The routine use of a molecular testing panel developed at UPMC greatly increases the likelihood of performing the correct initial surgery for patients with thyroid nodules and cancer, report researchers from the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter.

The test improved the chances of patients getting the correct initial surgery by 30 percent, according to the study.

“Before this test, about one in five potential thyroid cancer cases couldn’t be diagnosed without an operation to remove a portion of the thyroid,” said lead author Linwah Yip, M.D., assistant professor of surgery in Pitt’s School of Medicine and UPMC surgical oncologist.  Previously, “if the portion removed during the first surgery came back positive for cancer, a second surgery was needed to remove the rest of the thyroid. The molecular testing panel now bypasses that initial surgery, allowing us to go right to fully removing the cancer with one initial surgery. This reduces risk and stress to the patient, as well as recovery time and costs.”

Cancer in the thyroid, which is located in the “Adam’s apple” area of the neck, is now the fifth most common cancer diagnosed in women.  Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.

Previously, the most accurate form of testing for thyroid cancer was a fine-needle aspiration biopsy, where a doctor guides a thin needle to the thyroid and removes a small tissue sample for testing. However, in 20 percent of these biopsies, cancer cannot be ruled out. A lobectomy, which is a surgical operation to remove half of the thyroid, is then needed to diagnose or rule-out thyroid cancer. In the case of a postoperative cancer diagnosis, a second surgery is required to remove the rest of the thyroid.

Researchers have identified certain gene mutations that are indicative of an increased likelihood of thyroid cancer, and the molecular testing panel developed at UPMC can be run using the sample collected through the initial, minimally invasive biopsy, rather than a lobectomy. When the panel shows these mutations, a total thyroidectomy is advised.

Dr. Yip and her colleagues followed 671 UPMC patients with suspicious thyroid nodes who received biopsies. Approximately half the biopsy samples were run through the panel, and the other half were not. Patients whose tissue samples were not tested with the panel had a 2.5-fold higher statistically significant likelihood of having an initial lobectomy and then requiring a second operation.

“We’re currently refining the panel by adding tests for more genetic mutations, thereby making it even more accurate,” said co-author Yuri Nikiforov, M.D., Ph.D., professor in the Department of Pathology at Pitt and director of thyroid molecular diagnostics at the UPMC/UPCI Multidisciplinary Thyroid Center. “Thyroid cancer is usually very curable, and we are getting closer to quickly and efficiently identifying and treating all cases of thyroid cancer.” UPMC

Thanks to effective vaccination, polio is considered nearly eradicated. Each year only a few hundred people are stricken worldwide. However, scientists of the University of Bonn, together with colleagues from Gabon, are reporting alarming findings: a mutated virus that was able to resist the vaccine protection to a considerable extent was found in victims of an outbreak in the Congo in 2010. The pathogen could also potentially have infected many people in Germany.
   
The polio epidemic in the Congo in 2010 was especially serious. 445 people were verifiably infected, mostly young adults. The disease was fatal for 209 of them. This high mortality rate is surprising. Also important was the fact that many of those affected had apparently been vaccinated: Surveys indicated that half of the patients remembered having received the prescribed three vaccination dosages. To date the vaccination has been considered a highly effective weapon for containing the polioviruses that cause the disease.

‘We isolated polio-viruses from the deceased and examined the viruses more closely’, explains Dr. Jan Felix Drexler, who is in the meantime working in the Netherlands. He carried out the study during his employment at the Institute for Virology of the University Hospital of Bonn under the supervision of Prof. Christian Drosten, together with his colleagues from Gabon, Dr. Gilda Grard and Dr. Eric Leroy. ‘The pathogen carries a mutation that changes its form at a decisive point.’ The result: the antibodies induced by the vaccination can hardly block the mutated virus and render it harmless.

The researchers have examined the success with which the new pathogen evades the immune system. To this purpose, they tested, among others, blood samples from 34 medical students of the University of Bonn. All of them were vaccinated in childhood with the usual methods against polio. And very successfully, as an initial test showed: The antibodies in the blood of the test subjects had no problem combating ‘normal’ polio viruses. The situation was different with the mutated virus; the immune reaction was much weaker here. ‘We estimate that one in five of our Bonn test subjects could have been infected by the new polio virus, perhaps even one in three’, says Prof. Drosten. University Hospital of Bonn

Using next generation DNA sequencing, Dartmouth scientists have identified potentially actionable mutations in cancers of the appendix. When specific mutations for a cancer type are identified, patients can be treated with chemotherapy or other targeted agents that work on those mutations.
Little is known about the molecular biology of two types of appendix tumours, low-grade appendiceal mucinous neoplasm (LAMN) and adenocarcinoma, but both can lead to pseudomyxoma peritonea (PMP), a critical condition in which cancerous cells grow uncontrollably along the wall of the abdomen and can crush digestive organs.

Dartmouth pathologists studied 38 specimens of LAMN and adenocarcinoma tumors (some of which had progressed to PMP) from their archives to look for shared genetic errors that might be responsible for the abnormal cell growth. Tissue samples were sequenced using the AmpiSeq Hotspot Cancer Panel v2, which pathologists had verified for the clinical screening of mutations in 50 common cancer-related genes for which treatments exist. This was the first study making use of a multigene panel in appendiceal cancers to support the use of potential targeted therapies.

‘We routinely use this molecular profiling approach on all of our lung adenocarcinomas, melanomas, colon cancers, and gliomas,’ said Gregory Tsongalis, PhD, principal investigator for the study and director of Molecular Pathology at Dartmouth-Hitchcock Norris Cotton Cancer Center. He says examining an individual tumour profile has the potential to significantly alter patient outcome in a positive way.

KRAS and GNAS mutations were the most common alterations identified in the study. Twelve distinct abnormalities were mapped to the KRAS gene. Additional mutations were identified (i.e., AKT1, APC, JAK3, MET, PIK3CA, RB1, and STK11 for LAMN and TP53, GNAS, and RB1 for adenocarcinoma) in the four sample types studied. Seven of these mutations were shared by more than one group, which suggests there is some molecular similarity.

‘These findings suggest that tumours of the appendix, although rare and very aggressive, are distinct entities and have subclasses of disease within each category that are different from each other based on their mutation profile,’ said Tsongalis. ‘New therapeutic approaches may be able to target those pathways that are mutated in these tumour types.’

This laboratory research has the potential to change clinical practice if physicians now develop treatment plans to target the identified genetic mutations. ‘Our success in the Dartmouth-Hitchcock Medical Center Department of Pathology at the Norris Cotton Cancer Center is attributed to our multidisciplinary approach to these discoveries, which truly allow us to bring scientific findings from the bench to the bedside,’ said Tsongalis. Norris Cotton Cancer Center at Dartmouth-Hitchcock

Scientists at A*STAR’s Institute of Medical Biology (IMB) and the Bioinformatics Institute (BII) have found new clues to early detection and personalised treatment of ovarian cancer, currently one of the most difficult cancers to diagnose early due to the lack of symptoms that are unique to the illness.

There are three predominant cancers that affect women – breast, ovarian and womb cancer. Of the three, ovarian cancer is of the greatest concern as it is usually diagnosed only at an advanced stage due to the absence of clear early warning symptoms. Successful treatment is difficult at this late stage, resulting in high mortality rates. Ovarian cancer has increased in prevalence in Singapore as well as other developed countries recently. It is now the fifth most common cancer in Singapore amongst women, with about 280 cases diagnosed annually and 90 deaths per year.

IMB scientists have successfully identified a biomarker of ovarian stem cells, which may allow for earlier detection of ovarian cancer and thus allow treatment at an early stage of the illness.

The team has identified a molecule, known as Lgr5, on a subset of cells in the ovarian surface epithelium. Lgr5 has been previously used to identify stem cells in other tissues including the intestine and stomach, but this is the first time that scientists have successfully located this important biomarker in the ovary. In doing so, they have unearthed a new population of epithelial stem cells in the ovary which produce Lgr5 and control the development of the ovary. Using Lgr5 as a biomarker of ovarian stem cells, ovarian cancer can potentially be detected earlier, allowing for more effective treatment at an early stage of the illness (see Annex A).

Of the different types of ovarian cancers detected, high-grade serous ovarian carcinoma (HG-SOC) is the most prevalent of epithelial ovarian cancers. It has also proven to be one of the most lethal ovarian cancers, with only 30 per cent of such patients surviving more than five years after diagnosis. HG-SOC remains poorly understood, with a lack of biomarkers identified for clinical use, from diagnosis to prognosis of patient survival rates.

By applying bioinformatics analysis on big cancer genomics data, BII scientists were able to identify genes whose mutation status could be used for prognosis and development of personalized treatment for HG-SOC.

The gene, Checkpoint Kinase 2 (CHEK2), has been identified as an effective prognostic marker of patient survival. HG-SOC patients with mutations in this gene succumbed to the disease within five years of diagnosis, possibly because CHEK2 mutations were associated with poor response to existing cancer therapies.

Mortality after diagnosis currently remains high, as patients receive similar treatment options of chemotherapy and radiotherapy despite the diverse nature of tumour cells within tumours and across different tumour samples. With these findings, personalised medicine for ovarian cancer could be developed, with targeted treatment that would be optimised for subgroups of patients. A*Star

Scientists have known that abnormal brain growth is associated with autism spectrum disorder. However, the relationship between the two has not been well understood.
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that mutations in a specific gene that is disrupted in some individuals with autism results in too much growth throughout the brain, and yet surprisingly specific problems in social interactions, at least in mouse models that mimic this risk factor in humans.
‘What was striking is that these were basically normal animals in terms of behaviour, but there were consistent deficits in tests of social interaction and recognition—which approximate a major symptom of autism,’ said Damon Page, a TSRI biologist who led the study. ‘This suggests that when most parts of the brain are overgrown, the brain somehow adapts to it with minimal effects on behaviour in general. However, brain circuits relevant to social behaviour are more vulnerable or less able to tolerate this overgrowth.’
Autism spectrum disorder is a neurodevelopmental disorder involving a range of symptoms and disabilities involving social deficits and communication difficulties, repetitive behaviours and interests, and sometimes cognitive delays. The disorder affects in approximately one percent of the population; some 80 percent of those diagnosed are male.
In a previous study, Page and colleagues found that mutations in Pten causes increased brain size and social deficits, with both symptoms being exacerbated by a second ‘hit’ to a gene that regulates levels of the neurotransmitter serotonin in the brain. In the new study, the TSRI team set out to explore whether mutations in Pten result in widespread or localised overgrowth within the brain, and whether changes in brain growth are associated with broad or selective deficits in tests of autism-relevant behaviours in genetically altered mice. The team tested mice for autism spectrum disorder-related behaviours including mood, anxiety, intellectual, and circadian rhythm and/or sleep abnormalities.
The researchers found that Pten mutant mice showed altered social behaviour, but few other changes—a more subtle change than would have been predicted given broad expression and critical cellular function of the gene.
Intriguingly, some of the more subtle impairments were sex-specific. In addition to social impairments, males with the mutated gene showed abnormalities related to repetitive behavior and mood/anxiety, while females exhibited additional circadian activity and emotional learning problems.
The results raise the question of how mutations in PTEN, a general regulator of growth, can have relatively selective effects on behavior and cognitive development. One idea is that PTEN mutations may desynchronize the normal pattern of growth in key cell types—the study points to dopamine neurons—that are relevant for social behaviour.
‘Timing is everything,’ Page said. ‘Connections have to form in the right place at the right time for circuits to develop normally. Circuitry involved in social behaviour may turn out to be particularly vulnerable to the effects of poorly co-ordinated growth.’ Scripps University