Diagnostic Related Groups.    Thus, it came to be that the diagnostics was considered a “commodity”.  In order to be competitive, a laboratory had to provide “high complexity” tests that were drawn in by a large volume of “moderate complexity”tests.

Part 3. Biomarkers in Medical Practice

Case in Point 1.

A Solid Prognostic Biomarker

HDL-C: Target of Therapy or Fuggedaboutit?

Steven E. Nissen, MD, MACC, Peter Libby, MD

DisclosuresNovember 06, 2014

Steven E. Nissen, MD, MACC: I am Steve Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic. I am here with Dr Peter Libby, chief of cardiology at the Brigham and Women’s Hospital and professor of medicine at Harvard Medical School. We are going to discuss high-density lipoprotein cholesterol (HDL-C), a topic that has been very controversial recently. Peter, HDL-C has been a pretty good biomarker. The question is whether it is a good target.

Peter Libby, MD: Since the early days in Berkley, when they were doing ultracentrifugation, and when it was reinforced and put on the map by the Framingham Study,[1] we have known that HDL-C is an extremely good biomarker of prospective cardiovascular risk with an inverse relationship with all kinds of cardiovascular events. That is as solid a finding as you can get in observational epidemiology. It is a very reliable prospective marker. It’s natural that the pharmaceutical industry and those of us who are interested in risk reduction would focus on HDL-C as a target. That is where the controversies come in.

Dr Nissen: It has been difficult. My view is that the trials that have attempted to modulate HDL-C or the drugs they used have been flawed. Although the results have not been promising, the jury is yet out. Torcetrapib, the cholesteryl ester transfer protein (CETP) inhibitor developed by Pfizer, had anoff-target toxicity.[2] Niacin is not very effective, and there are a lot of downsides to the drug. That has been an issue, but people are still working on this. We have done some studies. We did our ApoA-1 Milano infusion study[3]about a decade ago, which showed very promising results with respect to shrinking plaques in coronary arteries. I remain open to the possibility that the right drug in the right trial will work.

Dr Libby: What do you do with the genetic data that have come out in the past couple of years? Sekar Kathiresan masterminded and organized an enormous collaboration[4] in which they looked, with contemporary genetics, at whether HDL had the genetic markers of being a causal risk factor. They came up empty-handed.

Dr Nissen: I am cautious about interpreting those data, like I am cautious about interpreting animal studies of atherosclerosis. We have both lived through this problem in which something works extremely well in animals but doesn’t work in humans, or it doesn’t work in animals but it works in humans. The genetic studies don’t seal the fate of HDL. I have an open mind about this. Drugs are complex. They work by complex mechanisms. It is my belief that what we have to do is test these hypotheses in well-designed clinical trials, which are rigorously performed with drugs that are clean—unlike torcetrapib—and don’t have off-target toxicities.

An Unmet Need: High Lp(a) Levels

Dr Nissen: I’m going to push back on that and make a couple of points. The HPS2-THRIVE study was flawed. They studied the wrong people. It was not a good study, and AIM-HIGH[8] was underpowered. I am not putting people on niacin. What do you do with a patient whose Lp(a) is 200 mg/dL?

Dr Libby: I’m waiting for the results of the PCSK9 and anacetrapib studies. You can tell me about evacetrapib.[9]Reducing Lp(a) is an unmet medical need. We both care for kindreds with high Lp(a) levels and premature coronary artery disease. We have no idea what to do with them other than to treat them with statins and lower their LDL-C levels.

Dr Nissen: I have taken a more cautious approach with respect to taking people off of niacin. If I have patients who are doing well and tolerating it (depending on why it was started), I am discontinuing niacin in some people. I am starting very few people on the drug, but I worry about the quality of the trial.

Dr Libby: So you are of the “don’t start don’t stop” school?

Dr Nissen: Yes. It’s difficult when the trial is fatally flawed. There were 11,000 patients from China in this study. I have known for years that if you give niacin to people of Asiatic ethnic descent, they have terrible flushing and they won’t continue the drug. One question is, what was the adherence? The adverse events would have been tolerable had there been efficacy. The concern here is that this study was destined to fail because they studied a low LDL/high HDL population, a group of people for whom niacin just isn’t used.

Triglycerides and HDL: Do We Have It Backwards?

Dr Libby: What about the recent genetic[10] and epidemiologic data that support triglycerides, and apolipoprotein C3 in particular as a causal risk factor? Have we been misled through all of the generations in whom we have been adjusting triglycerides for HDL-C and saying that triglycerides are not a causal risk factor because once we adjust for HDL, the risk goes away? Do you think we got it backwards?

Dr Nissen: The tricky factor here is that because of this intimate inverse relationship between triglycerides and HDL, we may be talking about the same phenomenon. That is one of the reasons that I am not certain we are not going to be able to find a therapy. What if you had a therapy that lowered triglycerides and raised HDL-C? Could that work? Could that combination be favorable? I want answers from rigorous, well-designed clinical trials that ask the right questions in the right populations. I am disappointed, just as I have been disappointed by the fibrate trials.[11,12] There is a class of drugs that raises HDL-C a little and lowers triglycerides a lot.

Dr Nissen: But the gemfibrozil studies (VA-HIT[13] and Helsinki Heart[14]) showed benefit.

The Dyslipidemia Bar Has Been Raised

Dr Libby: Those studies were from the pre-statin era. We both were involved in trials in which patients were on high-dose statins at baseline. Do you think that this is too high a bar?

Dr Nissen: The bar has been raised, and for the pharmaceutical industry, the studies that we need to find out whether lowering triglycerides or raising HDL is beneficial are going to be large. We are doing a study with evacetrapib. It has 12,000 patients. It’s fully enrolled. Evacetrapib is a very clean-looking drug. It doesn’t have such a long biological half-life as anacetrapib, so I am very encouraged that it won’t have that baggage of being around for 2-4 years. We’ve got a couple of shots on goal here. Don’t forget that we have multiple ongoing studies of HDL-C infusion therapies that are still under development. Those have some promise too. The jury is still out.

Dr Libby: We agree on the need to do rigorous, large-scale endpoint trials. Do the biomarker studies, but don’t wait to start the endpoint trial because that’s the proof in the pudding.

Dr Nissen: Exactly. We have had a little controversy about HDL-C. We often agree, but not always, and we may have a different perspective. Thanks for joining me in this interesting discussion of what will continue to be a controversial topic for the next several years until we get the results of the current ongoing trials.

Case in Point 2.

NSTEMI? Honesty in Coding and Communication?

Melissa Walton-Shirley

November 07, 2014

The complaint at ER triage: Weakness, fatigue, near syncope of several days’ duration, vomiting, and decreased sensorium.

The findings: O2sat: 88% on room air. BP: 88 systolic. Telemetry: Sinus tachycardia 120 bpm. Blood sugar: 500 mg/dL. Chest X ray: atelectasis. Urinalysis: pyuria. ECG: T-wave-inversion anterior leads. Echocardiography: normal left ventricular ejection fraction (LVEF) and wall motion. Troponin I: 0.3 ng/mL. CT angiography: negative for pulmonary embolism (PE). White blood cell count: 20K with left shift. Blood cultures: positive for Gram-negative rods.

The treatment: Intravenous fluids and IV levofloxacin—changed to ciprofloxacin.

The communication at discharge: “You had a severe urinary-tract infection and grew bacteria in your bloodstream. Also, you’ve had a slight heart attack. See your cardiologist immediately upon discharge-no more than 5 days from now.”

The diagnoses coded at discharge: Urosepsis and non-ST segment elevation MI (NSTEMI) 410.1.

One year earlier: This moderately obese patient was referred to our practice for a preoperative risk assessment. The surgery planned was a technically simple procedure, but due to the need for precise instrumentation, general endotracheal anesthesia (GETA) was being considered. The patient was diabetic, overweight, and short of air. A stress exam was equivocal for CAD due to poor exercise tolerance and suboptimal imaging. Upon further discussion, symptoms were progressive; therefore, cardiac cath was recommended, revealing angiographically normal coronaries and a predictably elevated left ventricular end diastolic pressure (LVEDP) in the mid-20s range. The patient was given a diagnosis of diastolic dysfunction, a prescription for better hypertension control, and in-depth discussion on exercise and the Mediterranean and DASH diets for weight loss. Symptoms improved with a low dose of diuretic. The surgery was completed without difficulty. Upon follow-up visit, the patient felt well, had lost a few pounds, and blood pressure was well controlled.

Five days after ER workup: While out of town, the patient developed profound weakness and went to the ER as described above. Fast forward to our office visit in the designated time frame of “no longer than 5 days’ postdischarge,” where the patient and family asked me about the “slight heart attack” that literally came on the heels of a normal coronary angiogram.

But the patient really didn’t have a “heart attack,” did they? The cardiologist aptly stated that it was likely nonspecific troponin I leak in his progress notes. Yet the hospitalist framed the diagnosis of NSTEMI as item number 2 in the final diagnoses.

The motivations on behalf of personnel who code charts are largely innocent and likely a direct result of the lack of understanding of the coding system on behalf of us as healthcare providers. I have a feeling, though, that hospitals aren’t anxious to correct this misperception, due to an opportunity for increased reimbursement. I contacted a director of a coding department for a large hospital who prefers to remain anonymous. She explained that NSTEMI ICD9 code 410.1 falls in DRG 282 with a weight of .7562. The diagnosis of “demand ischemia,” code 411.89, a slightly less inappropriate code for a nonspecific troponin I leak, falls in DRG 311 with a weight of .5662. To determine reimbursement, one must multiply the weight by the average hospital Medicare base rate of $5370. Keep in mind that each hospital’s base rate and corresponding payment will vary. The difference in reimbursement for a large hospital bill between these two choices for coding is substantial, at over $1000 difference ($4060 vs $3040).

Although hospitals that are already reeling from shrinking revenues will make more money on the front end by coding the troponin leak incorrectly as an NSTEMI, when multiple unnecessary tests are generated to follow up on a nondiagnostic troponin leak, the amount of available Centers for Medicare & Medicaid Services (CMS) reimbursement pie shrinks in the long run. Furthermore, this inappropriate categorization generates extreme concern on behalf of patients and family members that is often never laid to rest. The emotional toll of a “heart-attack” diagnosis has an impact on work fitness, quality of life, cost of medication, and the cost of future testing. If the patient lived for another 100 years, they will likely still list a “heart attack” in their medical history.

As a cardiologist, I resent the loose utilization of one of “my” heart-attack codes when it wasn’t that at all. At discharge, we need to develop a better way of communicating what exactly did happen. Equally important, we need to communicate what exactly didn’t happen as well.

Case in Point 3.

Blood Markers Predict CKD Heart Failure 

Published: Oct 3, 2014 | Updated: Oct 3, 2014

Elevated levels of high-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predicted heart failure in patients with chronic kidney disease followed for a median of close to 6 years, researchers reported.

Compared with patients with the lowest blood levels of hsTnT, those with the highest had a nearly five-fold higher risk for developing heart failure and the risk was 10-fold higher in patients with the highest NT-proBNP levels compared with those with the lowest levels of the protein, researcher Nisha Bansal, MD, of the University of Washington in Seattle, and colleagues wrote online in the Journal of the American Society of Nephrology.

A separate study, published online in theJournal of the American Medical Association earlier in the week, also examined the comorbid conditions of heart and kidney disease, finding no benefit to the practice of treating cardiac surgery patients who developed acute kidney injury with infusions of the antihypertensive drug fenoldopam.

The study, reported by researcher Giovanni Landoni, MD, of the IRCCS San Raffaele Scientific Institute, Milan, Italy, and colleagues, was stopped early “for futility,” according to the authors, and the incidence of hypotension during drug infusion was significantly higher in patients infused with fenoldopam than placebo (26% vs. 15%; P=0.001).

Blood Markers Predict CKD Heart Failure

The study in patients with mild to moderate chronic kidney disease (CKD) was conducted to determine if blood markers could help identify patients at high risk for developing heart failure.

Heart failure is the most common cardiovascular complication among people with renal disease, occurring in about a quarter of CKD patients.

The two markers, hsTnT and NT-proBNP, are associated with overworked cardiac myocytes and have been shown to predict heart failure in the general population.

However, Bansal and colleagues noted, the markers have not been widely used in diagnosing heart failure among patients with CKD due to concerns that reduced renal excretion may raise levels of these markers, and therefore do not reflect an actual increase in heart muscle strain.

To better understand the importance of elevated concentrations of hsTnT and NT-proBNP in CKD patients, the researchers examined their association with incident heart failure events in 3,483 participants in the ongoing observational Chronic Renal Insufficiency Cohort (CRIC) study.

All participants were recruited from June 2003 to August 2008, and all were free of heart failure at baseline. The researchers used Cox regression to examine the association of baseline levels of hsTnT and NT-proBNP with incident heart failure after adjustment for demographic influences, traditional cardiovascular risk factors, makers of kidney disease, pertinent medication use, and mineral metabolism markers.

At baseline, hsTnT levels ranged from ≤5.0 to 378.7 pg/mL and NT-proBNP levels ranged from ≤5 to 35,000 pg/mL. Compared with patients who had undetectable hsTnT, those in the highest quartile (>26.5 ng/mL) had a significantly higher rate of heart failure (hazard ratio 4.77; 95% CI 2.49-9.14).

Compared with those in the lowest NT-proBNP quintile (<47.6 ng/mL), patients in the highest quintile (>433.0 ng/mL) experienced an almost 10-fold increase in heart failure risk (HR 9.57; 95% CI 4.40-20.83).

The researchers noted that these associations remained robust after adjustment for potential confounders and for the other biomarker, suggesting that while hsTnT and NT-proBNP are complementary, they may be indicative of distinct biological pathways for heart failure.

Even Modest Increases in NP-proBNP Linked to Heart Failure

The findings are consistent with an earlier analysis that included 8,000 patients with albuminuria in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, which showed that hsTnT was associated with incident cardiovascular events, even after adjustment for eGFR and severity of albuminuria.

“Among participants in the CRIC study, those with the highest quartile of detectable hsTnT had a twofold higher odds of left ventricular hypertrophy compared with those in the lowest quartile,” Bansal and colleagues wrote, adding that the findings were similar after excluding participants with any cardiovascular disease at baseline.

Even modest elevations in NT-proBNP were associated with significantly increased rates of heart failure, including in subgroups stratified by eGFR, proteinuria, and diabetic status.

“NT-proBNP regulates blood pressure and body fluid volume by its natriuretic and diuretic actions, arterial dilation, and inhibition of the renin-aldosterone-angiotensin system and increased levels of this marker likely reflect myocardial stress induced by subclinical changes in volume or pressure, even in persons without clinical disease,” the researchers wrote.

The researchers concluded that further studies are needed to develop and validate risk prediction tools for clinical heart failure in patients with CKD, and to determine the potential role of these two biomarkers in a heart failure risk prediction and prevention strategy.

Fenoldopam ‘Widely Promoted’ in AKI Cardiac Surgery Setting

The JAMA study examined whether the selective dopamine receptor D agonist fenoldopam mesylate can reduce the need for dialysis in cardiac surgery patients who develop acute kidney injury (AKI).

Fenoldopam induces vasodilation of the renal, mesenteric, peripheral, and coronary arteries, and, unlike dopamine, it has no significant affinity for D2 receptors, meaning that it theoretically induces greater vasodilation in the renal medulla than in the cortex, the researchers wrote.

“Because of these hemodynamic effects, fenoldopam has been widely promoted for the prevention and therapy of AKI in the United States and many other countries with apparent favorable results in cardiac surgery and other settings,” Landoni and colleagues wrote.

The drug was approved in 1997 by the FDA for the indication of in-hospital, short-term management of severe hypertension. It has not been approved for renal indications, but is commonly used off-label in cardiac surgery patients who develop AKI.

Although a meta analysis of randomized trials, conducted by the researchers, indicated a reduction in the incidence and progression of AKI associated with the treatment, Landoni and colleagues wrote that the absence of a definitive trial “leaves clinicians uncertain as to whether fenoldopam should be prescribed after cardiac surgery to prevent deterioration in renal function.”

To address this uncertainty, the researchers conducted a prospective, randomized, parallel-group trial in 667 patients treated at 19 hospitals in Italy from March 2008 to April 2013.

All patients had been admitted to ICUs after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or low output of urine for ≥6 hours). A total of 338 received fenoldopam by continuous intravenous infusion for a total of 96 hours or until ICU discharge, while 329 patients received saline infusions.

The primary end point was the rate of renal replacement therapy, and secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion.

Study Showed No Benefit, Was Stopped Early

Yale Lampoon – AA Liebow.   1954

Not As a Doctor
[Fourth Year]

These lyrics, sung by John Cole, Jack Gariepy and Ed Ransenhofer to music borrowed from Gilbert and Sullivan’s The Mikado, lampooned Averill Liebow, M.D., a pathologist noted for his demands on students. (CPC stands for clinical pathology conference.)

If you want to know what this is,
it’s a medical CPC
Where we give the house staff
the biz, for there’s no one so
wise as we!
We pathologists show them how,
Although it is too late now.
Our art is a sacred cow!

American physician, born 1911, Stryj in Galicia, Austria (now in Ukraine); died 1978.

Averill Abraham Liebow, born in Austria, was the “founding father” of pulmonary pathology in the United States. He started his career as a pathologist at Yale, where he remained for many years. In 1968 he moved to the University of California School of Medicine, San Diego, where he taught for 7 years as Professor and Chairman, Department of Pathology.

His studies include many classic studies of lung diseases. Best known of these is his famous classification of interstitial lung disease. He also published papers on sclerosing pneumocytoma, pulmonary alveolar proteinosis, meningothelial-like nodules, pulmonary hypertension, pulmonary veno-occlusive disease, lymphomatoid granulomatosis, pulmonary Langerhans cell histiocytosis, pulmonary epithelioid hemangioendothelioma and pulmonary hyalinizing granuloma .

As a Lieutenant Colonel in the US Army Medical Corps, He was a member of the Atomic Bomb Casualty Commission who studied the effects of the atomic bomb in Hiroshima and Nagasaki.

We thank Sanjay Mukhopadhyay, M.D., for information submitted.

As a resident at UCSD, Dr. Liebow held “Organ Recitals” every morning, including Mother’s day.  The organs had to be presented in specified order… heart, lung, and so forth.  On one occasion, we needed a heart for purification of human lactate dehydrogenase for a medical student project, so I presented the lung out of order.  Dr. Liebow asked where the heart was, and I told the group it was noprmal and I froze it for enzyme purification (smiles).  In the future show it to me first. He was generous to those who showed interest.  As I was also doing research in Nathan Kaplan’s laboratory, he made special arrangements for me to mentor Deborah Peters, the daughter of a pulmonary physician, and granddaughter of the Peters who collaborated with Van Slyke.  I mentored many students with great reward since then.  He could look at a slide and tell you what the x-ray looked like.  I didn’t encounter that again until he sent me to the Armed Forces Institute of Pathology, Washington, DC during the Vietnam War and Watergate, and I worked in Orthopedic Pathology with Lent C. Johnson.  He would not review a case without the x-ray, and he taught the radiologists.

Part 3

My Cancer Genome from Vanderbilt University: Matching Tumor Mutations to Therapies & Clinical Trials

Reporter: Aviva Lev-Ari, PhD, RN

GenomOncology and Vanderbilt-Ingram Cancer Center (VICC) today announced a partnership for the exclusive commercial development of a decision support tool based on My Cancer Genome™, an online precision cancer medicine knowledge resource for physicians, patients, caregivers and researchers.

Through this collaboration, GenomOncology and VICC will enhance My Cancer Genome through the development of a new genomics content management tool. The MyCancerGenome.org website will remain free and open to the public. In addition, GenomOncology will develop a decision support tool based on My Cancer Genome™ data that will enable automated interpretation of mutations in the genome of a patient’s tumor, providing actionable results in hours versus days.

Vanderbilt-Ingram Cancer Center (VICC) launched My Cancer Genome™ in January 2011 as an integral part of their Personalized Cancer Medicine Initiative that helps physicians and researchers track the latest developments in precision cancer medicine and connect with clinical research trials. This web-based information tool is designed to quickly educate clinicians on the rapidly expanding list of genetic mutations that impact cancers and enable the research of treatment options based on specific mutations. For more information on My Cancer Genome™visit www.mycancergenome.org/about/what-is-my-cancer-genome.

Therapies based on the specific genetic alterations that underlie a patient’s cancer not only result in better outcomes but often have less adverse reactions

Up front fee

Nominal fee covers installation support, configuring the Workbench to your specification, designing and developing custom report(s) and training your team.

Per sample fee

GenomOncology is paid on signed-out clinical reports. This philosophy aligns GenomOncology with your Laboratory as we are incentivized to offer world-class support and solutions to differentiate your clinical NGS program. There is no annual license fee.

Part 4

Clinical Trial Services: Foundation Medicine & EmergingMed to Partner

Reporter: Aviva Lev-Ari, PhD, RN

Foundation Medicine and EmergingMed said today that they will partner to offer clinical trial navigation services for health care providers and their patients who have received one of Foundation Medicine’s tumor genomic profiling tests.

The firms will provide concierge services to help physicians

  • identify appropriate clinical trials for patients
  • based on the results of FoundationOne or FoundationOne Heme.

“By providing clinical trial navigation services, we aim to facilitate

  • timely and accurate clinical trial information and enrollment support services for physicians and patients,
  • enabling greater access to treatment options based on the unique genomic profile of a patient’s cancer

Currently, there are over 800 candidate therapies that target genomic alterations in clinical trials,

  • but “patients and physicians must identify and act on relevant options
  • when the patient’s clinical profile is aligned with the often short enrollment window for each trial.

These investigational therapies are an opportunity to engage patients with cancer whose cancer has progressed or returned following standard treatment in a most favorable second option after relapse.  The new service is unique in notifying when new clinical trials emerge that match a patient’s genomic and clinical profile.

Google signs on to Foundation Medicine cancer Dx by offering tests to employees

By Emily Wasserman

Diagnostics luminary Foundation Medicine ($FMI) is generating some upward momentum, fueled by growing revenues and the success of its clinical tests. Tech giant Google ($GOOG) has taken note and is signing onto the company’s cancer diagnostics by offering them to employees.

Foundation Medicine CEO Michael Pellini said during the company’s Q3 earnings call that Google will start covering its DNA tests for employees and their family members suffering from cancer as part of its health benefits portfolio, Reuters reports.

Both sides stand to benefit from the deal, as Google looks to keep a leg up on Silicon Valley competitors and Foundation Medicine expands its cancer diagnostics platform. Last month, Apple ($AAPL) and Facebook ($FB) announced that they would begin covering the cost of egg freezing for female employees. A diagnostics partnership and attractive health benefits could work wonders for Google’s employee retention rates and bottom line.

In the meantime, Cambridge, MA-based Foundation Medicine is charging full speed ahead with its cancer diagnostics platform after filing for an IPO in September 2013. The company chalked up 6,428 clinical tests during Q3 2014, an eye-popping 149% increase year over year, and brought in total revenue for the quarter of $16.4 million–a 100% leap from last year. Foundation Medicine credits the promising numbers in part to new diagnostic partnerships and extended coverage for its tests.

In January, the company teamed up with Novartis ($NVS) to help the drugmaker evaluate potential candidates for its cancer therapies. In April, Foundation Medicine announced that it would develop a companion diagnostic test for a Clovis Oncology ($CLVS) drug under development to treat patients with ovarian cancer, building on an ongoing collaboration between the two companies.

Foundation Medicine also has its sights set on China’s growing diagnostics market, inking a deal in October with WuXi PharmaTech ($WX) that allows the company to perform lab testing for its FoundationOne assay at WuXi’s Shanghai-based Genome Center.

a nod to the deal with Google during a corporate earnings call on Wednesday, according to a person who listened in. Pellini said Google employees were made aware of this new benefit last week.

Foundation Medicine teams with MD Anderson for new trial of cancer Dx

Second study to see if targeted therapy can change patient outcomes

August 15, 2014 | By   FierceDiagnostics

Foundation Medicine ($FMI) is teaming up with the MD Anderson Cancer Center in Texas for a new trial of the the Cambridge, MA-based company’s molecular diagnostic cancer test that targets therapies matched to individual patients.

The study is called IMPACT2 (Initiative for Molecular Profiling and Advanced Cancer Therapy) and is designed to build on results from the the first IMPACT study that found

  • 40% of the 1,144 patients enrolled had an identifiable genomic alteration.

The company said that

  • by matching specific gene alterations to therapies,
  • 27% of patients in the first study responded versus
  • 5% with an unmatched treatment, and
  • “progression-free survival” was longer in the matched group.

The FoundationOne molecular diagnostic test

  • combines genetic sequencing and data gathering
  • to help oncologists choose the best treatment for individual patients.

Costing $5,800 per test, FoundationOne’s technology can uncover a large number of genetic alterations for 200 cancer-related genes,

  • blending genomic sequencing, information and clinical practice.

“Based on the IMPACT1 data, a validated, comprehensive profiling approach has already been adopted by many academic and community-based oncology practices,” Vincent Miller, chief medical officer of Foundation Medicine, said in a release. “This study has the potential to yield sufficient evidence necessary to support broader adoption across most newly diagnosed metastatic tumors.”

The company got a boost last month when the New York State Department of Health approved Foundation Medicine’s two initial cancer tests: the FoundationOne test and FoundationOne Heme, which creates a genetic profile for blood cancers. Typically,

  • diagnostics companies struggle to win insurance approval for their tests
  • even after they gain a regulatory approval, leaving revenue growth relatively flat.

However, Foundation Medicine reported earlier this week its Q2 revenue reached $14.5 million compared to $5.9 million for the same period a year ago. Still,

  1. net losses continue to soar as the company ramps up
  2. its commercial and business development operation,
  • hitting $13.7 million versus a $10.1 million deficit in the second quarter of 2013.


There has been a remarkable transformation in our understanding of

  • the molecular genetic basis of cancer and its treatment during the past decade or so.

In depth genetic and genomic analysis of cancers has revealed that

  • each cancer type can be sub-classified into many groups based on the genetic profiles and
  • this information can be used to develop new targeted therapies and treatment options for cancer patients.

This panel will explore the technologies that are facilitating our understanding of cancer, and

  • how this information is being used in novel approaches for clinical development and treatment.
Oncology _ Reprted by Dr. Aviva Lev-Ari, Founder, Leaders in Pharmaceutical Intelligence

Opening Speaker & Moderator:

Lynda Chin, M.D.
Department Chair, Department of Genomic Medicine
MD Anderson Cancer Center

  • Who pays for PM?
  • potential of Big data, analytics, Expert systems, so not each MD needs to see all cases, Profile disease to get same treatment
  • business model: IP, Discovery, sharing, ownership — yet accelerate therapy
  • security of healthcare data
  • segmentation of patient population
  • management of data and tracking innovations
  • platforms to be shared for innovations
  • study to be longitudinal,
  • How do we reconcile course of disease with PM
  • phinotyping the disease vs a Patient in wait for cure/treatment


Roy Herbst, M.D., Ph.D.
Ensign Professor of Medicine and Professor of Pharmacology;
Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital

Development new drugs to match patient, disease and drug – finding the right patient for the right Clinical Trial

  • match patient to drugs
  • partnerships: out of 100 screened patients, 10 had the gene, 5 were able to attend the trial — without the biomarker — all 100 patients would participate for the WRONG drug for them (except the 5)
  • patients wants to participate in trials next to home NOT to have to travel — now it is in the protocol
  • Annotated Databases – clinical Trial informed consent – adaptive design of Clinical Trial vs protocol
  • even Academic MD can’t read the reports on Genomics
  • patients are treated in the community — more training to MDs
  • Five companies collaborating – comparison og 6 drugs in the same class
  • if drug exist and you have the patient — you must apply PM

Summary and Perspective:

The current changes in Biotechnology have been reviewed with an open question about the relationship of In Vitro Diagnostics to Biopharmaceuticals switching, with the potential, particularly in cancer and infectious diseases, to added value in targeted therapy by matching patients to the best potential treatment for a favorable outcome.

This reviewer does not see the movement of the major diagnostics leaders entering into the domain of direct patient care, even though there are signals in that direction.  The Roche example is perhaps the most interesting because Roche already became the elephant in the room after the introduction of Valium,  subsequently bought out Boehringer Mannheim Diagnostics to gain entry into the IVD market, and established a huge presence in Molecular Diagnostics early.  If it did anything to gain a foothold in the treatment realm, it would more likely forge a relationship with Foundation Medicine.  Abbott Laboratories more than a decade ago was overextended, and it had become the leader in IVD as a result of the specialty tests, but it fell into difficulties with quality control of its products in the high volume testing market, and acceeded to Olympus, Roche, and in the mid volume market to Beckman and Siemens.  Of course, Dupont and Kodak, pioneering companies in IVD, both left the market.

The biggest challenge in the long run is identified by the ability to eliminate many treatments that would be failures for a large number of patients. That has already met the proof of concept.  However, when you look at the size of the subgroups, we are not anywhere near a large scale endeavor.  In addition, there is a lot that has to be worked out that is not related to genomic expression by the “classic” model, but has to take into account the emrging knowledge and greater understanding of regulation of cell metabolism, not only in cancer, but also in chronic inflammatory diseases.

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11:30AM 11/13/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Reporter: Aviva Lev-Ari, PhD, RN


REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

11:30 a.m. – Keynote Speaker – Role of Genetics and Genomics in Pharmaceutical Development


Role of Genetics and Genomics in Pharmaceutical Development

There was a time when pharmaceutical companies attempted to develop drugs that could be used to treat large populations of individuals diagnosed with a particular disease. These drugs were used to treat large groups of patients and were not always effective for all patients. The paradigm of drug development is changing where highly targeted drugs that would be highly effective in specific sub populations of patients are becoming the new norm. Dr. Skovronsky will describe how the pharmaceutical industry as a whole and Lilly in particular is taking advantage of the new knowledge about the genetic basis of disease to develop highly effective therapies.

Role of Genetics and Genomics in Pharmaceutical Development

Daniel Skovronsky, M.D., Ph.D.
Vice President of Tailored Therapeutics, Lilly



Alzheimer’s Disease

  •  early detection
  • how do drugs work in Alzheimer’s Disease (AD) – difficult to conduct Clinical Trials
  • Personalized the treatment as early on as possible: looking inside the brain and track the disease
  • images of the pathology of AD – Amyloid imaging using agents
  • diagnostics test on autopsy of AD brains after death
  • Risk of Progression
  • amyloid deposition over time – Dynamics of accumulations
  • Autopsy of brains of AD: MANY AD patients have negative scans
  • Clinical Trial definition of AD: 22% did not have amyloid — WERE TREATED WITH ANTI Amyloid DRUGS (22% Solanezumab, 16% Bapineuzumab)
  • 1/2 have DX of AD and treated with targeted drug — have negative Scans for Amyloid deposits — NOT PROGRESSING
  • those progressing are those with Positive Scans
  • 18 month and 36 month – Progression of Amyloid — Only at Positive scans
  • A4 Trial Dx Florbetapir
  • Rx solanezumab – symptomatic dementia vs AD
  • Markers o=for the disease – Neural degeneration – Tau in temporal lobe
  • Treat patient with start of Tau — avoid progression to amyloid deposition



  • Companion Diagnostics (CD) vs Therapeutics – start to find the biomarkers at the same time: Drug and Diagnostics
  • DNA, RNA, Protein
  • Diagnostics –>> translation
  • CLIA lab at Eli Lilly for companion diagnostics
  • Biomarker Negative vs Positive ans a spectrum of results
  • Immunohistochemistry (IHC) for protein expression – simple assay, complicated test
  • two different agent at two different albs — give two different diagnostics
  • Tumor heterogeneity: Glioblastoma
  • Tissue scarce resource — it is separated in time Biopsy taken at different times
  • Detection of chromosomal – Liquid Biopsy – Exosomes
  • mRNA, miRNA
  • Summary: Prime key porters to quickly bring therapies to patients


– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf










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4:00PM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Reporter: Aviva Lev-Ari, PhD, RN


REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

4:00 p.m. Panel Discussion Novel Approaches to Personalized Medicine

Novel Approaches to Personalized Medicine

Genetic and genomic knowledge is helping the development of new drugs, therapies and prognostic tests. As a result, there are new approaches, new partnerships and new business models that are emerging. In some cases, diseases that were considered incurable not too long ago are now being tackled with highly targeted therapies. In other cases the uncertainties associated with assessing potential aggressiveness of disease are being eliminated. This panel will provide examples of new business paradigms that are emerging from the application of personalized medicine.

Novel Approaches to Personalized Medicine


Meghan FitzGerald, Ph.D. @cardinalhealth
President, Cardinal Health Specialty Solutions

Chief Genome Officer – next steps in companies, Genomics Index will replace the Biotech Index

Most Interesting person in Genomics: Marc Levin,


2. Chris Garabedian @Sarepta
President and CEO, Sarepta

  • Applications of genomics to Infectious diseases, therapeutics – design of drugs, Duchenne Muscular Dystrophy (DMD)
  • technology safe working, one drug very effective, 60 alternative drugs, not enough patients to power clinical trials


4. Shawn Marcell
President & CEO, Metamark Genetics

  • Prostatic Cancer – Use of genomics tools to diagnose and treat Prostate cancer
  • US market is the best for Genomics innovations because venture capital Market is mature, FDA is negotiable, CMP well established
  • Business model: platform, good test big market, commercialize, clinical data — PM has a different Business model: Delivery of Test results need to be different
  • IPO 2016


1. Scott Schell, M.D., Ph.D. – surgical oncology @KEWGroup
President and CEO, KEW Group

  • Large scale platform, strategic partnerships with Oncology Practices,
  • Immuno oncologists, repository of data
  • 80% of cancers are treated in the community 20% at Academic centers. Integration of knowledge, patients wish to stay in the community
  • phase I approval at record high levels

3. Gabriel Bien-Willner, M.D., Ph.D. @MolecularHealth
Medical Director, MolecularHealth, Inc.

  • Diagnostics Tools in Analytics. Clinicians do not have the training in Genomics – position firm to create Lab reports and consulting MDs using Analytics for Clinicians



– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf








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11:00AM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Reporter: Aviva Lev-Ari, PhD, RN


REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

11:00 Keynote Speaker – Past, Present and Future of Personalized Medicine

Past, Present and Future of Personalized Medicine

Keynote Speaker

Mirella Marlow, M.A., M.B.A.
Programme Director, Centre for Health Technology Evaluation,
National Institute for Health and Clinical Excellence (NICE) @NICEcomms

PM in the UK

Clinical evidence and cost effectiveness needed for PM

UK Government life sciences policy

Scale of PM:

2013 – 10 million pound

2020 – 60 million pound

Innovative healthcare to promote economic growth

  • Genomics England 100,000  – new scientific discovery and kick start the UK genomics industry
  • BIS – accelerate Skills & Training for the Genomics Industries
  • UK Precision Medicine Catapult development of tests and commercialization of innovation in diagnostics

1 Billion Pound NIHR in UK

  • tissue banks – Biobank
  • Farr Institute – “big data”
  • develop methodologies for starter research

National Institute Care Excellence

– standards for NP

Benefits of PM

  • right treatment
  • responding subgroups
  • earlier treatments
  • dosing
  • reduce side effects

Companion Diagnostics in NICE – Technology Appraisals

  • elevate a test like evaluate a drug ad part of Diagnostics
  • Treatment: GIST — >>Biomarker: KitCD117

Diagnostics assessment Program

  • 9 EGFR-TK – mutation testing –
  • Mutation Analysis Services

NICE support to Companies – Company engagement

  • discuss product pipeline and value proposition
  • orientation to the process
  • Scientific Advice on Clinical Trial Design
  • workshops for Pharma and for Diagnostics — are different
  • online tool being developed – standardize the Advise for Fee — get Accredited Advisors in the Fields of Genomics, Diagnostics
  • Post guidance – evidence gaps, clinical utility and economic evidence
  • Update guidance – research questions guiding Guidance for the industry
  • Indirect Research facilitation: protocol external funding identify clinical context ethics +GCP leading to Publication within 2 years

UK and Genetics: Kirk and Watson on DNA

UK – 60 million patients under one National Universal Health Care System

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf




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8:20AM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Reporter: Aviva Lev-Ari, PhD, RN


REAL TIME Coverage of the Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com


8:20 a.m. Special Guest Keynote Speaker – The Future of Personalized Medicine

The Future of Personalized Medicine

Special Guest Speaker

Margaret Hamburg, M.D.
Commissioner of Food and Drugs Administration

[Her Father was President of IOM said at the introduction to the Keynote]

How to ask the right question is what HMS taught me best 

Increasing the knowledge of Biology, response to disease, preventive strategies.

2004 — Monumental year — One year after completion of sequencing the Genome

2008/9 – Breast Cancer – pharmacotherapy approved, a protein involved in triggering the disease.Target therapy – risk of disease identified

WHAT FDA is doing on Genetics Information as PARTNERS in Medicine

25% of drugs approved are Targeted therapies

LABELING drugs on genetic information

diagnostics test — identify good respondents

Companion Diagnostics – should be used in Targeted therapies. IGF1, HER2 expression and amplification

PM more important in ONCOLOGY , HepB, Cystic Fibrosis, differential response, CVD – expansion, more to be done

In 2002 — a Program to discuss Genetic information VSDS – New Genomics Program, National Center for Toxicology Research a participants

Translational Scientist are added.

Completion Genome sequencing — push to PM 2011 – Genomics evaluation Team for Safety.

Challenge – Drug, Biologics – interaction need coordination by Agency to discuss challenges and collaboration with out side Group.

Developers of Targeted therapies: Orphan Drugs, Biomarkers – expedited review to promote innovations, fast track breakthrough therapies. Opportunities of Scientist to engage discussion with FDA

 – ALL hands on Deck Approach at FDA – making products available, i.e. SCLC (small cell lung cancer)

Since 2005 – 25 Guidance Reports, i.e., Orphan Drugs and on Companion Diagnostics to be developed in tandem with drug development.

Companion Diagnostics – 3 month review, enforcement and direction – in the framework

FDA — needs to keep up with development in the Diagnostics and in the disease ares.

Illumina – Assays using SNIPS – FDA assesses a shared curated DB on mutation, reduce the review time significantly

FDA – NGS – reference libraries, Genomics Reference and Storage of genomics data

Tools and Capabilities  – support regulatory and science, statistical methods of analysis — implemented for Breast Cancer — signaled the way of new Partnerships and New Clinical Trials formats and methods in its development.

New diagnostics – AMP Program Alzheimer’s Disease, rheumatoid arthritis (RA), inflammatory bowel syndrome (IBS)

What Science is needed for the Regulators to effectively HELP spar innovation.

Pharmacogenomics, Pharmacogenetics — MAPPING the Human Genome and all other areas of “OMICS” – moving from Lab to bedside — requires expertise in Disease prevention, Difference in patients life, Standard medical practice

  • Biology and Pathways
  • Biomarkers
  • New diagnostics
  • Increased communication Universities, new paradigms models and continual effort of SHARING and coordination of shared resources


– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf





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The Role of Medical Imaging in Personalized Medicine

Writer & reporter: Dror Nir, PhD

The future of personalized medicine comprise quantifiable diagnosis and tailored treatments; i.e. delivering the right treatment at the right time. To achieve standardized definition of what “right” means, the designated treatment location and lesion size are important factors. This is unrelated to whether the treatment is focused to a location or general. The role of medical imaging is and will continue to be vital in that respect: Patients’ stratification based on imaging biomarkers can help identify individuals suited for preventive intervention and can improve disease staging. In vivo visualization of loco-regional physiological, biochemical and biological processes using molecular imaging can detect diseases in pre-symptomatic phases or facilitate individualized drug delivery. Furthermore, as mentioned in most of my previous posts, imaging is essential to patient-tailored therapy planning, therapy monitoring, quantification of response-to-treatment and follow-up disease progression. Especially with the rise of companion diagnostics/theranostics (therapeutics & diagnostics), imaging and treatment will have to be synchronized in real-time to achieve the best control/guidance of the treatment.

It is worthwhile noting that the new RECIST 1.1 criteria (used in oncological therapy monitoring) have been expanded to include the use of PET (in addition to lymph-node evaluation).


In previous posts I already discussed many examples concerning the use of medical imaging in personalized medicine: e.g. patients’ stratification; Imaging-biomarkers is Imaging-based tissue characterization, the future of imaging-biomarkers in diagnostic; Ultrasound-based Screening for Ovarian Cancer, imaging-based guided therapies; Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma, treatment follow-up; the importance of spatially-localized and quantified image interpretation in cancer management, and imaging-based assessment of response to treatment; Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging

Browsing through our collaborative open-source initiative one can find many more articles and discussions on that matter; e.g. Tumor Imaging and Targeting: Predicting Tumor Response to Treatment: Where we stand?, In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

In this post I would like to highlight the potential contribution of medical imaging to development of companion diagnostics. I do that through the story on co-development of Vintafolide (EC145) and etarfolatide (Endocyte/Merck). Etarfolatide is a folate-targeted molecular radiodiagnostic imaging agent that identifies tumors that overexpress the folate receptor. The folate receptor, a glycosylphosphatidylinositol anchored cell surface receptor, is overexpressed on the vast majority of cancer tissues, while its expression is limited in healthy tissues and organs. Folate receptors are highly expressed in epithelial, ovarian, cervical, breast, lung, kidney, colorectal, and brain tumors. When expressed in normal tissue, folate receptors are restricted to the lungs, kidneys, placenta, and choroid plexus. In these tissues, the receptors are limited to the apical surface of polarized epithelia. Folate, also known as pteroylglutamate, is a non-immunogenic water-soluble B vitamin that is critical to DNA synthesis, methylation, and repair (folate is used to synthesize thymine).

Vintafolide (EC145) delivers a very potent vinca chemotherapy directly to cancer cells by targeting the folate receptor expressed on cancer cells. Approximately 80-90 percent of ovarian and lung cancers express the receptor, as do many other types of cancer. Clinical data have shown that patients with metastases that are all positive for the folate receptor, identified by etarfolatide, benefited the most from the treatment with vintafolide, the corresponding folate-targeted small molecule drug conjugate.

Having both drug and imaging agent rely on folate receptors within the patients body Endocyte’s strategy was to develop the imaging agent and to use it to accelerate R&D and regulation. Endocyte and Merck entered into a partnership for vintafolide in April 2012. Under this partnership Merck was granted an exclusive license to develop, manufacture and commercialize vintafolide. Endocyte is responsible for conducting the PROCEED Phase 3 clinical study in women with platinum resistant ovarian cancer and the Phase 2b second line NSCLC (non-small cell lung cancer) study named TARGET. Merck is responsible for further clinical studies in additional indications. This Co-development of a diagnostic and therapeutic agent, was conducted according to the FDA guidance on personalized medicine and resulted with vintafolide gaining, already in 2012, status of orphan drug in EMA.


 The following is an extract from a post by Phillip H. Kuo, MD, PhD, associate professor of medical imaging, medicine, and biomedical engineering; section chief of nuclear medicine; and director of PET/CT at the University of Arizona Cancer Center.


Figure 1 — Targeted Radioimaging Diagnostic and Small Molecule Drug Conjugate

Etarfolatide is comprised of the targeting ligand folic acid (yellow), which has a high folate receptor binding affinity, and a Technetium-99m–based radioimaging agent (turquoise). Etarfolatide identifies metastases that express the folate receptor protein in real time (A). The folic acid-targeting ligand is identical to that found on vintafolide, the corresponding therapeutic small molecule drug conjugate, which also contains a linker system (blue) and a potent chemotherapeutic drug (red) (B).



Figure 2 — Whole-Body Scan With 111In-DTPA-Folate 

Diagnostic images of whole-body scans obtained following administration of the targeted radioimaging agent 111In-DTPA-folate, which is constructed with the same folic acid ligand as that engineered in etarfolatide. The healthy patient image on the left shows no folate receptor-positive abdominal tumor. Instead, only healthy kidneys (involved in excretion) are revealed. The patient on the right shows folate receptor-positive tumors in the abdomen and pelvis. Patients with metastases, identified with the companion imaging diagnostic etarfolatide as folate receptor-positive are most likely to respond to treatment with the corresponding small molecular drug conjugate vintafolide. Note: Vintafolide currently is being evaluated in a phase 3 clinical trial for platinum-resistant ovarian cancer and a phase 2 trial for non–small-cell lung cancer. Both studies also are using etarfolatide.


Figure 3 — Vintafolide’s Mechanism of Action

Folate is required for cell division, and rapidly dividing cancer cells often express folate receptors to capture enough folate to support rapid cell growth. Elevated expression of the folate receptor occurs in many human malignancies, especially when associated with aggressively growing cancers. The folate-targeted small molecule drug conjugate vintafolide binds to the folate receptor (A) and subsequently is internalized by a natural endocytosis process (B). Once inside the cell, vintafolide’s serum-stable linker selectively releases a potent vinca alkaloid compound (C) to arrest cell division and induce cell death.


I think that those of you who reached this point in my post deserve a special bonus! So here it is: A medical-imaging initiative that is as ambitious and complex as the initiative to send humans into deep-space.

This is the The European Population Imaging Infrastructure initiative of the Dutch Federation of University Medical Centres (NFU) and the Erasmus University Medical Centre Rotterdam, Department of Radiology, chaired by Professor Gabriel P. Krestin. The NFU has made available initial funding for the development of this initiative.

The European Population Imaging Infrastructure closely cooperates with the European Biomedical Imaging Infrastructure Project EURO-BioImaging which is currently being developed.

The ultimate aim of the infrastructure is to help the development and implementation of strategies to prevent or effectively treat disease. It supports imaging in large, prospective epidemiological studies on the population level. Image specific markers of pre-symptomatic diseases can be used to investigate causes of pathological alterations and for the early identification of people at risk.

More information on this infrastructure and on the role of the European Population Imaging Infrastructure in this can be found in the Netherlands Roadmap for Large-Scale Research Facilities, the applicaton for funding of the Roadmap Large Scale Research Facilities Application form of the Roadmap EuroBioImaging, and on the Euro-BioImaging website.

Certainly, while making progress with this initiative, many lessons will be learned. I recommend to explore this site and Enjoy!

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