When performed in tandem, two molecular biology laboratory tests distinguish, with near certainty, pancreatic lesions that mimic early signs of cancer but are completely benign. The lesions almost never progress to cancer, so patients may be spared unnecessary pancreatic cancer screenings or operations. The two-test combination is the only one to date that can accurately and specifically identify these benign pancreatic lesions. Its utility was described in one of the largest studies of patients with this form of pancreatic lesion by researchers from Indiana University, Indianapolis.
Between 2 to 3 percent of all patients have some type of pancreatic lesions or cysts revealed on routine abdominal diagnostic radiology scans. Nearly all of these patients will later develop pancreatic cancer. The most common and deadliest form of pancreatic cancer—pancreatic adenocarcinoma—has a five-year survival rate of 12 to 14 percent for early-stage disease and 1 to 3 percent for advanced disease, according to the American Cancer Society.
A small percentage of patients have serous cystic neoplasms (SCN) that do not harbour malignant potential or progress to cancer. Nevertheless, these patients undergo imaging or other surveillance every six months to spot changes indicative of cancer, or they undergo an operation to remove part of the gland as a precaution because SCN are difficult to find using standard diagnostic methods. More than 60 percent of SCN are not predicted preoperatively3 and 50 to 70 percent are missed or incorrectly diagnosed on radiology scans.4
However, the researchers determined that two proteins can play a significant role in ruling out pre-cancer and cancer. Vascular endothelial growth factor A (VEGF-A) is a protein associated with promotion of new blood vessel formation. VEGF-A is upregulated in many tumours, and its expression can be correlated with a tumour’s stage. Its utility in the diagnosis of pancreatic cysts was discovered by researchers at Indiana University. Carcinoembryonic antigen (CEA) is a protein associated with cell adhesion. It is present in low levels in healthy individuals, but it is increased with certain types of cancers.
Tests for each of these proteins in pancreatic cyst fluid have accurately distinguished SCN from other types of pancreatic lesions. In the present study, VEGF-A, alone, singled out SCN with a sensitivity of 100 percent and specificity of 83.7 percent, and CEA had a 95.5 percent sensitivity and 81.5 percent specificity.
Together, however, the tests approached the gold standard of pathologic testing: The combination had a sensitivity of 95.5 percent and specificity of 100 percent for SCN. Authors of the study concluded that results of the VEGF-A/CEA test could have prevented 26 patients from having unnecessary surgery.

American College of Surgeons
www.facs.org/media/press-releases/2017/pancreatic062217

Investigators at The Saban Research Institute of Children’s Hospital Los Angeles have developed and tested a new biomarker assay for quantifying disease and detecting the presence of neuroblastoma even when standard evaluations yield negative results for the disease.  In a study, led by Araz Marachelian, MD, of the Children’s Center for Cancer and Blood Diseases, researchers provide the first systematic comparison of standard imaging evaluations versus the new assay that screens for five different neuroblastoma-associated genes and determine that the new assay improves disease assessment and provides prediction of disease progression. 
Neuroblastoma is a cancer of the nervous system that exists outside the brain and typically is diagnosed in children 5 years or age or younger. Forty-five percent of patients have high-risk, metastatic tumours (stage 4) when diagnosed.
While children with neuroblastoma often respond to therapy and many are declared to be in a “remission” based on standard tests, many will still relapse. “Clearly, there is some remaining tumour in the body that we cannot detect with standard tests and physicians have a hard time predicting if a patient is likely to relapse,” said Marachelian, who is medical director of the New Approaches to Neuroblastoma (NANT) consortium, headquartered at CHLA.
The new assay, which was developed in the laboratories of Robert Seeger, MD, and Shahab Asgharzadeh, MD, at CHLA, tests for five different genes that are specific to neuroblastoma. The test evolved to address the need for a better way to quantify the disease and fully understand its impact on the patient. Previously, assays used for detecting disease screened for only one NB-associated gene at a time, which was less effective. Instead of running five different tests, the research team figured out a way to test for multiple neuroblastoma-associated genes, simultaneously, using a different technology platform. This test can quantify infinitesimal amounts of tumour, akin to finding “a needle in a haystack”.
According to Marachelian, in a population of patients with relapsed or refractory neuroblastoma, it is important to understand if the therapeutics given to patients are working. But standard clinical evaluations such as scans (CT, MRI and MIBG) and bone marrow evaluation can be limited in their ability to do this because of variability and an inability to indicate severity of disease or how aggressive the treatment should be.
“With imaging scans, disease that is starting to grow versus disease that is getting better can look very similar when you first look,” explained Marachelian, who is also an assistant professor of Clinical Pediatrics at the Keck School of Medicine of the University of Southern California. “This assay could have the potential to be like an advance warning system – we can see if things are getting worse and be poised to take action. Alternately, if we see things are getting better or the disease is no longer detectable even with this very sensitive test, we can decrease the treatment to protect the patient from unnecessary exposure to toxicity and side effects.”

Children’s Hospital Los Angeles
www.chla.org/press-release/finding-needle-haystack-new-biomarker-assay-detects-neuroblastoma-greater-sensitivity

Couples who are undergoing pre-implantation genetic diagnosis (PGD) in order to avoid transmission of inherited diseases, such as Duchenne muscular dystrophy or cystic fibrosis, should also have their embryos screened for abnormal numbers of chromosomes at the same time, say Italian researchers.
By doing this, only embryos that are free not only of the genetic disease, but also of chromosomal abnormalities (aneuploidy), would be transferred to a woman’s womb, giving her the best chance of achieving a successful pregnancy, and avoiding the risk of implantation failure, miscarriage, or even live births that could be affected by conditions such as Down syndrome (in which there is an extra chromosome) or Turner syndrome (in which a girl has only one x chromosome rather than the normal two).
In a study reporting on the world’s largest series of double genetic tests the researchers carried out simultaneous PGD and pre-implantation genetic screening (PGS) on cells taken in a single biopsy.
They took between five and ten cells from the outer layer of 1122 blastocysts (the early collection of cells that begin to form about five days after an egg has been inseminated with sperm and which go on to develop into an embryo) and, after PGD and PGS, 218 blastocysts were transferred to the women’s wombs, resulting in 99 pregnancies and the birth of 70 healthy babies by January 2017, when the paper was written. This is a pregnancy rate of 49%, which is higher than the average clinical pregnancy rate of between 22-32% reported in the general population of couples undergoing in vitro fertilisation (IVF). At the time of writing the paper, 13 further pregnancies were ongoing and now 12 have resulted in the birth of healthy babies, while one miscarried. This gives a delivery rate of 38.6%. A total of 91 healthy blastocysts remain frozen awaiting transfer.
Dr Maria Giulia Minasi, laboratory director at the Centre for Reproductive Medicine, European Hospital, Rome, Italy, and first author of the study, said: “Importantly, we found that while 55.7% of the biopsied blastocysts did not carry a genetic disease or changes in the structures of chromosomes, only 27.5% of them also had the right number of chromosomes. Without performing pre-implantation genetic screening for aneuploidy, 316 blastocysts, which appeared to be healthy but had abnormal numbers of chromosomes, could have been transferred, leading to implantation failures, miscarriages or sometimes live births of babies affected by aneuploidy. For the couples involved, and particularly the women, these outcomes can be emotionally devastating.”
As a result of their findings, Dr Minasi and her colleagues believe that when couples undergo PGD, they should also have PGS.

The European Society of Human Reproduction and Embryology
www.eshre.eu/Press-Room/Press-releases-2017/Simultaneous-PGD-and-PGS-screening-on-cells-in-a-single-biopsy.aspx

A consortium including St. Jude Children’s Research Hospital and the Children’s Oncology Group has performed an unprecedented genomic sequencing analysis of hundreds of patients with T-lineage acute lymphoblastic leukaemia (T-ALL). The results provide a detailed genomic landscape that will inform treatment strategies and aid efforts to develop drugs to target newly discovered mutations.
The data will also enable researchers to engineer better mouse models to probe the leukaemia’s aberrant biological machinery.
The project’s 39 researchers were led by Charles Mullighan, M.D., MBBS, a member of the St. Jude Department of Pathology, with co-corresponding authors Jinghui Zhang, Ph.D., chair of the St. Jude Department of Computational Biology, and Stephen Hunger, M.D., of the Children’s Hospital of Philadelphia.
"This first comprehensive and systematic analysis in a large group of patients revealed many new mutations that are biologically significant as well as new drug targets that could be clinically important," Mullighan said. "Leukaemias typically arise from multiple genetic changes that work together. Most previous studies have not had the breadth of genomic data in enough patients to identify the constellations of mutations and recognize their associations."
T-ALL is a form of leukaemia in which the immune system’s T cells acquire multiple mutations that freeze the cells in an immature stage, causing them to accumulate in the body. ALL is the most common type of childhood cancer, affecting about 3,000 children nationwide each year. T-ALL constitutes about 15 percent of those cases. While about 90 percent of children with ALL can be cured, many still relapse and require additional treatment.
The multi-institutional effort involved sequencing the genomes of 264 children and young adults with T-ALL—the largest such group ever analysed. The study involved sophisticated analysis of multiple types of genomic data, led by Yu Liu, Ph.D., a postdoctoral fellow in Zhang’s Computational Biology laboratory and first author of the study. Their analyses identified 106 driver genes—those whose mutations trigger the malfunctions that block normal T cell development and give rise to cancer. Half of those mutated genes had not been previously identified in childhood T-ALL.
The study enabled the researchers to compare the frequencies of mutations among patients whose cancerous cells were sequenced at the same detailed level, Mullighan said. Also important, he said, was that all the patients had uniform treatment, which enabled the researchers to draw meaningful associations between the genetics of their cancer and the response to different treatments. Such associations will enable better diagnosis and treatment of T-ALL with existing drugs.
Researchers analysed the cancerous T cells as well as those that treatments had rendered non-cancerous. Comparing the two populations of cells could reveal valuable clues about why specific treatments were successful in thwarting particular cancer-causing mutations.
The findings revealed significant unexpected findings. "We went into this study knowing that we didn’t know the full genomic landscape of T-ALL," Hunger said. "But we were surprised that over half of the new targets and mutations were previously unrecognized. It was particularly unexpected and very striking that some mutations were exclusively found in some subtypes of T-ALL, but not others."
Cancers are driven by mutations in genes that are the blueprint for protein enzymes in signaling pathways in cells—the biological equivalent of circuits in a computer. While a cancer may arise from an initial founding mutation, that mutation triggers a cascade of other mutations that help drive the cancer.
The new genomic analysis confirmed that T-ALL was driven by mutations in known signalling pathways, including JAK–STAT, Ras and PTEN–PI3K.
However, the new analysis identified many more genetic mutations in those known pathways. The findings offered more targets for drugs to shut down the aberrant cells. "So the frequency of the patients that are potentially amenable to these targeted approaches is higher than we appreciated before," Mullighan said.
The researchers also found cases in which the same T-ALL subtype had mutations in different pathways triggered by the same cancer-causing founding mutation. "We believe this finding suggests we can target such subtypes with an inhibitor drug for one of the pathways, and it’s likely to be effective," Mullighan said.
The multitude of new mutations uncovered in the new study will also enable researchers to use genetic engineering to create mouse models that more accurately reflect human cancer, he said. Such models are invaluable for understanding the biological machinery of T-ALL, as well as testing new drug strategies. "We now have a launching pad, if you will, to design mouse models that include multiple genetic mutations to more faithfully reflect the leukemias we see in humans," Mullighan said.

St. Jude Children’s Research Hospital
www.stjude.org/media-resources/news-releases/2017-medicine-science-news/genomic-analysis-of-key-acute-leukemia-will-likely-yield-new-therapies.html

A small study by researchers at the National Institutes of Health suggests that mutations in the gene CABLES1 may lead to Cushing syndrome, a rare disorder in which the body overproduces the stress hormone cortisol.  
The excess cortisol found in Cushing syndrome can result from certain steroid medications or from tumours of the pituitary or adrenal glands. Symptoms of the disease include obesity, muscle weakness, fatigue, high blood pressure, high blood sugar, depression and anxiety.
Researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), in collaboration with researchers at other institutions in the United States, France and Canada, scanned tumour and cell tissue from 146 children with pituitary tumours evaluated for Cushing syndrome at the NIH Clinical Center. Researchers also scanned the genes of tumours from some of the children. Investigators in France scanned the genes of an additional 35 adult patients with Cushing syndrome and pituitary tumours.
The research team found that four of the patients have mutant forms of CABLES1 that do not respond to cortisol. This is significant because, when functioning normally, the CABLES1 protein, expressed by the CABLES1 gene, slows the division and growth of pituitary cells that produce the hormone adrenocorticotropin (ACTH). In turn, ACTH stimulates the adrenal gland to produce cortisol, which then acts on the pituitary gland to halt the growth of ACTH-producing cells, effectively suppressing any tumour development. Because cortisol does not affect the four mutant forms of CABLES1 discovered by the researchers, these genes leave production of ACTH-releasing cells unchecked.
“The mutations we identified impair the tumour suppressor function in the pituitary gland,” said the study’s senior author Constantine A. Stratakis, M.D., director of the NICHD Division of Intramural Research. “This discovery could lead to the development of treatment strategies that simulate the function of the CABLES1 protein and prevent recurrence of pituitary tumors in people with Cushing syndrome.”

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
www.nichd.nih.gov/news/releases/Pages/060117-pituitary-tumor.aspx