How to diagnose and manage Heparin-Induced Thrombocytopenia (HIT)?
by Pr Yves Gruel – Professor of Hematology, Trousseau Hospital and University Francois Rabelais, Tours (France)

Type II Heparin-Induced Thrombocytopenia (HIT) is an immune-mediated adverse effect of heparin treatment. Although rare, this complication can be serious and possibly life threatening.

Approximately one third of hospitalized patients are exposed to heparins. It is therefore of great importance to know how to:

• diagnose HIT in order to identify the patients who will benefit from an alternative anticoagulant treatment

• avoid HIT overdiagnosis to minimize the risks of bleedings and the costs associated with the use of alternative anticoagulants

This webinar will focus on HIT pathophysiology, and will outline the necessity of an accurate diagnosis and how it can be achieved. Alternative anticoagulant treatment options will also be discussed.

This 30-minute presentation will be followed by a 15-minute live chat with the speaker.

Pr Gruel is the Head of the Hematology Department at Trousseau University Hospital in Tours and is also leading the Hemophilia Care Center.
Apart from his clinical activity focusing on bleeding and thrombotic disorders, his main research topics are today heparin-induced thrombocytopenia (HIT) and the role of specific coagulation proteins in cancer.

He is currently the President of GEHT (French study Group on Haemostasis and Thrombosis), and Chairman of the ISTH Scientific and Standardization Committee on Platelet Immunology.

Save the date! Friday January 31st 2014 at 4:00 p.m. CET (Central European Time)

To attend this webinar, please register at www.stagowebinars.com.

Changes to two previously unstudied genes are the centrepiece of a new theory regarding the cause and development of endometriosis, a chronic and painful disease affecting 1 in 10 women.

The discovery by Northwestern Medicine scientists suggests epigenetic modification, a process that enhances or disrupts how DNA is read, is an integral component of the disease and its progression. Matthew Dyson, PhD, research assistant professor of Obstetrics and Gynecology-Reproductive Biology Research and Serdar Bulun, MD, chair of Obstetrics and Gynecology also identified a novel role for a family of key gene regulators in the uterus.

‘Until now, the scientific community was looking for a genetic mutation to explain endometriosis,’ said Dr. Bulun, a member of the Center for Genetic Medicine and the Robert H. Lurie Comprehensive Cancer Center. ‘This is the first conclusive demonstration that the disease develops as a result of alterations in the epigenetic landscape and not from classical genetic mutations.’

Women develop endometriosis when cells from the lining of the uterus, usually shed during menstruation, grow in other areas of the body. The persistent survival of these cells results in chronic pelvic pain and infertility. Although the cause of the disease has remained unknown on a cellular level, there have been several different models established to explain its development.

Endometriosis only occurs in menstruating primates, suggesting that the unique evolution behind uterine development and menstruation are linked to the disease. Scientists consider retrograde menstruation – cells moving up the fallopian tubes and into the pelvis – as one probable cause.
Previous models, however, have been unable to explain why only 10 percent of women develop the disease when most experience retrograde menstruation at some point. Nor do they explain instances of endometriosis that arise independent of menstruation.

Bulun and Dyson propose that an epigenetic switch permits the expression of the transcription factor GATA6 rather than GATA2, resulting in progesterone resistance and disease development.

‘We believe an overwhelming number of these altered cells reach the lining of the abdominal cavity, survive and grow,’ said Dr. Bulun, obstetrician-gynaecologist-in-chief at Northwestern Memorial’s Prentice Women’s Hospital. ‘These findings could someday lead to the first non-invasive test for endometriosis.’

Clinicians could then prevent the disease by placing teenagers predisposed to this epigenetic change on a birth control pill regimen, preventing the possibility of retrograde menstruation in the first place.

Dyson will also look to use the epigenetic fingerprint resulting from the presence of GATA6 rather than GATA2 as a potential diagnostic tool, since these epigenetic differences are readily detectable.

‘These findings have the potential to shift how we view and treat the disease moving forward,’ Dr. Bulun said. Feinberg School of Medicine

UCSF scientists say new finding could lead to more accurate prognosis
The stiffening of breast tissue in breast-cancer development points to a new way to distinguish a type of breast cancer with a poor prognosis from a related, but often less deadly type, UC San Francisco researchers have found in a new study.
The findings may lead eventually to new treatment focused not only on molecular targets within cancerous cells, but also on mechanical properties of surrounding tissue, the researchers said.
In a mouse model of breast cancer, scientists led by Valerie Weaver, PhD, professor of surgery and anatomy and director of the Center for Bioengineering and Tissue Regeneration at UCSF, identified a biochemical chain of events leading to tumour progression. Significantly, this chain of events was triggered by stiffening of scaffolding tissue in the microscopic environment surrounding pre-cancerous cells. The stiffening led to the production of a molecule that can be measured in human breast cancer tissue, and which the researchers found was associated with worse clinical outcomes.
‘This discovery of the molecular chain of events between tissue stiffening and spreading cancer may lead to new and more effective treatment strategies that target structural changes in breast cancers and other tumours,’ Weaver said.
In the mouse experiments, Janna Mouw, PhD, a UCSF associate specialist who works in Weaver’s lab, found that tissue stiffening in microscopic scaffolding known as the extracellular matrix, or ECM, increases signalling by ECM-associated molecules, called integrins. The integrins in turn trigger a signalling cascade within cells that leads to the production of a tumour-promoting molecule called miR-18a.
Unlike most cellular signalling molecules thus far studied by scientists, miR-18a is not a protein or a hormone, but rather a microRNA, another type of molecule recognised in recent years to play an important role in the lives of cells. The miR-18a dials down the levels of a protective, tumour-suppressing protein called PTEN, which often is disabled in cancerous cells, leading to abnormal biochemical signalling that can promote cancer growth. University of California – San Francisco

The CYP1B1*3 genotype is a potential marker for poor prognosis for men with castration resistant prostate cancer who received docetaxel-based therapy. Men carrying the homozygous CYP1B1*3 genotype (o) had reduced survival times compared to patients carrying at least one copy of the unmutated form of the gene (*).

Docetaxel remains the frontline standard of care for castration-resistant prostate cancer (CRPC), which grows without stimulation from male hormones. However, patient responses to this drug are highly variable. Researchers at CCR can now search a patient’s genome for a specific genomic variant (called a polymorphism) that predicts lesser responses to docetaxel among CRPC patients.
Led by William Douglas Figg, Sr., Pharm.D., a Senior Investigator in CCR’s Medical Oncology Branch, and Staff Scientist, Tristan Sissung, Ph.D., from the Pharmacogenetics Core of the Clinical Pharmacology Program, the clinical team studied a commonly inherited polymorphism in the cytochrome P450 1B1 (CYP1B1) gene. Specifically, the 432ValVal polymorphism in CYP1B 9 (called the CYP1B1*3 polymorphism) was shown to reduce a patient’s survival following docetaxel treatment by more than half—from 30.6 to 12.8 months in combination trials, and from 15.3 to 7.5 months in trials that compared docetaxel alone to prednisone alone. Figg and colleagues conclude that testing for CYP1B1*3 should guide docetaxel treatment decisions in patients with CRPC, because it could spare many from taking a drug unlikely to help them. Similarly, CYP1B1*3 testing could inform treatment decisions involving docetaxel and other therapies in breast, ovarian, and non-small cell lung cancers.
While examining the mechanism of action for docetaxel, which inhibits microtubule disassembly, Figg and his team noted that this drug was being metabolized similarly by cells whether or not they carried the CYP1B1*3 variant, based upon clearance data, which was the same for the differing genotypes. They wanted to know what was occurring at the biochemical level. They knew that the CYP1B1 enzyme metabolizes endogenous steroids, including estrogen, so they looked at how estrogen metabolites interact with tubulin, which makes up microtubules. They found that the estrogen metabolite estradiol-3,4 quinone interferes with docetaxel’s ability to promote tubulin formation and binds directly with docetaxel, creating a drug-estrogen adduct.
Based on these findings, Figg and colleagues proposed that CYP1B1*3 interferes with docetaxel therapy by boosting the production of a metabolite that displaces docetaxel from its target and by creating adducts with more limited potency than the drug itself. ‘Patients who harbor the variant make more estradiol-3,4 quinone, which may work against docetaxel efficacy, while patients who have the wild-type gene make less of it and respond better to the drug, ‘ explains Sissung.
The frequency varies among racial and ethnic groups worldwide, with approximately 20 percent of the Caucasian population harboring the CYP1B1*3 variant. ‘We want to limit the number of people who receive docetaxel without experiencing benefits from the treatment,’ said Figg.
Figg has now patented the use of CYP1B1*3 genotyping in blood samples to mark patients unlikely to benefit from docetaxel treatment in CRPC. ‘We think this genetic marker has value, and we are willing to work with other groups to validate the findings prospectively,’ he said. ‘The goal is to make sure this test reaches the market so it can be used to improve treatment planning.’ Center for Cancer Research

A new technology developed by Harvard Medical School researchers at the Massachusetts General Hospital Center for Systems Biology allows the simultaneous analysis of hundreds of cancer-related protein markers from minuscule patient samples gathered through minimally invasive methods. This powerful and sensitive technology uses antibodies linked to unique DNA ‘barcodes’ to detect a wide range of target proteins.

It could serve as a tool to help clinicians gain insights into the biology of cancer progression as well as determine why certain cancer therapies stop working or are ineffective to begin with.

Minimally invasive techniques—such as fine-needle aspiration or circulating tumour cell analysis—are increasingly employed to track treatment response over time in clinical trials, as the tests can be simple and cheap to perform. Fine-needle aspirates are also much less invasive than core biopsies or surgical biopsies, since very small needles are used. The challenge has been to comprehensively analyse the very few cells that are obtained via this method.

‘What this study sought to achieve was to vastly expand the information that we can obtain from just a few cells,’ explained Cesar Castro, HMS instructor in medicine at Mass General and a co-author of the paper. ‘Instead of trying to procure more tissue to study, we shrank the analysis process so that it could now be performed on a few cells.’

Until now, pathologists have been able to examine only a handful of protein markers at a time for tumour analyses. With this new technology, the researchers have demonstrated the ability to look at hundreds of markers simultaneously, down to the single-cell level.

‘We are no longer limited by the scant cell quantities procured through minimally invasive procedures,’ Castro said. ‘Rather, the bottleneck will now be our own understanding of the various pathways involved in disease progression and drug target modulation.’

The new method uses an approach known as DNA-barcoded antibody sensing, in which unique DNA sequences are attached to antibodies against known cancer marker proteins. The DNA ‘barcodes’ are linked to the antibodies with a special type of glue that breaks apart when exposed to light. When mixed with a tumour sample, the antibodies seek out and bind to their targets; then a light pulse releases the unique DNA barcodes of these bound antibodies that are subsequently tagged with fluorescently labelled complementary barcodes. The tagged barcodes can be detected and quantified via imaging, revealing which markers are present in the sample.

After initially demonstrating and validating the technique’s feasibility in cell lines and single cells, the team tested it on samples from patients with lung cancer. The technology was able to reflect the great heterogeneity—differences in features such as cell-surface protein expression—of cells within a single tumour and to reveal significant differences in protein expression between tumours that appeared identical under the microscope. Examination of cells taken at various time points from participants in a clinical trial of a targeted therapy drug revealed patterns that distinguished those who did and did not respond to treatment.

‘We showed that this technology works well beyond the highly regulated laboratory environment, extending into early-phase clinical trials,’ said Castro, who is also a medical oncologist in the Mass General Cancer Center and director of the Cancer Program within the hospital’s Center for Systems Biology. ‘In this era of personalised medicine, we could leverage such technology not only to monitor but actually to predict treatment response. By obtaining samples from patients before initiating therapy and then exposing them to different chemo-therapeutics or targeted therapies, we could select the most appropriate therapy for individual patients.’ Harvard Medical School