Posts Tagged ‘early diagnosis’

UPDATED Previously undiscerned value of hs-troponin

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


UPDATED on 5/1/2019

High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study

Originally published ;0

Background: We assessed whether plasma troponin I measured by a high-sensitivity assay (hs-TnI) is associated with incident cardiovascular disease (CVD) and mortality in a community-based sample without prior CVD.

Methods: ARIC study (Atherosclerosis Risk in Communities) participants aged 54 to 74 years without baseline CVD were included in this study (n=8121). Cox proportional hazards models were constructed to determine associations between hs-TnI and incident coronary heart disease (CHD; myocardial infarction and fatal CHD), ischemic stroke, atherosclerotic CVD (CHD and stroke), heart failure hospitalization, global CVD (atherosclerotic CVD and heart failure), and all-cause mortality. The comparative association of hs-TnI and high-sensitivity troponin T with incident CVD events was also evaluated. Risk prediction models were constructed to assess prediction improvement when hs-TnI was added to traditional risk factors used in the Pooled Cohort Equation.

Results: The median follow-up period was ≈15 years. Detectable hs-TnI levels were observed in 85% of the study population. In adjusted models, in comparison to low hs-TnI (lowest quintile, hs-TnI ≤1.3 ng/L), elevated hs-TnI (highest quintile, hs-TnI ≥3.8 ng/L) was associated with greater incident CHD (hazard ratio [HR], 2.20; 95% CI, 1.64-2.95), ischemic stroke (HR, 2.99; 95% CI, 2.01-4.46), atherosclerotic CVD (HR, 2.36; 95% CI, 1.86-3.00), heart failure hospitalization (HR, 4.20; 95% CI, 3.28-5.37), global CVD (HR, 3.01; 95% CI, 2.50-3.63), and all-cause mortality (HR, 1.83; 95% CI, 1.56-2.14). hs-TnI was observed to have a stronger association with incident global CVD events in white than in black individuals and a stronger association with incident CHD in women than in men. hs-TnI and high-sensitivity troponin T were only modestly correlated (r=0.47) and were complementary in prediction of incident CVD events, with elevation of both troponins conferring the highest risk in comparison with elevation in either one alone. The addition of hsTnI to the Pooled Cohort Equation model improved risk prediction for atherosclerotic CVD, heart failure, and global CVD.

Conclusions: Elevated hs-TnI is strongly associated with increased global CVD incidence in the general population independent of traditional risk factors. hs-TnI and high-sensitivity troponin T provide complementary rather than redundant information.


* Corresponding Author; email: 


UPDATED on 8/14/2018

Siemens Launches High-sensitivity Troponin Test for Faster Diagnosis of Heart Attacks

The new troponin I assays can detect lower levels of troponin compared to conventional testing

July 25, 2018 — The U.S. Food and Drug Administration (FDA) cleared Siemens Healthineers high-sensitivity troponin I assays (TnIH) for the Atellica IM and ADVIA Centaur XP/XPT in vitro diagnostic analyzers from Siemens Healthineers to aid in the early diagnosis of myocardial infarctions.

The new tests can shorten the time doctors need to diagnose a life-threatening heart attacks. The time to first results is 10 minutes. When a patient experiencing chest pain enters the emergency department, a physician orders a blood test to determine whether troponin is present. As blood flow to the heart is blocked, the heart muscle begins to die in as few as 30 to 60 minutes and releases troponin into the bloodstream.

The company said its high-sensitivity performance of the two new Siemens TnIH assays offers the ability to detect lower levels of troponin at significantly improved precision at the 99th percentile, and detect smaller changes in a patient’s troponin level as repeat testing occurs. This design affords clinicians greater confidence in the results with precision that provides the ability to measure slight, yet critical, changes to begin treatment.[1,2]

Chest pain is the cause of more than 8 million visits annually nationwide to emergency departments, but only 5.5 percent of those visits lead to serious diagnoses such as heart attacks.[3] Armed with data to properly triage patients sooner or to exclude myocardial infarctions, the Siemens Healthineers TnIH assays can help support testing initiatives tied to improving patient experience.

“Our emergency department is overcrowded with patients. If we can do a more efficient job at triaging patients to receive the proper level of care and to discharge the patients who do not need to stay in the emergency department, this will have a tremendous economic advantage for our healthcare system,” said Alan Wu, M.D., chief of clinical chemistry and toxicology at Zuckerberg San Francisco General Hospital and Trauma Center.

Siemens is launching the product at the 70th AACC Annual Scientific Meeting and Clinical Lab Expo taking place July 31 to Aug. 2 in Chicago.

For more information:

Watch the related VIDEO: Use of High Sensitivity Troponin Testing in the Emergency Department — Interview with James Januzzi, M.D., Massachusetts General Hospital



1. Eggers K, Jernberg T, Ljung L, Lindahl B. High-Sensitivity Cardiac Troponin-Based Strategies for the Assessment of Chest Pain Patients—A Review of Validation and Clinical Implementation Studies. Clin Chem. 2018;64(7). DOI: 10.1373/clinchem.2018.287342

2. Collinson P. High-sensitivity troponin measurements: challenges and opportunities for the laboratory and the clinician. Annals of Clinical Biochemistry. 2016;53(2) 191–195. DOI: 10.1177/0004563215619946

3. Hsia RY, Hale Z, Tabas JA. A National Study of the Prevalence of Life-Threatening Diagnoses in Patients With Chest Pain. JAMA Intern Med. 2016;176(7):1029–1032. DOI:10.1001/jamainternmed.2016.2498



Troponin Rise Predicts CHD, HF, Mortality in Healthy People: ARIC Analysis

Veronica Hackethal, MD

Increases in levels of cardiac troponin T by high-sensitivity assay (hs-cTnT) over time are associated with later risk of death, coronary heart disease (CHD), and especially heart failure in apparently healthy middle-aged people, according to a report published June 8, 2016 in JAMA Cardiology[1].

The novel findings, based on a cohort of >8000 participants from the Atherosclerosis Risk in Communities (ARIC) study followed up to 16 years, are the first to show “an association between temporal hs-cTnT change and incident CHD events” in asymptomatic middle-aged adults,” write the authors, led by Dr John W McEvoy (Johns Hopkins University School of Medicine, Baltimore, MD).

Individuals with the greatest troponin increases over time had the highest risk for poor cardiac outcomes. The strongest association was for risk of heart failure, which reached almost 800% for those with the sharpest hs-cTnT rises.

Intriguingly, those in whom troponin levels fell at least 50% had a reduced mortality risk and may have had a slightly decreased risk of later HF or CHD.

“Serial testing over time with high-sensitivity cardiac troponins provided additional prognostic information over and above the usual clinical risk factors, [natriuretic peptide] levels, and a single troponin measurement. Two measurements appear better than one when it comes to informing risk for future coronary heart disease, heart failure, and death,” McEvoy told heartwire from Medscape.

He cautioned, though, that the conclusion is based on observational data and would need to be confirmed in clinical trials. Moreover, high-sensitivity cardiac troponin assays are widely used in Europe but are not approved in the US.

An important next step after this study, according to an accompanying editorial from Dr James Januzzi (Massachusetts General Hospital, Boston, MA), would be to evaluate whether the combination of hs-troponin and natriuretic peptides improves predictive value in this population[2].

“To the extent prevention is ultimately the holy grail for defeating the global pandemic of CHD, stroke, and HF, the main reason to do a biomarker study such as this would be to set the stage for a biomarker-guided strategy to improve the medical care for those patients at highest risk, as has been recently done with [natriuretic peptides],” he wrote.

The ARIC prospective cohort study entered and followed 8838 participants (mean age 56, 59% female, 21.4% black) in North Carolina, Mississippi, Minneapolis, and Maryland from January 1990 to December 2011. At baseline, participants had no clinical signs of CHD or heart failure.

Levels of hs-cTnT, obtained 6 years apart, were categorized as undetectable (<0.005 ng/mL), detectable (≥0.005 ng/mL to <0.014 ng/mL), and elevated (>0.014 ng/mL).

Troponin increases from <0.005 ng/mL to 0.005 ng/mL or higher independently predicted development of CHD (HR 1.41; 95% CI 1.16–1.63), HF (HR 1.96; 95% CI 1.62–2.37), and death (HR 1.50; 95% CI 1.31–1.72), compared with undetectable levels at both measurements.

Hazard ratios were adjusted for age, sex, race, body-mass index, C-reactive protein, smoking status, alcohol-intake history, systolic blood pressure, current antihypertensive therapy, diabetes, serum lipid and cholesterol levels, lipid-modifying therapy, estimated glomerular filtration rate, and left ventricular hypertrophy.

Subjects with >50% increase in hs-cTnT had a significantly increased risk of CHD (HR 1.28; 95% CI 1.09–1.52), HF (HR 1.60; 95% CI 1.35–1.91), and death (HR 1.39; 95% CI 1.22–1.59).

Risks for those end points fell somewhat for those with a >50% decrease in hs-cTnT (CHD: HR 0.47; 95% CI 0.22–1.03; HF: HR 0.49 95% CI 0.23–1.01; death: HR 0.57 95% CI 0.33–0.99).

Among participants with an adjudicated HF hospitalization, the group writes, associations of hs-cTnT changes with outcomes were of similar magnitude for those with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).

Few biomarkers have been linked to increased risk for HFpEF, and few effective therapies exist for it. That may be due to problems identifying and enrolling patients with HFpEF in clinical trials, Dr McEvoy pointed out.

“We think the increased troponin over time reflects progressive myocardial injury or progressive myocardial damage,” Dr McEvoy said. “This is a window into future risk, particularly with respect to heart failure but other outcomes as well. It may suggest high-sensitivity troponins as a marker of myocardial health and help guide interventions targeting the myocardium.”

Moreover, he said, “We think that high-sensitivity troponin may also be a useful biomarker along with [natriuretic peptides] for emerging trials of HFpEF therapy.”

But whether hs-troponin has the potential for use as a screening tool is a question for future studies, according to McEvoy.

In his editorial, Januzzi pointed out several implications of the study, including the possibility for lowering cardiac risk in those with measurable hs-troponin, and that HF may be the most obvious outcome to target. Also, optimizing treatment and using cardioprotective therapies may reduce risk linked to increases in hs-troponin. Finally, long-term, large clinical trials on this issue will require a multidisciplinary team effort from various sectors.

“What is needed now are efforts toward developing strategies to upwardly bend the survival curves of those with a biomarker signature of risk, leveraging the knowledge gained from studies such as the report by McEvoy et al to improve public health,” he concluded.



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Chemotherapy Benefit in Early Breast Cancer Patients

Larry H Bernstein, MD, FCAP, Curator



Agendia’s MammaPrint® First and Only Genomic Assay to Receive Level 1A Clinical Utility Evidence for Chemotherapy Benefit in Early Breast Cancer Patients

  • Clinical high-risk patients with a low-risk MammaPrint® result, including 48 percent node-positive, had five-year distant metastasis-free survival rate in excess of 94 percent, whether randomized to receive adjuvant chemotherapy or not
  • MammaPrint could change clinical practice by substantially de-escalating the use of adjuvant chemotherapy and sparing many patients an aggressive treatment they will not benefit from
  • Forty-six percent overall reduction in chemotherapy prescription among clinically high-risk patients

April 19, 2016 / B3C newswire / Agendia, Inc., together with the European Organisation for Research and Treatment of Cancer (EORTC) and Breast International Group (BIG), announced results from the initial analysis of the primary objective of the Microarray In Node-negative (and 1 to 3 positive lymph node) Disease may Avoid ChemoTherapy (MINDACT) study at the American Association for Cancer Research Annual Meeting 2016 in New Orleans, LA.

Using the company’s MammaPrint® assay, patients with early-stage breast cancer who were considered at high risk for disease recurrence based on clinical and biological criteria had a distant metastasis-free survival at five years in excess of 94 percent.The MammaPrint test—the first and only genomic assay with FDA 510(k) clearance for use in risk assessment for women of all ages with early stage breast cancer—identified a large group of patients for whom five-year distant metastasis–free survival was equally good whether or not they received adjuvant chemotherapy (chemotherapy given post-surgery).

“The MINDACT trial design is the optimal way to prove clinical utility of a genomic assay,” said Prof. Laura van ’t Veer, CRO at Agendia, Leader, Breast Oncology Program, and Director, Applied Genomics at UCSF Helen Diller Family Comprehensive Cancer Center. “It gives the level 1A clinical evidence (prospective, randomized and controlled) that empowers physicians to clearly and confidently know when chemotherapy is part of optimal early-stage breast cancer therapy.  In this trial, MammaPrint (70-gene assay) was compared to the standard of care physicians use today, to decide what is the best treatment option for an early-stage breast cancer patient.”

The MINDACT trial is the first prospective randomized controlled clinical trial of a breast cancer recurrence genomic assay with level 1A clinical evidence and the first prospective translational research study of this magnitude in breast cancer to report the results of its primary objective.

Among the 3,356 patients enrolled in the MINDACT trial, who were categorized as having a high risk of breast cancer recurrence based on common clinical and pathological criteria (C-high), the MammaPrint assay reduced the chemotherapy treatment prescription by 46 percent.Using the 70-gene assay, MammaPrint, 48 percent of lymph-node positive breast cancer patients considered clinically high-risk (Clinical-high) and genomic low-risk (MammaPrint-low) had an excellent distant metastasis-free survival at five years in excess of 94 percent.

“Traditionally, physicians have relied on clinical-pathological factors such as age, tumor size, tumor grade, lymph node involvement, and hormone receptor status to make breast cancer treatment decisions,” said Massimo Cristofanilli, MD, Associate Director of Translational Research and Precision Medicine at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University in Chicago. “These findings provide level 1A clinical utility evidence by demonstrating that the detection of low-risk of distant recurrence reported by the MammaPrint test can be safely used in the management of thousands of women by identifying those who can be spared from a toxic and unnecessary treatment.”

MINDACT is a randomized phase III trial that investigates the clinical utility of MammaPrint, when compared (or – “used in conjunction with”) to the standard clinical pathological criteria, for the selection of patients unlikely to benefit from adjuvant chemotherapy. From 2007 to 2011, 6,693 women who had undergone surgery for early-stage breast cancer enrolled in the trial (111 centers in nine countries). Participants were categorized as low or high risk for tumor recurrence in two ways: first, through analysis of tumor tissue using MammaPrint at a central location in Amsterdam; and second, using Adjuvant! Online, a tool that calculates risk of breast cancer recurrence based on common clinical and biological criteria.

Patients characterized in both clinical and genomic assessments as “low- risk” are spared chemotherapy, while patients characterized as “high- risk” are advised chemotherapy. Those with conflicting results are randomized to use either clinical or genomic risk (MammaPrint) evaluation to decide on chemotherapy treatment.

The MINDACT trial is managed and sponsored by the EORTC as part of an extensive and complex partnership in collaboration with Agendia and BIG, and many other academic and commercial partners, as well as patient advocates.

“These MINDACT trial results are a testament that the science of the MammaPrint test is the most robust in the genomic breast recurrence assay market.  Agendia will continue to collaborate with pharmaceutical companies, leading cancer centers and academic groups on additional clinical research and in the pursuit of bringing more effective, individualized treatments within reach of cancer patients,” said Mark Straley, Chief Executive Officer at Agendia. “We value the partnership with the EORTC and BIG and it’s a great honor to share this critical milestone.”

Breast cancer is the most frequently diagnosed cancer in women worldwide(1). In 2012, there were nearly 1.7 million new breast cancer cases among women worldwide, accounting for 25 percent of all new cancer cases in women(2).

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Author: Ziv Raviv, PhD


Cancer is one of the top causes of death in the Western world and one of the emergence outcomes of modern society after the industrial era. In high-income countries more than two thirds of all people live beyond the age of 70 and many of them die of chronic diseases e.g., cardiovascular disease, chronic lung disease, cancers, diabetes or dementia. It would not be wrong to assume that cancer was always there, yet now in the modern era it is only much more manifested and very common. The reasons of cancer being a new epidemic lies within several concepts: (i) the overall increase in life expectancy of human population, especially in the Western world, which is a consequence of better hygienic conditions and health care systems, that dealt well with old times epidemics,  altogether expose “modern epidemics” where cancer is one of them as stated. Indeed, many types of cancer are of elderly population; (ii) the excess exposure to environmental hazardous materials and factors (e.g., air pollution, tobacco products, sun irradiation, asbestos etc); and (iii) the life style that characterizes modern life i.e., the consistence being of man in the Western society under stress conditions. For nearly a half century there has been a worldwide war on cancer. Much capital has been spent while still millions of lives were lost from cancer. Yet with all this effort little has changed in this battle and the rate of cancer remained constant. Moreover, despite many drugs developed to treat cancer after it has already developed, there is still no change in the amount of people that will actually develop cancer. Thus our approach of fighting cancer should be changed.

Much research effort is spent over the genetic background of cancer. The genetic factor was always there probably and what has been changed is the environment, namely the interactions between the genetic grounds with socio-environmental causes are the factors that have been changed. Thus the new scientific approach in cancer research should consists a broad perspective that will integrate all risk factors, internal as well as external, in order that a great portion of cancer research effort would be directed toward the interaction between socio-environment causes and genetics. The best example should come from lung cancers. It is most prevalent that smoking tobacco products has an undoubtedly direct initiation effect on most of lung cancer types i.e., tobacco smoking is the very common cause among many lung cancer patients. Tobacco smoking became common in the last century and there is a direct and clear correlation between lung cancer incidence and smoking, supporting the notion that lung cancer is a modern disease that arose from modern life style behavior (smoking) and environmental factors (passive smoking). Indeed, not every smoker gets lung cancer and there are many types of lung cancers with various severities. This is the place where genetics play a role. Thus, understanding the relationship between genetic and socio-environmental risk factors could assist fighting lung cancer. Prevention of smoking is the most cost-effective means of fighting lung cancer; however, tobacco smoking is still widespread. Thus there are also psychological considerations that have to be taken in account when coming to deal with the issue of treating tobacco-dependent lung cancer.

Along the history of cancer research , the major efforts were taken in the rode of understanding the molecular mechanisms of tumorigenesis and its genetic background. From the single cell level molecular mechanism of deregulation of intracellular signaling and factors that control the cell fate, through the mechanisms of cancer metastasis, back to cancer stem cells and forward to tumors microenvironment and the relationships of cancer with the immune system. These efforts have tremendous importance on understanding the biology of cancer and had led, and further will, to the development of anti-cancer treatments. However, since cancer is a very complex disease, where multiple intracellular and systematical factors are orchestrated, the benefits of single agent therapy developed from the ever efforts of cancer research is very limited. Modern concept in anti-cancer therapy is the personalized medicine approach, where in an ideal condition a person would undergo a genetic test for his tumor to realize what are the genetic and molecular essences of his disease, and following that, to make a tailor-made anti-cancer regimen. With the modern tools of genetics and gene sequencing, it should be readily to perform such genetic (and epigenetic) screens. However, it is not certain that specific drug(s) aimed to deal with these genetic/molecular moieties would be available in the foreseeing time. In addition, in such screening the genetic signature of cancer is obtained after the tumor is already established.

Many socio-environmental causes for cancer are known, although this knowledge is not always estimated correctly to its full extent and implication on cancer therapy. Cancer research in its current platform is extremely expensive. Developing new drugs are highly costly, take many years to develop and are complicated to produce. Thus cancer prevention programs are extremely essential to be developed as a better general cancer therapy approach. It is not hard to envisage how the reducing of cancer incidences is very economical in terms of hospitalization days and costs of drugs that are being paid from governmental subsidies. It is by far much more chipper to invest finance and efforts on cancer prevention programs. Such agenda should include educative programs aimed for teenagers and the overall population, together with plans for good dietary and relaxed life style; increasing the population awareness of environmental hazardous that can causes cancer; raising taxes on cigarettes and enforcing anti-smokers rules and regulations; enforcement of industrial anti-pollution regulations; developing and supporting anti-cancer vaccinations research and development; encouraging people to carry out routine checks for early detection of cancer and of genetic background that should be conducted in prevention centers in hospitals and within the community.

An inseparable matter embedded well under the big umbrella called cancer prevention programs is the continuous search for cancer biomarkers. As early detection is crucial to positive cancer prognosis, the need of finding, developing, and establishing detection methods for the identification of cancer biomarkers is priceless. Developing such tools of early detection would be very helpful in preventing cancer or at least favoring the chances of complete cure. An ideal cancer biomarker should be detectable upon routine blood tests, yet that is not always possible. By early detection of the disease early signs, much capital could be saved on hospitalization days and expensive and inefficient treatment of advanced staged cancer patients.

Major resistance to such comprehensive cancer prevention programs could come up from the pharmaceutical companies and from cancer research scientists, as much of the research and developing and costs efforts would be lost. It is not suggested herein to abandon completely the ongoing contemporary cancer research efforts, yet it is a wishful thinking that there will be a shift in the research of cancer toward the integration of prevention and basic cancer research, a matter that should yield better treatments and reducing cancer incidences. Moreover, shifting into cancer prevention-directed research could bring also prosperity to the drug companies as new treatments such as vaccinations to cancer would be developed. It is hard to perceive in present times the world without the vaccination to papillomavirus (HPV) that prevents many incidences of cervical cancer. The companies developed and selling these vaccinations surly had made fortune out of it.

In summary, developing new comprehensive prevention programs would be beneficial hence to the patients, the society and governmental authorities, reducing the burden of cancer incidences and the terrible consequences of this awful disease on human society.

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The Incentive for “Imaging based cancer patient’ management”

Author and Curator: Dror Nir, PhD

It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on “smart imaging” applications. These could be accompanied by highly sensitive and specific bio-markers, which are expected to be delivered by pharmaceutical companies in the upcoming decade. In the context of this post, smart imaging refers to imaging systems that are enhanced with tissue characterization and computerized image interpretation applications. It is expected that such systems will enable gathering of comprehensive clinical information on cancer tumors, such as location, size and rate of growth.

What is the main incentive for promoting cancer patients’ management based on smart imaging? 

It promises to enable personalized cancer patient management by providing the medical practitioner with a non-invasive and non-destructive tool to detect, stage and follow up cancer tumors in a standardized and reproducible manner. Furthermore, applying smart imaging that provides valuable disease-related information throughout the management pathway of cancer patient will eventually result in reducing the growing burden of health-care costs related to cancer patients’ treatment.

Let’s briefly review the segments that are common to all cancer patients’ pathway: screening, treatment and costs.


Screening for cancer: It is well known that one of the important factors in cancer treatment success is the specific disease staging. Often this is dependent on when the patient is diagnosed as a cancer patient. In order to detect cancer as early as possible, i.e. before any symptoms appear, leaders in cancer patients’ management came up with the idea of screening. To date, two screening programs are the most spoken of: the “officially approved and budgeted” breast cancer screening; and the unofficial, but still extremely costly, prostate cancer screening. After 20 years of practice, both are causing serious controversies:

In trend analysis of WHO mortality data base [1], the authors, Autier P, Boniol M, Gavin A and Vatten LJ, argue that breast cancer mortality in neighboring European countries with different levels of screening but similar access to treatment is the same: “The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality”.

In prostate cancer mortality at 11 years of follow-up [2],  the authors,Schröder FH et. al. argue regarding prostate cancer patients’ overdiagnosis and overtreatment: “To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected”.

The lobbying campaign (see picture below)  that AdmeTech ( is conducting in order to raise the USA administration’s awareness and get funding to improve prostate cancer treatment is a tribute to patients’ and practitioners’ frustration.




Treatment: Current state of the art in oncology is characterized by a shift in  the decision-making process from an evidence-based guidelines approach toward personalized medicine. Information gathered from large clinical trials with regard to individual biological cancer characteristics leads to a more comprehensive understanding of cancer.

Quoting from the National cancer institute ( website: “Advances accrued over the past decade of cancer research have fundamentally changed the conversations that Americans can have about cancer. Although many still think of a single disease affecting different parts of the body, research tells us through new tools and technologies, massive computing power, and new insights from other fields that cancer is, in fact, a collection of many diseases whose ultimate number, causes, and treatment represent a challenging biomedical puzzle. Yet cancer’s complexity also provides a range of opportunities to confront its many incarnations”.

Personalized medicine, whether it uses cytostatics, hormones, growth inhibitors, monoclonal antibodies, and loco-regional medical devices, proves more efficient, less toxic, less expensive, and creates new opportunities for cancer patients and health care providers, including the medical industry.

To date, at least 50 types of systemic oncological treatments can be offered with much more quality and efficiency through patient selection and treatment outcome prediction.

Figure taken from presentation given by Prof. Jaak Janssens at the INTERVENTIONAL ONCOLOGY SOCIETY meeting held in Brussels in October 2011

For oncologists, recent technological developments in medical imaging-guided tissue acquisition technology (biopsy) create opportunities to provide representative fresh biological materials in a large enough quantity for all kinds of diagnostic tests.


Health-care economics: We are living in an era where life expectancy is increasing while national treasuries are over their limits in supporting health care costs. In the USA, of the nation’s 10 most expensive medical conditions, cancer has the highest cost per person. The total cost of treating cancer in the U.S. rose from about $95.5 billion in 2000 to $124.6 billion in 2010, the National Cancer Institute ( estimates. The true sum is probably higher as this estimate is based on average costs from 2001-2006, before many expensive treatments came out; quoting from : “new drugs often cost $100,000 or more a year. Patients are being put on them sooner in the course of their illness and for a longer time, sometimes for the rest of their lives.”

With such high costs at stake, solutions to reduce the overall cost of cancer patients’ management should be considered. My experience is that introducing smart imaging applications into routine use could contribute to significant savings in the overall cost of cancer patients’ management, by enabling personalized treatment choice and timely monitoring of tumors’ response to treatment.



  1. 1.      BMJ. 2011 Jul 28;343:d4411. doi: 10.1136/bmj.d4411
  2. 2.      (N Engl J Med. 2012 Mar 15;366(11):981-90):

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A model approach

Larry H. Bernstein, MD

Executive Summary:

Sepsis is the most costly diagnosis in hospitalized patients and carries a high financial risk as a comorbidity and payment penalty under the new severity of illness CMS reimbursement guidelines as a patient safety hazard for failure to diagnose in a timely manner.  We carried out two studies of the early recognition of sepsis and related diseases in patients seen in the emergency department related to admission to the intensive care unit (ICU)(New YorkMethodistHospital) under the leadership of Lawrence Melniker, MD, Chairman of the Pharmacy and Therapeutics Committee.  The widely used SIRS criteria and the C-reactive protein, a long established acute phase protein, are each by themselves insufficient because of the low false negative rate of the former and the skewness and long tail of the latter related to uncurtailed noise from inconsequential inflammatory disease.  Using the elevated neutrophil count and left shift has proved to be elusive as well.  We and many others have established the validity of the European studies showing a marked benefit from using the procalcitonin (PCT, Brahms), and we propose to seize on the opportunity to calibrate the measurement of granulocyte maturation to the PCT.  The study would have to be carried out on a Sysmex instrument for accuracy and ease of use.  The Sysmex IG parameter is a measure of immature granulocyte counts and includes metamyelocytes, myelocytes and promyelocytes.

Background Study

Neutrophils thought to play a significant role in the early microvascular changes, are thought to be a key factor in the evolution of organ failure in the pathogenesis of severe sepsis and septic shock.  The mechanism of action of any drug or combination antibiotic combination therapy could potentially influence IG responses so that IG may be a useful way to monitor responses to therapy and disease progression by a simple, widely used hemocytometer that incorporates flow cytometry for cell identification.

An evaluation of the diagnostic performance of the Sysmex IG parameter and the procalcitonin (PCT, Brahms) assays when compared to existing practices and treatment decision guidelines is proposed following the establishment of a validated of a critical-decision cutoff for patients over 6 years old of 2.8% +0.2%.  Statistically significant numbers of samples representing the following patient groups would be assessed:

Group 1: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and do not fulfill criteria that warrant treatment with  antibiotic for the assessed state.

Group 2: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and are placed on antibiotic therapy (Infection) as a result of the investigation.

Group 3: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and are classified as having SIRS (Systemic Inflammatory Response Syndrome according to the equivalent of New York Methodist Hospital classification of SEPSIS (based on a modified Xigris (discontinue by Lilly) screening criteria, irrespective of the treatment option followed.

Group 4: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and have evidence of organ failure (New York Methodist Hospital classification of SEVERE SEPSIS; Xigris screening criteria for ACUTE ORGAN DYSFUNCTION.)

Diagnostic performance of both the Sysmex IG parameter and the procalcitonin (PCT, Brahms) assays are to be assessed as tools for sub-classification according to existing practices.

The ability of the IG parameter to detect the myeloid response associated prior to and increased with the onset of microvascular damage will be assessed. The potential to detect the IG response to predict progression towards multiple organ dysfunction could be an indication to initiate pharmacological therapy at a stage prior to significant evidence of organ failure.

The potential to use the IG parameter as a tool for monitoring responses to antibiotic and single or combination therapy could be assessed if the increase in IG shows good diagnostic performance alone or in combination as a necessary feature for decision-making.




GROUP 2: INFECTION–Does your patient have one or more of the following infection criteria?

  • Documented or Suspected–Does the patient have positive culture results (from blood, sputum, urine, etc.)?
  • Anti-Infective Therapy–Is the patient receiving antibiotic, antifungal, or other anti-infective therapy?
  • Pneumonia–Is there documentation of pneumonia (x-ray, etc.)?
  • WBCs–Have WBCs been found in normally sterile fl uid (urine, CSF, etc.)?
  • Perforated Viscus–Does the patient have perforated hollow organ (bowel)?
  • GROUP 3: SIRS-Does your patient have two or more of the following SIRS criteria?
  • Temperature–Is the patient’s temperature > 38°C (> 100.4°F) or < 36°C (< 96.8°F)?
  • Heart Rate–Is the patient’s heart rate > 90 bpm?
  • Respiratory Rate–Is the patient’s respiratory rate > 20 breaths/min?
  • WBC Count–Is the patient’s WBC count > 12,000/mm3, < 4000/mm3, absolute neutrophil count > 11,000/mm3, or are there > 2.8% immature granulocytes (myelocytes and metamyelocytes) discounting 10% band neutrophils and the less mature promyelocytes for left shift?
  • GROUP 4: ACUTE ORGAN DYSFUNCTION-Does your patient have one or more of the following organ dysfunction critera?
  • Cardiovascular–Does the patient have a systolic BP ≤ 90 mmHg or mean arterial pressure ≤ 70 mmHg (for at least 1 hour despite fl uid resuscitation) or require vasopressor support?
  • Respiratory–Does the patient have a PaO2/FiO2 ratio ≤ 250, PEEP > 7.5 or require mechanical ventilation?
  • Renal–Does the patient have low urine output (eg, <0.5 mL/kg/hr for 1 hour despite adequate fl uid rescuscitation),
  • increased creatinine (>50% increase from baseline) or require acute dialysis?
  • Hematologic–Does the patient have a low platelet count (< 100,000/mm3) or PT/PTT > upper limit of normal?
  • Metabolic–Does the patient have a low pH with high lactate (eg, pH < 7.30 and plasma lactate > upper limit of normal?
  • Hepatic–Are the patient’s liver enzymes > 2x upper limit of normal?
  • CNS-Does the patient have altered consciousness or reduced Glasgow Coma Score?

Guidelines For Management

Sepsis, Severe Sepsis, and Septic Shock

A. Definitions


Presence or Suspicion of infection and one or more of the following conditions

  • Fever (core temperature >38.3°C)
  • Hypothermia (core temperature <36°C)
  • Heart rate >90/min or >2 SD above the normal value for age
  • Tachypnea > 20/min or >2 SD above the normal value for age
  • Altered mental status
  • Leukocytosis (WBC count >12,000/µL)
  • Leukopenia (WBC count <4000/µL)
  • Neutrophilia as defined above
  • Normal WBC count with >2.8% immature granulocytes (IG)


Severe Sepsis

Sepsis and at least one New Organ Dysfunction

Organ dysfunction variables:

  • Altered level of consciousness or reduced Glasgow coma score
  • Arterial hypoxemia (PaO2/FIO2 <300)
  • Acute oliguria – urine output <0.5 mL/kg/hr)
  • Creatinine > 2.0 mg/dL or > 50% increase from baseline
  • Coagulation abnormalities (INR >1.5 or aPTT >60 secs)
  • Thrombocytopenia (Platelet count <100,000/µL)
  • Hyperbilirubinemia (Plasma total bilirubin > 2.0 mg/dL or 35 mmol/L)


Tissue perfusion variables:

  • Hyperlactatemia (>2 mmol/L)
  • Metabolic acidosis  ( pH < 7.30)


Hemodynamic variables:

  • Transient arterial hypotension (SBP <90, MAP <70, or SBP decrease >40 mm Hg from baseline) (Hypotension corrected with adequate volume resuscitation)


Septic Shock

Severe Sepsis and Persistent Arterial Hypotension

Screening Tool for Sepsis

Emergency Department, Med-Surg Floors, and Critical Care Units


1. Is the patient’s history suggestive of a NEW infection?                                                             ___ Yes ___No


[Check any that apply]

Pneumonia or Empyema

(  )

Skin/soft tissue infection

(  )

Urinary tract infection

(  )

Wound infection

(  )

Acute abdominal infection

(  )

Bone/joint infection

(  )


(  )

Bloodstream catheter

(  )


(  )

Implantable device

(  )


(  )



2. Are any two of the following signs, symptoms, or findings of infection

*both* – Present and New – to the patient?                                                                                    ___ Yes ___No


[Check any that apply]


> 38.3 °C (101.0 oF)


< 36 °C     (96.8°F)

(  )

(  )


(WBC count >12,000/µL)


(WBC count <4000/µL)

(  )

(  )

Tachycardia > 90 bpm

Tachypnea > 20 bpm

Altered mental status

(  )

(  )

(  )


(serum glucose >120 mg/dL

– in the absence of diabetes)

(  )

If The Answer Is “YES” To BOTH Questions 1 And 2,




  • Immediately obtain:
    • CBC with differential
    • Comprehensive metabolic panel
    • Procalcitonin
    • C-reative protein (CRP)
    • Lactate level
    • ABG
    • Blood cultures
    • Liver function tests
    • Coagulation profile
    • Urine analysis
    • CXR
    • Pulse co-oximetry

3. Are any of the following organ dysfunctioncriteria *both* – Present & New – in an organ remote from the site of the infection? 

___ Yes ___No



Organ Dysfunction Criteria


  • SBP < 90 mmHg or MAP < 65 mmHg
  • SBP decrease > 40 mm Hg from baseline
  • Bilateral pulmonary infiltrates with a:
New or increased O2 supplementation requirement to maintain SpO2 > 90%   OR
  • PaO2/FiO2 ratio < 300
  • Creatinine > 2.0 mg/dl (176.8 mmol/L)
  • Urine Output < 0.5 ml/kg/hour for > 2 hours
  • Bilirubin > 2 mg/dl (34.2 mmol/L)
  • Platelet count < 100,000
  • Coagulopathy (INR >1.5 or aPTT >60 secs)
  • Lactate > 2 mmol/L (18.0 mg/dl)

Note: the remote organ stipulation is waived in the case of bilateral pulmonary infiltrates


If suspicion of infection AND organ dysfunctionare present,

the patient meets the criteria for SEVERE SEPSIS


èInitiate severe sepsis protocol to achieve these goals <6 hrs



6-Hr Goals for Severe Sepsis
1)    Mean arterial pressure > 65 mm of Hg
2)    Urine output > 0.5 ml/kg/hr [average sized adult > 30-40 cc/hr]
3)    CVP > 8-10 mm Hg or Sonographic Signs of adequate filling pressures
4)    SVO2 > 70%

Early Goal-Directed Therapy for Severe Sepsis

[For Emergency Department / Med-Surg Floors / Critical Care Medicine settings]


First 6 hrs


  • Severe sepsis identified by screening                 Yes                  No
  • Blood cultures sent                                           Yes                  No
  • Serum lactate sent                                             Yes                 No
  • Patient hypotensive with
    • Systolic Blood Pressure <90 or                   Yes                  No
    • Mean Arterial Pressures < 65 mm of Hg     Yes                  No

0 – 1 hr Management

1)      Start fluid bolus normal saline 20 ml/kg at 500 – 1000ml over 30 minutes and re-evaluate blood pressure and urine output (expected value >0.5ml/kg/hr)

2)      Re-evaluate 10 minutes after fluid bolus

3)      If blood pressure is stabilized, continue fluids at maintenance rate [No CVP Monitoring Needed]

4)      O2 supplementation to maintain SaO2 > 90% — ventilatory support, if indicated

1 – 2 hrs Management

5)      If patient remains hypotensive [Med-Surg MUST Call for CVP Monitoring Approval]

  • ABG, if not done already
  • Measure CVP or Sonographic Signs of adequate filling pressure:                                           When possible:
    • Central Venous Catheterization with
    • Central Venous Pressure Transducer/Monitor



For CVP < 8-10 mm Hg and MAP < 65 mm Hg


  • Repeat fluid bolus 20 ml/kg at 500 –1000 ml over 30 minutes until:
    • Patient has CVP > 8-10 mm Hg
      • Continue fluid boluses to correct CVP > 8-10 mm Hg


  • Signs of volume overload on physical examination
  • If patient is unstable
    • May start norepinephrine infusion at this time

For CVP > 8-10 mm Hg and MAP < 65 mm Hg


  • Start norepinephrine infusion to achieve MAP >65 mm Hg


1 – 2 hrs Management (continued)


6)      Stat antibiotics (suggested agents – adjust for creatinine clearance)


  1. a.      Community Acquired Pneumonia  – Follow hospital protocol
  2. b.      Healthcare Associated Pneumonia – Follow hospital protocol
  3. Urinary tract infection (choose one)
    1. Ceftriaxone 1 gm IVPB (Community Acquired)

ii. Cefipime 1 gm IVPB (Hospital Acquired)

  1. Ciprofloxacin 400 mg IVPB (For PCN or Cephalosporin allergy)
  2. Suspected intra-abdominal infection (choose one)
    1. Cefipime 1 gm IVPB and Metronidazole 500 mg IVPB

ii. Ciprofloxacin 400 mg IVPB and Metronidazole 500 mg IVPB

  1. Piperacillin /Tazobactam 3.75 gm IVPB



2 – 6 hrs Management

6) Admit/Transfer the patient to Critical Care Medicine setting

7) Repeat lactate level in 4 hrs, if lactate > 4 mmol /L:                                                      Measure SVO2

8)  If SVO2 < 70 % & HCT < 30%:                                                                               Consider transfusion of PRBC to achieve HCT > 30%

9) Repeat SVO2 after optimization of CVP > 8-10 mm Hg & HCT > 30%:         Consider inotropic therapy

10) If SVO2 remains < 70%:                                                                                           Start Dobutamine infusion at 5 micrograms/kg/minute

6 –24 hrs Management [Critical Care Medicine]


   11) Evaluate for Relative Adrenal Insufficiency:                                                                      Send serum cortisol level and order cosyntropin test

12)While waiting for cortisol level:                                                                                   Start Decadron 4 mg IV

13) For blood sugar > 150 mg/dl:                                                                                                Start Critical Care Medicine Insulin protocol

14) Evaluate for drotrecogin alpha administration:                                                          Use Hospital protocol

15) If patient is on a ventilator, evaluate for ALI/ARDS:                                                  Start ARDS ventilator protocol in appropriative patients

16 If patient remain hypotensive and CVP > 8-10 mm Hg:                                                           Start Vasopressin infusion at 0.04 units per minute

Summary Approach to Problem

Objective: To sub-classify patients presenting to ICU into GROUPS 1-4 as described above, and to record the appropriate treatment decision (Antibiotics, and other).  Statistically significant numbers of patients representing each of the sub-groups will be included in the study.  Diagnostic performance of both the Sysmex IG parameter and the procalcitonin (PCT, Brahms) assays will be assessed as potential tools to differentiate groups 1 from 2, 2 from 3 and 3 from 4.

If the IG and/or procalcitonin tests are deemed valuable as markers of the microvascular damage which precedes multiple organ damage associated with sepsis, the potential exists to motivate for application as an index for the initiation of innovative drug therapy at an earlier stage, in an effort to prevent disease progression to multiple organ failure.  If data supports this change, the potential for monitoring responses to investigated antibiotic therapy in patients with raised IG and / or PCT values should be assessed.

Methods: A prospective, observational study from one or several large community or academically-linked hospitals following IRB requirements. A total of 1000 consecutive patients presenting to ICU with presumed infection/sepsis will be enrolled.  Clinical and diagnostic sub-classification according to groups 1-4 above have to be performed, in conjunction with a Sysmex CBC, Diff and IG, as well as a procalcitonin (PCT, Brahms) assay.

Results:  Statistically significant numbers of patients representing each of the 4 groups will be documented, and their treatment (antibiotic/combination drug) will be recorded.

Statistical assessment: At a minimum, ROC curve analysis of IG (and PCT) versus Group 1-4 classifications will be done. ROC curve analysis of IG (and PCT) versus therapy decisions will also be performed.  If successful, the capability of the parameters to monitor treatment responses will be assessed by serial measurements over time. A method of anomaly characterization developed by Gil David and Prof. Ronald Coifman of Yale University will be applied using key indicators to classify the patients such as WBC, percent neutrophils, IG, PCT, subclass 1-4, treatment, outcome (LOS in ICU, LOS, died).

Study Design:
Type study: Prospective and not interventional
Patient population: 1000 patients, admitted to ICU with suspected severe infection / SIRS / Sepsis.

Diagnostic information: Concurrent information gathered will be in accordance with Xigris Screening recommendations for severe sepsis, and theHospital guidelines for management of sepsis, severe sepsis and septic shock as described above.  Including – respiratory rate, heart rate, fever, location, primary and secondary diagnoses, APACHE score and SOFA score, antibiotic use, target therapy/other use etc.



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