Royal Philips and LabPON, the first clinical laboratory to transition to 100% histopathology digital diagnosis, recently announced its plans to create a digital database of massive aggregated sets of annotated pathology images and big data utilizing Philips IntelliSite Pathology Solution. The database will provide pathologists with a wealth of clinical information for the development of image analytics algorithms for computational pathology and pathology education, while promoting research and discovery to develop new insights for disease assessment, including cancer.
Deep learning algorithms have the potential to improve the objectivity and efficiency in tumour tissue diagnosis. In recent years, ‘deep learning’ techniques for image analysis have quickly become the state of the art in computer vision and has surpassed human performance in a number of tasks. The challenge for executing deep learning techniques is having access to a database with sufficient high volume and high quality data from which to develop the algorithms. As one of the largest pathology laboratories in the Netherlands, LabPON will contribute its repository of approximately 300,000 whole slide images (WSI) they prospectively create each year to the database. This will contain de-identified datasets of annotated cases that are manually commented by the pathologist, and will comprise of a wide variety of tissue and disease types, as well as other pertinent diagnostic information to facilitate deep learning.
“Deep learning focuses on the development of advanced computer programs that automatically understand and digitally map tissue images in considerable detail: The more data available, the more refined the computer analysis will be.” Said Peter Hamilton, Group Leader Image Analytics at Philips Digital Pathology Solutions. “Together, LabPON and Philips have the competence and skills to realize this.”
During a time where the pathologist shortage is mounting and cancer caseloads are increasing, the accurate diagnosis and grading of cancer has become increasingly complex, placing significant pressures on pathology services. Technologies such as computational pathology, could help pathologists with tools to work in the most efficient way possible.
“The role of the pathologist remains important by making the definitive diagnosis, which has a high impact on the patient’s treatment. Software tools could help to relieve part of the pathologists’ work such as identifying tumour cells, counting mitotic cells or identifying perineural and vaso-invasive growth, as well as carrying out measurements in a more accurate and precise way,” said Alexi Baidoshvili, pathologist at LabPON. “This ultimately could help to improve the quality of diagnosis and make it more objective.”
Next to the development of computational algorithms for diagnostic use, Philips intends to make available the database to research institutions and other partners through its translational research platform. This could enable selected parties to interrogate and combine massive datasets with the goal to discover new insights that ultimately could be translated into new personalized treatment options for patients.
www.philips.com/digitalpathology

Specific genetic errors that trigger congenital heart disease (CHD) in humans can be reproduced reliably in Drosophila melanogaster – the common fruit fly – an initial step toward personalized therapies for patients in the future.

“Studying CHD in fruit flies provides a fast and simple first step in understanding the roles that individual genes play in disease progression,” says Zhe Han, Ph.D., a principal investigator and associate professor in the Center for Cancer & Immunology Research at Children’s National Health System and senior author of the paper. “Our research team is the first to describe a high-throughput in vivo validation system to screen candidate disease genes identified from patients. This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors,” Han says.

Some 134 genes have been implicated in causing CHD, a birth defect that affects 8 in 1,000 newborns, according to the National Institutes of Health. The research team led by Han used high-throughput techniques to alter the activity of dozens of genes in flies’ hearts simultaneously in order to validate genes that cause heart disease.

“Our team was able to characterize the effect of these specific genetic alterations on heart development, structure and activity,” Han adds. “The development of the human heart is a complicated process in which a number of different cell types need to mature and differentiate to create all of the structures in this essential organ. The precise timing of those cellular activities is critical to normal heart development, with disruptions in the structure of proteins called histones linked to later heart problems.”.

Of 134 genes studied by the research team, 70 caused heart defects in fruit flies, and several of the altered genes are involved in modifying the structure of histones. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional and developmental roles for these genes, including a subgroup encoding histone H3K4 modifying proteins. The scientists then corroborated their work by reliably reproducing in flies the effect of specific genetic errors identified in humans with CHD.

“This may allow researchers to replicate individual cases of CHD, study them closely in the laboratory and fashion treatments personalized to that patient specifically,” he adds. “Precise gene-editing techniques could be used to tailor-make flies that express a patient’s specific genetic mutation. Treating CHD at the level of DNA offers the potential of interrupting the current cycle of passing along genetic mutations to each successive generation.”

Children’s National Health System childrensnational.org/news-and-events/childrens-newsroom/2017/studying-chd-in-fruit-flies

Scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health are the first to report immune signatures differentiating two subgroups of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): “classical” and “atypical.” This complex, debilitating disease is characterized by symptoms ranging from extreme fatigue after exertion to difficulty concentrating, headaches, and muscle pain.
Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses.
To uncover evidence of these disease types, first author Mady Hornig, MD, director of translational research at CII and associate professor of Epidemiology at Mailman, and colleagues used immunoassays to measure levels of 51 immune biomarkers in cerebrospinal fluid samples taken from 32 cases of classical and 27 cases of atypical ME/CFS. All study participants were diagnosed using the same standard criteria, but atypical cases either had prior histories of viral encephalitis, illness after foreign travel or blood transfusion, or later developed a concurrent malady—seizure disorders, multiple sclerosis-like demyelinating disorders, Gulf War Illness, or a range of cancers—at rates much higher than seen in the general population.
Their analysis revealed lower levels of immune molecules in individuals with atypical ME/CFS than those with a classical presentation and course of illness, including dramatically lower levels of interleukin 7 (IL7), a protein linked to viral infections, and interleukin 17A (IL 17A) and chemokine (C-X-C motif) ligand 9 (CXCL9), inflammatory molecules implicated in a variety of neurological disorders.
“We now have biological evidence that the triggers for ME/CFS may involve distinct pathways to disease, or, in some cases, predispose individuals to the later development of serious comorbidities,” says Hornig. “Importantly, our results suggest that these early biomarker profiles may be detectable soon after diagnosis of ME/CFS, laying a foundation for better understanding of and treatments for this complex and poorly understood illness.”
“Early identification of patients who meet the usual clinical criteria when first diagnosed but then go on to develop atypical features would help clinicians like myself identify and treat these complex cases and even prevent fatal outcomes,” says co-author Daniel L. Peterson, MD, principal clinician at Sierra Internal Medicine in Incline Village, NV.
The new study builds on earlier research by Hornig and collaborators that found robust evidence of distinct stages in ME/CFS. A pair of 2015 publications based on analyses of blood and cerebrospinal fluid showed differences in the immune signatures of ME/CFS patients who had the disease for three years or less as compared with those who had been ill for more than three years. The researchers reported that patients were flush with cytokines and chemokines until around the three-year mark—suggesting an over-activated immune response in that phase of the illness; thereafter the immune system showed evidence of “exhaustion,” and levels of immune molecules dropped.
In the new study, both subsets of ME/CFS patients showed signs of an unbalanced or dysregulated immune system within the central nervous system, with immune markers different than those seen in healthy individuals. However, the dampened immune profiles previously observed after the three-year mark were only observed in individuals with the classical form of the disease, not in those with atypical ME/CFS. Among subjects in the atypical group, levels of cytokines and chemokines were more likely to remain steady or increase.
According to Hornig, instead of the immune exhaustion seen in later phases of classical ME/CFS, atypical patients may be experiencing a “smouldering inflammatory process” in which the immune system is still working to recover, although she acknowledges that much work remains to be done to confirm this hypothesis. Alternatively, these findings could suggest a pathway to disease in atypical individuals that involves biomarkers not captured in the 51-molecule assay, potentially even involving non-immune-related processes. Atypical individuals may also have genetic susceptibilities that lead their immune systems to respond differently than in classical cases.

Columbia University Mailman School of Public Health]
www.mailman.columbia.edu/public-health-now/news/scientists-discover-biological-evidence-atypical-chronic-fatigue-syndrome

A multi-institutional group of researchers, led by investigators at Children’s Hospital Los Angeles and the University of Michigan, have identified a simple and inexpensive tool for assessing the prognosis of paediatric brain tumours called ependymomas. Their study, which demonstrates the epigenetic mechanism behind these tumours, may offer future opportunities for novel therapeutic options.

Childhood posterior fossa ependymomas (PF) are tumours found largely in the hind brain (consisting of the cerebellum, pons and the brainstem) of children. Routine assessment of tumour grade and other markers in PF ependymomas do not correlate well with outcomes in these tumours, highlighting the need for new prognostic markers. Genomic sequencing efforts have not identified mutations in these tumours, and the origin of PF ependymomas remains obscure.

While lacking recurrent genetic mutations, a subset of these tumours exhibit alterations in DNA methylation. In this study, the researchers looked at modification of histones – protein components of the chromatin around which DNA winds, and which play a role in gene regulation – in particular, histone H3.

Co-lead investigator, Sriram Venneti, MD, PhD, of the Department of Pathology at the University of Michigan, observed that histone H3 is modified differently in paediatric posterior fossa ependymoma. Specifically, 80 percent of these tumours exhibited loss of the H3K27me3 a repressive mark, while 20 percent of tumours retained H3K27me3.  Researchers went back and looked at MRIs and outcomes of children treated for these tumours and identified that tumours with loss of H3K27me3 tumours behaved more aggressively and showed poor overall survival.  This suggests that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.

“Detection of H3K27me3 by immunohistochemical staining is a widely available and cost effective surrogate molecular marker.  This test can be readily implemented in most departments of pathology and provides a much-needed tool to risk stratify and identify ependymoma patients who would potentially benefit from epigenetic therapies,” said co-lead investigator Alexander R. Judkins, MD, of the Department of Pathology and Laboratory Medicine at CHLA and Keck School of Medicine of the University of Southern California.

This loss in H3K27me3, along with other epigenetic changes, was similar to that observed in another type of paediatric brain tumour of the hind brain region termed diffuse intrinsic pontine gliomas (DIPGs).  This suggests that both of these tumours arise from similar epigenetic states. Intriguingly, researchers found that certain progenitor cells in this part of the brain also showed low H3K27me3, suggesting – as both tumours share epigenetic similarities – that low methylation of H3K27me3 is important to the development of tumours in this region of the brain.

Children’s Hospital of Los Angeles www.chla.org/press-release/biomarker-identified-aid-prognosis-pediatric-ependymomas