Body

A team of researchers from the National University of Singapore (NUS) has developed a novel technology that could sensitively and accurately detect and classify cancer cells, as well as determine the disease aggressiveness from the least invasive biopsies. With this new technology called STAMP (Sequence-Topology Assembly for Multiplexed Profiling), comprehensive disease information can be obtained faster, at a much earlier stage of the clinical workflow, allowing doctors to decide and administer treatments earlier and more effectively.

A biopsy, which involves removing a small amount of tissue from the body, is the main way for doctors to diagnose most cancers. While less invasive biopsy procedures are preferred, they can yield insufficient samples, resulting in incomplete and/or inconclusive diagnosis. A definitive diagnosis and further analysis such as cancer staging can only be made post-surgery; this long-waited information is then used to guide subsequent treatment decisions.

The STAMP technology overcomes many challenges of this clinical workflow to enable early and informative cancer diagnostics. STAMP uses programmable DNA barcodes to measure billions of protein markers in a single test - the amount as well as the distribution of these protein markers in a cell - from a small clinical sample. Using breast cancer as a model, STAMP achieves a high diagnostic accuracy of above 94 per cent, comparable with gold-standard tissue pathology, and reveals important clinical information which currently can only be obtained through post-surgery tissue analysis - all directly from a fine needle aspiration (FNA) biopsy, the least invasive form of biopsy.

Led by Assistant Professor Shao Huilin from the NUS Institute for Health Innovation & Technology (NUS iHealthtech), the 10-member research team spent over two years to develop STAMP.

"Our STAMP technology leverages the unique properties of DNA to form 3D barcodes. These barcodes can be used to measure diverse protein markers as well as detect the markers' specific locations in cells. By mapping these marker distribution patterns in cells, STAMP can provide an early indication of disease aggressiveness. Current pathology techniques only measure a small subset of protein markers and require several days of extensive processing. In comparison, STAMP is a million times more sensitive, provides highly informative analysis from scarce samples, and can be completed in as little as two hours," said Asst Prof Shao.

The team's technology breakthrough was published by the prestigious scientific journal Nature Biomedical Engineering. The study was also featured in News & Views by the journal and selected as the cover story for its September 2019 issue.

Tracks billions of protein markers in a single test

Comprehensive analysis of protein expression and distribution holds great promise for discovery of biomarkers, early disease detection, and rationalising of treatment options. However, current approaches involve imaging and microscopy techniques, which are complex, time-consuming, and have a limited multiplexing capability. STAMP was conceptualised and developed to address these challenges.

The blueprint of life, DNA exists in nature as long 'ribbons' to store massive genetic information through its combination of base codes. Aside from this well-known linear form, DNA can be precisely engineered to fold into 3D nanostructures with enhanced stability. STAMP leverages these two important properties of DNA - a large capacity to store information as well as its programmability to fold and unfold into different structures - to engineer convertible barcodes. These STAMP barcodes can be used to measure billions of protein markers in a single test and identify the specific locations of these protein markers in cells.

"To label diverse protein markers in cells, STAMP uses DNA barcodes which are folded as compact nanostructures. These 3D barcodes achieve a high labelling efficiency and remain stable against biological degradation. Each 3D barcode is further given a localisation label to encode protein marker location and distribution within the cell," explained Mr Noah Sundah, a doctoral student from NUS iHealthtech as well as NUS Department of Biomedical Engineering, and first author of the study.

"To perform analysis, these 3D barcodes are unfolded on-demand through heating to release a pool of linear DNA, which can be easily analysed using established technologies such as PCR and DNA sequencing. In this way, the expression of a very large number of protein markers and their distribution in cells can be sensitively measured in a single test," Mr Sundah added.

To facilitate clinical processing and measurement, the research team implemented the STAMP technology on a small microfluidic chip that is about half the size of a credit card. Test results could be generated from small amounts of clinical samples, and each test is estimated to cost US$36.

Effective test for cancer diagnosis, subtyping, and measuring aggressiveness

To validate STAMP's performance, the research team conducted a clinical study involving 69 breast cancer patients. FNA biopsies were collected from each patient and analysed using STAMP. For comparison, gold-standard pathology analysis was performed on post-surgery tissues for all patients.

The STAMP analysis of the FNA samples demonstrated a high level of accuracy of more than 94 per cent for cancer diagnosis and subtyping, making it equally accurate as pathology analysis of surgical tissues. Importantly, based on its comprehensive protein marker analysis, STAMP was also able to accurately identify disease aggressiveness from the scarce biopsy samples.

Next steps

A provisional patent has been filed for STAMP. Asst Prof Shao and her team are currently in discussions with industry partners to further develop and commercialise this technology. The technology is expected to reach the market within the next five years.

Moving forward, the research team hopes to expand the applications of STAMP to other types of cancer, such as brain, lung, and gastric cancer, as well as validate the technology in other samples, such as blood and ascites.

Which of these is not a risk factor for prediabetes?

A) Overweight

B) Age 45 or older

C) Being white

D) Exercise less than three times per week

The correct response is C -- the actual risk factor being African American, Latino, Native American or Asian American. If you didn't get it right, don't feel badly. Chances are your doctor wouldn't either, according to the results of a new national survey of primary care physicians (PCPs) conducted by Johns Hopkins Medicine researchers.

In a report on their findings in the Journal of General Internal Medicine (JGIM), the researchers say their survey of 1,000 randomly selected PCPs revealed significant gaps in the group's overall knowledge of risk factors, diagnostic criteria and recommended management/prevention practices for prediabetes.

The researchers also say the gaps may result from a health care education and reimbursement system that encourages doctors to prioritize treating diabetes once the disease occurs rather than working with patients to prevent it.

"Our survey findings suggest that these gaps contribute to doctors underscreening for and missing diagnoses of prediabetes, and in turn, not referring patients to type 2 diabetes prevention programs," says Eva Tseng, M.D., M.P.H., an assistant professor of general internal medicine at the Johns Hopkins University School of Medicine and lead author of the JGIM paper.

"Along with closing the PCP knowledge gaps our survey identified, we believe the problem needs to be addressed at the health care system level," says Nisa Maruthur, M.D., M.H.S., a Johns Hopkins associate professor of medicine and a co-author of the JGIM paper. "This includes concerted efforts to make both health care providers and patients more aware of available type 2 diabetes prevention programs, encouraging patient enrollment in these programs, and getting insurance companies to understand their value and cover the costs."

According to the U.S. Centers for Disease Control and Prevention, prediabetes is a serious health condition in which blood sugar levels are higher than normal, but not high enough to meet the threshold for type 2 diabetes. The federal agency says that some 84 million Americans ages 18 or older -- more than one out of three -- have prediabetes but 90% don't know it. If diagnosed early, experts say, lifestyle changes such as weight loss and regular exercise can prevent or delay the development of type 2 diabetes and the increased risks it poses for heart disease, stroke, kidney failure and nerve damage.

For their new study, the Johns Hopkins researchers sent surveys to 1,000 PCPs randomly selected from the American Medical Association's Physician Masterfile which includes data on more than 1.4 million physicians, residents and medical students in the United States. Candidates for the survey included general practitioners who had completed residency training, general internists and family physicians.

Survey questions evaluated a physician's knowledge of (1) risk factors that should prompt prediabetes screening, laboratory criteria for diagnosing prediabetes, and recommendations for prediabetes management, (2) practice behaviors regarding prediabetes management and (3) perceived barriers and potential interventions to improve prediabetes management.

For example, from a list of risk factor, PCPs were asked to select the ones that would lead them to order prediabetes screening for a patient. In another example, they were queried about their knowledge, understanding and use of prediabetes screening such as fasting blood glucose, two-hour oral glucose tolerance and hemoglobin A1c (HbA1c) tests -- all standard measures of blood sugar.

The researchers received 298 completed surveys, or 34% of the 888 ultimately found eligible for inclusion in the study. "Our results revealed that there are substantial gaps in the knowledge that PCPs have in all three categories we tested," Tseng says.

For instance:

- On average, respondents selected just 10 out of 15 correct risk factors for prediabetes, most often missing that African Americans and Native Americans are two groups at high risk.

- Only 42% of respondents chose the correct values of the fasting glucose and Hb1Ac tests that would identify prediabetes.

- Only 8% knew that a 7% weight loss is the minimum recommended by the American Diabetes Association as part of a diabetes prevention lifestyle change program.

"Our results also suggests that 25% of PCPs may be identifying people as having prediabetes when they actually have diabetes, which could lead to delays in getting those patients proper diabetes care and management," Maruthur says.

Based on their findings, the researchers suggest strategies to address the PCP knowledge gaps about prediabetes, as well as the system-level obstacles to preventing type 2 diabetes. These include better educating physicians about diabetes prevention, providing easier access for both PCPs and their patients to national diabetes prevention lifestyle change programs, increasing insurance coverage of such programs, and offering new tools to help PCPs improve the procedures and practices by which they diagnose and treat patients with prediabetes.

"We believe that what was learned from our survey can have implications for changing national guidelines and policies regarding type 2 diabetes prevention, including establishing measures of quality for diagnosing and managing prediabetes," Tseng says. "The public can help by advocating for more insurers to cover prevention programs, along with insisting that public health stakeholders expand access to and availability of these interventions."

By combing through the entire genetic sequences of a person with a lung scarring disease and 13 of the person’s relatives, Johns Hopkins Medicine researchers say they have found a coding error in a single gene that is likely responsible for a rare form of the disease and the abnormally short protective DNA caps on chromosomes long associated with it.

The error was found in the DNA sequence of the gene ZCCHC8, and it decreases by half the production of a protein needed to keep those caps — called telomeres — at a critical length, say the researchers. The finding, they add, means the flaw likely will become part of a small but growing list of diagnostic markers for so-called short telomere syndromes.

A new and simple blood test has been found to efficiently and accurately detect the presence of aggressive prostate cancer, according to research by Queen Mary University of London.

In combination with the current prostate specific antigen (PSA) test, the new test could help men avoid unnecessary and invasive biopsies, over-diagnosis and over-treatment.

Prostate cancer is the most common cancer in Western men, with 1.3 million new cases being diagnosed each year worldwide. It is currently detected using a blood test that measures PSA levels. Although it provides early diagnosis, the PSA blood test has a low specificity (high false positives) with about 75 per cent of all PSA positive results ending up with negative biopsies that do not find cancer.

When a high PSA level in the blood is detected, the patient undergoes a tissue biopsy of the prostate gland, which is invasive and carries a significant risk of bleeding and infection. On biopsy, the majority of patients with elevated PSA levels are found not to have cancer.

Additionally, most diagnosed early-stage prostate cancers are not fatal if left untreated. The current practice of the combined PSA test and biopsy for prostate cancer therefore results in unnecessary biopsies and over-diagnosis and overtreatment of many men.

The new prostate cancer test (the Parsortix® system from ANGLE plc) detects early cancer cells, or circulating tumor cells (CTCs), that have left the original tumour and entered the bloodstream prior to spreading around the body. By measuring intact living cancer cells in the patient's blood, rather than the PSA protein which may be present in the blood for reasons other than cancer, it potentially provides a more accurate test for prostate cancer.

The study, published in the Journal of Urology, looked at the use of the CTC test in 98 pre-biopsy patients and 155 newly diagnosed prostate cancer patients enrolled at St Bartholomew's Hospital in London.

The research team found that the presence of CTCs in pre-biopsy blood samples were indicative of the presence of aggressive prostate cancer, and efficiently and non-invasively predicted the later outcome of biopsy results.

When the CTC tests were used in combination with the current PSA test, it was able to predict the presence of aggressive prostate cancer in subsequent biopsies with over 90 per cent accuracy, better than any previously reported biomarkers.

Additionally, the number and type of CTCs present in the blood was also indicative of the aggressiveness of the cancer. Focusing on more aggressive prostate cancer may reduce over-treatment and unnecessary biopsies for benign and non-aggressive conditions.

Lead researcher Professor Yong-Jie Lu from Queen Mary University of London said: "The current prostate cancer test often leads to unnecessary invasive biopsies and over-diagnosis and overtreatment of many men, causing significant harm to patients and a waste of valuable healthcare resources. There is clearly a need for better selection of patients to undergo the biopsy procedure.

"Testing for circulating tumour cells is efficient, non-invasive and potentially accurate, and we've now demonstrated its potential to improve the current standard of care. By combining the new CTC analysis with the current PSA test, we were able to detect prostate cancer with the highest level of accuracy ever seen in any biomarker test, which could spare many patients unnecessary biopsies. This could lead to a paradigm shift in the way we diagnose prostate cancer."

As this is a single centre study, the results need to be further validated in other independent research centres before the CTC test is available either privately or on the NHS in the UK, which could take a further 3-5 years. Clearance by the US Food and Drug Administration could also take 3-5 years.

This work was funded by Orchid Cancer Appeal, Cancer Research UK and ANGLE plc (which manufactures the Parsortix system). The funding sources had no role in the design of the study; the collection, analysis, or interpretation of the data; or the writing of the research paper.

DALLAS, Texas - Baylor University Medical Center at Dallas, a part of Baylor Scott & White Health, today announces that a third family has welcomed a baby after the mother participated in a landmark uterus transplant clinical trial.

The family has asked for privacy at this time, but they are revealing images of their baby girl to the world. The images can be seen online:

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This birth is the latest medical milestone in the uterus transplant clinical trial at Baylor University Medical Center at Dallas, being conducted through Baylor Scott & White Research Institute. This latest birth was the result of an altruistic living-donor transplant, in which neither the donor nor the recipient knows the identity of the other.

"We are honored to have helped this family welcome their new baby and humbled by the selfless act of the organ donor who made this pregnancy a possibility," said Giuliano Testa, MD, principal investigator of the uterus transplant clinical trial at Baylor University Medical Center, chief of abdominal transplantation, and chairman, Baylor Annette C. and Harold C. Simmons Transplant Institute.

"Each delivery is further evidence that uterus transplantation is a viable option for women with absolute uterine factor infertility," said Liza Johannesson, MD, PhD, gynecologic surgeon and medical director of uterus transplantation at Baylor University Medical Center.

Baylor University Medical Center at Dallas is among the first in the U.S. to explore uterus transplantation, which is being studied as a new infertility treatment option for women with absolute uterine factor infertility, meaning their uterus is nonfunctioning or nonexistent. The clinical trial team led by principal investigator Giuliano Testa, MD, has now performed a total of 20 uterus transplants, making it the largest program in the world.

As a major academic medical center with one of the nation's top transplant programs, Baylor University Medical Center at Dallas attributes the success of this clinical trial to a multidisciplinary team of physicians, nurses, and research investigators in a range of specialties including transplant, gynecology, obstetrics, maternal/fetal medicine and psychology. The medical team has more than 35 years of experience helping women have babies while taking immunosuppressive medications following organ transplantation. With the support of Baylor Scott & White Research Institute, this innovative program is committed to advancing the science of uterus transplantation for the benefit of the broader medical community and women living with uterine factor infertility.

The uterine transplant clinical trial is one of many research trials Baylor University Medical Center and Baylor Scott & White Research Institute have conducted. Baylor Scott & White Research Institute provides the resources and infrastructure needed to safely and effectively accelerate medical breakthroughs and bring forward innovative new treatment models. Each year, Baylor Scott & White Research Institute oversees the management of nearly 2,000 active trials, spanning 50 specialty areas, at sites across Baylor Scott & White Health.

Philanthropic support for this innovative clinical trial was provided by Baylor Scott & White Foundation - Dallas. The Foundation is seeking additional funds to continue this research, which could potentially benefit other women with absolute uterine infertility via this pioneering procedure.

New research reveals the mechanism that allows breastfeeding babies to absorb large amounts of calcium and build healthy bones--a discovery that could lead to treatment for osteoporosis and other bone diseases later in life.

"We build our bone mineral density until we're early adults and then stop, so we think of osteoporosis as a disease of the elderly," said Megan Beggs, a pediatric dietitian and PhD candidate in physiology at the University of Alberta who led the study.

"Really, it's a pediatric disease with consequences in old age, so understanding what's happening at these younger ages, when bones are being built, is critical."

The researchers identified calcium-absorbing channels in the lower two-thirds of the small intestines of breastfed infant mice in a paper published in the journal Cellular and Molecular Gastroenterology and Hepatology.

Previous work had revealed that in adult mammals, most calcium absorption takes place in the upper part of the small intestines, where food spends much less time.

"It seems to be pretty much the opposite is happening in infants," said Beggs.

Babies need to take in massive amounts of calcium in the first year of life to build the cartilage they are born with into the body's 206 bones. This mineral deposition continues at a lower rate until around age 25.

This is the first time the infant mechanism for absorbing calcium has been understood. U of A pediatric nephrologist Todd Alexander, Beggs' PhD supervisor and senior author of the paper, said that's partly because women and children's health has not traditionally been the subject of medical study. He said the research required specially adapted lab equipment to perform experiments on the tiny intestines of genetically altered infant mice.

Alexander said understanding this mechanism could be the first step in reversing diseases that cause weak bones in humans.

"You can imagine that if you have someone who has poor bone health, such as an elderly person or a sick child in neonatal intensive care who has not been able to breastfeed, it would be very useful therapeutically to turn this pathway on for them," Alexander said.

The researchers said their future research will look at the mechanism in pigs, which are even closer physiologically to humans than mice, and they will test their hypothesis that it is a hormone in breast milk that is responsible for regulating the channels.

"Understanding that would allow us to either take the active ingredient out of breast milk or synthesize it as an additive so we could give it to people as a tablet or an injection," said Alexander.

The researchers said such a practical application for humans could be five to 10 years away.

Barcelona--Patients with Stage IV squamous non-small cell lung cancer enrolled in clinical trial to test the immunotherapy atezolizumab and chemotherapy against chemotherapy alone experienced a longer survival rate, among a subgroup of patients with high PD-LI.

The data for the Impower131 Trial was presented today by Dr. F. Cappuzzo, from Azienda Unità Sanitaria Locale della Romagna, Ravenna/Italy at the IASLC 2019 World Conference on Lung Cancer, hosted by the International Association for the Study of Lung Cancer.

IMpower131 is a randomized Phase III trial of atezolizumab + chemotherapy vs chemotherapy alone as first-line therapy in Stage IV squamous NSCLC, which is the most advanced form of the disease. The five-year survival rate for those diagnosed with stage IV lung cancer is less than 10 percent.

The multi-center trial enrolled 1021 patients-- the 343 patients in Arm B received atezolizumab + carboplatin + nab-paclitaxel 100 mg/m2 qw. There were 340 patients enrolled in Arm C who received carboplatin + nab-paclitaxel for four or six cycles followed by best supportive care.

The proportion of patients with high positive or negative PD-L1 expression was similar between arms. Median overall survival in the Intention to Treat population was 14.2 months in Arm B vs 13.5 months in Arm C not crossing the boundary for statistical significance. In the PD-L1-high subgroup, median overall survival was 23.4 vs 10.2 months, respectively. Treatment-related Grade 3-4 AEs and treatment-related adverse effects occurred in 68.0% and 21.0% (Arm B) and 57.5% and 10.5% (Arm C) of patients; no new safety signals were identified, consistent with previous analyses.

Final overall survival in Arm B vs C did not cross the boundary for statistical significance but clinically meaningful overall survival improvement was observed in the PD-L1-high subgroup, despite not being formally tested.

"The study provides additional evidence on the efficacy of immunotherapy in patients with lung cancer. The strong benefit observed in high PD-L1 expressors highlights relevance of biomarkers for patient selection," Dr. Cappuzzo said.

Barcelona-- Pooled data on two clinical trials demonstrate patients taking nivolumab realized a greater than five-fold increase in five-year overall survival rate compared with the chemotherapy docetaxel. The presentation was made today by Dr. Scott Gettinger of Yale Comprehensive Cancer Center, New Haven, Conn., at the IASLC 2019 World Conference on Lung Cancer, hosted by the International Association for the Study of Lung Cancer.

Historically, outcomes for advanced non-small cell lung cancer have been poor, with five-year survival rates less than five percent with conventional chemotherapy. Nivolumab, a programmed death-1 inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase three trials, CheckMate 017 and CheckMate 057, which demonstrated improved overall survival compared to docetaxel.

In CheckMate 017 and 057, 854 patients with advanced NSCLC, ECOG performance status 0 to 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab or docetaxel until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. The researchers set overall survival as the primary endpoint for both studies.

At five-year follow-up, 50 nivolumab patients and nine docetaxel patients were alive. Baseline characteristics of five-year survivors in both arms were similar to the overall population and patients who survived less than one year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression greater than one percent on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term overall survival and progression-free survival benefit compared to docetaxel with five-year survival rates of 13.4 percent vs 2.6 percent and progression-free survival rates 8.0 percent compared to 0 percent. The overall survival benefit with nivolumab compared with docetaxel was observed across subgroups, including patients with tumor PD-L1 expression "CheckMate 017 and 057 are the first phase three trials to report five-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than five-fold increase in five-year OS rates with nivolumab (13.4 percent) compared with docetaxel (2.6 percent). Nivolumab remained well tolerated with no new safety signals," according to Dr. Gettinger.

Victoria, B.C. & Toronto, Ont. -- A new study found that Japanese-American adults who are not obese have a much higher prevalence of diabetes than non-obese non-Hispanic white Americans (8.0% vs. 4.5%). The study was conducted by researchers at the University of Victoria, University of Toronto, and University at Albany, SUNY.

"In this study of non-obese adults, Japanese Americans had twice the odds of diabetes compared to non-Hispanic whites, and this difference remained even after adjustments were made for known risk factors of diabetes including age, sex, income, education and health behaviors," stated lead author Karen Kobayashi, Associate Dean Research and Graduate Studies in the Faculty of Social Sciences, professor in the Department of Sociology and a research affiliate at the Institute on Aging and Lifelong Health at the University of Victoria.

"Among non-obese Japanese Americans, younger respondents, never smokers and those with a post-secondary degree were less likely to have diabetes. Those born abroad had a comparable prevalence of diabetes to Japanese-Americans born in the United States. In contrast to our expectations, gender, poverty status and exercise were not associated with the prevalence of diabetes, once age was taken into account," reported co-author Keith Tsz-Kit Chan, assistant professor, School of Social Welfare, University at Albany, SUNY.

"Older age was a particularly strong risk factor for diabetes. One-quarter of non-obese Japanese Americans aged 80 and older had diabetes," reported co-author Adity Roy, a graduate of the University of Toronto.

"Although Japanese-Americans and white Americans with diabetes were equally likely to receive foot exams and hemoglobin A1C checks, both groups would benefit from targeted outreach because more than one-quarter of respondents had not received these treatments at an optimal frequency in the preceding year," stated co-author Mushira Mohsin Khan, a doctoral student in the Department of Sociology and a research affiliate at the Institute on Aging and Lifelong Health at the University of Victoria.

"Since two-thirds of Japanese-Americans with diabetes were not obese, it is clearly important that family doctors and other health-care professionals regularly screen their Japanese-American patients for diabetes, even if they are not overweight and they have no known risk factors for diabetes," said co-author professor Esme Fuller-Thomson, Sandra Rotman Endowed Chair at the University of Toronto's Factor-Inwentash Faculty of Social Work and Director of the Institute for Life Course & Aging.

The study examined a representative sample of community-dwelling Californians aged 18 and older from seven combined waves of the California Health Interview Survey (CHIS) conducted between 2007 and 2016. The study sample was restricted to Japanese Americans (n = 2,295) and non-Hispanic whites (n = 119,651) who were non-obese, defined as having a body mass index (BMI) of less than 30.

Researchers at the Johns Hopkins Kimmel Cancer Center discovered that a cell adhesion protein, E-cadherin, allows breast cancer cells to survive as they travel through the body and form new tumors, a process termed metastasis. Their conclusions, obtained through laboratory experiments and in mouse models, help explain how metastasis works in the most common form of breast cancer, invasive ductal carcinoma. E-cadherin appears to limit molecular stresses within the cancer cells and allow them to survive long enough to form new tumors. The finding, published online in the Sept. 4 issue of Nature, could lead to new ways to prevent breast cancers from recurring in patients.

"Previously, researchers thought that it was essential for cancer cells to lose E-cadherin in order to metastasize," says study leader Andrew Ewald, Ph.D., professor of cell biology and co-director of the Cancer Invasion and Metastasis Program at Johns Hopkins Kimmel Cancer Center. "This was difficult to reconcile with the fact that breast tumors in patients typically continue to express E-cadherin. Our study was designed to test the role of this protein during metastasis."

The overwhelming majority of breast and other cancer deaths are caused by metastasis; consequently, preventing metastasis is a crucial cancer research goal, he says.

Scientifically, metastasis is characterized by many separate stages, including when cancer cells invade healthy breast tissue, escape the primary tumor, enter and survive within blood vessels, exit into new organs, then survive and seed a new tumor in a distant organ, such as the lungs.

Cancer cells break free from the primary tumor early in metastasis and much research has focused on how cancer cells stick together at the molecular level, through the protein E-cadherin. In some cancers, such as a form of breast cancer known as invasive lobular carcinoma, genetic mutations that eliminate E-cadherin appear to be pivotal for metastasis to occur.

However, other types of cancer -- such as invasive ductal carcinoma, the most common form of breast cancer, responsible for more than 80% of all breast cancer diagnoses -- retain this protein or even overexpress it, a discrepancy that scientists couldn't explain.

To investigate this discrepancy, Ewald and his colleagues tested the role of E-cadherin in three experimental models of invasive ductal carcinoma that represent common subtypes of human breast cancer: luminal, basal, and triple negative breast cancer. These subtypes have different patterns of gene expression and different average patient outcomes.

First, they tested the role of E-cadherin during cancer invasion. Across all three models, loss of the E-cadherin gene dramatically increased the cancer cells' ability to invade healthy tissue. For example, in a mouse model, tumors that made E-cadherin invaded along 6% of their tumor borders, while those without E-cadherin invaded along 82% of their borders.

However, losing E-cadherin sabotaged every other biological stage of metastasis in all three breast cancer models, in both lab experiments and animal models. Cells without E-cadherin got lost while migrating and died in large numbers at every step after leaving the primary tumor. The few that did manage to migrate and survive didn't proliferate in new organs and rarely formed new tumors, Ewald reports.

"The good news," he says, "is that our study reveals that the process of metastasis, even in ideal laboratory settings, appears to be exceedingly inefficient." Research suggests that about 99% of cells that leave primary tumors die and never form new tumors.

The study results suggest that breast cancer cells need adhesive connections to survive and eventually spread and kill patients. "Our future research aims to understand how to target the survival signals related to E-cadherin and prevent metastases from forming, thereby saving patients' lives," Ewald says.

Delay in referral to specialty care for patients who have symptoms of colorectal cancer may lead to poor health outcomes. A retrospective cohort study in the Netherlands reviewed the time to specialty referral for a group of 309 patients with colorectal cancer who initially presented with symptoms to their primary care doctor. In univariable and multivariable analyses, those who initially presented with red flag symptoms, such as rectal bleeding or unintended weight loss, experienced shorter wait time than those who presented with non-alarming gastrointestinal symptoms. Univariable analysis showed that female patients and patients without a registered family history of the disease were also more likely to have a longer wait period. Of the 10% of patients with the longest wait times for referral to specialty care all patients had received an alternative initial diagnosis from their primary care physicians. These patients usually presented with conditions that obscured concern for colorectal cancer, such as hemorrhoids, fissures and inflammatory bowel disease. Initial diagnoses were not always reconsidered when complaints persisted and follow-up consultations were sometimes omitted.

The study points to a relationship between long time to referral of colorectal cancer in primary care and low cancer suspicion. There is potential for reducing longest times to referral of colorectal cancer patients in primary care by earlier reconsideration of the initial hypothesis and implementing strict follow-up consultations.

Results from a new study indicate that older hospitalized patients with cancer may have a high risk of being malnourished and experiencing symptoms such as no appetite and nausea, according to findings published early online in CANCER, a peer-reviewed journal of the American Cancer Society.

Many individuals with cancer experience malnutrition, which can negatively affect clinical outcomes during treatment. To study the issue, Nivaldo de Pinho, PhD, MSc, of the National Cancer Institute José Alencar Gomes da Silva, in Rio de Janeiro, and his colleagues evaluated the prevalence of malnutrition across different age groups in patients with cancer in Brazil. They also examined symptoms that interfere with obtaining sufficient nutrition, or "nutrition impact symptoms." The study included 4,783 patients with cancer who were hospitalized in November 2012 in public hospitals in Brazil. The average age of patients was 56.7 years.

The overall prevalence of malnutrition was 45 percent, with a higher prevalence in individuals aged 65 years and older (55 percent) and a lower prevalence in those aged 50 years and younger (36 percent). According to results from a questionnaire that assessed nourishment, patients with a high score--indicating a critical need to improve nutrition--had a higher prevalence of nutrition impact symptoms, with no appetite being the most prevalent (58.1 percent), followed by nausea (38.3 percent), dry mouth (37.1 percent), and vomiting (26.0 percent).

The results highlight the need for assessments of malnutrition and underlying risk factors soon after patients with cancer are hospitalized, in order to take steps to ensure that patients have adequate nutrition.

"With these findings, we can indicate to professionals that intensive nutritional counseling from the age of 50 years and older is needed to prevent and treat symptoms of nutritional impact. This can improve caloric and protein intake and prevent malnutrition and weight loss so common to these patients," said Dr. de Pinho.

HAMILTON, ON (Sept. 10, 2019) - More than 1,125,000 men around the world have the inherited bleeding disorder of hemophilia, and 418,000 of those have a severe version of the mostly undiagnosed disease, says a new study led by McMaster University researchers.

This is three times what was previously known. Only 400,000 people globally were estimated to have the disorder which is caused by a defect in the F8 or F9 gene which encodes instructions for making the factor proteins that helps blood clot. For those with hemophilia, lack of treatment leads to chronic and disabling joint disease, while bleeding into organs and brain hemorrhages can lead to disability and death.

Hemophilia, which is found almost only in men, is currently treated with infusions of factor to prevent or stop debilitating bleeds, but treatment is expensive and scarce in many countries.

The international research team was also able to calculate, for the first time, the prevalence of hemophilia among babies at birth, which enabled them to estimate that the life expectancy of those with hemophilia is significantly less than other people, particularly in lower-income countries where there is lack of treatment.

There are two main types of hemophilia: Hemophilia A has the factor 8 (F8) gene defect, and hemophilia B has a factor 9 (F9) gene defect.

They found that, per 100,000 males, 21 will have hemophilia A or B, seven of whom severely; among newborns, per 100,000 males, 29 will have hemophilia A or B, of whom 12 will have the severe form of disease.

Putting the numbers together, the 'life expectancy disadvantage' associated with hemophilia may be estimated and varies depending with the availability of care. For those born with hemophilia, the chances of living a life of normal duration and quality will be reduced by 64% in upper-middle income countries, 77% in middle income and up to 93% in low income countries.

The study will be published in the Annals of Internal Medicine on Sept. 10.

"This paper is a milestone in our journey to providing care for hemophilia patients worldwide," said Dr. Alfonso Iorio, lead author of the paper, professor health research methods, evidence, and impact at McMaster University and director of the Hamilton-Niagara hemophilia program at Hamilton Health Sciences.

"Knowing how many patients are expected in each country given its population is an important measure of the efficiency of the health care system. Knowing how many patients should be there, and how many less instead are reported to national and international registries is a measure of the work left to be done," he said.

"Knowing how many patients are out there will enable health care systems to estimate the resources needed to treat the disease, and enable drug manufacturers to increase the investment in research to match the demand of a patient population three times larger than we previously thought."

For the World Federation of Hemophilia, Iorio assembled an international team of researchers from France, U.S. and U.K. to perform a meta-analysis of the registry data in countries with the most comprehensive registries of hemophilia, which were Australia, Canada, France, Italy, New Zealand and the U.K.

"This work is also a proof of the value of long-term studies in the field of rare diseases," said Iorio.

A related editorial published in the journal said the magnitude of the global gaps in care for people with hemophilia is daunting.

A dietary supplement, sarcosine, may help with schizophrenia as part of a holistic approach complementing antipsychotic medication, according to a UCL researcher.

In an editorial published in the British Journal of Psychiatry, Professor David Curtis (UCL Genetics, Evolution & Environment and QMUL Centre for Psychiatry) suggests the readily available product could easily be incorporated into treatment plans, while calling for clinical trials to clarify the benefit and inform guidelines.

"Sarcosine represents a very logical treatment and the small number of clinical trials so far do seem to show that it can be helpful. It certainly seems to be safe and some patients report feeling better on it," he said.

"Sarcosine may be a helpful treatment for schizophrenia but we should be carrying out further studies in order to find out for sure."

Sarcosine naturally occurs in foods such as egg yolks, turkey and legumes, and can be bought as a dietary supplement, sometimes promoted as a 'brain health supplement', with various claims being made that are not all backed up by adequate evidence.

Professor Curtis writes that there is now good evidence from multiple lines of study that some patients with schizophrenia may have defects in the functioning of receptors for glutamate, a common neurotransmitter in the brain, and that sarcosine can help glutamate receptors to work better.

Researchers have been accumulating evidence that if these glutamate receptors did not function properly then people could develop psychosis and other symptoms of schizophrenia.

Professor Curtis and colleagues have recently added to the evidence, showing that genetic variants which damage this receptor increase the risk of schizophrenia.

The only risk identified so far seems to be that some people taking sarcosine to treat schizophrenia who are also on antidepressants may experience hypomania (disinhibition and euphoria), which Professor Curtis says highlights the importance of consulting with health professionals before taking sarcosine.

"Some studies have used it on its own as a treatment but I think the obvious thing to try first would be for patients to take it alongside their regular antipsychotic medication, in order to produce further improvement," said Professor Curtis.

He says that health professionals need to be aware of sarcosine so that they know how to respond if a patient asks them about it, given that it's increasingly being used as an alternative therapy.

"I would encourage psychiatrists to review the evidence, and while they may reach different conclusions, it seems reasonable to conclude that suggesting sarcosine to a patient with schizophrenia would be defensible and evidence-based.

"Because it is freely available and fairly cheap, there is nothing to stop somebody with schizophrenia from buying it and trying it themselves, which underscores the need for health professionals to get our heads around it. I would certainly warn them not to stop their regular medication and to continue following the advice of their psychiatrist," he said.

Genetic testing for all metastatic breast cancer patients may be an optimal strategy for identifying additional patients with increased risk as well as response to targeted therapies, according to research published in JAMA Oncology.

In the study, 100 patients were tested regardless of whether they met the current National Comprehensive Cancer Network (NCCN) guidelines. Among the 14 patients who did test positive for a pathogenic or likely pathogenic variant, 43% (six patients) did not meet the NCCN guidelines.

The study has clinical significance because of the recent approval of a PARP inhibitor for patients with HER2/ERBB2 negative breast cancer with germline BRCA1 and BRCA2 pathogenic variants. The U.S. Food and Drug Administration in October 2018 approved the PARP inhibitor talazoparib for that breast cancer.

"We found almost twice as many mutations than what we would have found if we adhered to NCCN guidelines, and some of those patients could go on clinical trials that could therapeutically help their disease," said senior author, Ben Ho Park, MD, PhD, the Donna S. Hall Chair in Breast Cancer at Vanderbilt University Medical Center and co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center.

Participants in the study included 76 white patients, 12 black patients, six Asian patients, three Hispanic patients and three of other racial/ethnic identification. Two of the patients were male.