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E-News

New point-of-care test quickly detects Lyme neuroborreliosis

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A new research-based point-of-care test has been developed in Finland for detecting the Lyme neuroborreliosis spread by ticks. The test makes rapid initiation of antibiotic treatment possible for patients with borreliosis, which reduces the post-treatment symptoms related to the disease. At the same time, unnecessary antibiotic treatments can be avoided.
The diagnosis of Lyme neuroborreliosis, a tick-borne infection of the nervous system, relies on infection symptoms, cerebrospinal fluid tests, and detection of the antibody production by the activated immune response.
A Finnish company, Reagena, has developed a new point-of-care test to accompany these methods. The test speeds up the diagnostics and helps to target antibiotic treatment appropriately. The idea for the test was developed by Assistant Professor in Bacteriology, Specialist in Clinical Microbiology Jukka Hytönen from the University of Turku whose research group also validated the test.
The new point-of-care test measures CXCL13 concentration in cerebrospinal fluid, since a high CXCL13 concentration is almost exclusively related to untreated neuroborreliosis. Therefore, the CXCL13 chemokine concentration in the cerebrospinal fluid is a new, important biomarker in the diagnostics of neuroborreliosis. The CXCL13 concentration increases more rapidly in early neuroborreliosis than the antibody concentration in the cerebrospinal fluid, and on the other hand, it declines rapidly after the initiation of antibiotic treatment.
– We have demonstrated that this point-of-care test is extremely efficient. As a result, we suggest that the diagnostic practice for neuroborreliosis in Finland would be reorganised so that the CXCL13 concentration would be measured immediately after the lumbar puncture for cerebrospinal fluid. In the current practice, the concentration results may take up to a week, whereas the new point-of-care test provides quick results, says Hytönen.
With the new test, antibiotic treatment can be targeted to those patients with a high probability of neuroborreliosis. According to Hytönen, it is important to note that a rapidly initiated treatment reduces the post-treatment symptoms related to neuroborreliosis. At the same time, unnecessary treatment initiated just in case can be avoided, which is essential in order to minimise the negative effects related to antibiotics and to prevent the development of antibiotic resistance of bacteria.
Doctors Often Initiate Antibiotic Treatments without Laboratory Results
The clinical pictures of borreliosis vary from local skin infection to infections of the central nervous system, joints or the heart. A typical red rash, the so called erythema migrans lesion, developing and spreading around the tick bite should always be treated with antibiotics without laboratory tests.
– If the rash does not develop or is not diagnosed in the early stages of borreliosis, for example due to its location, the infection may spread to other organs from the skin. Symptoms of the disseminated disease include various neurological symptoms, such as facial nerve paralysis and different types of pain in the limbs and body, notes Hytönen.
The diagnosis of Lyme neuroborreliosis is always clinical-based, meaning it is based on the symptoms experienced by the patient and the doctor’s findings, but laboratory tests are necessary to support the diagnostics. At the moment, the most important laboratory test in the diagnostics of neuroborreliosis is the assay of Borrelia-specific antibodies from the patient’s blood and cerebrospinal fluid.
University of Torkuwww.utu.fi/en/news/news/Pages/New-Point-of-care-Test-Quickly-Detects-Lyme-Neuroborreliosis.aspx

Normal tissue BRCA1 methylation associated with risk for high-grade ovarian cancer

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Germline mutations in certain genes are known to cause inherited cancer. Thus, individuals carrying mutations in the so-called breast cancer type I and II genes (BRCA1 and BRCA2) are highly prone to breast as well as ovarian cancers. In cancers, both gene mutations and aberrant regulation of genes (promoter inhibition by methylation of DNA) are known to play pivotal roles regulating cancer growth.
An issue of controversy has been whether aberrant promoter methylation in normal tissue may be a cancer risk factor. Researchers from Haukeland University Hospital in Bergen, Norway, and colleagues analysed for potential impact of normal tissue BRCA1 methylation on ovarian cancer risk. Analysing white blood cells from 934 patients and 1,698 healthy controls, they found BRCA1 methylation among 6.4% of patients diagnosed with ovarian cancer, contrasting 4.2% among controls. Importantly, elevated BRCA1 methylation was confined to patients diagnosed with so-called high-grade serous tumours, the most aggressive variant of ovarian cancer, which also is the variant associated with BRCA1 mutations. Among patients with high-grade serous cancers, methylation was detected among 9.6% of individuals, corresponding to an almost 3-fold increase in risk for individuals harbouring methylation (age-adjusted odds ratio of 2.91). As for non-serous or low-grade serous cancers, methylation frequency resembled controls (5.1% and 4.0%, respectively). In the same report, the researchers replicated these findings in an independent validation study in which they found methylation among 9.1% of patients with high-grade serous cancers versus 4.3% among controls.
According to the authors, it is important to note that white blood cell BRCA1 methylation was detected also among newborns and young adults, indicating that normal tissue BRCA1 methylation may occur as a prenatal event. These findings have significant implications to the understanding of normal tissue methylation and strongly indicate that events occurring before birth influence cancer risk later in life.
bioengineer.orgbioengineer.org/normal-tissue-brca1-methylation-associated-with-risk-for-high-grade-ovarian-cancer/

Organoid profiling personalizes treatments for pancreatic cancer

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Patient-derived organoids, hollow spheres of cells cultured from tumours, can quickly and accurately predict how patients with pancreatic cancer respond to a variety of treatments, facilitating a precision-medicine approach to the deadly disease. The ability to use organoids as a treatment tool was investigated by an international team of researchers led by Dr. David Tuveson, M.D., Ph.D., Cold Spring Harbor Laboratory (CSHL) Professor and Chief Scientist for The Lustgarten Foundation.
“We’ve identified an approach to prioritize treatment strategies for pancreas cancer patients, with the goal of giving them the best shot at survival and the best shot at a good quality of life,” says Dr. Hervé Tiriac, a researcher in Tuveson’s lab and first author of the paper published today in Cancer Discovery.
With only 8 percent of patients surviving 5 years beyond their diagnosis, pancreatic cancer is one of the deadliest cancer types. Currently, surgical removal of the cancerous tissue is the only effective treatment, but because the disease progresses so quickly, only 15 percent of patients are eligible for the procedure. Surgery-ineligible patients can be treated with drugs or chemotherapy, but patient response is highly varied and there is no good method to determine which treatment is best for any given patient.
For several years, Tuveson has been honing organoid technology to improve research into the disease. Aside from taking only as little as six weeks to grow, a major advantage of organoids is that they can be derived from patients with even very advanced pancreatic cancer, using tiny biopsies.
In this latest development, the Tuveson team generated a library of 66 organoids derived from pancreatic ductal adenocarcinoma (PDAC) tumor specimens at various stages of the disease. The researchers demonstrated that the organoids provide an effective precision-medicine “pharmacotyping,” or drug-testing, pipeline. To do this, “we culture the organoid from the patient’s cancer and then test all possible standard-of-care drugs as well as experimental drugs,” Tiriac explains.
The team assessed RNA levels in individual organoids—a way to measure gene activity—to predict the sensitivity of an organoid to the five chemotherapies currently administered to pancreatic cancer patients. They found that three so-called “signatures” of gene activity in the organoids correctly identified patients who had responded well to these drugs. “The signatures should enable physicians to choose the best initial chemotherapy treatment for pancreatic cancer,” Tuveson says.
Tuveson and his team plan to further refine the gene signatures through additional experiments, and to test in clinical trials the ability of signatures found in organoids to predict the responses of pancreatic cancer patients.

Cold Spring Harbour Laboratory
www.cshl.edu/organoid-profiling-personalizes-treatments-for-pancreatic-cancer/

Genomics tool for more accurate identification of rare mutations in cancer cells

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A new computational method developed by researchers at the New York Genome Center (NYGC) allows scientists to identify rare gene mutations in cancer cells with greater accuracy and sensitivity than currently available approaches.
The technique is called Lancet and represents a major advance in the identification of tumour cell mutations, a process known as somatic variant calling.
"With its unique ability to jointly analyse the whole genome of tumour and matched normal cells, Lancet provides a useful tool for researchers to conduct more accurate genome-wide somatic variant calling," notes first author Giuseppe Narzisi, PhD, Senior Bioinformatics Scientist, NYGC.
To identify gene mutations in cancer cells, researchers sequence the genomes of tumour cells and normal cells. Current computational methods then involve comparing both tumour and normal to a reference genome and looking for differences unique to the tumour. Lancet instead uses an approach called micro-assembly to reconstruct the complete sequences of small regions of the genome without relying on a reference. Because the approach does not rely on a reference to identify variants, it also works well in regions of the genome where comparing reads to a reference is challenging for technical reasons. By using a data structure called a coloured de Bruijn graph, Lancet jointly analyses the tumour and normal DNA, providing greater sensitivity to find rare variants unique to the tumour while also providing greater accuracy of differentiating tumour variants from those present in healthy tissue in that individual. Using Lancet to combine the sequencing data from the normal and tumour cells represents a more powerful way of identifying mutations, Dr. Narzisi said, since users are no longer dependent on analysing sequence data from tumour and normal cells separately.
In the study, through extensive experimental comparison on synthetic and real whole-genome sequencing datasets, the researchers demonstrated that Lancet performed better and had higher accuracy and better sensitivity to detect somatic variants compared to the most widely-used somatic variant callers.
"In our study, we show that existing tools are not that precise in scoring mutations, so that some candidate variants which were highly scored by some tools ended up being false positives," Dr. Narzisi said. "That becomes a problem when you want to prioritize which variants to validate using other technologies or you want to move forward with a clinical study. You may end up focusing on variants that do not exist."
EurekAlertwww.eurekalert.org/pub_releases/2018-03/nygc-ngt032218.php

Clearbridge BioMedics and Leica Biosystems to co-market automated solutions for circulating tumour cell (CTC) analysis

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Clearbridge BioMedics and Leica Biosystems have today announced a partnership, co-marketing each other’s products to support circulating tumour cell (CTC) research. This is specifically for the Clearbridge BioMedics ClearCell® FX CTC enrichment system and the Leica Biosystems’ BOND RX staining platform. This new partnership provides an integrated and automated workflow for CTC enrichment and immunostaining, improving on major challenges in CTC liquid biopsy testing, such as handling and standardization.
The ClearCell® FX System is an automated CTC enrichment system, powered by the patented CTChip® FR1 microfluidics biochip. Using a label-free approach, the ClearCell® FX System retrieves wholly-intact and viable CTCs from a standard blood draw. The gentle sorting principle retains high cell integrity and cell surface antigen expression. This coupled with single-step CTC retrieval, provides a seamless integration into pathology lab workflows.
Automated CTC staining on a glass slide is then performed on Leica Biosystems’ BOND RX. The BOND RX platform is an open and flexible system that efficiently automates staining for immunofluorescence (IF), immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) assays. It provides a high-throughput workflow with exceptional consistency and minimal hands-on time.
Linking these two advanced technologies will empower researchers and laboratories with an integrated solution for CTC enrichment and immunostaining, accelerating the development of clinical applications using CTCs.
“The global liquid biopsy market has been growing significantly and will continue to grow, due to trends such as rising prevalence of cancer, preference for personalized medicine and the move towards non-invasive procedures. Today’s partnership announcement between Leica Biosystems and Clearbridge BioMedics provides clinical research laboratories with a seamless end-to-end enrichment and immunostaining solution for CTCs. This will support the development of new therapies and diagnostics for cancer patients,” said Dr Michael Paumen, CEO of Clearbridge BioMedics. www.clearbridgebiomedics.comwww.leicabiosystems.com

Study of thyroid cancer genetics finds new mutations, suggests immunotherapy

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University of Colorado Cancer Center researchers recently completed the largest-ever study of thyroid cancer genetics, mining the data of 583 patient samples of advanced differentiated thyroid cancer and 196 anaplastic thyroid cancers. In addition to identification of specific genes that may drive these cancers and thus provide attractive targets for treatment, the researchers found that in several samples of advanced differentiated and anaplastic thyroid cancer (the most aggressive and dangerous forms of the disease), mechanisms meant to repair faulty DNA had been broken. These broken repair mechanisms led to a subset of thyroid cancers accumulating a high number of genetic alterations – and this “high mutation burden” is a marker recognized by the FDA to recommend treatment with anti-cancer immunotherapies.
“Anaplastic thyroid cancer is a particularly terrible cancer – people wonder what makes it so bad, and advanced thyroid cancer causes significant morbidity. I’ve had a very productive relationship with Foundation Medicine, primarily to study rare salivary gland cancers and I’m pleased that we’ve been able to extend our collaboration to the study of thyroid cancers to hopefully answer some of these questions,” says Daniel Bowles, MD, clinical and translational investigator at CU Cancer Center and Head of Cancer Research at the Denver Veterans Administration Medical Center.
Bowles worked with first author Nikita Pozdeyev, MD, PhD, to analyse tumour samples submitted by oncologists from around the United States to Foundation Medicine for genetic analysis that could inform treatment strategies. Interestingly, the fact that clinicians who submitted these samples were specifically seeking possible treatment strategies meant that the majority of samples were from advanced cancers.
“Genetic analysis of early-stage thyroid cancers is most often not necessary – we successfully treat these tumours with surgery and radioactive iodine,” Pozdeyev says. “But with distant metastases, genetic information becomes important for treatment. Because oncologists had sought this genetic information, our study is enriched for advanced cases.”
The researchers point out that even large treatment centres are likely to only a few of these most dangerous, anaplastic thyroid cancers every year. Due to the current study’s industry-academia collaboration, the researchers were able to explore 196 of these anaplastic thyroid cancers, “giving us sufficient analytical power to use machine learning and statistical analysis to make sense of the data,” Pozdeyev says.
In addition to finding that some anaplastic thyroid cancers carried a high overall mutation burden that could make immunotherapy an attractive treatment option, the group found specific genetic changes driving anaplastic cancers, including amplifications of the genes KDR, KIT and PDGFRA. These genes encode a kind of on-off switch called “receptor tyrosine kinases” that many cancer cells use to speed their growth and proliferation. In this case, these receptor tyrosine kinases happen to be targeted by the drug lenvatinib, which earned FDA approval for use in kidney cancer.  In collaboration with Drs. Bryan Haugen and Rebecca Schweppe, the researchers treated a cohort of thyroid cancer cell lines with lenvatinib, finding that it was the cell line with amplification of KDR, KIT and PDGFRA that was especially sensitive to the drug, hinting that treatment with lenvatinib may be an attractive strategy against a subset of anaplastic thyroid cancers.

University of Colorado Cancer Centerwww.coloradocancerblogs.org/largest-ever-study-of-thyroid-cancer-genetics-finds-new-mutations-suggests-immunotherapy/

Researcher creates ‘Instagram’ of immune system, blending science, technology

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Being on the cutting edge of science and technology excites Hollings Cancer Center (HCC) researcher Carsten Krieg, Ph.D. Each day, he walks into his lab that houses a mass cytometry machine aptly labelled Helios. Krieg explains how it can heat plasma up to 6,000 degrees Celsius, levels comparable to temperatures found on the sun.
This allows the German native, who recently joined the faculty of the Medical University of South Carolina’s departments of immunology and dermatology, to accomplish an interesting feat. He creates a sort of ‘Instagram’ of a person’s immune system. For cancer patients on experimental immunotherapy treatments, the practical application is obvious and exciting, he said.
“What I use here is a very new and nerdy technology, which is called mass cytometry, that allows you with a very high sensitivity to make pictures of your immune system. And this is possible because there’s artificial intelligence, machine learning combined with algorithms that can make a very complex system easy to visualize.”
Basically, how it works is that researchers stain cells using rare metal-conjugated antibodies that target surface and intracellular proteins. “Normally in biological tissues, there are no rare metals, so this technique offers greater sensitivity in detecting targets.”
Inside the Helios, the cells are ionized using an inductively-coupled plasma. The ions derived from each stained cell are maintained in discrete clouds that can be detected in a mass spectrometer. The technique can potentially detect up to 100 markers per cell, although, due to practical restrictions, about 40 are more realistic, he said. Then researchers use artificial intelligence and bioinformatics to create a two-dimensional mapping that can read the results, creating an Instagram of millions of blood cells.
This is critical as Krieg and other cancer researchers hope to advance the field of immunotherapy. Though immunotherapy has shown great promise, the vast majority of patients either don’t respond, have adverse side effects or relapse. Krieg, who comes to HCC from the University Research Priority Program (URPP) in Zurich, Switzerland, wanted to know if the technology could be used to predict which patients might respond to certain treatments.
While in Zurich, he and his colleagues decided to use the technique to study melanoma. The research identified biomarkers in the blood that can predict whether metastatic melanoma cancer patients will respond positively to immunotherapy. The goal was to see if a blood test for these biomarkers could identity those who are likelier to benefit, while allowing “non-responders” to begin other treatments without losing time, he said. “It’s a decision instrument for physicians and for the health care system.”
It’s also a powerful research tool as it gets to the mechanisms behind what makes immunotherapy work. The recent study found an immune cell type known as classical monocytes in the peripheral blood may be a potential biomarker for patients who will respond to anti-PD-1 immune checkpoint therapy in metastatic melanoma. “Surprisingly, what we clearly found is that it’s the frequency of monocytes that is enhanced in responders over non-responders before immunotherapy.”
Hollings Cancer Centeracademicdepartments.musc.edu/newscenter/2018/hcc-krieg-instagram/index.html

Genetic link found between the immune system and lymphoma

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People who inherit genetic changes which alter the function of their immune system are at increased risk of developing Hodgkin lymphoma, a major new study reports.
Scientists at The Institute of Cancer Research, London, identified six new genetic changes that increase the risk of developing Hodgkin lymphoma – one of the most common cancers in young adults.
Many of the DNA changes seemed to affect the function of the immune system, and three had previously been associated with autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or lupus.
The researchers stressed that the link did not mean people with autoimmune diseases are at increased risk of lymphoma, but did offer important genetic clues for understanding both lymphoma and autoimmune diseases better.
One of the genetic changes discovered increases the risk of Hodgkin lymphoma by more than a third and others by at least 15% each – information that could point to new targeted drugs for the disease.
Research at the ICR is underpinned by generous contributions from our supporters. Find out more about how you can contribute to our mission to make the discoveries to defeat cancer.
Scientists at the ICR analysed genetic data from 5,314 cases of Hodgkin lymphoma and 16,749 controls, from four different European studies.
The study is the largest of its kind for Hodgkin lymphoma.
For most people, Hodgkin lymphoma can be successfully treated with first-line therapies – but there is a need for new treatments for those for whom first line treatment has failed.
The researchers identified six new single-letter changes in DNA that were linked to the development of Hodgkin lymphoma – and five of these affect the way a type of white blood cell, called B cells, develop.
Hodgkin lymphoma is a cancer of the B cells – which are responsible for producing antibodies as a critical component of the immune system.
The study also picked out clear differences in genetic risk between two different subtypes of Hodgkin Lymphoma – nodular sclerosis Hodgkin Lymphoma (NSHL) and mixed cellularity Hodgkin Lymphoma (MCHL).
For example, a single-letter change located in DNA near the gene LPP increased the risk of NSHL by 37%, but had little effect on the risk of developing MCHL.
Professor Richard Houlston, Professor of Molecular and Population Genetics at the ICR, said: “Hodgkin lymphoma is a cancer of immune cells called B cells, and our study links the risk of the disease to changes in the genes that control how B cells develop. Interestingly, we found that some of the genetic changes we have linked to Hodgkin lymphoma have previously been associated with the risk of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
“It doesn’t mean that if you develop an autoimmune disease you are at increased risk of lymphoma, but it does offer fascinating genetic clues to these diseases. The new information could point towards new ways of diagnosing, treating, or even helping to prevent Hodgkin lymphoma.”
Institute of Cancer Research
www.icr.ac.uk/news-archive/genetic-link-found-between-the-immune-system-and-lymphoma

Greiner Bio-One looks back on successful year

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Greiner Bio-One had a successful business year in 2017, further reinforcing its market position thanks to strong growth, new sites and innovative product solutions. The takeover of its long-standing, exclusive distribution partners VACUETTE España and VACUETTE Portugal in March 2017 has enabled greater proximity to customers and targeted market cultivation. As a result of that takeover, Greiner Bio-One now has its own subsidiaries on two further key markets in Europe. In addition, the headquarters in Kremsmünster were expanded and an investment was made in a warehouse facility at the site in Hungary.

In July 2017, Greiner Bio-One acquired 90% of shares in Vigmed Holding AB, a listed technology and trade company based in Helsingborg, Sweden. That has enabled I.V. catheters with a safety mechanism to be added to the Preanalytics safety products range. Another innovation on the market is the MiniCollect Complete tube – a version in which the MiniCollect standard tube is irreversibly assembled in a carrier tube. That enhancement enables easier, more efficient and more hygienic handling, since both blood collection and subsequent analyses can be performed using the same sample vessel.
In addition, Greiner eHealth Technologies (GeT) achieved a significant success in 2017 with the implementation of its digital, fully process-optimized system solution for preanalytical and postanalytical processes as a pilot project at the Styria General Hospital (Austria). By combining VACUETTE barcode tubes with a software solution, GeT plays an important part in optimizing preanalytical and postanalytical processes and ensuring enhanced data privacy, patient safety and quality.
Thanks to the new and innovative NIMBUS and STARlet CX platforms of the BioScience division, all manual pipetting steps of the PapilloCheck HPV test can be automated and qualitative detection of HPV (human papillomavirus) is faster and more efficient. Together with technology provided by cooperation partner Nano3D Biosciences in Houston (USA), the CELL-STAR cell culture vessels with a cell-repellent service achieve particularly good results in the cultivation of 3D cell structures.

Greiner Bio-One has set itself ambitious goals for 2018. One focus will be on expanding its market position in Asia and North America. In addition, it plans to establish new distribution subsidiaries outside of Europe. The further expansion of services and product training courses  
for customers will also play a key role this year. Production capacity will be increased at several sites worldwide. In Frickenhausen (Germany), construction of a new high-bay warehouse is set to be completed and work is scheduled to begin on the second phase of extending the office and production areas. www.gbo.com/preanalytics

Genetic link to IBS identified in women

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New research coordinated from Karolinska Institutet links certain DNA variants to increased risk of irritable bowel syndrome (IBS) in women. The findings might help explain why IBS is more common in women than in men.
Irritable bowel syndrome is the most common gastrointestinal disorder. More than 10 per cent of the population, women more than men, suffer from recurrent symptoms including abdominal pain, gas, diarrhoea and constipation. What causes IBS is largely unknown, which hampers the development of effective treatment for many patients. Genetic predisposition to IBS is recognised, although poorly investigated.
Now an international research team led by scientists from Karolinska Institutet in Sweden have identified DNA variants that are associated with increased risk of IBS, but only in women.
“Exploiting the large UK Biobank resource, as well as several patient cohorts from European and US expert centres, we have been able to study genetic predisposition to IBS with increased statistical power, better than ever before,” says corresponding author Mauro D’Amato, visiting professor at Karolinska Institutet’s Department of Medicine in Solna and coordinator of the bellygenes initiative that led to the discovery.
The researchers used genotype data from more than 300,000 UK Biobank participants in a genome-wide association study (GWAS). They found DNA variants that associate with increased risk of a doctor’s diagnosis of IBS in women but not in men, specifically from a region on chromosome 9 previously reported to also influence puberty timing in women (age at first menstruation).
By following up this result in 2,045 patients from IBS expert centres in Sweden, Belgium, the Netherlands, Italy and the US, the researchers observed further associations with constipation-predominant IBS as well as harder stools, again only in women.
“Although we cannot point to individual genes at this early stage, we believe these results are exciting, as they converge with existing data on female preponderance and a role of sex-hormones in IBS,” says Mauro D’Amato.
Karolinska Instituteki.se/en/news/genetic-link-to-ibs-identified-in-women

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