Body

CHAMPAIGN, Ill. -- Roughly 80% of people with myotonic dystrophy - a common form of muscular dystrophy - experience dangerous heart ailments, and heart rhythm defects are the second-leading cause of death in those with the condition. In a new study, researchers traced the molecular events that lead to heart abnormalities in myotonic dystrophy and recreated the disease in a mouse model.

They report their findings in the journal Developmental Cell.

"In this study, we discovered that the genetic abnormalities associated with myotonic dystrophy lead to the overproduction of an alternative-splicing factor that regulates how cells process other proteins," said Auinash Kalsotra, a professor of biochemistry at the University of Illinois at Urbana-Champaign who led the work. He is a faculty member in the Carl R. Woese Institute for Genomic Biology and in the Cancer Center at Illinois.

The alternative-splicing factor comes in two forms, called muscle and nonmuscle RBFOX2. Both alter RNA transcripts by splicing them before they are translated into proteins. The nonmuscle form of the protein is elevated in the heart muscles of people with myotonic dystrophy, the researchers found.

"When we engineered mice to express this wrong version of the protein in the heart, they developed the same heart irregularities seen in humans with myotonic dystrophy," Kalsotra said. "We decided to investigate further why expression of the nonmuscle RBFOX2 variant in the heart triggers arrhythmias."

"By looking at cardiac gene-expression data and focusing on which gene transcripts are altered by the nonmuscle RBFOX2 in myotonic dystrophy patients, we discovered that it induces abnormal splicing of proteins that make up the major potassium and sodium channels in heart cells," said Chaitali Misra, a postdoctoral research scientist in the Kalsotra laboratory and the first author of the study. "These channels are essential to the propagation of electrical signals across heart muscle, and their aberrant splicing causes major cardiac conduction defects."

"This disrupts the normal rhythm and function of the heart in individuals with myotonic dystrophy," Kalsotra said.

"Our results have answered a long-standing question of why myotonic dystrophy patients develop cardiac dysfunctions and offers new insights into previously unknown mechanisms causing arrhythmias in the heart," he said. "We expect these findings will help explore new approaches for treating cardiac arrhythmias and bring us closer to finding a cure for this disease."

OAK BROOK, Ill. - Healthy men and women have different blood flow characteristics in their hearts, according to a new study published in the journal Radiology: Cardiothoracic Imaging. Researchers said the results could be used to help create quantitative standards that adjust for gender to provide improved assessment of cardiac performance.

Differences in the hearts of men and women have long been known. For instance, women's hearts are smaller in size and beat faster than men's, on average. However, much less is known about the way that blood flows through the hearts of men and women and how that relates to cardiac performance.

For the new study, researchers used a sophisticated imaging technique called 4D flow MRI to study gender differences in the left ventricle, the heart's main pumping chamber. They derived various blood flow parameters from MRI scans obtained from 20 men and 19 women and correlated them with cardiac function.

The data showed some significant differences between the genders. Kinetic energy, which is one indicator of energy expenditure during contraction and filling of the heart, was significantly higher in the left ventricles of men. Vorticity, a measure of regions of rotating flow that form during different points of the cardiac cycle, was higher in women, as was strain, a measure of left ventricular function.

"Using the MRI data, we found differences in how the heart contracts in men and woman," said study lead author David R. Rutkowski, Ph.D., postdoctoral researcher at the University of Wisconsin in Madison. "There was greater strain in the left ventricle wall of women and a higher vorticity in the blood volume. We hypothesize that these two things are related."

The study and the methods it employed have a number of potential applications, Dr. Rutkowski noted, including improved understanding of why the hearts of men and women respond differently to physiological stresses and disease. The results also add information that might one day improve clinical assessment of the heart.

"These blood flow metrics would be useful as reference standards because they are derived from healthy people, so we could use these to compare with someone who is unhealthy," Dr. Rutkowski said.

Dr. Rutkowski emphasized that the ability of 4D flow MRI to provide numbers for various blood flow parameters is especially important.

"There's been a push in the last couple of decades to make MRI more quantitative," he said. "So instead of looking at something and saying it looks normal or different, we can get a number to go with that visual information."

The researchers are currently using 4D flow MRI to look at patients with atrial fibrillation, an irregular heartbeat that can lead to serious complications. Their hope is that MRI will help detect patterns and relationships in the atria, the upper chambers of the heart, similar to those found in the ventricles.

"The goal of our work in general is to move from qualitative MRI to more quantitative MRI," Dr. Rutkowski said. "Getting blood flow and velocity information is just one more metric that is being developed to make MRI more quantitative."

Philadelphia, February 27, 2020 - In a groundbreaking discovery, researchers at Children's Hospital of Philadelphia (CHOP) developed a new imaging method that allows scientists to view the enteric nervous system (ENS) - a key part of the human colon - in three dimensions by making other colon cells that normally block it invisible. The ENS has previously only been visible in thin tissue slices that provide limited clinical information. The findings were published online today in the journal Gastroenterology.

The ENS regulates many key functions of the bowel, such as the movement of food and nutrients, secretion of fluid, repair of the bowel lining and control of blood flow. Because the ENS has many nerve cell types that allow it to respond to changing conditions within the bowel independent of the brain or spinal cord, the ENS is sometimes called the body's "second brain."

The ENS is difficult to see with conventional imaging methods because it is buried within the bowel wall. Defects in the ENS cause Hirschsprung disease, a birth defect that requires surgical intervention, as well as other conditions in which food is unable to move properly through the bowel. ENS defects may also contribute to common problems like irritable bowel syndrome (IBS).

"Having three-dimensional images of the colon enteric nervous system provides us with new insight into the cells that control bowel function and may help us better understand disorders of the colon," said Robert Heuckeroth, MD, PhD, a pediatric gastroenterologist in the Division of Gastroenterology, Hepatology and Nutrition at CHOP, Research Director and Norman and Irma Braman Endowed Chair of CHOP's Lustgarten Center for GI Motility and senior author of the study. "To do this work, we had to invent a new way to make the colon invisible, stain the cells we were interested in seeing and generate thousands of images."

Using mouse and human colon tissues, the study team developed an imaging method that combined several techniques, including tissue and cell staining, the use of pinhole microscopes and quantitative analysis to characterize the cells of the colon in three dimensions. By not sectioning tissue, this new approach preserves the associations with other bowel cells in three-dimensional space. This is important in assessing bowel motility, which requires many cell types to work together to coordinate muscle contration and relaxation.

In total, the study team created 280 confocal Z-stacks - the process that allows them to render the images in three dimensions - and was able to acquire quantitative data from 14 adult human colons. Additionally, they were able to visualize the ENS in children with Hirschsprung disease.

"We believe our new approach will help us understand bowel diseases in more detail and could lead to new approaches to therapy," Heuckeroth said.

The images generated from the study are now available on a public database.

One of the most frequent problems when treating cancer is that the tumours develop resistance to therapies, that is to say, at some point treatments cease to be effective to stop tumour growth. This is especially relevant in patients with aggressive diseases such as pancreatic cancer or patient with metastases, who for this reason often undergo frequent changes in treatment. Now, a study led by the Spanish National Cancer Research Centre (CNIO) in collaboration with researchers from the Weill Cornell Medicine Center and Pfizer Inc. (United States), proposes a novel combined approach to avoid pancreatic cancer resistance to chemotherapy, and thus achieve that the treatments eliminate these tumour cells effectively. The work will be published in the journal Cancer Cell.

Effective therapies in breast cancer

One of the characteristics of cancer is the alteration of the cell cycle, that is, the alteration of normal activity related to cell growth, maturation and death. Concerning this, there are molecules called CDK4 and CDK6 that are involved in uncontrolled cell growth, which ends up generating a tumour mass.

In recent years, drugs have been developed that inhibit the action of CDK4 and CDK6 and are very effective in stopping the growth of advanced breast cancer. Their clinical use, in combination with hormone therapy, has been approved in the United States since 2015 and in Europe since 2017 for patients with this type of cancer. The success of this combination has made it the standard treatment for these patients. However, until now it was not clear if these benefits could be extended to other types of cancer.

"A problem with CDK4/6 inhibitors is a consequence of their mechanism of action that prevents tumour cells from multiplying," explains Marcos Malumbres, Head of the CNIO Cell Division and Cancer Group and principal investigator of the project. "Most of the current chemotherapies -involving, for example, platinum or taxol derivatives-, act only on tumour cells that are dividing. Therefore, if we inhibit CDK4/6 and thus prevent these cells from dividing, we prevent chemotherapies from working properly. For this reason, until now it was believed that we could not combine CDK4/6 inhibitors with classical chemotherapy."

Not at the same time, but after

During her predoctoral work at the CNIO, researcher Beatriz Salvador decided to design a new strategy in which CDK4/6 inhibitors would be used not at the same time as chemotherapy, but after chemotherapy to prevent the recovery of tumour cells. The results of the study show that administering CDK4/6 inhibitors after the drugs commonly used against various metastatic tumours prevents tumour cells from resisting these treatments and growing again after chemotherapy.

The study was carried out both in genetically modified mouse models and in mice with grafts from patients with pancreatic adenocarcinoma, one of the most aggressive tumours with the worst prognosis. While tumour cells treated with taxol or other agents repair the damage caused by these therapeutic agents in a few days, subsequent treatment with CDK4/6 inhibitors prevented this repair of the tumour cells and caused them to continue accumulating damage, thus preventing that they started growing again. "All animals treated with this combination showed a stable tumour, while mice that were not treated this way died rapidly," continues Malumbres.

Classical chemotherapy is still the most common treatment for patients with metastatic cancer, not only for breast and pancreatic cancer but for most tumour types. "Being able to use CDK4/6 inhibitors to prevent tumour cells from recovering from these treatments can open new avenues for improving the effectiveness of these therapies in various types of cancer that are currently treated with classical radiotherapy or chemotherapy," Malumbres says. That is, this finding could have a positive impact on thousands of patients who are currently being treated with these therapies. "However, this strategy must be validated in the clinic. We are currently in contact with pharmaceutical companies to address this proposal in clinical trials, probably in breast and lung cancer."

What The Study Did: Researchers in this study estimated the potential water conservation and financial savings generated by eliminating running water for hand scrubbing before surgery in favor of exclusive use of an alcohol-based scrub at a large ophthalmic surgical hospital.

Authors: Alana Grajewski, M.D., of the University of Miami Miller School of Medicine, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamaophthalmol.2020.0048)

Editor's Note: Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

Boston - Starting medication to treat opioid use disorder within 30 days of being discharged from the hospital due to injection drug use-related endocarditis - a type of serious heart infection - improves health outcomes, a new study shows. Led by researchers at Boston Medical Center's Grayken Center for Addiction, the results showed that those who receive medication in that timeframe are less likely to overdose or be readmitted to the hospital within a year. Given that the underlying cause of many endocarditis inpatient hospitalizations is opioid use disorder, the findings highlight the importance of offering and prescribing medications to treat opioid use disorder while these patients are in the hospital, and connecting them to treatment after discharge.

Endocarditis is becoming increasingly common among young people who inject drugs, often leading to the need for valve replacement surgery. It is also associated with increased mortality and costs around injection drug use given the lengthy hospital stays, as well as an increased incidence of rehospitalizations.

The three FDA-approved prescription medications used to treat opioid use disorder are methadone, buprenorphine and naltrexone. These evidence-based medications have been shown to improve mortality and retention in care for people with opioid use disorder. However, data suggests that a minority of patients with opioid use disorder receive one of these medications, particularly around hospitalizations.

The researchers analyzed data from the MarketScan Commercial Claims and Encounters database, focusing on individuals over the age of 18 diagnosed with opioid use disorder who were hospitalized for endocarditis between 2010 and 2016. The cohort included 768 individuals with an average age of 39 years.

The study results show that receiving medication within 30 days of the initial hospitalization cut the risk for rehospitalization in half compared to those who did not receive medication. Only six percent (44) of patients received medication to treat opioid use disorder in the 30 days following hospitalization for endocarditis; buprenorphine was prescribed to 41 of those 44 patients. Those who received medication were, on average, 25 years old. There were 41 overdoses in the group of individuals who did not receive medication within the 30 days after discharge.

"This is among the first data to show the life-saving impact that medications to treat opioid use disorder can have on patients with injection drug use-related endocarditis," said Joshua Barocas, MD, an infectious disease physician and researcher at Boston Medical Center. "Given the increase in injection drug use-related infections, it is critical to treat the underlying opioid use disorder, which often leads to these serious complications and inpatient hospitalizations."

Barocas, also an assistant professor of medicine at Boston University School of Medicine, notes that medications to treat opioid use disorder should be part of a comprehensive treatment plan that includes linkage to outpatient care and access to harm reduction services. "We need to ensure that patients have access to the evidence-based treatment and services that will help reduce their risk of infection and overdose, as well as help them achieve long-term recovery."

PHILADELPHIA - Tracking brain cancer with a blood test instead of a surgical biopsy may greatly improve quality of life for glioblastoma (GBM) patients and provide critical information for their care, but it is not feasible in all cases. Now new research from the Perelman School of Medicine at the University of Pennsylvania and Penn's Abramson Cancer Center shows brain imaging may be able to predict when a blood test known as a liquid biopsy would or would not produce clinically actionable information, allowing doctors to more efficiently guide patients to the proper next steps in their care. The key is the ability to image two things - the blood brain barrier and a type of immune cell called macrophages - which, this study found, correlate with the amount of circulating DNA in the bloodstream. The journal Neuro-Oncology Advances published the findings today.

About 12,000 Americans are diagnosed with GBM each year, making it the most common malignant primary brain tumor in adults. It's also the deadliest, with a five-year survival rate between five and 10 percent. The tumors themselves usually contain multiple genetic mutations, which means treatments that focus on one target are normally only partially effective at best. Further, tracking these mutations over time can be difficult, since getting a new tissue sample requires a repeat brain surgery. This is a particularly important issue for GBM, since almost all patients experience a recurrence, and when the disease comes back, it often returns with a vastly different genetic makeup.

Liquid biopsy is an alternative way to monitor some cancers, including GBM. With a simple blood test, doctors can measure the amount of cfDNA - circulating DNA that cancer and other cells shed into the blood - as well as circulating tumor DNA (ctDNA), which is the DNA specifically shed by cancer. However, unlike other parts of the body, the brain is protected by what's called the blood brain barrier, a security gate that controls what gets in and what gets out. Depending on how hard it is for circulating DNA to get in and out of the brain, there may not be evidence of disease in the blood, meaning a liquid biopsy is not helpful in all cases.

This study begins to address that problem by adding imaging to the equation. The researchers show that an MRI can actually provide a picture of how leaky the blood brain barrier is, and that the higher the volume of tumor with a leaky blood brain barrier, the higher the levels of cfDNA and ctDNA are likely to be in a patient's blood.

The study also found a correlation between the amount of cfDNA and the density of macrophages - a type of white blood cell that make up a large percentage of the cells inside a GBM and represent a major barrier to the immune system fighting the tumor.

"By better understanding the macrophage makeup in a given patient's tumor, researchers may be able to identify which patients are the best candidates for treatments targeted against macrophages, or for immunotherapy in general," said the study's lead author Seyed Ali Nabavizadeh, MD, an assistant professor of Radiology at Penn.

In addition to showing how imaging may predict the feasibility of liquid biopsy in GBM, the researchers say it also points to promise of what the combination can find. However, they say further study is needed to understand how this information can affect treatment outcome and disease progression.

"The more information we have about a tumor, the better. The combination of being able to measure the integrity of the blood brain barrier, understanding the density of macrophages, and tracking the tumor through liquid biopsy may be able to help us tailor our treatment decisions so that each patient is getting precision therapy that gives them the best chance of seeing a benefit," said the study's senior author Stephen Bagley, MD, MSCE, an assistant professor of Hematology-Oncology.

Scientists at Trinity College Dublin have identified a rare, new cell in the immune system with "Jekyll and Hyde properties". These cells play a key protective role in immunity to infection but - if unregulated - also mediate tissue damage in autoimmune disorders.

The findings should help us design more effective vaccines to prevent infections such as MRSA, and may also assist help us develop of new therapies for autoimmune diseases, such as multiple sclerosis or rheumatoid arthritis.

The research was funded by Science Foundation Ireland and led by Kingston Mills, Professor of Experimental Immunology, and Dr Sarah Edwards and Dr Caroline Sutton, Postdoctoral Fellows in the School of Biochemistry and Immunology in the Trinity Biomedical Sciences Institute. Their findings were published today [Thursday 27th February 2020] in The Journal of Experimental Medicine.

The immune system functions to control infection, utilising various immune cells, such as T cells to respond to and control invading microbes. However, if these immune cells are not highly regulated, they can attack and damage body tissues, leading to the development of autoimmune diseases.

Molecules called T cell receptors (TCRs) allow T cells to recognise components of infectious agents with exquisite specificity. The TCRs enable T cells to respond to and eventually eliminate the infectious agent.

Professor Kingston Mills said:

"Until now scientists thought that there were two discrete populations of T cells, expressing either 'αβ' or 'γδ' TCRs. The αβs are the most common T cells in the body. They play a key role in remembering prior infection or immunisation and thereby help protect us against re-infection and mediate vaccine-induced protective immunity. The γδs are more prevalent at mucosal surfaces, such as the lung or gut, and provide an immediate first line of defence against pathogens that invade through these routes."

"We have discovered a new cell type that expresses both αβ and γδ TCRs. This rare population of chimeric or hybrid αβ-γδ T cells has properties of both αβ and γδ T cells. Importantly, they are normally highly activated and poised to act as first responders to control bacterial infection. However, given this high level of activation, they are effectively 'Jekyll and Hyde cells' because in certain contexts they can also precipitate autoimmune responses."

Using a model of Staphylococcus aureus infection, Professor Mills and his team found that these cells are rapidly mobilised during infection and play a key role in quickly eliminating the microbes from the body.

The induction of these hybrid αβ-γδ T cells may thus represent a novel approach in the design of more effective vaccines against Staph aureus and other infectious diseases, while advancing our ability to control their response may yield additional therapeutic options.

Professor Mills added:

"In a model of autoimmune disease, we found that the hybrid T cells can also trigger the inflammatory cascade that mediates tissue damage in autoimmunity. Therefore, approaches for inhibiting these highly activated immune cells in susceptible individuals may open up new approaches for the treatment of autoimmune diseases such as psoriasis and multiple sclerosis."

SCOTTSDALE, Az., February 27, 2020 -- A new phase II trial finds that a combination of radiation therapy and immunotherapy led to encouraging survival outcomes and acceptable toxicity for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). The combination of radiation and pembrolizumab may offer a new treatment option for patients who are ineligible for cisplatin chemotherapy, part of standard treatment for the disease. Findings will be presented at the 2020 Multidisciplinary Head and Neck Cancers Symposium, taking place February 27-29 in Scottsdale, Arizona.

The single-arm trial was designed specifically for patients who normally would receive platinum chemotherapy together with radiation but may not be able to tolerate its side effects, most often due to preexisting hearing problems that place patients at risk of permanent hearing loss. Preexisting kidney damage and nerve damage also tend to be aggravated by cisplatin and place patients at risk for permanent side effects.

"That is a common dilemma in the exam room because cisplatin, while effective, tends to be particularly toxic for patients and can lead to permanent side effects for some," explained lead author Jared Weiss, MD, an associate professor of medicine at the University of North Carolina Lineberger Comprehensive Cancer Center. "I will have patients I want to treat with platinum chemotherapy, but I also want to align treatment with their values. Is the patient willing to accept a risk of deafness or exacerbated ringing in their ears? These are not acceptable consequences for most people."

The single-arm trial included 29 patients with locally advanced HNSCC. All patients would have ideally received cisplatin with their radiation but were ineligible for platinum chemotherapy. Patients were treated with three cycles of pembrolizumab and concurrent radiation therapy over six weeks, followed by three additional cycles of the immunotherapy drug.

With a median follow-up of 21 months, the rates of one-year progression-free and overall survival were 76% [95% CI 56-88] and 86% [67-95], respectively. Estimated two-year PFS was 71% [49-84] and estimated two-year OS was 75% [51-88]. For patients with p16+ oropharynx cancer, the one-year PFS and OS rates were 88% and 94%, respectively; for the other patients, the rates were 58% and 75%, respectively.

Most toxicities were mild (grade 1-2) with the exception of grade 3-4 lymphopenia, which affected 59% of patients. "This toxicity profile is better than what patients generally experience with cisplatin and radiation," explained Dr. Weiss. "It was more consistent with what we see from radiation therapy alone, with the exception of a high rate of lymphopenia that warrants additional study."

While engaging PD-1/PD-L1 blockade following chemoradiotherapy has improved survival in lung cancer, this trial is one of the first to show its potential efficacy for head and neck cancers. "There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects. And the opposite direction also seems to be true - radiation therapy needs a functional immune system to work, and our hope was that pembrolizumab might be a radiation sensitizer for these patients," said Dr. Weiss.

Additionally, unlike chemoradiation therapy, the combination of radiation and pembrolizumab pairs two active modalities that can be curative by themselves. "If you look back to the historic studies, radiation alone often cures patients with this disease. Some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease," said Dr. Weiss. "And so, our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it in a more straightforward way as a 'second shot on goal' toward cure."

Dr. Weiss cautioned that findings need confirmation in a randomized trial before the combination is recommended to patients.

Dr. Weiss will present "Progression-free survival, overall survival and immunophenotyping outcomes for patients with stage III-IV head and neck cancer and cisplatin contraindication treated with definitive radiotherapy plus pembrolizumab" tomorrow during the symposium's Oral Abstract Session. The study was funded by Merck. Email press@astro.org for a copy of the abstract or presentation slides from the meeting.

SCOTTSDALE, Az., February 27, 2020 -- A new clinical trial suggests that immunotherapy given before other treatments for oral cavity cancers can elicit an immune response that shrinks tumors, which could provide long-term benefit for patients. Findings will be presented at the 2020 Multidisciplinary Head and Neck Cancers Symposium, taking place February 27-29 in Scottsdale, Arizona.

In the randomized phase II trial, two neoadjuvant doses of nivolumab given with or without ipilimumab led to complete or partial tumor shrinkage in most cases and did not delay any patients from continuing on to standard treatment. These promising responses could translate into improved outcomes for patients with an especially difficult and painful type of cancer.

"With roughly three weeks of treatment, we were able to trigger significant tumor regression. In a couple cases, there were complete pathological responses, and in other cases, there was very little tumor left. Both the single drug and the two-drug combination led to visible tumor shrinkage, and, albeit with relatively early follow-up, the majority of these patients have no evidence of disease recurrence," said lead author Jonathan D. Schoenfeld, MD, MPH, senior physician at the Dana-Farber/Brigham and Women's Cancer Center and associate professor of radiation oncology at Harvard Medical School. "Our hope is that even a couple doses of immunotherapy can stimulate an immune response that continues to prevent the cancer from coming back after patients have surgery and other therapy."

The trial enrolled 30 adults newly diagnosed with tumors in their tongue, gums or other part of the mouth; all tumors were stage T2 or higher, and over half of the patients' cancers had spread to their lymph nodes. After receiving two doses of the PD-1 blocker nivolumab either alone or in combination with a single dose of the CTLA-4 blocker ipilimumab over the course of three weeks, no patients were delayed from surgery, the first component of standard treatment for this disease.

Most patients (52%) experienced clinical reduction of their primary tumor after immunotherapy, and four patients (one in the single-drug group, three in the combination group) had more than 90% pathologic response. While these exploratory results are promising, Dr. Schoenfeld noted that direct comparisons with the current standard of care are needed to determine whether the single-agent or combination therapy can lead to durable responses and improve patient survival. The researchers also want to understand why immunotherapy worked better with some patients than others and identify additional immune targets that could further enhance the treatment.

Twenty-one of the 30 patients experienced side effects possibly related to treatment, and grade 3-4 toxicities for five patients (33%) in the combination group and two patients (14%) in the single-drug group. Dr. Schoenfeld said his team was encouraged by these results; by comparison, for example, more than half of patients experienced serious adverse events with the same combination in trials for high-risk resectable melanoma.

While immunotherapy drugs generally are used after other treatments have failed and a patient's cancer has spread, this study adds to a growing body of research on immunotherapy given prior to surgery for patients with newly diagnosed, curable disease. "The preoperative setting is interesting because patients' immune systems haven't been affected by prior treatment. The tumor is actually in place to serve as a focal point for an immune response, so it may be easier for the body's immune system to recognize and target the tumor," explained Dr. Schoenfeld.

"Oral cavity cancer is a notoriously difficult cancer with high rates of disease recurrence and death, and the side effects from standard treatment tend to be particularly challenging because the treated area is essential for speaking, swallowing and breathing," he continued. "We're excited about moving immunotherapy earlier to treat more of these curative patients and, in the future, possibly reduce how aggressive their other treatments need to be."

Dr. Schoenfeld will present "Neoadjuvant Nivolumab +/- Ipilimumab in Patients with Oral Cavity Cancer" (Abstract 1) today during the symposium's Plenary Session. The study was funded by Bristol-Myers Squibb. Email press@astro.org for a copy of the abstract or presentation slides from the meeting.

A new national survey from the American Society of Anesthesiologists (ASA) finds physician anesthesiologists are being forced out of network as insurance companies terminate their contracts, often with little or no notice.

Initial results find 42% of respondents had contracts terminated in the last six months. Additionally, 43% of respondents experienced dramatic payment cuts from insurers, both mid-contract and at renewal, in some cases by as much as 60%. Some of the impacted contracts were signed less than six months ago.

The informal, non-scientific survey, which was distributed earlier this month, received responses from 76 practice groups in 33 states. It confirms anecdotal complaints that proposed surprise medical bill legislation has coincided with a significant number of insurance contract terminations and unilateral lower payment adjustments by health insurance companies.

"This survey appears to confirm what we have been hearing from our members: that insurers may be forcing more physicians to be out of network to shore up their profits while negatively impacting patients," said ASA President Mary Dale Peterson, M.D., MSHCA, FACHE, FASA. "ASA is committed to ending surprise medical bills and is extremely disappointing to hear that insurance companies may be taking advantage of current legislative efforts to hurt patients and physicians."

Survey respondents came from a variety of groups of different sizes, from 35-member physician groups to large national groups. The responses also indicated that United Healthcare Insurance Company was noted as the insurer most associated with these changes, but Aetna, Cigna, and Blue Cross Blue Shield also were mentioned.

While the timing alone suggests insurance companies are motivated by factors related to anticipated legislative changes on surprise medical bills, some survey respondents reported they were specifically told by insurers this was the case.

This trend is why ASA supports a solution to surprise medical bills that does not further empower insurers to engage in these outrageous negotiating techniques - techniques that create more out-of-network physicians. ASA believes any solution should include a fair, market-based mechanism for physician anesthesiologists to be paid for their life-saving health care services, including a robust independent dispute resolution process where payment disputes between insurers and physicians can be resolved without the involvement of the patient.

"Currently, a very small percentage - approximately 8% - of anesthesiologist claims, nationwide, are out of network, often for reasons outside the control of the physician" added Dr. Peterson. "ASA will continue to closely monitor the activities of these insurance companies to track how their actions will exacerbate the public's exposure to surprise medical bills. Clearly, giving more power to the insurance companies is not the answer."

One respondent noted an insurance company: "abruptly terminated our longstanding contract a few months ago. A few days later we were offered a new contract with a 60% reduction in our professional fees. We were advised by our consultant that commercial payers are emboldened to force anesthesiology groups into accepting severe pay reductions in the face of new Surprise Medical Billing laws."

Another respondent noted: "We have been in network with all carriers for the last 30 years" until an insurance company "offered without negotiation a greater than 60% reduction in rate or we had to go out of network. We were, therefore, forced out of network. We are making every effort to ensure that our patients do not get caught in the middle of this nefarious insurance practice." The insurance company "mentioned the balance billing (or surprise medical bills) legislation in our discussions."

Philadelphia, February 26, 2020 - The Roberts Individualized Medical Genetics Center (RIMGC) at Children's Hospital of Philadelphia (CHOP) launched in 2014 as a first-of-its-kind system to help families navigate the complex process of genetic and genomic testing and standardize how genetic testing is performed across different clinical disciplines.

In a special report published today in the journal Pediatrics, RIMGC researchers, physicians, and genetic and financial counselors describe the success of the model, their plans to build on that success for the future, and the important lessons learned from their first four years in operation. As a trailblazer in the development of a center dedicated to genetic and genomic testing, the team also provides a framework for making such a center work, as other hospital systems around the country look to replicate the first-of-its kind model pioneered at CHOP.

Whole genome sequencing has the potential to revolutionize the practice of medicine by allowing for the development of highly-targeted therapies and more nuanced treatment strategies. The practice will also accelerate research into difficult-to-treat conditions and help clinicians diagnose new diseases that would have otherwise remained a mystery. As the technology becomes more widely available, the cost to patients and the healthcare system has decreased significantly while demand has broadened across all specialties.

Despite these benefits, genome sequencing is relatively new to the field of medicine, and for all the issues the technology solves, new issues have arisen, such as developing the infrastructure to support this growing field, working with health insurance companies to impart its necessity, and educating families about the importance of this information to their health.

"We saw a need to standardize our hospital's approach to genetic and genomic testing, and we believe we have succeeded tremendously in this endeavor, especially since no other hospital had attempted a model like the one we established prior to the founding of the RIMGC," said Ian Krantz, MD, Director of the RIMGC, Director of the Center for Cornelia de Lange Syndrome and Related Diagnoses, a Distinguished Chair in the Department of Pediatrics at CHOP and senior author of the report.

"As this report outlines, even in a relatively short time, our Center has grown in response to clinical and research demands," Krantz added. "We thought it was important to share what we've learned as more hospitals look to the model we've created to establish similar centers."

During its first four years, of the 1172 genomic (exome) sequencing tests ordered by RIMGC clinicians, 26% yielded a positive diagnosis, 37% yielded an uncertain diagnosis, and 28% yielded a negative diagnosis, while 6.5% yielded a diagnosis for a candidate gene - meaning a novel gene not previously associated with a known disease or diagnosis - and 1.2% yielded a dual diagnosis, meaning that two genes were identified as being responsible for symptoms.

To illustrate the complexity of the cases reviewed by the RIMCG, the report includes five examples of patients with medical conditions that were properly diagnosed thanks to the resources provided by the team. These examples highlight a small number of the cases seen at the Center, including:

An infant experiencing severe cardiac issues who received a life-saving cardiac transplant because exome sequencing results revealed two genetic mutations.

A 34-month-old patient who had previously tested negative for cystic fibrosis but exhibited symptoms and was revealed to have a gene that increased the risk of the disease thanks to more robust and precise genetic testing offered by the RIMGC.

An 11-year-old patient who received the proper diagnosis of Brown-Vialetto-Van Leare syndrome, a progressive hearing loss disorder that can lead to other issues such as vision loss, severe neurologic impairment and early death, which led to treatment that stopped the condition's progression.

However, the report highlights hurdles that still exist, such as the amount of time spent working with insurance companies to justify genetic testing and a lack of understanding among parents and patients. For example, of the 3,483 referrals to the RIMGC, 994 were not seen for a variety of reasons, including insurance denials (324), unreachable parents (217), or patient or parents declining consultation (196).

Since its launch, the RIMGC has more than quadrupled its full-time staff, and consistent assessment of the Center's clinical load has led to an expansion of services. In spite of this rapid growth, the team says the RIMGC presents a cost-saving model by centralizing these services and avoiding dozens of individual clinical departments having to hire their own genetic counselors and specialized administrative and medical support staff.

"Since the Center opened, we have seen how the demand for genetic and genomic services will require a different approach beyond what traditional divisions and departments specializing in this field are able to provide," said Livija Medne, MS, LCGC, co-director of the RIMGC and co-first author of the paper. "Our experience shows how a model like this allows for those growing needs to be properly met and sufficiently supported."

"We are deeply thankful to the Roberts family, whose generous support has pioneered the cutting-edge work we are doing in the RIMGC," Krantz said. "Their philanthropic commitment has enabled us to help thousands of patients and establish diagnoses of rare diseases that may have otherwise been missed, in turn allowing for improved management and treatment. Collectively, this experience will play a pivotal role in advancing our understanding of the impact that genetic and genomic testing will have in the years to come."

CLEVELAND, Ohio (February 26, 2020)--Increased fat distribution during menopause has long been shown to increase insulin resistance and the risk of diabetes. A new study based on data from the Women's Health Initiative (WHI) shows that being metabolically unhealthy increases diabetes risk, even in women of normal weight. Results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

As women age and transition through menopause, the prevalence of diabetes increases. More specifically, postmenopausal women who have increased abdominal fat are at risk for type 2 diabetes because of the development of insulin resistance and glucose intolerance. Recent studies have suggested that even women of normal weight may be at increased risk of diabetes if they are metabolically unhealthy. Metabolic health is based on the combined levels of blood sugar, triglycerides, and high-density lipoprotein cholesterol, as well as blood pressure and waist circumference.

In this newest study, researchers sought to determine the relationship between various metabolic weight categories and diabetes risk in the postmenopausal women who participated in the WHI. They concluded that metabolically unhealthy women of normal weight, as well as metabolically healthy women who are overweight, had about a two-fold increased risk for developing diabetes. This confirmed that even women of normal weight could be at risk of diabetes, depending on their metabolic health. In comparison, women who were metabolically unhealthy and overweight were four times more likely to develop the disease.

Findings were published in the article "Incidence of diabetes according to metabolically healthy or unhealthy normal weight or overweight/obesity in postmenopausal women: the Women's Health Initiative."

"This study provides evidence that being of normal weight yet metabolically unhealthy is associated with increased risk for diabetes. Educating women about the importance of maintaining a healthy weight and controlling cardiometabolic risk factors for diabetes and heart disease is important," says Dr. Stephanie Faubion, NAMS medical director.

Aggressive colorectal cancers set up an interactive network of checkpoints to keep the immune system at bay, scientists report.

Immune checkpoints found throughout the body are intended to protect your body from being attacked by your immune system. But in the structural framework a tumor lays down, they instead protect the tumor, says Dr. Yan Cui, immunologist in the Georgia Cancer Center and Department of Biochemistry and Molecular Biology at the Medical College of Georgia at Augusta University.

In tumors, this structural framework is called cancer-associated fibroblasts, or CAFs, and Cui's lab has found that in some cancers with a lot of CAFs, like more aggressive colorectal cancer, this often large mass of cells expresses high levels of the enzyme CD73, a common immune checkpoint.

CD73 works to silence the immune response by converting the cell fuel adenosine triphosphate, or ATP, which activates the immune response, back to its constituent adenosine, which suppresses it.

But that is just the beginning of the story of CAFs, which work both like a fence to keep immune cells out of a tumor and like a dictator to suppress those that make it in, says Cui, corresponding author of the study in Nature Communications.

In what she calls a feedforward loop, the scientists have found that as the tumor and its CAFs grow, natural cell death occurs in the tumor. The high levels of CD73 present readily convert ATP released by those dying tumor cells to adenosine, which suppresses the immune response by activating the adenisone receptor A2A, which is highly expressed on immune cells.

More importantly, through extensively collaborative work with AU and international researchers, they discovered that adenosine converted by CD73 also simultaneously activates another one of its receptors, A2B, which is highly expressed on CAFs and promotes the CAFs to make even more CD73.

"CD73 expressed on CAFs functions in a self-serving process via the adenosine-A2B pathway to amplify their own CD73 expression and further suppress the immune response," Cui says.

"CAFs are very immunosuppressive because they carry these checkpoints," she adds. High levels of CAFs can also mean low levels of T cells, drivers of the immune response, and while there may be a lot of immune cells on the scene, they don't appear to be attacking the tumor.

Strategic, effective targeting of these synergistic pathways in tumors with a lot of CAFs could help improve their attack and treatment success, Cui and her colleagues suggest.

While A2A and A2B are both adenosine receptors, they are not redundant, Cui notes, because they work differently to suppress the immune response.

Rather, as they found in their studies in human colorectal cancer cells and animal models, simultaneously inhibiting A2A and A2B action while neutralizing CD73, should enable the immune system to better attack these tumors, the scientists say.

Elevated CD73 levels in breast and ovarian as well as colorectal cancer already are associated with poor outcomes, and clinical trials of CD73 inhibitors and antibodies in combination with other treatments like immunotherapy as well as A2A antagonists are underway. However the crucial populations CD73 inhibitors target in the tumor microenvironment are not well defined and results are mixed, the scientists say. The source of CD73 in the microenvironment of a tumor also has remained a mystery.

There is evidence that CD73 can come from the tumor cells themselves, especially in tumors with low numbers of CAFs, as well as from immune cells, like regulatory T cells and myeloid cells, which both normally suppress the immune response as part of the body's natural checks and balances. These cells also are known to have and to use CD73. Cui isn't disputing that these cells are contributing CD73, but at least with some tumors, CAFs are a lot better at it. "In some tumors, they are a major source," she says.

Fibroblasts, a usual constituent of body tissues, are early recruits for tumors so they can grow and so they can educate them to become a connected network that does their bidding. "The tumors can educate them, can turn them into a bad guy," Cui says. Tumors also can secrete factors to recruit more fibroblasts through the blood circulation. After injecting tumor cells into a mouse, Cui has watched fibroblasts begin to move in and soon become efficient support machines.

"That's how tumors get started. They have to have them to survive, to grow, to build up," Cui says. "We have observed during tumor expansion, the cancer-associated fibroblast network can really expand tremendously," she says.

In fact, immunostaining of the tumor microenvironment of colorectal cancer with CAFs stained green looks like a lush forest.

Cancer-associated fibroblasts appear to result from fibroblasts that already are part of a healthy tissue structure and from mesenchymal stem cells, which can differentiate into many cell types, including bone and muscle, and can be adapted by the tumor microenvironment for its purposes.

CAF levels can be determined if a tumor biopsy is available and some investigators have reported progress in measuring CAF biomarkers in the blood.

A team of researchers have discovered a genetic mutation that reduces a patient's ability to exercise efficiently.

In a study published in The New England Journal of Medicine, a team including researchers from King's College London have found a link between a genetic mutation that affects cellular oxygen sensing and a patient's limited exercise capacity.

The team identified a patient who had a reduced rate of growth, persistent low blood sugar, a limited exercise capacity and a very high number of red blood cells.

The team carried out genetic and protein analysis of the patient, examined their respiratory physiology in simulated high altitude, measured their exercise capacity, and performed a series of metabolic tests.

The von Hippel-Lindau (VHL) gene is fundamental for cells to survive when oxygen availability is reduced. Following genetic analysis, an alteration on the VHL gene was identified and associated with impaired functionality in the patient's mitochondria, the powerhouse of the cell that uses oxygen to fuel cellular life. This reduced mitochondrial function efficiency limits the patient's aerobic exercise capacity compared to people without the mutation.

Dr Federico Formenti, School of Basic & Medical Biosciences, one of the leading authors of the study, comments: "The discovery of this mutation and the associated phenotype is exciting because it enables a deeper understanding of human physiology, especially in terms of how the human body senses and responds to reduced oxygen availability."

A new syndrome has been discovered that can alter the regulation of human metabolism and skeletal muscle function. This research puts the basis for the study of new mutations that affect the oxygen sensing pathways and the way these mutations are associated with the integrative function of the human body as a whole. Improving our understanding of these mechanisms may also contribute to the treatment of hypoxic conditions.