Each year, tens of thousands of patients have all or part of their thyroids removed to rule out cancer because of suspicious, but uncertain, cytology test results. In the majority of cases, the suspicious thyroid nodules are determined to be ultimately benign.
Now, new research led by Brigham and Women’s Hospital (BWH) finds that a novel, genomic diagnostic test that measures the expression of 167 genes has shown promise in improving pre-operative risk assessment by re-classifying otherwise indeterminate results from thyroid biopsies as either benign or suspicious.
‘Our findings show that the gene expression test can substantially reclassify otherwise inconclusive results from thyroid biopsies, said Erik Alexander, MD, lead author of the paper and a physician-researcher in the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women’s Hospital. ‘Currently, indeterminate thyroid nodules are usually referred for thyroid surgery given the unanswered question of thyroid cancer. While all care should be personalised, our findings suggest that this test has the potential to drastically reduce unnecessary surgery and allow physicians to monitor many patients in a more conservative fashion.’
Thyroid nodules are common and ultrasound-guided needle biopsies (fine needle aspiration) have been shown to accurately identify about 65-75 percent of nodules as benign. Approximately five-10 percent of diagnostic biopsies are malignant. The remaining biopsies produce indeterminate results – occurring about fifteen to thirty percent of the time. For these patients, there remains substantial concern for thyroid cancer, though the diagnosis is uncertain. Because of the concern for cancer, in most cases, all or part of the thyroid is removed for final diagnosis. However, the nodule is ultimately benign in seventy to eighty percent of cases. For these patients, surgery was not needed and the patient was unnecessarily exposed to the cost, risk and morbidity associated with this intervention.
In this research study, researchers enrolled 3,789 patients and collected 4,812 thyroid samples from nodules larger than 1 cm and evaluated the effectiveness of a novel gene expression test in 265 thyroid samples that were cytologically indeterminate (suspicious for cancer, though not conclusive) from 49 different academic and community hospital sites around the United States. Samples were simultaneously collected for the standard-of-care cytology analysis, as well as one or two additional needle sticks for inclusion in the study. If the cytology result was indeterminate, the study sample was then analysed using the gene expression test. Thyroid surgery was performed based on the judgement of the treating physician who was blinded to the test results. At completion of the study, the gene expression test results were compared to final histopathology diagnosis (the gold-standard diagnosis) provided by two blinded pathology experts following their review of the surgical tissue sample.
For all cytologically indeterminate nodules, the researchers found that when the gene expression test was benign, histopathological analysis of the nodule proved it benign 93 percent of the time. And when applied to lower risk subgroups of indeterminate thyroid samples labelled ‘atypia (or follicular lesion) of an undetermined significance’ or ‘follicular neoplasm,’ the accuracy improved to 94 and 95 percent, respectively.
‘This very high negative predictive value is comparable to that of a cytologically benign cytology result. Therefore, such a result will allow clinicians to recommend a more conservative approach of watching waiting in lieu of diagnostic surgery,’ said Alexander. ‘It is estimated that over 50 percent of current thyroid surgeries are performed unnecessarily (for cytologically indeterminate, though histopathologically benign nodules), and therefore could be impacted by the gene expression test.’ Brigham and Women’s Hospital

A DNA repair pathway-focused score has the potential to help determine if first-line platinum based chemotherapy can benefit advanced-stage ovarian cancer patients, according to a study.
Most ovarian cancer patients are diagnosed with advanced disease (stages III and IV). They undergo surgery to remove as much tumour as possible, and then undergo platinum-based chemotherapy. But tools to predict response to platinum-based chemotherapy in ovarian cancer patients have been inadequate.
In order to determine if a DNA repair pathway-focused score could help predict outcomes for ovarian cancer patients treated with platinum-based chemotherapy, Josephine Kang, M.D., Ph.D., of the Department of Radiation Oncology at Dana Farber Cancer Institute, and colleagues gathered gene expression data from The Cancer Genome Atlas (TCGA) database for patients with advanced stage ovarian cancer, and established a molecular score by looking at the genes involved in platinum-induced DNA damage repair pathways. The patients were placed either into low or high score categories, and the prognostic value of the score for overall survival, recurrence free survival, and progression-free survival was assessed.
The researchers found that patients with high scores showed a statistically significant improved overall survival compared to the patients with low scores. These patients’ score was positively correlated with complete response rate, recurrence-free survival, and progression-free survival. The researchers also found that the patients’ scores outperformed other known clinical factors in predicting overall survival in the TCGA dataset as well as in two additional validation sets. ‘Developing the ability to predict OS and outcomes to chemotherapy using prognostic markers such as the score is critical, particular in ovarian cancer, because there are presently no other good clinical measures to predict response to standard platinum-based chemotherapy,’ the authors write.
They also note the study’s limitations, namely that the score has not yet been tested prospectively in a clinical trial, although they do believe it is ready for testing. ‘With additional prospective validation in clinical trials, we hope that the score can become a powerful tool that is useful in stratifying advanced-stage ovarian cancer patients toward optimal treatments incorporating new treatment regimens vs. current standard of care,’ the authors write. EurekAlert

Fibroid uterine tumours affect an estimated 15 million women in the United States, causing irregular bleeding, anaemia, pain, and infertility. Despite the high prevalence of the tumours, which occur in 60 percent of women by age 45, the molecular cause has been unknown.
New Northwestern Medicine pre-clinical research has for the first time identified the molecular trigger of the tumour — a single stem cell that develops a mutation, starts to grow uncontrollably and activates other cells to join its frenzied expansion.
‘It loses its way and goes wild,’ said Serdar Bulun, MD, the chair of obstetrics and gynaecology at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. ‘No one knew how these came about before. The stem cells make up only 1.5 percent of the cells in the tumour, yet they are the essential drivers of its growth.’
The stem cell initiating the tumour carries a mutation called MED12. Recently, mutations in the MED12 gene have been reported in the majority of uterine fibroid tissues. Once the mutation kicks off the abnormal expansion, the tumours grow in response to steroid hormones, particularly progesterone.
For the study, researchers examined the behaviour of human fibroid stem cells when grafted into a mouse, a novel model initiated by Northwestern scientist Takeshi Kurita, PhD, a research associate professor of obstetrics and gynaecology. The most important characteristic of fibroid stem cells is their ability to generate tumours. Tumours originating from the fibroid stem cell population grew 10 times larger compared to tumours initiated with the main cell population, suggesting a key role of these tumour stem cells is to initiate and sustain tumour growth.
‘Understanding how this mutation directs the tumor growth gives us a new direction to develop therapies,’ said Bulun, also the George H. Gardner Professor of Clinical Gynecology. University Feinberg School of Medicine

Researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma. EurekAlert

One hundred million treatments of Coartem Dispersible (artemether-lumefantrine), an antimalarial developed especially for children with Plasmodium falciparum malaria, have been delivered by Novartis to 39 malaria-endemic countries, Medicines for Malaria Venture (MMV) has announced.
This antimalarial is the product of the partnership between MMV and Novartis. It is the first WHO prequalified child-friendly artemisinin-combination therapy (ACT) and addresses an unmet need for paediatric medicines. Young children in Africa are disproportionately affected by malaria, with 86% of malaria deaths occurring in children under the age of five years.
Ahead of the international community’s call for better child-friendly medicines, MMV and Novartis signed an agreement in 2003 to develop the first paediatric ACT. The child-friendly formulation was launched in 2009.
Focused measures have been taken to facilitate the uptake of this medicine, including registration in 39 malaria-endemic countries, a without-profit pricing model and special packaging designed to improve compliance. These measures have not only led to increased demand but also to an accelerated uptake, underlining the advantage of the paediatric formulation. By reaching this one hundred million treatments milestone, the Novartis Malaria Initiative and MMV have proven that drug development partnerships can truly advance the fight against malaria.