Archive for the ‘Bio Instrumentation in Experimental Life Sciences Research’ Category

State of the art in oncologic imaging of breast.

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Computational Biology/Systems and Bioinformatics, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Reproductive Biology & Bio Instrumentation, Technology Transfer: Biotech and Pharmaceutical, tagged American Society of Clinical Oncology, Biology, breast cancer, Cancer - General, Clinical trial, Conditions and Diseases, FDA, FDG PET, Food and Drug Administration, health, medicine, MRI, National Institutes of Health, oncologic imaging, oncology, PEM, Personalized medicine, PET/MRI, Proceedings of the National Academy of Sciences of the United States of America, research, United States on January 21, 2013| 2 Comments »

State of the art in oncologic imaging of breast.

Author-Writer: Dror Nir, PhD

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Word Cloud By Danielle Smolyar

In the coming posts I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging^†^‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications.

In this post I summaries the chapter on breast cancer imaging.

Breast Cancer Imaging

As a start the authors describes the evolution in the ACS imaging guidelines for breast cancer screening. Most interesting to learn is how age limits are changing. The most recent: “In 2010, the Society of Breast Imaging and the Breast Imaging Commission of the ACS issued recommendations for breast cancer screening to provide guidance in light of the controversies and emerging technologies.5 These recommendations were based on multiple prospective randomized trials as well as population-based experience.

Recommendations for screening with non-mammographic imaging are based not on evidence showing mortality reduction but largely on surrogate indicators, i.e., tumor size and nodal status, suggesting improved survival compared with women who are not screened.” I have referred to these guidelines in my recent post: Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

As long as imaging interpretation is based mainly on observations related to lesion morphology:

“The imaging characteristics of malignant lesions are nonspecific and usually do not allow a definitive diagnosis. When a biopsy is recommended based on mammography, it has a 25% to 45% likelihood of resulting in a diagnosis of carcinoma.11 Similar positive predictive values are reported for biopsies recommended based on MRI.”

It is worthwhile noting that these results do not reflect purely the specificity of the imaging device but rather the specificity of the whole workflow; i.e imaging, biopsy and histopathology. All imaging techniques have false negatives: Mammography screening of general population misses approximately 20% of the cancers. This rate increases as breast density increases. MRI is not applied to general population. When applied to highly suspicious cases MRI misses ~10% of the invasive cancers. Although ultrasound has proven to be useful in detecting cancer especially in women with dense breasts: Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need! Based on the literature reviewed by the authors of this paper they do not recommend routine sonography for these women.

For women with locally advanced breast cancer (Fig. 2) who undergo neoadjuvant therapy before breast surgery, the authors recommends post-treatment staging using MRI, which has been found to predict complete response with sensitivity above 60% and specificity as high as 90%.26

A 27-year-old female with locally advanced poorly differentiated invasive ductal carcinoma underwent evaluation of extent of disease before starting neoadjuvant chemotherapy. Sagittal fat-suppressed T1-weighted postcontrast MR images demonstrate an almost 6-cm heterogeneously enhancing mass (A) involving the skin of the lower breast (arrow) with (B) right axillary (arrow) and (C) right internal mammary adenopathy (arrow).

Same is recommended for women who have undergone lumpectomy if the surgical margins are positive. As post therapy follow-up, a new baseline mammogram of the treated breast is recommended followed by annual mammography.

In regards to emerging technology the following are discussed: Mammographic tomosynthesis – see also Improving Mammography-based imaging for better treatment planning

Contrast-enhanced digital mammography – “involves the injection of iodinated contrast material, as is done for computed tomography (CT); this enables hypervascular lesions to be seen with modified mammography technology, potentially providing the same information obtained through MRI. Little has been published on the clinical application of this technology, but diagnostic accuracy better than that of mammography and approaching that of MRI has been reported.31, 32”

MR choline spectroscopy – has been shown to improve the positive predictive value of breast MRI and may be useful in reducing the number of lesions that require biopsy (Fig. 4).33 Studies of spectroscopy have reported sensitivities of 70% to 100% and specificities of 67% to 100% in the detection of breast cancer. Decreasing choline concentrations may also be a useful indication of tumor response to treatment before any change in tumor volume can be detected.34, 35 Technical factors have limited the use of spectroscopy to lesions 1 cm in size or larger.”

Sagittal fat-suppressed T1-weighted postcontrast MR image is shown (A) of the right breast of a 48-year-old female who was status post–contralateral mastectomy for DCIS with the spectroscopy voxel placed over an enhancing mass (arrow). The magnified spectrum (B) demonstrated no choline peak. Biopsy yielded fibroadenoma.

Diffusion-weighted MRI (DW-MRI) – “adding DW-MRI data to other imaging characteristics of lesions on breast MRI may increase the positive predictive value of the examination, in turn decreasing the number of benign lesions requiring biopsy for diagnosis.” See also Imaging: seeing or imagining? (Part 2).

Axial T1-weighted fat-suppressed postcontrast MR image is shown (A) of the left breast of a 42-year-old female with biopsy-proven contralateral cancer undergoing evaluation of disease extent. An enhancing mass (arrow) was seen in the left breast. This mass (arrow) was also demonstrated on the axial diffusion-weighted MR image (B). Biopsy yielded fibroadenoma with atypical ductal hyperplasia and lobular carcinoma in situ.

Ultrasound-elastography – “Ultrasound elastography has been reported to differentiate benign from malignant breast lesions with sensitivities of 78% to 100% and specificities of 21% to 98%.39 When added to other US techniques, it may improve radiologists’ performance in distinguishing malignant breast lesions.”

Positron emission tomography (PET) – “alone or combined with CT, allows noninvasive, quantitative assessment of biochemical and functional processes at the molecular level in the body. It is most often performed with the radiolabeled glucose analogue [18F] fluorodeoxyglucose ([18F]FDG) to detect the elevated glucose metabolism that is a hallmark of cancer. In breast cancer, its utility depends on the pretest probability for advanced disease, and thus the clinical stage.” The authors found that the use of [18F] FDG PET to patients with stage I and II disease is “limited”. Specifically, they claim that it is not sufficiently accurate for axillary nodal staging in this subset of patients.40 The did find enough evidence to recommend the use of FDG PET in patients with advanced disease: “where it accurately defines disease extent,41 and frequently eliminates the need for other imaging tests, and provides an early readout of treatment response as well as prognostic information.”

Combined PET/MRI is mentioned as a promising technology for predicting response to therapy “but this remains to be proven”.

Positron emission mammography (PEM) – “adapts full-body PET imaging to the breast. In a multicenter study, the interpretation of PEM in conjunction with mammographic and clinical findings yielded a sensitivity of 91% and a specificity of 93% for breast cancer.47 “. However, the authors mention that its use for screening (applying to healthy women) has been criticized because of the need to administer a radioactive tracer.

Lung Cancer Imaging

To be followed…

Other research papers related to the management of breast cancer were published on this Scientific Web site:

The unfortunate ending of the Tower of Babel construction project and its effect on modern imaging-based cancer patients’ management

Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Introducing smart-imaging into radiologists’ daily practice.

Will Bio-Tech make Medical Imaging redundant?

Improving Mammography-based imaging for better treatment planning

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

Predicting Tumor Response, Progression, and Time to Recurrence

“The Molecular pathology of Breast Cancer Progression”

Personalized medicine gearing up to tackle cancer

Whole-body imaging as cancer screening tool; answering an unmet clinical need?

What could transform an underdog into a winner?

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Nanotech Therapy for Breast Cancer

A Strategy to Handle the Most Aggressive Breast Cancer: Triple-negative Tumors

Optical Coherent Tomography – emerging technology in cancer patient management

Breakthrough Technique Images Breast Tumors in 3-D With Great Clarity, Reduced Radiation

Closing the Mammography gap

Imaging: seeing or imagining? (Part 1)

Imaging: seeing or imagining? (Part 2)

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Ovarian Cancer and fluorescence-guided surgery: A report

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Imaging-based Cancer Patient Management, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged epithelial ovarian cancer, Fluorescence-guided surgery, fluorescent agent, folate receptor-α, Folate-FITC, FR-α, imaging-guided surgery, Multispectral fluorescence camera system, ovarian cancer, Tumor-specific agent on January 19, 2013| 8 Comments »

Ovarian Cancer and fluorescence-guided surgery: A report

Author, Editor: Tilda Barliya PhD

Surgery is being commonly used to diagnose, treat and even help prevent cancer. In which the surgeon will cut into the body to remove the cancer along with some surrounding healthy tissue to ensure that all of the cancer is removed. However distinguishing cancer cells from healthy ones during surgery can prove difficult, if not impossible. Sometimes lesions are detected only postoperatively, leading to more surgery down the line. Currently, surgeons rely on vision and touch to detect tumors during surgery but in many cases there is still no good way to determine a tumor’s margins.

In recent years, major progression has been made in imaging-guided surgery and doctors believe that use of fluorescent dye could boost survival rates by guiding them to tiny clusters of malignant cells.

The first fluorescence-guided surgery in ovarian cancer patients have yielded great results and are summarized herein.

Dr. Phillip Low, a Ralph C. Corely Distinguished Professor of Chemistry from Purdue University has invented a fluorescent imaging agent to a modified form of the vitamin folic acid, which acts as a “homing device” to seek out and attach to ovarian cancer cells (1)

” Of all gynecologic malignancies, epithelial ovarian cancer (EOC) is the most frequent cause of death, both in the United States and in Europe. The relative absence of a clear, distinctive clinical presentation in early stages, combined with the lack of a screening tool, often results in the disease being diagnosed only at more advanced stages. The overall 5-year survival rate is 45%, and for stages III and IV it is only 20–25%.” Cytoreduction surgery followed by chemotherapy is considereed the most effective treatment. Radiologic approaches such as X-ray, CT, MRI and ultrasound have been considered for use in assisting surgical procedures, but these are not tumor specific and generally are not useful for intraoperative applications. Therefore, a better tumor-specific detection strategy may drastically improve the patient survival.

The overexpression of folate receptor-α (FR-α) in 90–95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α–targeted fluorescent agent. Moreover, the absence of FR-α on healthy cells leads to high tumor-to-normal ratios.

Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting (http://spie.org/newsroom/technical-articles-archive/4003-shifting-the-paradigm-in-surgical-vision-with-fluorescence-molecular-imaging)

As a ligand of FR-α, folate has already been conjugated to DTPA for SPECT/CT imaging and to several PET tracers. It has also been linked to fluorescein for use in imaging metastatic disease in murine tumor models, although this was never tested in humans.

In this article, the authors have conjugated the folate to fluorescein isothiocyanate (FITC) for the use in surgery together with a real-time multispectral intraoperative fluorescence imaging system.

The authors have conducted the first clinical trial using the fluorescence-guided surgery in ovarian cancer patient. Described herein:

Tumor-specific fluorescent agent:

Targeting of the FR-α in ovarian cancer in patients, the imaging agent was produced at clinical grade according to GMP conditions by Endocyte Inc. Folate hapten (vitamin B9) was conjugated with fluorescein isothiocyanate (FITC), yielding folate-FITC (See Fitgure). Folate-FITC has an excitation wavelength of 495 nm and emits light at 520 nm. The conjugate has a very high sensitivity and clusters of cancer cells as small as one-tenth of a millimeter can be detected, as opposed to the earlier average minimal cluster size of 3 millimeters in diameter based on current methods of visual and tactile detection.

Folate-FITC was dissolved in 10 ml sterile normal saline and injected at a dose of 0.3 mg per kg body weight over a period of 10 min and was injected 2 hrs prior to the surgery.

Patients:

10 patients with different stages of the over cancer were recruited, The mean age of all patients was 61.2 ± 11.4 (mean ± s.d.). Four patients were diagnosed with a malignant epithelial ovarian tumor (two serous carcinomas, one undifferentiated carcinoma and one mucinous carcinoma) and one patient with a serous borderline tumor. Five patients were diagnosed with a benign ovarian tumor, as confirmed by histopathology: two fibrothecomas, one cellular fibroma, one cystic teratoma and one benign multicystic ischemic ovary.

Multispectral fluorescence camera system:

The camera system (developed by the Technical University Munich/Helmholtz Center) consists of a charge-coupled digital (EM-CCD) camera (Andor Technology) for sensitive fluorescence detection and two separate cameras for detection of intrinsic fluorescence and color (PCO AG). The system is controlled by a synchronized multi-CPU computer system (Dell Computer) for simultaneous processing of raw data and image registration and rendering. The system allows color imaging and simultaneous sensitive fluorescence detection in the visible light spectrum, as appropriate for FITC imaging. Surgery and imaging procedure are described in detail in the article (1). Shortly, a live imaging during surgery enabled the surgeon to locate the tumor and remove it, biopsy was taken for further histopathology.

Results:

Fluorescence was detectable intraoperatively in all patients with a malignant tumor and FR-αexpression but was absent in the patient with a malignant tumor but no FR-α expression and in those with benign tumors (Table 1)

Table 1: Demographics an individual data for patients

Study no.	Age (years)	Histopathology	FIGO stage	In vivo fluorescence	IHC FR-α expression	FM FITC
n = 10 patients. ++, strong; +, moderate; 0, weak; −, absent; FIGO, International Federation of Gynecology and Obstetrics; IHC FR-α, immunohistochemistry folate-receptor alpha; FM FITC, fluorescence microscopy for folate-FITC; n.a., not applicable.
Malignant tumor
1	72	Serous ovarian carcinoma	III	++	++	++
7	76	Serous ovarian carcinoma	III	+	+	+
9	64	Undifferentiated carcinoma	III	–	–	–
10	61	Mucineus ovarian carcinoma	III	+	+	+
Borderline tumor
5	48	Serous borderline tumor	I	0	+	0/+
Benign tumor
2	59	Fibrothecoma	n.a.	–	–	–
3	74	Fibrothecoma	n.a.	–	–	–
4	53	Mature cystic teratoma	n.a.	–	–	–
6	64	Benign multicystic ischemic ovary	n.a.	–	–	–
8	41	Fibroma	n.a.	–	–	–

Healthy tissue did not show any fluorescence signal either in vivo, ex vivo or on histopathological validation. In two separate still images of patients with ovarian cancer, the mean tumor-to-background ratio (as compared to healthy peritoneal surface) for ten demarcated fluorescent tumor deposits in each still image was 3.1 (± 0.8 s.d.). In the patient with a high-grade serous carcinoma and extensive peritoneal disseminated disease (stage III, FR-α positive), widespread tumor-specific fluorescence (white spots) was present throughout the abdominal cavity, as confirmed by ex vivo histopathology. Real-time image-guided excision of fluorescent tumor deposits of size <1 mm was feasible.

A video of the surgery is presented herein:

http://www.purdue.edu/newsroom/research/2011/110918LowSurgery.html

Detection of Tumor Deposits:

Five surgeons independently identified tumor deposits on three separate color images (shown on a representative image in (Left) and on their corresponding fluorescence image of precisely the same area (Right).

The number of tumor deposits detected by surgeons when guided by tumor-specific fluorescence (median 34, range 8–81) was significantly higher than with visual observation alone (median 7, range 4–22, P < 0.001).

Summary:

In this limited series, the authored showed that the use of intraoperative tumor-specific fluorescence imaging of the systemically administered FR-α–targeted agent folate-FITC offers specific and sensitive real-time identification of tumor tissue during surgery in patients with ovarian cancer and the presence of FR-α–positive tumors. Nevertheless, one patient presented with a malignant tumor that did not express FR-α, and consequently, no fluorescence was detected.

A major advantage over current imaging modalities is that an intraoperative fluorescence imaging system offers a large field of view for inspection and staging. This, in turn, may permit future patient-tailored surgical interventions and may decrease the number of needless extensive surgical procedures and the associated morbidity.
The second major advantage of intraoperative imaging as compared to current standard techniques is that it may guide the surgeon in debulking efforts, thus contributing to more efficient cytoreduction and ultimately improving the effect of adjuvant chemotherapy in patients with reduced tumor load
Improving the detection of cancer deposits to submillimeter size might ultimately improve survival rates, but whether this is the case needs to established by additional clinical studies.

Advantages:

In ovarian cancer, the FR-α appears to constitute a good target because it is overexpressed in 90–95% of malignant tumors, especially serous carcinomas.
Targeting ligand, folate, is attractive as it is nontoxic, inexpensive and relatively easily conjugated to a fluorescent dye to create a tumor-specific fluorescent contrast agent.

Disadvantages:

Overexpression of FR-α varies strongly between different solid tumors originating from different organs, a characteristic that reduces the general applicability of folate-FITC in cancer.
Many organs have autofluorescence in the excitation and emission parameters of the FITC dye.

Development of new fluorescent agents in the near-infrared spectrum will allow for identification of more deeply seated tumors, based on the stronger penetration properties of near-infrared dyes with an excitation wavelength >700 nm compared to FITC.

This is the first in-human proof-of-principle and the potential benefit of intraoperative tumor-specific fluorescence imaging in staging and debulking surgery for ovarian cancer using the systemically administered targeted fluorescent agent folate-FITC. Larger international multicenter studies using standardized, uniformly calibrated multispectral fluorescence camera systems combined with folate-FITC are needed to confirm our data and further elucidate the diagnostic (accuracy, sensitivity and specificity) and therapeutic value of the reported approach in larger series of ovarian cancer patients.

Note: Other similar approaches have been explored for brain tumors (3a, 3b) in human clinical trials using 5-aminolevulinic acid (5-ALA). We will not address this trial in this discussion.

Ref:

1. Gooitzen M van Dam, George Themelis, Lucia M A Crane, Niels J Harlaar, Rick G Pleijhuis, Wendy Kelder, Athanasios Sarantopoulos, Johannes S de Jong, Henriette J G Arts, Ate G J van der Zee, Joost Bart, Philip S Low & Vasilis Ntziachristos. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-αtargeting: first in-human results. Nature Medicine 17, 1315–1319 (2011). http://www.nature.com.rproxy.tau.ac.il/nm/journal/v17/n10/full/nm.2472.html

Click to access nm.2472.pdf

http://www.purdue.edu/newsroom/research/2011/110918LowSurgery.html

Video: http://www.youtube.com/watch?v=cPlRP0qrxts

http://www.guardian.co.uk/science/2011/sep/18/ovarian-cancer-fluorescence-detection

2. Lung cancer: http://emoryhealthmagazine.emory.edu/issues/2012/winter/briefs/a-yellow-brick-path/index.html

3a. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006 May;7(5):392-401.

3b. Clinical trial set up: http://clinicaltrials.gov/show/NCT01502280

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Building blocks of the universe: Top physicists teach about early galaxy formation at Jerusalem Winter School in Theoretical Physics

Posted in Bio Instrumentation in Experimental Life Sciences Research, tagged Avishai Dekel, Galaxy formation and evolution, Hebrew University of Jerusalem, Milky Way, Reinhard Genzel, Theoretical Physics on January 17, 2013| Leave a Comment »

Reporters: Aviva Lev-Ari, PhD, RN

Press Release 1/1/2013

Building blocks of the universe: Top physicists teach about early galaxy formation at Jerusalem Winter School in Theoretical PhysicsHeaded by Nobel Laureate, ten day School runs December 31 to January 10

Galaxies in formation

The 30th Jerusalem Winter School in Theoretical Physics opens on December 31 at the Israel Institute for Advanced Studies at the Hebrew University of Jerusalem. The topic this year is Early Galaxy Formation in LCDM Cosmology. One hundred students from around the world will participate in lectures and workshops by world-renowned experts in the field.

The 2004 Nobel Laureate in Physics and Hebrew University alumnus Prof. David Gross will head the school for the sixth time. Prof. Gross earned his bachelor’s degree in physics and mathematics from the Hebrew University of Jerusalem. He received the Nobel Prize for the discovery of asymptotic freedom in the theory of the strong interaction, the force operating between quarks.

Prof. Avishai Dekel, the Andre Aisenstadt Chair of Theoretical Physics at the Hebrew University’s Racah Institute of Physics, will manage the school with Prof. Reinhard Genzel from the Max Planck Institute for Extraterrestrial Physics. According to Prof. Dekel, ”Galaxy formation is the hot topic in physical cosmology today. Galaxies are the building blocks of the universe, and understanding the evolution of galaxies is an important step in understanding the formation of planets and life in the universe.”

Prof. Dekel is one of the world’s leading theoretical cosmologists. He developed the modern theory of galaxy evolution by flow of cold material from the cosmic fabric. In recent years he has focused on the early universe, one to five billion years after the Big Bang.

”The lectures at the school will start with the basics and reach the most advanced issues in current research,” added Prof. Dekel. “My research, for example, deals with a model for galaxy formation by streams of cold gas. This model replaces the hitherto accepted model, whereby the most influential process on galaxy evolution was clashes between galaxies.”

Professor Reinhard Genzel from the Max Planck Institute for Extraterrestrial Physics is one of the leading researchers in the subject of galaxy formation. He discovered the black hole at the center of the Milky Way Galaxy and he is one of the most prominent researchers of galaxies in the early universe. During the School he will talk about the evolution of galaxies.

The Winter School in Theoretical Physics takes place from 31 December to 10 January. All lectures are in English at the Israel Institute of Advanced Studies, Feldman Building, Edmond J. Safra campus in Givat Ram. Registration is required by email to shani@ias.huji.ac.il.

SOURCE:

http://www.huji.ac.il/cgi-bin/dovrut/dovrut_search_eng.pl?mesge135705649805872560

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Renal Denervation Safe in Real-World Setting: Preliminary results from the Global SYMPLICITY registry, 5/2013

Posted in Bio Instrumentation in Experimental Life Sciences Research, Cell Biology, Signaling & Cell Circuits, Ecosystems & Industrial Concentration in the Medical Device Sector, Frontiers in Cardiology and Cardiovascular Disorders, HTN, Medical Devices R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Renal Denervation, tagged American Heart Association, Baker IDI Heart and Diabetes Institute, Blood pressure, Boston Scientific, European Society of Cardiology, Hypertension, Mahfoud, Medtronic, Murray Esler, Perelman School of Medicine, SYMPLICITY on January 14, 2013| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 5/29, 2013

Renal Denervation Safe in Real-World Setting

By Todd Neale, Senior Staff Writer, MedPage Today

Published: May 25, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points:

PARIS — May 21-24, 2013

Out in everyday practice, renal denervation with the Symplicity device safely lowers blood pressure in patients with hypertension, preliminary results from the Global SYMPLICITY registry showed.

The Global SYMPLICITY registry is part of the clinical program evaluating the Symplicity device. It has been approved for use in Europe and elsewhere but remains restricted to investigational use in the U.S. Medtronic, which makes the Symplicity device, announced on Thursday that it has completed enrollment in Symplicity HTN-3, the pivotal U.S. trial.

The registry has a targeted enrollment of about 5,000 patients from about 200 centers worldwide; 149 sites spread throughout Canada, Mexico, South America, Europe, Africa, the Middle East, Asia, and Australia have already started collecting data.

Any patient who receives renal denervation can be included in the registry, and thus the study will include patients with hypertension and other conditions associated with increased sympathetic activity, including heart failure, insulin resistance, atrial fibrillation, sleep apnea, and chronic kidney disease.

European Society of Cardiology‘s recently published consensus paper on renal denervation, which recommended treatment in patients with a systolic blood pressure of 160 mm Hg or higher (or at least 150 mm Hg for type 2 diabetics) who were taking at least three antihypertensive medications, including a diuretic.

SOURCE:

Expert consensus document from the European Society of Cardiology on catheter-based renal denervation

http://eurheartj.oxfordjournals.org/content/early/2013/04/25/eurheartj.eht154.extract

Most of the first 617 patients included the registry (60%) were treated in accordance with the European Society of Cardiology’s recently published consensus paper on renal denervation, above.

About one-fifth of the patients (22%) started with a systolic blood pressure of at least 180 mm Hg, which was the average baseline blood pressure in the Symplicity HTN-1 and HTN-2 trials.

The average starting blood pressure overall was 164/89 mm Hg, and patients were taking an average of 4.35 medications. Common comorbidities included diabetes (38.2%), renal disease (30.1%), sleep apnea (16.3%), a history of cardiac disease (49%), heart failure (9.3%), and atrial fibrillation (11.9%).

The registry data showed significant drops in blood pressure measured both in the office and with 24-hour ambulatory monitoring, although the reductions were smaller than those seen in the clinical trials.

That’s not surprising, according to Mahfoud, because out in everyday practice blood pressure is not recorded as appropriately as in a clinical trial setting and poor compliance to medication becomes more of an issue. In fact, he said, a recent study showed that 47% of patients with resistant hypertension were not adherent to their medication regimens.

Also contributing to the smaller reductions in the real-world population is the fact that the average starting blood pressure was lower than in the clinical trials, Mahfoud said, adding that it is known that renal denervation induces greater reductions in blood pressure among those with the highest readings initially.

Mahfoud reported receiving institutional grant/research support from Medtronic, St. Jude, Recor, and serving as a consultant for St. Jude, Medtronic, Boston Scientific, and Cordis. Medtronic makes the Symplicity renal denervation device.

Primary source: European Association of Percutaneous Cardiovascular Interventions

SOURCE REFERENCE:

Mahfoud F, et al “Early results following renal denervation for treatment of hypertension in a real-world population: the Global SYMPLICITY registry” EuroPCR 2013.

http://www.pcronline.com/EuroPCR/EuroPCR-2013

Adverse Events:

Of the first 617 patients included in the registry, only two had vascular complications related to access during the procedure, and none had serious events stemming from delivery of the radiofrequency energy to the renal artery; the rate of vasospasm was 9%, according to Felix Mahfoud, MD, of Saarland University Medical Center in Homburg/Saar, Germany.Through 6 months of follow-up, there were two hospitalizations for hypertensive crisis, two myocardial infarctions, one new case of end-stage renal disease from nephrotoxic overdose, and one death that was not considered to be related to the procedure, he reported at the EuroPCR meeting here.The procedure was not only safe, but also effective at lowering blood pressure, with reductions in office-based readings ranging from 13/6 mm Hg among patients with a baseline systolic blood pressure of 140 mm Hg or higher to 28/18 mm Hg among those with a baseline systolic pressure of 180 mm Hg or higher at 3 months. The findings were similar at 6 months.

“The take-home message will be hopefully … that renal denervation is a safe procedure providing blood pressure lowering in patients with high blood pressure at baseline and that that procedure might have an impact on clinical outcomes,” Mahfoud said in an interview.

http://www.medpagetoday.com/MeetingCoverage/EuroPCR/39409

Positive Effects of Renal Denervation Ablation for Hypertension in Controlled Randomized SYMPLICITY HTN-2 Trial

Renal Nerve Ablation Effects on BP Lasting

Download Complimentary Source PDF

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: January 08, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Late-term results from a study of the safety and effectiveness of renal denervation to reduce hypertension mirrored positive results seen earlier in the randomized SYMPLICITY HTN-2 trial, researchers found.

The mean reduction in systolic blood pressure at 1 year post procedure was a significant 28.1 mmHg (P<0.001), similar to the mean 31.7 mmHg drop at 6 months (P=0.16 for the comparison), according to Murray Esler, MD, of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, and colleagues.

Those in the control group who crossed over to the intervention at 6 months also had a significant fall in systolic blood pressure from a mean 190 to 166 mmHg (P<0.001), researchers reported in the January issue of Circulation: Journal of the American Heart Association.

The increasing prevalence of hypertension is a worldwide phenomenon, with an estimated 1.56 billion predicted to be affected in 2025, the authors noted. Yet, many of these patients cannot control their blood pressure (with control being defined as a pressure <140/90 mmHg) even when taking three or more antihypertensive medications.

Esler and colleagues cited a 2005 study that found a range of 47% to 87% of people in North America and Europe whose blood pressure is not under control (Lancet 2005; 365: 217-223).

Renal denervation has shown promise in these patients who are refractory to medication. The percutaneous procedure uses energy such as radiofrequency waves to scar the renal artery in an attempt to disrupt the sympathetic nerves, thereby affecting blood pressure.

Three-year data from the nonrandomized SYMPLICITY HTN-1 study were in line with 2- and 1-year results, showing a mean drop of 33/19 mmHg associated with the intervention.

In the current study, researchers from the multi-center randomized controlled SYMPLICITY HTN-2 trial enrolled 106 patients with essential hypertension (systolic blood pressure ≥160 mmHg, or ≥150 mmHg for diabetics). Patients were taking at least three antihypertensive medications.

The initial 1-year data from the SYMPLICITY HTN-2 trial were reported at the 2012 American College of Cardiology meeting. The primary endpoint was a change in systolic blood pressure at 6 months. Also at the 6-month mark, patients in the control group were allowed to cross over and receive the treatment; they were then followed for 6 more months.

The 6-month data were based on 101 patients (49 in the treatment group versus 51 controls). The 1-year data were based on 47 patients in the primary treatment group and 35 per-protocol controls who crossed over. The crossover patients also had to have a systolic blood pressure of ≥160 mmHg.

The significant decrease of 28.1 mmHg in systolic blood pressure in the treatment arm at 1 year was matched by significant drops in diastolic blood pressure at 6 and 12 months, as well as in the crossover group at 6 months (P<0.001 for all).

The authors reported that 84% of initial denervation patients had a decrease of at least 10 mmHg at 6 months; at 1 year, the number was 79%. In the crossover group, that rate was 63% at 6 months.

Interestingly, there was no significant difference in the changes in medication — reduced dosage or fewer drugs — between the treatment arm and controls, despite the reduction in blood pressure for the treatment arm.

“These data further substantiate the safety of renal sympathetic denervation via delivery of controlled radiofrequency energy bursts,” Esler and colleagues concluded.

They also noted that renal function remained unchanged at both 6 and 12 months. A pilot study by the Melbourne group looking specifically at patients with chronic kidney disease found renal denervation to be safe in this population.

The limitations to the current study include the lack of 24-hour blood pressure monitoring and the lack of blinding among the staff measuring blood pressure. The investigators noted that the ongoing SYMPLICITY HTN-3 trial addresses these limitations.

This study was funded by Medtronic Ardian.

Esler and three co-authors reported receiving research support from Medtronic Ardian. During the conduct of the trial, senior author Sobotka was chief medical officer of Ardian, and was a medical adviser to Medtronic.

From the American Heart Association:

AHA Science News: Scientific Sessions 2010 – Symplicity HTN-2

Primary source: Circulation
Source reference:
Esler MD, et al “Renal sympathetic denervation for treatment of drug-resistant hypertension: One-year results from the Symplicity HTN-2 randomized, controlled trial” Circulation 2012; 126: 2976-2982.

SOURCE:

http://www.medpagetoday.com/Cardiology/Hypertension/36751?xid=NL_DHE_2013-01-09&eun=g388495d0r&userid=388495&email=dr.usman23@gmail.com&mu_id=5381424&goback=%2Egde_4346921_member_204232738

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Proteomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Resident-cell-based, Stem Cells for Regenerative Medicine, Technology Transfer: Biotech and Pharmaceutical, tagged Biology, Cancer - General, DNA, DNA Sequencing, Human Genome Project, Induced pluripotent stem cell, National Institutes of Health, Personalized medicine, Single-nucleotide polymorphism, Stem cell on January 13, 2013| 10 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer

THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine

http://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment

http://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-drug-selection-in-cancer-personalized-treatment-part-2/

Part 3:

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research

http://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

Part 4:

The Consumer Market for Personal DNA Sequencing

http://pharmaceuticalintelligence.com/2013/01/13/consumer-market-for-personal-dna-sequencing-part-4/

Part 3:

Personalized Medicine: Institute Profile – Coriell Institute for Medical Research

Coriell Institute for Medical Research, founded in 1953 and based in Camden, New Jersey, is an independent non-profit research center dedicated to the study of the human genome. Expert staff and pioneering programs in the fields of personalized medicine, cell biology, cytogenetics, genotyping, and biobanking drive our mission.

The emerging field of personalized medicine draws upon a person’s genomic information to tailor treatments and prescription drug dosing to optimize health outcomes. The Coriell Personalized Medicine Collaborative^® (CPMC^®) research study is seeking to understand the usefulness of genetic risk and pharmacogenomics in clinical decision-making and healthcare management.

Coriell has a distinguished history in cell biology. We are building upon this expertise by playing an important role in induced pluripotent stem (iPS) cell research. Induced pluripotent stem cells are powerful cells which can be made from skin or blood cells, and they are revolutionizing the way human disease is studied and how drugs are developed. Skin cells from a patient diagnosed with heart disease are being genetically reprogrammed into stem cells, and then transformed into beating cardiac cells. Researchers can now examine the heart-diseased cells to better understand the progression of heart disease and develop treatments and cures. Drug efficacy and safety can also be tested in this laboratory environment, providing an efficient model of drug discovery that delivers drugs to patients sooner. This technology, called “disease in a dish,” offers researchers the potential to study the myriad of human diseases, including Alzheimer’s disease, muscular dystrophy, and diabetes.

In addition to pioneering cutting-edge research initiatives, Coriell offers custom research services – including cell culture, cytogenetic analyses, and molecular biology – to the scientific community. Furthermore, Coriell’s Genotyping and Microarray Center is one of the nation’s largest centers, with high-throughput DNA analysis, CLIA-certified genotyping platforms systems from Illumina and Affymetrix.

Essential to the Institute’s support of international scientific research is the Coriell Biobank. From this renowned cell bank, we manage and distribute the world’s most diverse collection of cell lines, DNA, and other biological resources. The Coriell Biobank provided support to the Human Genome Project, a worldwide program to map the entire human genome, and to the International HapMap Project, a project providing an efficient tool to identify disease-causing genes.

The Coriell Cell Repositories provide essential research reagents to the scientific community by establishing, verifying, maintaining, and distributing cell cultures and DNA derived from cell cultures. These collections, supported by funds from the National Institutes of Health (NIH) and several foundations, are extensively utilized by research scientists around the world.

The Business Aspects of the Institute

Personalized Medicine

DNA, Genes, and SNPs

What is the CPMC Study?

CPMC Technology

CPMC FAQs

CPMC Advisors and Partners

Stem Cells

Induced Pluripotent Stem (iPS) Cells

iPS Cell Research at Coriell

Biobank Catalog

Working with Coriell

Research Services

Genotyping & Microarray

Molecular Biology

Research Design & Expertise

Stem Cells

Quality at Coriell

BioBanking

Overview

What is a Biobank?

How Coriell Banks Cells

Biobank Technology

Biobank Catalog

Working with Coriell

http://www.coriell.org/

http://www.coriell.org/assets/pdfs/discover-winter2012.pdf

http://www.ccr.coriell.org/

http://www.coriell.org/about/coriell-faqs

What is the Coriell Institute of Medical Research?

Founded in 1953, Coriell Institute for Medical Research is an independent, non-profit research organization dedicated to the study of the human genome and to supporting national and international research by providing biomaterials from its renowned biobank.

How did the Coriell Institute start?

Lewis L. Coriell, MD, PhD, a virology researcher and pediatrician, recognized the need for scientific research that would translate into better patient care. After seeing how his research helped to bring the Salk vaccine to polio patients across our nation, Dr. Coriell founded the South Jersey Medical Research Foundation. It was renamed the Institute for Medical Research in 1966 to recognize its broader reach, and, in 1985, to honor Dr. Coriell’s retirement, his name was added. For a look at our history, visit our timeline.

http://www.coriell.org/about/our-history

About the Founder

“You set up an experiment to test the theory, and most of the time it’s not the way you thought it would be. But that’s the way you learn. You go from hypothesis to hypothesis. And it’s exciting because that’s the way we learn to treat, to diagnose, and to prevent illness.”

Lewis L. Coriell, MD, PhD Virologist and Pediatrician June 19, 1911 – June 19, 2001

Lewis L. Coriell was born in the farming community of Sciotoville, in southern Ohio. While he was still a young child, his family moved to Montana toward more promising agricultural opportunities. It has been written that “the aspects of character, personality, temperament, and intellect that marked Dr. Coriell’s exceptional professional life… can easily be traced to his Montana upbringing.”ⁱ

Education and Early Career

Beginning his academic journey at the University of Montana, Lewis Coriell completed undergraduate studies in biology and subsequently earned a master’s degree in bacteriology and immunology in 1936. That same year, he married fellow student Ester Lentz; they would remain by each other’s side for the next 60 years. The newlyweds moved to the University of Kansas so he could pursue doctoral studies in immunology. While there, Dr. Coriell published his first article on an aspect of science he would revolutionize: The storage of cells by freezing them. Lewis Coriell earned his doctorate in 1940 and was awarded his medical degree in 1942. The young researcher was drawn to the field of virology – the study of viruses as they evolve and infect. At this time, bacterial infections presented themselves most often in children. This combination led Dr. Coriell to seek out a residency in pediatrics. As none were immediately available, he chose a cardiology residency at Henry Ford Hospital in Detroit. MI. As it happens, the Coriells’ time in Detroit was brief.

By 1943, World War II was raging and Dr. Coriell was called to service with the United States Army Medical Command’s Biological Research Division at Fort Detrick, MD. It was here that his research in cell cultivation began. After the war, Dr. Coriell began his ideal pediatric residency under Dr. Joseph Stokes, Jr., physician-in-chief at Children’s Hospital of Philadelphia (CHOP). To his delight, Dr. Stokes placed great emphasis on research and was instrumental in attracting federal funds to research childhood disease at his institution. The ability to translate research into patient care inspired Dr. Coriell. He saw how research was essential to the treatment of his patients suffering the devastating effects of viruses like small pox, mumps, and polio.

Adventures in Cell Culture

By the time Dr. Coriell arrived in Philadelphia, virologists knew they had to grow viruses in cell culture to prepare purified viruses for the manufacture of vaccines. However, contamination was rife in the laboratory and proving to be a major obstacle. At CHOP, along with his colleagues, Dr. Coriell perfected the technique to culture human tissue in a sterile host that does not produce its own antibodies. The ability to sustain living human cells in culture, and keep them from being contaminated, led to a key breakthrough in polio research – it enabled scientists to grow the polio virus and work toward the first vaccine.

Moving to Camden and Taking on Polio

By the early 1950’s, an acute infectious disease called polio was spreading from person to person very quickly across the United States, striking fear into citizens, costing children their lives and crippling those who survived. In 1949, Dr. Coriell arrived in Camden, NJ, as medical director of Camden Municipal Hospital, one of the country’s last infectious disease hospitals and home to the majority of the region’s polio patients. In 1951, Dr. Coriell was appointed field director of the Polio Prevention Study and directed the successful gamma globulin field trials.

By 1954, the Salk polio vaccine could be made in large quantities and was ready for human clinical trials. Based on his success shepherding the gamma globulin field trials, Dr. Coriell was chosen by the National Poliomyelitis Foundation to evaluate the Salk polio virus vaccine clinical trials in New Jersey, Pennsylvania, Maryland, and Virginia. The success of the evaluation program led to the release of the Salk vaccine on the national level. Before the trials began in 1955, approximately 20,000 new polio cases were being reported each year. By 1960, cases were reduced to 3,000 per year. By 1979, that number was just 10 each year. Recognizing his contribution, Dr. Coriell received the 1957 International Poliomyelitis Congress Presidential Medal. Soon after, he became chairman of the Committee on the Control of Infectious Diseases of the American Academy of Pediatrics which formulated the vaccination procedures for all children in this critical period.

In 1953, Dr. Coriell initiated a campaign to build the first non-profit academic medical research institute in South Jersey. Under his guidance, the Institute for Medical Research began research in cancer, human cytogenetics, infectious diseases, and methods to improve cell culture techniques. The history of the Institute’s accomplishments included Dr. Coriell’s foresight in calling for the establishment of a central tissue culture bank and cell registry to certify and maintain cell cultures. It began with a partnership with the National Institutes of Health to create the first standardized cell repository. Today, the Institute is home to the world’s most diverse collection of cell lines and DNA samples available to researchers.

Working with his colleague, Dr. Gary McGarrity, Dr. Coriell applied infection control technology – specifically laminar flow – to create the laminar flow hood that is vital to infection control in laboratories, operating rooms, and hospital rooms around the world.

Dr. Coriell’s pioneering techniques for characterizing, freezing, and storing non-contaminated cell cultures in liquid nitrogen constitute one of the greatest contributions to modern human genetics.

Retirement

Dr. Coriell retired in 1985. To honor the occasion, the institute he founded was renamed the Coriell Institute for Medical Research. He remained involved in several ways, as a member of the board and often speaking with groups about the Institute’s history. Following his retirement, Dr. Coriell was elected president of the prestigious College of Physicians of Philadelphia, the oldest medical society in America. Dr. Coriell is the only New Jersey physician to receive this honor.

Dr. Coriell, a pioneering researcher and physician, died on June 19, 2001, in Southern New Jersey. It was his 90th birthday.

A Legacy in Science

Dr. Coriell’s accomplishments in science are indeed many. Perhaps Dr. Coriell’s most enduring legacy was his generosity in knowledge and his ability to bring scientists together to explore research questions and collaborate on solutions. Several important names in science were drawn to join or spend time at the Institute; they included Warren W. Nichols, Ray Dutcher, Richard Mulivor, Etienne Lasfargues, Jesse Charney, Arthur Greene, Daniel Moore, and collaboration with Drs. Albert Levan and Joe Hin Tijo, who first discovered that humans have 46 chromosomes.

Dr. Coriell also created an institute that is a well-respected resident of the Greater Philadelphia region and known as a leader in research worldwide.

Coriell Today

Dr. Coriell’s vision is now our vision. Today, Coriell staff and scientists collaborate on scientific ideas and programs to improve human health.

The Coriell Personalized Medicine Collaborative® research study is studying the utility of using your genetic information to tailor treatments and medications for you. And building on Dr. Coriell’s innovations in cell biology, we are playing an important role in cutting-edge stem cell research to unlock the code of human disease, including Parkinson’s and heart disease. Coriell offers a range of custom research services that have long supported national and international science. In the field of biobanking, Coriell supports research all over the world from its renowned and diverse cell collections.

Our innovation today is a testament to Dr. Coriell’s pioneering past. More importantly, our innovation is a commitment to your future.

ⁱ O’Donnell, John. Coriell; The Coriell Institute for Medical Research and a Half Century of Science. Massachusetts: SHP, 2002.

Where is the Coriell Institute located?

Coriell is located at 403 Haddon Avenue, Camden, NJ 08103. For directions, click here We recommend that you park at 3 Cooper Plaza, a parking garage associated with the hospital, located directly across the street from Coriell. There is also a second hospital parking lot located on Benson Street, which is a block from the Institute.

For what is the Coriell Institute known?

Coriell Institute is a leader in the emerging field of personalized medicine – often called genome-informed medicine – which is the practice of using genetic information to better understand a patient’s risk for disease and response to medications. The Coriell Personalized Medicine Collaborative is a research study designed to study the utility of genetic information in clinical decision-making and patient care.

Coriell is also playing an important role in exploring the promise of induced pluripotent stem (iPS) cell biotechnologies. [Pluripotent refers to how cells can grow into many different types of cells.] We can take skin cells and reprogram them – essentially turn back time – to behave like a stem cell. These cells can then be triggered, using specific proteins, to become cardiac cells, neurons (brain cells), or insulin-producing pancreatic cells, amongst others. Over the years, Coriell has developed an extraordinary expertise in the culture of human cells, and much of the standard practices in cell culture were developed at Coriell. This includes the techniques for freezing and thawing cells, and sterile handling of cultures. As a result of our cell biology expertise, scientists from every major research center in the world draw upon the Coriell Cell Repositories, maintained in the world’s leading biobank, which contains cell lines and DNA representing approximately 650 diseases.

Who is on the Coriell Institute staff?

Coriell is home to approximately 120 scientific and operational staff. Michael Christman, PhD, is Coriell’s President and CEO; he is an expert in genomics and genetics. Joseph L. Mintzer is Coriell’s Executive Vice President and COO and manages the fiscal and operational aspect of the institute. Meet the rest of the Coriell leadership team here.

Who is on the Coriell Institute Board of Trustees?

Coriell is guided by a diverse Board of Trustees that includes corporate, medical, financial, and philanthropic leaders. Chairman of the Coriell Board is Robert P. Kiep III. Learn more about the Coriell Board of Trustees here.

How is Coriell Institute funded?

Coriell Institute has an annual operating budget of $17 million, about $11 million of which comes from federally- and state-funded grants and contracts. Private and corporate philanthropy provides the seed money to initiate new programs in science at Coriell – science that has the opportunity to advance discoveries in research which may not be occurring at other research institutes.

How can I support the research mission of Coriell Institute?

While the majority of Coriell’s operating revenue is derived from federally- and state-funded grants and contracts, the Institute also relies on private, foundation, and corporate philanthropy. Your support can advance the emerging field of personalized medicine to improve the practice of medicine. Your support also allows Coriell to pursue and support research in adult stem cell biology and genomics seeking to unlock the code of human disease.  There are many ways to give to Coriell: Outrights gifts, through your workplace giving programs, planned giving, volunteering your time and expertise, or attending or hosting a Coriell event. Visit our fund development page to learn more about how you can support scientific research.

How does Coriell Institute support international research?

The Coriell Cell Repositories offers essential research materials to the scientific community by establishing, verifying, maintaining, and distributing cell cultures and DNA. Since the first NIH-sponsored repository was established in 1964 – Coriell has distributed hundreds of thousands of cell lines and DNA samples to researchers in 64 countries. More than 7,000 peer-reviewed papers have been published citing almost 12,000 Coriell Repository samples.

What research services does Coriell Institute provide?  Coriell offers several best-in-class custom research services.

Coriell’s Genotyping and Microarray Center – one of the nation’s largest centers and CLIA-certified in 48 states – is a high-capacity facility with high-throughput systems from Affymetrix and Illumina.

The Coriell Institute Cytogenetics Laboratory is a state-of-the-art facility that combines conventional and molecular cytogenetic analyses with copy number and loss of heterozygosity (LOH) analyses by microarray. The laboratory is equipped with a network of five Applied Spectral Imaging work-stations that are used to perform G-banded karyotyping, and Fluorescent In Situ Hybridization (FISH).  Coriell also offers many preparative and diagnostic nucleic acid and molecular biology services, all subject to extensive quality controls.

And, the Coriell biobank is regarded as the most diverse collection of cell lines and DNA available to the international research community.

Does Coriell Institute engage in gene therapy or stem cell clinical trials?

Coriell Institute does not pursue research using human embryonic stem cells, nor do we conduct clinical trials on stem cell technologies. If you are interested in gene therapy or stem cell-related clinical trials, please visit http://www.clinicaltrials.gov.

What education does Coriell offer?

Coriell offers a course in cell culture: Advanced biology coupled with the history, theory, and techniques of maintaining live cells in long-term culture is offered to students.

Coriell also invites a limited number of motivated students into the Institute to participate in a Summer Experience program to gain insight into the workings of an independent research institute

How can I stay informed on what is happening at Coriell Institute?

Sign up for our email updates and you’ll receive periodic research news, notable donations, and upcoming events. Visit our Media Center regularly to read the latest news articles and Coriell press releases.

How can I get a quick overview of Coriell Institute?

Read our Coriell Fast Facts for a basic introduction to the Institute. For more information, explore the About section of our website.

Are Coriell Institute scientists and staff available for speaking engagements?

As their schedules permit, Coriell’s scientific and operational staffs enjoy the opportunity to highlight the work occurring at Coriell. Many hold joint faculty appointments at our region’s universities and teach an array of topics from business management and healthcare policy to the science of cell culture and stem cell research.

Coriell also participates in several outreach programs each year, including science festivals and conferences. We also host tours of our laboratories for business and governmental leaders and middle school and high school students.  16. Is Coriell Institute affiliated with Cooper Medical School of Rowan University? Yes; Coriell is looking forward to welcoming the new medical school and will be integral in teaching genetics and genomics to the next generation of healthcare providers.

The Power of Stem Cell Science

The promise of stem cell research lays in its application in understanding the progression of human disease, the ability to cure disease and reverse injury, and to better target therapies to optimize our health outcomes. Induced pluripotent stem (iPS) cell technology has the ability to revolutionize the way human disease is studied. Creating iPS cell lines from various rare and common disease states, as well as from various populations, will open the doors for pre-clinical research studies.

Let Our Expertise Make Your Research a Success

Coriell offers a range of custom research services that have long supported national and international science. Whether you are requesting a cell line for your research studies or submitting DNA samples for genotyping analysis, Coriell is committed to providing you with flexible, innovative, and results-oriented research services. Our laboratories are built to foster scientific collaboration, and your research will benefit from this collaborative environment.

Coriell’s Biobank and Cell Culture Laboratory have established the gold standard in the cryopreservation of biomaterials and the capacity to support varied research worldwide. The diverse collections of biological specimens managed by Coriell offer the scientific community the highest quality specimens, which are necessary for successful research endeavors. Since the first repository – a National Institutes of Health collection – was established at Coriell in 1964, hundreds of thousands of cell lines and DNA samples have been distributed to researchers in 64 countries; more than 7,000 peer-reviewed papers have been published citing almost 12,000 biospecimens from the Coriell Biobank.

Making Medicine Personalized for You

Our health is determined by many factors: the genetics we inherit; our innate personal traits of race, age and gender; our individual behavior; our family and community networks; and at the macro level, our economic, cultural, and environmental conditions. These factors are different for every person and will change over their lifespan. So too is a person’s experience with disease and how they respond to drugs or other medical interventions. Personalized medicine intends to make medical treatment as individual as the biology of one’s disease.

Personalized medicine has the potential to offer patients and their doctors several advantages, including:

The ability to make better informed clinical decisions.

A higher probability of desired health outcomes by using better-targeted therapies.

The reduced probability of adverse reactions from medications and treatments.

A focus on prevention and prediction of disease, rather than reaction to it.

Earlier disease intervention.

Reduced healthcare costs.

Preserving cells today for research tomorrow

Dr. Lewis Coriell’s pioneering techniques for characterizing, freezing, and storing cell cultures in liquid nitrogen constitute one of the greatest contributions to modern human research. Today, the Coriell Biobank is regarded as the most diverse collection of cell lines and DNA available to the international research community. In addition to these high-quality biospecimens, Coriell also maintains tissue, plasma, serum, urine, and cerebrospinal fluid.

Few organizations have the history of innovations in repository science that have been developed and implemented at Coriell. For nearly 60 years, Coriell has set the standard in biobanking services, including the experimental design, collection, processing, distribution, cryogenic preservation, and information management of human biomaterials used in research. By developing and maintaining biorepositories as national and international resources for the study of human diseases, aging, and neurological disease, Coriell is committed to providing the scientific community with well-characterized, cell cultures and DNA preparations, annotated with rich phenotypic data.

Catalog Collections

NIGMS Human Genetic Repository  The Human Genetic Cell Repository, sponsored by the National Institute of General Medical Sciences, provides scientists around the world with resources for cell and genetic research. The samples include highly characterized cell lines and high quality DNA. Repository samples represent a variety of disease states, chromosomal abnormalities, apparently healthy individuals and many distinct human populations.

NINDS Human Genetics DNA and Cell Line Repository  The National Institute of Neurological Disorders and Stroke is committed to gene discovery, as a strategy for identifying the genetic causes and correlates of nervous system disorders. The NINDS Human Genetics DNA and Cell Line Repository banks samples from subjects with cerebrovascular disease, epilepsy, motor neuron disease, Parkinsonism, and Tourette Syndrome, as well as controls.

NIA Aging Cell Repository  Sponsored by the National Institute on Aging (NIA), the AGING CELL REPOSITORY, is a resource facilitating cellular and molecular research studies on the mechanisms of aging and the degenerative processes associated with it. The cells in this resource have been collected over the past three decades using strict diagnostic criteria and banked under the highest quality standards of cell culture. Scientists use the highly-characterized, viable, and contaminant-free cell cultures from this collection for research on such diseases as Alzheimer disease, progeria, Parkinsonism, Werner syndrome, and Cockayne syndrome.

NHGRI Sample Repository for Human Genetic Research  The National Human Genome Research Institute (NHGRI) led the National Institutes of Health’s (NIH) contribution to the International Human Genome Project, which had as its primary goal the sequencing of the human genome. This project was successfully completed in April 2003. Now, the NHGRI’s mission has expanded to encompass a broad range of studies aimed at understanding the structure and function of the human genome and its role in health and disease.

American Diabetes Association, GENNID Study  The purpose of the American Diabetes Association (ADA), GENNID Study (Genetics of non-insulin dependent diabetes mellitus, NIDDM) is to establish a national database and cell repository consisting of information and genetic material from families with well-documented NIDDM. The GENNID Study will provide investigators with the information and samples necessary to conduct genetic linkage studies and locate the genes for NIDDM.

The Autism Research Resource  The State of New Jersey funded the initiation of a genetic resource to support the study of autism in families where more than one child is affected or where one child is affected and one demonstrates another significant and related developmental disorder. This resource now receives continuing support from the Coriell Institute for Medical Research. An open bank of anonymously collected materials documented by a detailed clinical diagnosis forms the basis of this growing database of information about the disease.

IPBIR Repository  The purpose of the IPBIR – Integrated Primate Biomaterials and Information Resource is to assemble, characterize, and distribute high-quality DNA samples of known provenance with accompanying demographic, geographic, and behavioral information in order to stimulate and facilitate research in primate genetic diversity and evolution, comparative genomics, and population genetics.

HD Community BioRepository  HD Community BioRepository is a secure, centralized repository that stores and distributes quality-controlled, reliable research reagents. Huntingtin DNAs are now available and antibodies, antigenic peptides, cell lines, and hybridomas will be added soon.

USIDNET Repository  The USIDNET DNA and Cell Repository has been established as part of an NIH-funded program – the US Immunodeficiency Network (www.usidnet.org) – to provide a resource of DNA and functional lymphoid cells obtained from patients with various primary immunodeficiency diseases. These uncommon disorders include patients with defects in T cell, B cell and/or granulocyte function as well as patients with abnormalities in antibodies/immunoglobulins, complement and other host defense mechanisms.

CDC Cell and DNA Repository  The Genetic Testing Reference Material Coordination Program of the Centers for Disease Control and Prevention (CDC) and the Coriell Institute for Medical Research announce the availability of samples derived from transformed cell lines for use in molecular genetic testing. The DNA samples prepared from these reference cell lines are available through the Coriell Cell Repositories. Diseases include cystic fibrosis (CF), 5′ 10′ methylenetetrahydrofolate reductase deficiency (MTHFR), HFE-associated hereditary hemochromatosis, Huntington disease (HD), fragile X syndrome, Muenke syndrome, connexin 26-associated deafness, and alpha-thalassemia.

Leiomyosarcoma Cell and DNA Repository  The Leiomyosarcoma Cell and DNA Repository has been established with an award from the National Leiomyosarcoma Foundation. This foundation provides leadership in supporting research of Leiomyosarcoma, improving treatment outcomes of those affected by this disease as well as fostering awareness in the medical community and general public.

COHORT Project  The Cooperative Huntington’s Observational Trial Repository has been established as a resource for the discovery of information related to Huntington’s disease and its causes, progressioin, treatments, and possible cures. This is a growing bank for DATA and SPECIMENS to accelerate research on Huntington’s disease.

YERKES Repository  The Yerkes National Primate Research Center of Emory University is an international leader in biomedical and behavioral research. For more than seven decades, the Yerkes Research Center has been dedicated to advancing scientific understanding of primate biology, behavior, veterinary care and conservation, and to improving human health and well-being.

NEI-AREDS Genetic Repository  The Age-Related Eye Disease Study was designed to learn about macular degeneration and cataract, two leading causes of vision loss in older adults. The study looked at how these two diseases progress and what their causes may be. In addition, the study tested certain vitamins and minerals to find out if they can help to prevent or slow these diseases. Participants in the study did not have to have either disease. (Enrollment was completed in January 1998.) Eleven medical centers in the United States took part in the study, and more than 4,700 people across the country were enrolled in AREDS. The study was supported by the National Eye Institute, part of the Federal government’s National Institutes of Health. The clinical trial portion of the study also received support from Bausch & Lomb Pharmaceuticals and was completed in October 2001. Learn about the results of the clinical trial on the National Eye Institute’s website: http://www.nei.nih.gov/amd/.

The Wistar Institute  The Wistar Institute collection at Coriell contains cell lines that have been developed by Wistar scientists. These materials are offered for non-commercial research conducted by universities, government agencies and academic research centers. The Wistar Institute collection currently contains a group of hybridomas that produce monoclonal antibodies that are useful in influenza research and vaccine development. Melanoma cell lines, derived from patients with a wide range of disease ranging from mild dysplasia to advanced metastatic cancer, will be added shortly. More information on The Wistar Institute, its research and scientists can be found at www.wistar.org.

J. Craig Venter Institute Human Reference Genome (HuRef)  The Human Reference Genetic Material Repository makes available DNA from a single individual, J. Craig Venter, whose genome has been sequenced and assembled. The DNA samples are prepared from a lymphoblastoid cell line established at Coriell Cell Repositories from a sample of peripheral blood. The DNA samples are available in 50 microgram aliquots. The lymphoblastoid cell line is not available for distribution..

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PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Posted in Bio Instrumentation in Experimental Life Sciences Research, CABG, Cardiac & Vascular Repair Tools Subsegment, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Coagulation Therapy and Internal Bleeding, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Interviews with Scientific Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Origins of Cardiovascular Disease, PCI, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Stents & Tools, Systemic Inflammatory Response Related Disorders, tagged Conventional PCI, Dade-Behring, fibrinogen, MICHAEL WARD, myocardial infarction, University of California San Francisco on January 10, 2013| 12 Comments »

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #13: PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity. Published on 1/10/2013

WordCloud Image Produced by Adam Tubman

Q&A Session between Dr. Michael Ward and Dr. Larry Bernstein presented for in our Research Category on

Interviews with Scientific Leaders

Primary research:

Ang L, et al “Elevated plasma fibrinogen rather than residual platelet reactivity after clopidogrel pre-treatment is associated with an increased ischemic risk during elective percutaneous coronary intervention” J Am Coll Cardiol2013; 61: 23-34.

Question by DR. MICHAEL WARD

How ironic that an old diagnostic parameter should
reappear in the limelight of diagnostic predictors.

Of course, decades ago, doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.

However, the diagnostic world, like the worlds of pharmaceuticals, medical devices, biologics, and other industries, always seek the ‘new kid on the block’ to differentiate themselves from the rest of the pack in the
marketplace.

So there was a binge (and still is) to seek new and exotic blood proteins that are surrogate markers for specific diagnoses or prognoses.

That is the irony, that in this case at least, fibrinogen has come full circle. Biology works in mysterious ways.

Answer by Dr. Larry Bernstein, MD, FCAP

Dear Dr. M. Ward:

Doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control
subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.

You are quite right that physicians used “sed rates” as a measure of inflammation, and more in Lupus Erythematosis, Rheumatoid Arthritis, Nephritides, Systemic Sclerosis, and so forth. The “sed rate” was not a part of the thinking about CVD, and PCI didn’t exist. Recently, MI post-PCI has been defined as a type (NSTEMI?).

Yes. In principle, the sed rate is related to fibrinogen and red-cell aggregation. I am not prepared to accept that a platelet count over 400,000 would make no contribution, even if many of the PCI related infarcts are within a range of 150-300,000. I don’t know how much power there is in the discussion. The role of tissue factor (plaque), and of platelets in hemostasis is undeniable.

The industry does look for every opportunity to seize on promising biomarkers. The coagulation assays developed at Dade-Behring (Dade, Dupont Division; then Dade) were far better and more explanatory that the “sed rate”. The sed rate measurement requires that you set up graduated tubes to watch the rate of sedimentation. It is not a walkaway procedure. Industry has been so good at introducing automation that led to high volume efficiency, that this led to the only part of hospital operations that had good accounting measures. The long trip to reducing personnel, but of course the profiles were a piece of cake. I continually reorganized to carve out services for immunology and toxicology, which took longer to get automated.

The only use for sed rate now is for Temporal Thrombosis (?).

In the early days Yale NH Hospital had some 5 Perkin Elmer HPLCs to measure calcium. Electrophoretic separation of isoenzymes was not helpful for managing patients. The procedure was run batchwise once a day. I was the first in CT to be running the immunoassay three times a day on the Roche COBAS Bio CFA., and Dupont put it on the ‘aca’. A med tech could run it at 3 am at Detroit Receiving, Bellevue, or Cook County, when the phone didn’t stop ringing for STAT results.

Physicians had expectations too. So we had the progression from AST, LDH, and CK to isoenzyme MBCK, and then there were the cancer biomarkers – CEA, CA-125, PSA, with much to be discussed.

Q&A is derived from the following Article in

MedPage Today

Published: January 07, 2013

Fibrinogen Level Tied to Poorer PCI Outcomes

By Todd Neale, Senior Staff Writer, MedPage Today

Published: January 07, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

An elevated serum fibrinogen level predicted worse short-term ischemic outcomes among patients undergoing elective percutaneous coronary intervention after pretreatment with clopidogrel, researchers found.

Significantly higher levels of fibrinogen were seen in patients with periprocedural myocardial infarction (MI) defined by either creatine kinase-myocardial band (CK-MB) or troponin (P<0.02 for both), according to Ehtisham Mahmud, MD, of the University of California, San Diego, and colleagues.

Those relationships remained consistent after adjustment for several factors, including platelet function, which was not itself associated with periprocedural MI, the researchers reported in the Jan. 8 issue of the Journal of the American College of Cardiology.

“The results of the current study suggest that an elevated fibrinogen level…is related to significant platelet cross-linking and thrombus formation independent of residual P2Y12 receptor-mediated platelet activity during clopidogrel therapy,” they wrote.

Higher risk of ischemic cardiovascular events has been observed with both high platelet reactivity after thienopyridine treatment and elevated serum fibrinogen.

“As an acute phase reactant involved in the final common pathway of the coagulation cascade and essential component of platelet cross-linking in thrombus formation, fibrinogen possesses a clear biological mechanism for its adverse cardiovascular effects,” Mahmud and colleagues wrote.

In fact, high levels of serum fibrinogen have been shown to contribute to high platelet reactivity during clopidogrel treatment, resulting in uncertainty about whether insufficient platelet inhibition and elevated fibrinogen levels are independent or interactive risk factors for ischemic events.

To explore the issue, the researchers looked at data from 189 patients undergoing elective PCI who were pretreated with clopidogrel, defined as 75 mg daily for at least 7 days or a 600-mg bolus at least 12 hours before study enrollment. The mean age of the patients was 63.8 and most (74.1%) were male.

Nearly two-thirds (63%) had undergone a previous PCI, and 18% had undergone revascularization with coronary artery bypass grafting (CABG).

Baseline platelet function was measured using the VerifyNow P2Y12 assay. Markers of ischemic myocardial injury, including troponin and CK-MB, were measured every 8 hours after PCI until hospital discharge.

Periprocedural MI defined by troponin I or T occurred in 13.9% of patients. Those who had an MI had significantly higher levels of fibrinogen (363.1 versus 309.1 mg/dL, P=0.017).

The rate of CK-MB-defined periprocedural MI was 5.8%. Patients with that outcome also had elevated levels of fibrinogen (403.4 versus 313.5 mg/dL, P=0.007).

Both differences remained significant after multivariate adjustment that accounted for platelet function and other inflammatory markers.

The researchers found that a fibrinogen level of 345 mg/dL or higher — a cutoff identified as having optimal combined sensitivity and specificity for CK-MB-defined periprocedural MI — was associated with periprocedural MI defined by either troponin or CK-MB (P<0.04 for both).

Those relationships were stronger when systemic inflammation was low (C-reactive protein ≤0.5 mg/dL).

The platelet reactivity measurements were not associated with either definition of periprocedural MI, which is inconsistent with the findings from several smaller studies. The authors noted, however, that “the significance of these negative findings may be limited due to inadequate study power.”

In discussing the limitations of the study, the researchers pointed out that “the findings … do not provide insight into whether the relationship between high platelet reactivity and ischemic cardiovascular events demonstrated in previous studies is a direct one or mediated through the effect of serum fibrinogen.”

To get to the bottom of that, they wrote, “future studies relating platelet reactivity and adverse cardiac events should measure baseline fibrinogen.”

Mahmud has received clinical trial support from Accumetrics, Eli Lilly, and sanofi-aventis, and is on the speakers bureau for Medtronic. One of his co-authors is a consultant for Abbott Vascular, Boston Scientific, St. Jude Medical, Medtronic, and sanofi-aventis.

From the American Heart Association:

ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention

Primary source: Journal of the American College of Cardiology
Source reference:
Ang L, et al “Elevated plasma fibrinogen rather than residual platelet reactivity after clopidogrel pre-treatment is associated with an increased ischemic risk during elective percutaneous coronary intervention” J Am Coll Cardiol2013; 61: 23-34.

Add Your Knowledge ™

Todd Neale

Senior Staff Writer

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University.

SOURCE:

http://www.medpagetoday.com/Cardiology/PCI/36734?goback=%2Egde_2184987_membe

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Nanotechnology, personalized medicine and DNA sequencing

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical Devices R&D Investment, Molecular Genetics & Pharmaceutical, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged Clinical trial, DNA, DNA Sequencing, Graphene, nanopore, Nanopore sequencing, nanotechnology, National Institutes of Health, Personalized medicine on January 9, 2013| 9 Comments »

Nanotechnology, personalized medicine and DNA sequencing

Author, reporter, Curator: Tilda Barliya PhD

Dr. Ritu Saxena’s exciting report on the fascinating work of Dr. Apostolia M. Tsimberidou “personalized medicine gearing up to tackle cancer”, inspired me to go back and review this topic and see how nanotechnology can be applied in personalized medicine.

To read the Dr. Saxena’s post, please see http://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

It is based on an interview with Dr. A. M. Tsimberidou based on her paper:

Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

http://www.ncbi.nlm.nih.gov/pubmed?term=22966018

In March 2011 Nature Reviews issued a special issue features discussions of the advances, challenges and progress in the field of personalized cancer medicine by key opinion leaders who presented at the Worldwide Innovative Networking (WIN) symposium (**).

So what is personalized medicine?

Personalized medicine is a huge movement in the modern medical world. It aims to move away from the traditional practice of prescribing standard doses of standard drugs for a condition to every patient, and shifts the focus onto targeting the precise drug and dose required according to the patient’s physiology.

This is achieved by detecting and tracking molecular biomarkers, which indicate the presence and level of activity of a particular biological system in a patient’s body, whether inherent or foreign.

Another major part of the emerging field of personalized medicine is pharmacogenomics – analyzing the genetic makeup of the patient to determine whether a particular medication will be successful, or if it will have any adverse effects. (1). This is particularly important in cancer treatment, where the chemotherapy drugs used can be very damaging to healthy cells as well as cancerous ones, and the exact genetics of the tumor cells can vary widely between patients, and even between locations in one patient’s body.

Personalized medicine involves:

Detection (DNA polymorphism, RNA and protein expression, metabolits, Lipids etc)
Diagnosis (imaging)
Prognosis and
Treatment (targeted-therapy)

Given the size symmetry, nanomaterials offer unprecedented sensitivity, capable of sensing biological markers and processes at the single-molecule or single-cell level either in vitro or in vivo. Techniques are being developed for high-throughput DNA sequencing using nanopores, to obtain genetic information from a patient so that targeted medication can be selected as rapidly as possible.

Cancer, a very complex disease, is propagated by various types of molecular aberrations which drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data.

One of the greatest promises of near-term nanotechnoloogy is cheaper DNA sequencing to speed the development of personalized medicine. (3)

Nanotechnology and DNA sequencing

Tumors are known to be highly heterogenetic, due to the many acquired aberration in the cancer cells. Therefore, there are not only genetic differences between different patients, but also genetic differences within the same patient; for example from different locations in the same patient, that can greatly affect the success of a therapy. Therefore, sensitive and extensive yet inexpensive whole-genome sequencing is of major medical need to enable the application personalized medicine. A review of the potential of this emerging nanotechnology “Nanopore sensors for nucleic acid analysis ” was published recently in Nature Nanotechnology (4).

The growing need for cheaper and faster genome sequencing has prompted the development of new technologies that surpass conventional Sanger chain-termination methods in terms of speed and cost. These second- and third-generation sequencing technologies — inspired by the $1,000 genome challenge proposed by the National Institutes of Health in 2004 (ref. 5) — are expected to revolutionize genomic medicine. Nanopore sensors are one of a number of DNA sequencing technologies that are currently poised to meet this challenge.

Nanopore Sequencing:

Nanopore-based sensing is attractive for DNA sequencing applications because it is a

label-free,
amplification-free,
single-molecule
requires low reagent volumes

approach that can be scaled for high-throughput DNA analysis.

This approach can be scaled up for high-throughput DNA analysis, it typically requires low reagent volumes, benefits from
relatively low cost and supports long read lengths, so it could potentially enable de novo sequencing and long-range haplotype mapping. Although, nanopore technology is not conceptually new and raised many skeptical opinions it has made major progress in the past few years and are thus worth sharing.

The principle of nanopore sensing is analogous to that of a Coulter counter. A nanoscale aperture (the nanopore) is formed in an insulating membrane separating two chambers filled with conductive electrolyte. Charged molecules (A,G,C,T) are driven through the pore under an applied electric potential (a process known as electrophoresis), thereby modulating the ionic current through the nanopore. This current reveals useful information about the structure and dynamic motion of the molecule.

Here’s an example for a nanopore-based sequencing device is a Graphene- chip that is used as trans-electrode membrane (5).

Electrical measurements on graphene membranes in which a single nanopore has been drilled show that the membrane’s effective insulating thickness is less than one nanometer. This small effective thickness makes graphene an ideal substrate for very high-resolution, high throughput nanopore-based single molecule detectors. The sensitivity of graphene’s in-plane electronic conductivity to its immediate surface environment, as influenced by trans-electrode potential, will offer new insights into atomic surface processes and sensor development opportunities. (4-6).

A nanopore-based diagnostic tool could offer various advantages:

it could detect target molecules at very low concentrations from very small sample volumes;
it could simultaneously screen panels of biomarkers or genes (which is important in disease diagnosis,
monitoring progression and prognosis);
it could provide rapid analysis at relatively low cost; and
it could eliminate cumbersome amplification and conversion steps such as PCR, bisulphite conversion and Sanger sequencing

Nanopores are likely to have an increasing role in medical diagnostics and DNA sequencing in years to come, but they will face competition from a number of other techniques. These include

single-molecule evanescent field detection of sequencing-by-synthesis in arrays of nanochambers (Pacific Biosciences),
sequencing by ligation on self-assembled DNA nanoarrays (Complete Genomics), and the
detection of H+ ions released during sequencing-by-synthesis on silicon field-effect transistors from multiple polymerase-template reactions (Ion Torrent).

However, the possibility of using nanopore-based sensors to perform long base reads on unlabelled ssDNA molecules in a rapid and costeffective manner could revolutionize genomics and personalized medicine.

Current trends suggest that many challenges in sequencing with biological nanopores

the high translocation velocity and the
lack of nucleotide specificity

have been resolved. Similarly, given the progress with solid-state nanopores, if the

translocation velocity could be reduced to a single nucleotide (which is ~3Å long) per millisecond, and if
nucleotides could be identified uniquely with an electronic signature (an area of intense research),

it would be possible to sequence a molecule containing one million bases in less than 20 minutes. Furthermore, if this technology could be scaled to an array of 100,000 individually addressed nanopores operating in parallel, it would be possible to sequence an entire human genome (some three billion base pairs) with 50-fold coverage in less than one hour.

Although, none of the nanopore-solid base sequencing technique have been used as a tool in a clinical trial, one UK-based biotechnology company has its way, nanopore sequencing may soon be available to the public. Earlier this year 2012 Oxford Nanopore Technologies (ONT) announced that it was on the verge of manufacturing a commercial nanopore sensor. [The company said that by year’s end it would release a $900 handheld model, which it claims can sequence a virus genome 48 000 bases long, and a larger, scalable model that could decode a human genome in as little as 15 minutes. In contrast, conventional systems cost upward of $500 000 and take weeks to sequence a human genome (7).]

REFERENCES

** http://www.nature.com/nrclinonc/focus/personalized-medicine/index.html

1. http://www.azonano.com/article.aspx?ArticleID=3078

2. G.E. Marchant. Small is Beautiful: What Can Nanotechnology Do for Personalized Medicine?. Current Pharmacogenomics and Personalized Medicine, 2009, 7, 231-237. http://www.benthamscience.com/cppm/Sample/cppm7-4/002AF.pdf

3. http://www.foresight.org/nanodot/?p=4992

4. Venkatesan BM and Bashi R. Nanopore sensors for nucleic acid analysis. Nature Nanotechnology 2011; 18: http://libna.mntl.illinois.edu/pdf/publications/127_venkatesan.pdf

5. Garaj S., Hubbard W., Reina A., King J., Branton D and Golovchenko JA. Graphene as a sub-nanometer trans-electrode membrane. Nature 2010 (9) 467(7312): 190-193. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956266/

6. Min SK., Kim WY., Cho Y and Kim KS. Fast DNA sequencing with a graphene-based nanochannel device. Nature Nanotechnology 2011; 6: 162-165. http://biophy.nju.edu.cn/lablog/wp-content/uploads/2011/10/Fast-DNA-sequencing-with-a-graphene-based.pdf

7. http://www.physicstoday.org/resource/1/phtoad/v65/i11/p29_s1?bypassSSO=1

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Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Bio Instrumentation in Experimental Life Sciences Research, Frontiers in Cardiology and Cardiovascular Disorders, Genomic Testing: Methodology for Diagnosis, HTN, Interviews with Scientific Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Mitral Valve: Repair and Replacement, Pharmacotherapy of Cardiovascular Disease, Resident-cell-based, Scientist: Career considerations, Stents & Tools, Valves & Tools, tagged Cardiac surgery, Cardiac Surgery Theatre, Heart disease, St. Jude Medical on January 8, 2013| 7 Comments »

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”

Interviewer: Aviva Lev-Ari, PhD, RN

Article ID #11: Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”. Published on 1/8/2013

WordCloud Image Produced by Adam Tubman

First segment: Interview with Dr. LCR, Cardiac Surgeon,

Interviews with Scientific Leaders Series

This is the first segment on this subject, in the Interviews with Scientific Leaders Series on our Open Access Online Scientific Journal.

This Segment and the following to be published in this Open Access Online Scientific Journal, are based on an e-mail exchange with a prominent Cardiac Surgeon who worked in the US and in China in Cardiac Surgery Theatres. The identity of the surgeon, I shall conceal. The opening segment provides background, the volume of procedures and the general overview of the medical devices in use.

Following segments will be based on an exchange of Question and Answers (Q&A) which I will be presenting to our Surgeon interviewee and his answers to these specific questions.

I plan to cover the following topics:

Cardiac Repair Procedures
Medical Devices in Use
Technology in Hospitals
Surgeons’ Training and
Cardiac Disease Severity

Background

Dr. LCR, M.D., F.R.C.S.(C), F.A.C.S., Cardiothoracic & Vascular Surgery is the Cardiac Surgeon in this Interview with Scientific Leaders.

Dr. LCR was born in Hong Kong, SAR, China and came to the US in 1972 for higher education and became a US citizen since 1979. He is a US medical school graduate, trained general surgeon (ABS re-certified till 12/2014) and Canadian trained cardiothoracic surgeon (ABTS re-certified till 12/2021). Dr. LCR is also a Fellow of The American College of Surgeons (F.A.C.S.) and an active member of The Society of Thoracic Surgeons (STS) since 1996. He practiced cardiothoracic and vascular surgery in the US between 1992 and 2007 when he accepted the invitation of the Foreign Experts Bureau of the Chinese government to teach/work cardiovascular surgery in China and has just returned to the US two month ago.

During those five and a half years in China, Dr. LCR worked at some of the top and largest cardiovascular programs (West China Hospital of Sichuan University at the city of Chengdu, 1,700 cardiac cases/year.

Dr. LCR worked in Guangdong Provincial Cardiovascular Institute at the city of Guangzhou, the third or fourth largest cardiac program in China, with 3,792 cardiac cases in 2011).

Dr. LCR has also authored or co-authored at least 6 scientific articles when he was in China, all published in the US cardiac journals.

Dr. LCR speaks two Chinese dialects fluently and read and write Chinese at an advanced level.

Below, we present the personal observation and opinions regarding “How the Operating Rooms (OR) are equipped and run in China and the US.”

Dr. LCR was professor of thoracic surgery at West China Hospital of Sichuan University from 06/2007 to 04/2008), the largest hospital in China, with 4,200 beds on one campus (there are three other campuses).

The hospital has 80 some OR’s and the out-patient department saw 2.5 million out-patients the year he was there. The department of Cardiac Surgery performed 1,700 cardiac surgical cases in 2007, with 4 OR’s.

All the major US cardiac surgery vendors were represented, prosthetic heart valves, sutures,etc.. For some “Reason” we only used St. Jude Medical‘s mechanical valves, and we must have put in more than 1,200 to 1,400 valves. They were sold to the Chinese patients the same price as they were sold in the US, about US$ 3,000 each (or 21,00 CNY), about 3.6 million USD of biz for St. Jude, just from a division of the hospital.

The top two heart surgery centers are located in Beijing. Fuwei hospital did 9,700 heart surgery, and the other Aszhen hospital did close to 6,000 in 2011.

The last hospital Dr. LCR worked for as an attending/consultant surgeon until September 2012, The Guangdong Provincial General Hospital (2,400 beds)-The Guangdong Provincial Cardiovascular Institute (480 beds) is probably the third or fourth largest heart surgery center in China, did 3,782 cardiac surgical cases in 2011, most likely exceeded 4,000 in 2012.

If you add the coronary stents put in by the cardiologists in China , the biz for the medical device vendors is immense. For every one coronary bypass we did, the cardiologists must have inserted 20 or more stents. Without a doubt — China is and will be the biggest market for a lot of things, including medical devices, and you are going to the right place. Good luck.

The Next segment will present Dr. LCR’s answers to specific questions I will be e-mailing him of the following topics:

Cardiac Repair Procedures
Medical Devices in Use
Technology in Hospitals
Surgeons’ Training and
Cardiac Disease Severity

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Whole-body imaging as cancer screening tool; answering an unmet clinical need?

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Imaging-based Cancer Patient Management, Population Health Management, Genetics & Pharmaceutical, tagged breast cancer, Cancer - General, Cancer screening, health, medicine, research, whole-body MRI, wohle-body imaging on January 3, 2013| 11 Comments »

Whole-body imaging as cancer screening tool; answering an unmet clinical need?

Author: Dror Nir, PhD

Sometimes technologies that were developed to answer clinical needs in a certain area are migrated to perform in a totally inappropriate area. A good example which I discussed several times in my posts is PSA.

Cancer patients’ prognoses, strongly depend on accurate tumor staging. It is also a prerequisite for therapy choice and planning. Whole-body imaging is frequently used in patients with advanced malignant diseases including presence of metastases as these may occur in any anatomic region. It is important to note that classifying a patient as harboring a potentially advanced disease is based on biopsy results of Sentinel Lymph-Nodes and not on imaging. Moreover, referring a patient to a whole-body imaging is a choice of the treating practitioner! Clearly, when the choice of treatment includes administration of drugs, the type of drugs to be used is determined by the characteristics of the primary tumor.

To date, the use of whole-body imaging for post treatment follow-up can be considered as anecdotal.

The most-used technologies for whole-body imaging are computed tomography (CT), positron emission tomography (PET) and MRI. The performance of these systems in detection of cancer metastases of more than 1cm in diameter is very similar and in general quite good, dependent on the primary disease and the body locations of the metastases. Alas, each of these modalities has its strengths and weakness in different cancer and different body locations. Therefore, in the last decade, combined modalities such as PET-CT and recently PET/MRI were introduced. In some cases [1-6] these are reported to show sensitivity of more than 90%.

To demonstrate the level of information produced during whole-body imaging procedure here is an example (taken from Whole-body MRI and PET-CT in the management of cancer patients). This resource includes additional, educating examples:

330_2006_183_Fig1_HTML

Fig. 1

From multimodality to single-step examination. Restaging in a 29-year-old woman treated for breast cancer and with newly elevated tumor markers and bone pain. 1a, 1b Radiograms of the skeleton were normal, but bone scintigraphy showed a pathological tracer uptake in the right pubic bone (arrow). Abdominal ultrasound exhibited a suspicious mass. 1c, 1d CT revealed tumor recurrence in the right breast and confirmed hepatic metastasis. 2a, 2b T1-weighted whole-body MRI depicted a metastasis in the right pubic bone (circle). 2c, 2d HASTE images of the thorax showed the tumor recurrence in the right breast (arrow) and dynamic contrast enhanced studies of the abdomen unmasked the liver metastasis

Before addressing the issue of using whole-body imaging as a screening tool I would like to draw attention to existence of other methods for screening and post treatment follow-up of cancer patients; e.g. detecting levels of cancer-specific bio-markers in the blood or urine or, in case of advanced disease, detecting the level of tumor cells circulating in the blood as presented in: Circulating Tumor Cells versus Imaging—Predicting Overall Survival in Metastatic Breast Cancer by G. Thomas Budd et.al.

“Abstract

Purpose: The presence of ≥5 circulating tumor cells (CTC) in 7.5 mL blood from patients with measurable metastatic breast cancer before and/or after initiation of therapy is associated with shorter progression-free and overall survival. In this report, we compared the use of CTCs to radiology for prediction of overall survival.

Experimental Design: One hundred thirty-eight metastatic breast cancer patients had imaging studies done before and a median of 10 weeks after the initiation of therapy. All scans were centrally reviewed by two independent radiologists using WHO criteria to determine radiologic response. CTC counts were determined ∼4 weeks after initiation of therapy. Specimens were analyzed at one of seven laboratories and reviewed by a central laboratory.

Results: Inter-reader variability for radiologic responses and CTC counts were 15.2% and 0.7%, respectively. The median overall survival of 13 (9%) patients with radiologic nonprogression and ≥5 CTCs was significantly shorter than that of the 83 (60%) patients with radiologic nonprogression and <5 CTCs (15.3 versus 26.9 months; P = 0.0389). The median overall survival of the 20 (14%) patients with radiologic progression and <5 CTCs was significantly longer than the 22 (16%) patients with ≥5 CTCs that showed progression by radiology (19.9 versus 6.4 months; P = 0.0039).

Conclusions: Assessment of CTCs is an earlier, more reproducible indication of disease status than current imaging methods. CTCs may be a superior surrogate end point, as they are highly reproducible and correlate better with overall survival than do changes determined by traditional radiology. “

I would like first to present the following publication that could explain why people can easily be drawn why whole-body screening is an effective way to detect early cancers:

Enthusiasm for cancer screening in the United States by Schwartz LM, Woloshin S, Fowler FJ Jr, Welch HG SO, JAMA. 2004; 291(1):71.:

“ CONTEXT: Public health officials, physicians, and disease advocacy groups have worked hard to educate individuals living in the United States about the importance of cancer screening.

OBJECTIVE: To determine the public’s enthusiasm for early cancer detection.

DESIGN, SETTING, AND PARTICIPANTS: Survey using a national telephone interview of adults selected by random digit dialing, conducted from December 2001 through July 2002. Five hundred individuals participated (women aged>or =40 years and men aged>or =50 years; without a history of cancer).

MAIN OUTCOME MEASURES: Responses to a survey with 5 modules: a general screening module (eg, value of early detection, total-body computed tomography); and 4 screening test modules: Papanicolaou test; mammography; prostate-specific antigen (PSA) test; and sigmoidoscopy or colonoscopy.

RESULTS: Most adults (87%) believe routine cancer screening is almost always agood idea and that finding cancer early saves lives (74% said most or all the time). Less than one third believe that there will be a time when they will stop undergoing routine screening. A substantial proportion believe that an 80-year-old who chose not to be tested was irresponsible: ranging from 41% with regard to mammography to 32% for colonoscopy. Thirty-eight percent of respondents had experienced at least 1 false-positive screening test; more than 40% of these individuals characterized that experience as “very scary” or the “scariest time of my life.” Yet, looking back, 98% were glad they had had the initial screening test. Most had a strong desire to know about the presence of cancer regardless of its implications: two thirds said they would want to be tested for cancer even if nothing could be done; and 56% said they would want to be tested for what is sometimes termed pseudodisease (cancers growing so slowly that they would never cause problems during the person’s lifetime even if untreated). Seventy-three percent of respondents would prefer to receive a total-body computed tomographic scan instead of receiving 1000 dollars in cash.

CONCLUSIONS: The public is enthusiastic about cancer screening. This commitment is not dampened by false-positive test results or the possibility that testing could lead to unnecessary treatment. This enthusiasm creates an environment ripe for the premature diffusion of technologies such as total-body computed tomographic scanning, placing the public at risk of over testing and overtreatment.”

Whole-body screening is promoted as a one-stop shop for painlessly detecting hidden cancer and preventing cancer-related deaths. It is big business in the United States and in Canada where private clinics have begun offering full-body diagnostic procedures for a fee. The tests and procedures are often marketed to healthy people as a way to scan for hidden abnormalities or cancers, affording people the peace of mind that they are in good health [7 – 9].

When used in this manner, the evidence shows that whole-body cancer screening offers no proven health benefits and that it, in fact, exposes people to a number of unnecessary health risks. The problem I see is that the public is not exposed to “scientific publications” but is exposed to commercial ones!

References

Written by: Dror Nir, PhD

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The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

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Acute Coronary Syndrome

Tool Identifies Risk in Stenting ACS Patients

By Todd Neale, Senior Staff Writer, MedPage Today

Published: November 19, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A new, easy-to-calculate risk score developed for patients with non-ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) had better prognostic accuracy than other widely used risk scores, researchers found.

The ACUITY-PCI risk score includes six variables — insulin-treated diabetes, renal insufficiency, baseline cardiac biomarker elevation or ST-segment deviation, presence of a bifurcation lesion, small vessel/diffuse coronary artery disease, and extent of coronary artery disease, according to Gregg Stone, MD, of Columbia University Medical Center in New York City, and colleagues.

The 1-year rate of death or MI significantly increased from 5.3% in the lowest risk tertile to 9.1% in the middle tertile to 19% in the highest tertile (P<0.001), the researchers reported in the November issue of JACC: Cardiovascular Interventions.

Discrimination and calibration were greater with the ACUITY-PCI score than with other established scores.

“Although the TIMI and the GRACE scores have been shown to be valuable prognostic tools at the time of hospital admission for selecting pharmacological strategies and identifying those patients most likely to benefit from an invasive strategy, they have not been optimized for patients undergoing PCI and, thus, have relatively poor prognostic power to further risk stratify acute coronary syndrome patients undergoing PCI,” Stone and colleagues wrote.

“The ACUITY-PCI score is therefore intended to supplement the TIMI and GRACE scores when an invasive strategy has been undertaken and PCI is being considered.”

The researchers created the risk score using data from 1,692 patients enrolled in the angiographic substudy of the ACUITY trial, which was a comparison of heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin (Angiomax) plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone in patients with ACS undergoing an early invasive strategy. They then validated the score using another 846 patients from the same study.

Multivariate analysis revealed six variables that were significantly associated with 1-year mortality and MI and were included in the score. The researchers assigned points based on the strength of the predictor:

Insulin-treated diabetes (12 points)
Renal insufficiency (12 points)
Baseline cardiac biomarker elevation or ST-segment deviation (8 points)
Bifurcation lesion (4 points)
Small vessel/diffuse coronary artery disease (2 points)
Extent of coronary artery disease (1 point for each 10 mm of disease)

The C-statistic for the risk score — a measure of discrimination — was 0.67 in the derivation cohort and 0.70 in the validation cohort. In the validation cohort, the chi-square statistic for calibration was 6.2 and the index of separation was 0.44.

All of those values were better than those seen for four other established risk scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX. In addition, the net reclassification improvement with the new score ranged from 9% to 38% and the integrated discrimination index varied from 1.9% to 2.7%.

The researchers noted that the ACUITY-PCI score also was a good predictor of 1-year definite or probable stent thrombosis, with a C-statistic of 0.72.

In another study in the same journal, George Dangas, MD, PhD, of Mount Sinai Medical Center in New York City, and colleagues — including Stone — reported on the development of a risk score specifically for stent thrombosis in patients with ACS undergoing PCI.

The study included 6,139 patients from the HORIZONS-AMI and ACUITY trials, which included those with ST-segment elevation MI (STEMI) in the former trial and those with non-STEMI and unstable angina in the latter. The researchers used 4,093 patients for the derivation cohort and 2,046 for the validation cohort.

The risk score included 10 variables that were significantly associated with the risk of Academic Research Consortium-defined definite or probable stent thrombosis at 1 year:

Type of acute coronary syndrome (4 points for STEMI, 2 points for non-ST-segment elevation ACS with ST deviation, and 1 point for non-ST-segment elevation ACS without ST changes)
Current smoking (1 point)
Insulin-dependent diabetes (2 points)
Prior PCI (1 point)
Baseline platelet count (1 point for 250 to 400 K/µL and 2 points for more than 400 K/µL)
Absence of pre-PCI heparin therapy (1 point)
Aneurysmal/ulcerated lesion (2 points)
Baseline TIMI flow grade 0/1 (1 point)
Final TIMI flow grade less than 3 (1 point)
Number of treated vessels (1 point for two vessels and 2 points for three vessels)

Scores from 1 to 6 are considered low risk, 7 to 9 are intermediate risk, and 10 or higher are high risk.

The rates of stent thrombosis at 1 year were 1.36%, 3.06%, and 9.18% across the three risk tertiles in the derivation cohort (P<0.001 for trend), with a similar trend seen in the validation cohort.

The C-statistics were 0.67 in the derivation cohort and 0.66 in the validation cohort. Performance was comparable for events occurring both early (within the first 30 days) and late (from 1 month to 1 year).

“We believe that the development and initial validation of this stent thrombosis risk score can be a useful tool for both clinical practice and future clinical investigation (future analyses of trials or registries), as it can be a simple way to risk stratify patients immediately following a procedure,” Dangas and colleagues wrote. “The risk score could also be used in the informed consent process to better inform patients of their individual risk of stent thrombosis.”

But Ron Waksman, MD, and Israel Barbash, MD, of MedStar Washington Hospital Center in Washington, D.C., noted some limitations of the tool, including the pooling of different types of patients, the exclusion of important variables associated with stent thrombosis risk, and the use of mostly first-generation drug-eluting stents in the trials.

“It is imperative that the user of such a prediction tool be aware of its capabilities and performance, as well as its limitations, in various clinical scenarios,” they wrote in an accompanying editorial.

“A newly developed risk score for stent thrombosis should be robust and should be tested across broad study populations, stents, and antiplatelet regimens. A new model should also be validated in a setting different from the one in which it was derived,” they wrote. “Unfortunately, this is not the case with the newly proposed model.”

“Until such an encompassing tool is developed and validated,” they wrote, “one should rely on the known stent thrombosis risk factors and tailor an appropriate treatment for each patient.”

The ACUITY trial was funded by The Medicines Company and Nycomed.

Stone has served as a consultant to Abbott Vascular, Boston Scientific, Medtronic, and The Medicines Company. His co-authors reported relationships with Abbott, Regado, Ortho McNeil, Janssen, Merck, Maya Medical, AstraZeneca, Sanofi/Bristol-Myers Squibb, Eli Lilly, and Daiichi Sankyo.

The HORIZONS-AMI trial was supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and The Medicines Company.

Dangas has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb, The Medicines Company, sanofi-aventis, and Abbott Vascular. His co-authors reported relationships with sanofi-aventis, The Medicines Company, Abbott Vascular, Bristol-Myers Squibb, Cordis, AstraZeneca, Daiichi Sankyo, Eli Lilly, Maquet, Roche, Boehringer Ingelheim, Liposcience, Merck, Pozen, Gilead Sciences, WebMD, the NIH, Pfizer, Johnson & Johnson, Schering-Plough, Merck Sharpe and Dohme, GlaxoSmithKline, Regado Biosciences, Boston Scientific, and Bristol-Myers Squibb/Sanofi.

Waksman and Barbash reported that they had no conflicts of interest.

From the American Heart Association:

2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention

Primary source: JACC: Cardiovascular Interventions
Source reference:
Palmerini T, et al “A new score for risk stratification of patients with acute coronary syndromes undergoing percutaneous coronary intervention: the ACUITY-PCI (Acute Catheterization and Urgent Intervention Triage Strategy-Percutaneous Coronary Intervention) risk score” JACC Cardiovasc Interv 2012; 5: 1108-1116.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Dangas G, et al “Development and validation of a stent thrombosis risk score in patients with acute coronary syndromes” JACC Cardiovasc Interv 2012; 5: 1097-1105.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Waksman R, Barbash I “The appropriate use of risk scores” JACC Cardiovasc Interv 2012; 5: 1106-1107.

Todd Neale

Senior Staff Writer

SOURCE:

http://www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/36010

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