An international team of researchers led by KU Leuven has developed a new test to help doctors diagnose ovarian tumours and choose the most appropriate treatment. The researchers have recently described the test called ADNEX `

Existing predication models for ovarian cancer discriminate between benign and malignant tumours but lack accuracy and are unable to sub-classify different types of malignant tumour. This makes determining the appropriate treatment difficult, since some ovarian tumours require more serious treatment than others.

The new test developed by Professor Ben Van Calster (KU Leuven) in cooperation with the International Ovarian Tumour Analysis group (IOTA) not only discriminates between benign and malignant tumours but also makes it possible to accurately identify and classify malignant tumours into four types: borderline, stage 1 invasive, stage II-IV invasive and secondary metastatic.

The test is based on the patient’s clinical information, a simple tumour marker blood test and features that can be identified on an ultrasound scan. In addition to identifying the type of tumour, the test also expresses the confidence of the diagnosis as a percentage.

Doctors can use the test in a clinical database or by entering the patient’s details into a smartphone app, which was demonstrated to gynaecologists at the International Society for Ultrasound in Obstetrics and Gynecology World Congress in Barcelona last month. The authors of the study say doctors could start using ADNEX straight away.

Successful treatment depends in large part on the correct identification of the type of tumour, but this can be difficult. As a result, many women with ovarian cancer are not referred to the right specialist and some undergo more serious operations than necessary. A benign ovarian tumour often does not even need treatment at all.

But for malignant tumours especially, determining the tumour type is crucial to selecting the right specialist surgeon and treatment.

The researchers developed the test using data from almost 6,000 ovarian cancer patients, which were gathered and analysed by the IOTA group led by Professor Dirk Timmerman of UZ Leuven (University Hospitals Leuven), KU Leuven’s network of research hospitals. University of Leuven

Partnering with head and neck surgeons, pathologists at Dartmouth Hitchcock Medical Center’s Norris Cotton Cancer Center developed a new use for an old test to determine if a patient’s cancer is recurring, or if the biopsy shows benign inflammation of mucosal tissues. Lead author Candice C. Black, DO explains how her team confirmed the utility of ProExC, an existing antibody cocktail commonly used for pathology tests of the uterine cervix. The team’s goal remained sorting out problems presented by the frequently equivocal pathology results when surgeons need to determine the difference between true pre-neoplasia and merely inflammatory/reactive biopsies.

‘In reality, the biopsies we receive from head and neck patients are often tiny and poorly oriented. Particularly in smokers and other post-treatment patients, inflammation may cause reactive epithelial atypia that is difficult to distinguish from dysplasia,’ reported Dr. Black. ‘This new use of the ProExC antibody cocktail allows us to provide the head and neck surgeons with key information about which patients have post-therapy complications versus those with true tumour recurrence.’

The World Health Organization (WHO) provides two systems for classifying dysplasia, and both have been criticized as being too subjective and failing to predict disease progression. A spectrum of histologic aberrations in mucosal membranes can mimic dysplasia, as well as neo-plastic cytologic and architectural changes. This is the first attempt to use ProExC as a diagnostic adjunct in the detection of head and neck mucosal biopsies.

Pathologists used 64 biopsies from the Dartmouth archives to setup groups of patients who had and had not progressed to cancer, and found statistically significant differences between the progression cases and the controls in terms of the stain scores using ProExC. ‘The surgeons wanted to know if the mucosa was neoplastic or just inflamed and reactive. The old-school answer of ‘atypia’ simply isn’t sufficient to make decisions about therapeutic interventions,’ described Black. Norris Cotton Cancer Center at Dartmouth-Hitchcock

A novel study by the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) found that an increase in a gene known as Leo1 affects other genes that are directly implicated in acute myelogenous leukaemia (AML), increasing the incidence of cancer.

Led by Associate Professor Chng Wee Joo, Deputy Director and Senior Principal Investigator at CSI Singapore and Director of the National University Cancer Institute, Singapore, the scientists discovered that inhibition of Leo1 and Leo1 downstream signalling pathways provide an avenue for targeted treatment of AML.

In addition, this is the first study to suggest that the protein PRL-3 plays a role in the regulation of ribonucleic acid (RNA) related processes, a finding which advances the understanding of how the protein contributes to cancer progression. The team’s work represents the first large-scale quantitative survey of proteins regulated by PRL-3 in leukaemia.

The elevated expression of PRL-3 has been implicated in the progression and metastasis of an array of cancer types, including gastric, ovarian, cervical, lung, liver, and breast. In particular, the protein PRL-3 is overexpressed in about half of AML patients and associated with poor survival. Assoc Prof Chng and his team were the first to report that elevated PRL-3 protein expression occurs in about 47 per cent of AML cases while being absent from normal myeloid cells in bone marrow. As a result, PRL-3 is deemed as an attractive therapeutic target that spares normal tissues.

Previously, knowledge of the mechanisms of PRL-3 was limited. In this study, the researchers used a new, advanced SILAC-based mass spectrometry to identify all the protein changes induced by PRL-3 in a comprehensive manner. Using this approach, they discovered that the gene Leo1 serves as a novel target of PRL-3 phosphatase, and inhibition of Leo1 as well as Leo1 downstream signalling pathways provide an avenue for PRL-3 targeted therapy for AML patients.

In the next phase of research, the team is validating several important proteins directly downstream of Leo1 that can possibly be used as biomarkers and drug targets to improve treatment for leukaemia with PRL-3 overexpression.

Assoc Prof Chng said, ‘Our previous studies showed that PRL-3 is clinical and biologically important in acute myelogenous leukaemia, and may therefore be a useful treatment target. In the current study, we have taken the work further by understanding how PRL-3 confers cancer properties to the leukaemia cells. This now provides a framework for rational design of a treatment based on mechanistic understanding. In the process, we will also develop biomarkers to better select patients for the treatment and hence, progress towards personalising treatment for leukaemia patients.’ EurekAlert

Targeted therapies are a growing and ground-breaking field in cancer care in which drugs or other substances are designed to interfere with genes or molecules that control the growth and survival of cancer cells. Now, scientists at Virginia Commonwealth University Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) have identified a novel interaction between a microRNA and a gene that could lead to new therapies for the most common and deadly form of brain tumour, malignant glioma.

In a study, a team of scientists led by Luni Emdad, M.B.B.S., Ph.D., and Paul B. Fisher, M.Ph., Ph.D., provided the first evidence of an important link between a specific microRNA, miR-184, and a cancer promoting gene, SND1, in the regulation of malignant glioma. miR-184 is known to suppress tumour development by regulating a variety of genes involved in cancer growth, while SND1 has been shown to play a significant role in the development of breast, colon, prostate and liver cancers. Through a variety of preclinical experiments, the team demonstrated that increasing the expression of miR-184 slows the growth and invasive characteristics of glioma cells through direct regulation of SND1. Additionally, they showed that reduced levels of SND1 led to reduced levels of STAT3, a gene that has been shown to promote the most lethal characteristics of brain cancer.

‘Patients suffering from brain tumours are in desperate need of improved therapies,’ says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM. ‘We’re hopeful that this new understanding of the relationship between miR-184 and SND1 ultimately will lead to the development of new drugs that reduce SND1 expression and improve patient outcomes.’

Prior studies have shown that levels of miR-184 are unusually low in tissue samples from patients with malignant gliomas. Using advanced computer analysis techniques designed to study and process biological data, the researchers identified SND1 among a handful of other genes that miR-184 helps regulate. Knowing SND1 is implicated in a variety of cancers and having previously defined its role in liver cancer, Emdad, Fisher and their colleagues explored this relationship further. They confirmed low levels of miR-184 expression in human glioma tissue samples and cultured cell lines as well as an increase in the expression of SND1 compared to normal brain tissue. Using data from a large public brain tumour database called REMBRANDT, the researchers confirmed that patients with lower levels of SND1 survived longer than those with elevated SND1 expression.

‘We still have a long way to go and many challenges to overcome before we will have therapies that are ready for clinical use, but this is a significant first step in the process,’ says Emdad, member of the Cancer Molecular Genetics research program at Massey, assistant professor in the VCU Department of Human and Molecular Genetics and member of the VIMM. ‘Future studies will aim to explore the relationship between SND1 and STAT3, identify additional microRNAs that may be relevant to malignant glioma and explore the effects of drugs that block SND1 expression in more advanced preclinical models.’ EurekAlert

Investigators at Nationwide Children’s Hospital have developed an analysis “pipeline” that slashes the time it takes to search a person’s genome for disease-causing variations from weeks to hours.

“It took around 13 years and $3 billion to sequence the first human genome,” says Peter White, PhD, principal investigator and director of the Biomedical Genomics Core at Nationwide Children’s and the study’s senior author. “Now, even the smallest research groups can complete genomic sequencing in a matter of days. However, once you’ve generated all that data, that’s the point where many groups hit a wall. After a genome is sequenced, scientists are left with billions of data points to analyse before any truly useful information can be gleaned for use in research and clinical settings.”

To overcome the challenges of analysing that large amount of data, Dr. White and his team developed a computational pipeline called “Churchill.” By using novel computational techniques, Churchill allows efficient analysis of a whole genome sample in as little as 90 minutes.

“Churchill fully automates the analytical process required to take raw sequence data through a series of complex and computationally intensive processes, ultimately producing a list of genetic variants ready for clinical interpretation and tertiary analysis,” Dr. White explains. “Each step in the process was optimized to significantly reduce analysis time, without sacrificing data integrity, resulting in an analysis method that is 100 percent reproducible.”

The output of Churchill was validated using National Institute of Standards and Technology (NIST) benchmarks. In comparison with other computational pipelines, Churchill was shown to have the highest sensitivity at 99.7 percent; highest accuracy at 99.99 percent and the highest overall diagnostic effectiveness at 99.66 percent.

“At Nationwide Children’s we have a strategic goal to introduce genomic medicine into multiple domains of paediatric research and healthcare. Rapid diagnosis of monogenic disease can be critical in new-borns, so our initial focus was to create an analysis pipeline that was extremely fast, but didn’t sacrifice clinical diagnostic standards of reproducibility and accuracy” says Dr. White. “Having achieved that, we discovered that a secondary benefit of Churchill was that it could be adapted for population scale genomic analysis.”

By examining the computational resource use during the data analysis process, Dr. White’s team was able to demonstrate that Churchill was both highly efficient (>90 percent resource utilization) and scaled very effectively across many servers. Alternative approaches limit analysis to a single server and have resource utilization as low as 30 percent. This efficiency and capability to scale enables population-scale genomic analysis to be performed. Nationwide Children’s Hospital