Body

Orthopedic surgeons at Hospital for Special Surgery (HSS) performed successful microsurgery to repair damaged nerves and restore muscle strength and movement to patients experiencing paralysis from Parsonage-Turner Syndrome (PTS), according to a study published online ahead of print in The Journal of Hand Surgery.

Parsonage-Turner Syndrome affects the nerves controlling the shoulder, arm and hand. "We published data on the first successful surgical treatment in patients who experienced some degree of paralysis due to this mysterious disorder," said Scott Wolfe, MD, director of the Center for Brachial Plexus and Traumatic Nerve Injury at HSS and lead investigator.

Also known as neuralgic amyotrophy, Parsonage-Turner Syndrome most frequently manifests as sudden, severe pain in the shoulder and upper arm, often with no known cause. The intense pain, which usually subsides within a couple of weeks, is followed by progressive weakness. Many patients find they are unable to move their affected shoulder, elbow or hand. The area and degree of paralysis depend on the nerves affected and the muscles they control.

There is no known cure, but doctors generally prescribe pain medication, steroids and physical therapy to help relieve symptoms. Although many patients eventually recover and regain function of their arm, it sometimes takes several years.

For those who do not get better, limited use of their arm or even complete paralysis can be devastating. "Imagine going for months with this condition and not knowing if or when you're going to get better. Because recovery can take a year or longer, patients have been told to wait, and there's this feeling of uncertainty," says O. Kenechi Nwawka, MD, director of the Division of Ultrasound Research at HSS, who performs ultrasound in PTS patients to locate the damaged nerves. "Many patients who come to HSS feel relieved because they have found a group of specialists that really understands their condition."

Dr. Wolfe and colleagues set out to determine if patients who weren't improving could be helped by neurolysis, a microsurgical procedure to repair the injured nerve. The doctors hypothesized that successful surgery would allow patients with PTS to regain strength and movement.

To help patients with Parsonage-Turner Syndrome, a multidisciplinary team of specialists is essential. The first step is for a physiatrist to identify which muscles are involved and assess the nerve injury and loss of function. This is achieved through electrodiagnostic testing, which is used again at a later date to look for signs that the nerve is recovering.

It is also critical to pinpoint the exact location of the damaged nerve or nerves with MRI and ultrasound. Hospital for Special Surgery is one of few centers nationwide with the highly specialized team of hand surgeons, physiatrists and radiologists who could pursue such an undertaking.

"Without this team of experts in these varied, but related fields, we could not have made as much progress in a relatively short period of time," said Dr. Wolfe. "It is not only the members of the team, but the spirit of collaboration among my medical and surgical colleagues at HSS that sets us apart from other institutions."

The HSS study enrolled 24 patients with PTS, all of whom had suffered paralysis of their arm or hand. A physiatrist performed electromyography (EMG) to measure muscle and nerve function in all the patients.

"EMG testing is first used to confirm and make the definitive diagnosis of PTS," explained physiatrist Joseph Feinberg, MD, medical director of the Center for Brachial Plexus and Traumatic Nerve Injury at HSS. "A damaged nerve will generally start to recover in six to nine months, and additional EMG testing can indicate if there are early signs of nerve regeneration. If the nerve is starting to regenerate, the patient will likely regain muscle strength, so surgery is generally not needed. However, if there is no sign of regeneration within six to nine months of PTS onset, then recovery is less likely, and surgery may be considered."

Patients in the study met the following criteria: 12 months had passed without improvement since the onset of Parsonage-Turner Syndrome, or there was no evidence of clinical or electrodiagnostic improvement after six months as documented by three successive EMG and clinical exams.

A high-resolution MRI technique known as magnetic resonance neurography (MRN) was performed to zero in on the location of the nerve damage. Previously, radiologists at HSS had documented "hourglass-like" constrictions of the nerve, an anomaly that is unique to patients with PTS. Essentially, a band squeezing the nerve makes it look like an hourglass on the digital image. The MRI, along with high-resolution ultrasound images, is essential in surgical planning.

"Magnetic resonance neurography and ultrasound images give the surgeons a roadmap, a target to treat," explained Darryl Sneag, MD, director, Peripheral Nerve, MRI at HSS. "Instead of having to explore the entire nerve in an arm, the images pinpoint the exact location of the constriction, so the surgeon doesn't have to spend hours searching for it."

Hourglass-like constrictions of affected nerves were identified in each study patient, and the images were correlated with EMG findings. Eleven out of the 24 patients opted for neurolysis surgery by Dr. Wolfe and his colleague, Steve Lee, MD.

"Once we localized the tiny constrictions in the nerve with imaging, we could confine our surgery to that site, and we could locate the lesion with millimeter precision," said Dr. Wolfe. "Looking through a microscope with 25X magnification, we then repaired the constricted nerve by releasing the compressive bands around it."

The mean time from PTS onset to surgery was 12.5 months. At patient follow-up of almost 15 months after the procedure, nine of the 11 patients who had surgery showed clinical improvement, having regained muscle strength and movement. EMG testing revealed significant motor unit recovery from nerve regeneration.

Out of the 13 patients who did not have surgery, only three had recovered strength during follow-up, which took place almost three years after PTS onset.

"Microsurgical neurolysis to repair the hourglass constrictions was associated with dramatic and significantly improved clinical outcomes and nerve regeneration compared to nonsurgical management," Dr. Wolfe noted. "Therefore, we recommend considering it as a treatment option for patients with chronic Parsonage-Turner Syndrome who have failed to improve with nonoperative treatment."

A new study led by researchers at Queen Mary University of London provides potential novel biomarkers for predicting patient responsiveness to disease modifying anti-rheumatic drugs (DMARDs).

Rheumatoid Arthritis (RA) patients are commonly treated with disease modifying anti-rheumatic drugs (DMARDs) despite the fact that up to 50% of patients are unresponsive to treatment. Up until now, there has been no way to find out whether a patient will effectively respond to treatment.

The new study, published in the science journal Nature Communications, demonstrates that by measuring levels of certain small molecules produced from essential fatty acids in a patient's blood that are involved in regulating inflammation (known as 'specialized pro-resolving mediators'), predictions can be made about an individual's ability to respond to these drugs.

Lead author Professor Jesmond Dalli from Queen Mary University of London said: "Currently a large proportion of patients with RA are unresponsive to DMARDs and are therefore unnecessarily exposed to their side effects. In addition, it can currently take up to six months from treatment initiation to determine whether someone will or will not respond to these medicines. For the patients who do not respond to the treatment, the disease gets worse before they are able to find a treatment that is more likely to work for them.

"The research was conducted using blood from healthy RA patients who were both responsive and unresponsive to treatment. The blood was collected before treatment initiation or six months after treatment commenced. We then measured the levels of protective molecules using mass spectrometry-based methodologies that were coupled with artificial intelligence methodologies to identify molecules that can predict responses to treatment."

The paper recommends that the blood levels of the mediator group identified in the study should be measured to predict the responsiveness RA patients to DMARD treatment.

The team plan to conduct a larger study to evaluate if these initial findings can be applied to a bigger patient group.

A team of researchers from the Germans Trias i Pujol Hospital and Research Institute (IGTP) and the Hospital del Mar Medical Research Institute (IMIM) has shown that regularly consuming foods rich in omega-3 fatty acids, from both animal and vegetable origins, strengthens the heart's membranes and helps improve the prognosis in the event of a myocardial infarction.

To arrive at these conclusions, they used data from 950 patients. The omega-3 levels in the blood of these individuals were determined when they were admitted to hospital to be treated for the heart attack. This measurement indicates, very accurately, how much of these fats the patients had eaten in the weeks prior to the sampling, in other words, before the heart attack. The patients were monitored for three years after being discharged, and the researchers observed that having high levels of omega-3 in the blood at the time of the infarction, which had been consumed in the weeks leading up to the heart attack, was associated with a lower risk of complications. The results of the study have just been published in the prestigious Journal of the American College of Cardiology.

The benefits of omega-3 fatty acids

Eicosapentaenoic acid (EPA) is a type of omega-3 fatty acid found in oily fish. When we eat oily fish on a regular basis, EPA is incorporated into the phospholipids in the membranes of the cardiomyocytes, protecting them from a wide variety of heart stressors. This enrichment of the myocardial membranes limits the damage caused in the event of a heart attack.

The major novelty of this study is that it also focused on another omega-3 fatty acid, of vegetable origin, known as alpha-linolenic acid (ALA). This fat, which is found in walnuts as well as soybeans and their derivatives, is far less well studied than marine omega-3s. The researchers observed that EPA and ALA do not compete, but are complementary to one another. While high levels of EPA are associated with a lower risk of hospital readmission from cardiovascular causes, higher levels of ALA are associated with a reduced risk of death.

Antoni Bayés, clinical director of Cardiology at Germans Trias, concludes: "Incorporating marine and vegetable omega-3s into the diet of patients at risk of cardiovascular disease is an integrative strategy for improving both their quality of life and prognosis if they suffer a heart attack."

Aleix Sala, a researcher at IMIM-Hospital del Mar and responsible for the blood testing, states: "The article is important because it highlights the complementary (and non-competitive) effects of the two types of omega-3."

Trust or disappointment in government crisis management is an important factor for the general mood, shows a study by the University of Zurich based on surveys in Israel and Switzerland. At the end of April, Israelis were twice as disappointed with their government institutions during the pandemic as Swiss citizens. In Switzerland, a certain fatalism made for less negative feelings.

A clinical social-psychological study by the University of Zurich has examined the development of negative emotions and mood during the Covid-19 pandemic. At the end of April the researchers interviewed around 600 people from all age groups in both Switzerland and Israel. They first examined the extent of the pandemic-related risks and restrictions to everyday life experienced up to that point in each country. No differences between the two countries were found in this regard: According to their own estimates, the Swiss and the Israeli respondents were equally affected by the risk of infection or quarantine measures.

More negative mood in Israel

Nevertheless, the Israelis reported finding the situation more burdensome and experiencing more negative feelings than the Swiss. To find out why, the study focused on perceived loss of control, fatalism and sense of disappointment in or betrayal by one's own government institutions. "The main cause of negative feelings and moods associated with Covid-19 is that people are disappointed in their own government institutions," says Prof. Andreas Maercker of the Department of Psychology at UZH. "In a situation as threatening as a pandemic, people look to the public authorities, whose responsibilities include supporting and protecting individuals. If insufficient support is provided, this is a serious source of concern."

Loss of control and fatalism

According to the study, interventions that helped people feel they could individually protect themselves against the virus had the potential to lessen the negative effects - but only in Israel. In Switzerland that was not the case. In terms of accepting one's own fate, fatalistic attitudes were more pronounced in Israel, but did not influence how scared the Israeli people were of Covid-19. "For Swiss people, however, surrendering to fate went along with less fear of Covid-19. Fatalism therefore seems to have had a protective effect during the pandemic in Switzerland," says first author Rahel Bachem. According to the authors, this social psychological difference between the two countries is based on the fact that Israelis have to live with a permanent sense of threat in their country and therefore generally think more fatalistically, regardless of the current threat from Covid-19. There was no correlation between fatalism and negative mood among the population. This is an interesting scientific finding, as fatalism is generally regarded as a risk factor for mental health in emergency situations. However, this was not the case during the Covid-19 pandemic.

Importance of well-planned crisis management

The study shows how important the actions of government institutions are during a pandemic crisis. For Maercker, this confirms the vital importance of trust in government crisis measures. In addition, although Covid-19 is a global phenomenon, prevention and intervention strategies must be adapted to local contexts.

Cancer remodels the architecture of our chromosomes so the disease can take hold and spread, researchers at the University of Virginia have revealed.

This remodeling is important because the arrangement of the components in our chromosomes actually affects the workings of our genes. With these renovations, cancer begins making a comfortable home for itself inside our cells.

"Even when the genetic code in DNA sequence may largely remain the same, the three-dimensional structure of chromosomes in cancer can be very different from our normal cells," said researcher Chongzhi Zang, PhD, a computational biologist with UVA's Center for Public Health Genomics. "A better understanding of the cancer genome structure can give us insights for developing new drugs to specifically target the Achilles' heel of each cancer."

Understanding Cancer

To make its desired changes inside our chromosomes, cancer relies on a protein called "CCCTC-binding factor," or CTCF for short. CTCF occurs naturally in our cells. In healthy cells, it plays an important role in maintaining the chromosome structure and turning genes on and off as needed. But cancer, Zang found, highjacks CTCF for its own purposes. CTCF appears where it shouldn't, and it doesn't bind where it should. This alters the three-dimensional organization of our chromosomes and changes the way genes work.

To understand CTCF's role in cancer, Zang and his team dived deep into genomic data collected from human tissues and cancer samples. They identified patterns of CTCF remodeling in six different cancers, including T-cell acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, colorectal cancer, lung cancer, and prostate cancer.

"We developed an innovative data science approach to collect and integrate thousands of publicly available datasets to make these findings," Zang said. "It's exciting to see how many new scientific discoveries can be made solely by analyzing the big data that's already out there."

The researchers validated their findings by looking specifically at T-cell acute lymphoblastic leukemia, but they say further research into changes into CTCF binding will help scientists better understand the origins of other cancers as well. (Faulty CTCF binding also has been linked with developmental disorders and other conditions, so understanding it may also offer important insights into those diseases as well.)

"The abnormal patterns of CTCF binding that we found is probably a signature existing in every cancer type," Zang said. "These findings brought us one small step closer to fully unraveling the molecular mechanism of cancer, an extremely complex disease."

Leesburg, VA, October 27, 2020--According to an open-access article in ARRS' American Journal of Roentgenology (AJR), fluorine-18-labeled fluciclovine PET/MRI demonstrated utility in the initial staging of high-risk prostate cancer, as well as for evaluating the response to androgen deprivation therapy (ADT).

Between January 2018 and February 2019, 14 men with newly diagnosed high-risk prostate cancer and negative or equivocal conventional staging imaging were enrolled in this prospective pilot study (ClinicalTrials.gov registration number NCT03264456). "All patients underwent pretreatment 18F-fluciclovine PET/MRI including multiparametric prostate MRI; twelve underwent 18F-fluciclovine PET/MRI after surgery or between ADT and radiotherapy," explained lead investigator Samuel Joseph Galgano from the University of Alabama at Birmingham's multidepartment team.

For all 14 patients, the biopsy-proven lesion in the prostate gland was accurately identified on both MRI and 18F-fluciclovine PET/MRI, and the activity noted on PET/MRI correlated with both the MRI-defined intraprostatic lesions and biopsy-proven prostate cancer. Suspected pelvic regional nodal metastases were detected in 3 patients on MRI vs 7 patients on PET/MRI. Of the three patients with suspected nodal metastases on MRI, 18F-fluciclovine PET/MRI was concordant for lymph node metastases and demonstrated additional suspected lymph node metastases not detected on MRI alone.

Ten of the 14 patients underwent ADT prior to radiation therapy. The primary intraprostatic lesion was accurately identified in all 10 patients, 7 of whom demonstrated suspicious lymph nodes on the pretreatment PET/MRI. Following ADT, all 10 patients demonstrated a decrease in tracer activity either with the primary intraprostatic lesion, all suspicious lymph nodes detected on the pretreatment 18F-fluciclovine PET/MRI, or both.

"Given the FDA approval and widespread availability of 18F-fluciclovine," the authors of this AJR article concluded, "the findings could have impact in the immediate future in guiding initial management of patients with prostate cancer."

The co-authors are employees of the Protein-Cell Interactions Lab of Kazan Federal University (Natalia G. Evtugina, Alina D. Peshkova, and Lab Head Rustem I. Litvinov) in cooperation with Interregional Clinical Diagnostic Center, Kazan, Russia (Arseniy A. Pichugin) and University of Pennsylvania (John W. Weisel and Rustem I. Litvinov by his primary employment).

It is well-known that surgeries can be complicated by life-threatening thromboses that are hard to predict and not easy to prevent. The authors managed to find a new prognostic laboratory sign of the imminent postoperative thrombosis; remarkably, this sign appears on the first postoperative day, a few days before deep vein thrombosis of the lower limbs develops. The laboratory indication of the upcoming thrombosis is the impaired contraction or shrinkage of a clot made from the blood of a patient. It has been shown that if blood clot contraction is normally strong and fast, the risk of thrombotic complications is quite small. On the contrary, if on the first day after surgery clot contraction is suppressed, there is a high likelihood of thrombosis development, and immediate prophylactic measures should be taken to prevent this adverse postoperative complication. This study is a continuation of a series of publications in international scientific journals on a novel and original clinical laboratory assay based on the quantitative characterization of the blood clot contraction kinetics.

The published work is a vivid example of translational medicine that uses accomplishments of fundamental biomedical science to promote enhancements in the prevention, diagnosis, and therapies of diseases. Based on the basic studies of molecular and cellular mechanisms underlying blood clot contraction, the authors consistently implement their laboratory test into clinical practice to aid physicians who often deal with the problems of bleeding and thrombosis. An important feature of severe thrombotic complications is that they occur in various diseases, which emphasizes the extreme importance of research and development in this field.

The potential area of practical applications of the clot contraction assay is growing gradually but surely. The authors continue to use the test to evaluate the risk of thrombotic complications in other pathologies, such as COVID-19, fetal loss and miscarriage, autoimmune diseases, and other conditions associated with disorders of blood clotting.

To allow meaningful comparison between COVID-19 vaccine candidates and ensure that the most effective candidates are deployed, researchers working on different vaccines should collaborate and assess vaccine efficacy using standardised methods

Determining whether a vaccine can protect against severe disease and death from COVID-19 might not be possible in clinical trials, and will likely require long-term, ongoing studies after any candidate is licenced and deployed

Whilst controlled human infection studies (challenge trials) may allow rapid assessment of vaccine efficacy, it is unclear if results from these studies, which are likely to only include young volunteers, will predict vaccine efficacy in older adults

Collaboration and standardised approaches for assessing different vaccine efficacy endpoints are key for meaningful comparison of different COVID-19 vaccine candidates to ensure that the most effective vaccines are deployed, say authors of an opinion piece based on a review of evidence, and published in The Lancet Infectious Diseases journal.

A candidate vaccine against SARS-CoV-2 might act against infection, disease, or transmission, and a vaccine capable of reducing any of these elements could contribute to control of the COVID-19 pandemic. In their Review, the authors highlight key challenges for assessing the efficacy of potential COVID-19 vaccines, to provide insight into the seemingly simple question, "Does this COVID-19 vaccine work?".

Author of the Review, Dr Susanne Hodgson, University of Oxford, UK, said: "It is unlikely that we will see a single vaccine winner in the race against COVID-19. Different technologies will bring distinct advantages that are relevant in different situations, and additionally, there will probably be challenges with manufacturing and supplying a single vaccine at the scale required, at least initially. Taking a standardised approach to measuring the success of vaccines in clinical trials will be important for making meaningful comparisons, so that the most effective candidates can be taken forward for wider use." [1]

Currently, there are 44 candidates in clinical assessment, with a further 154 in preclinical development, reflecting a range of vaccine technologies [2]. The authors argue that to help compare efficacy between these and future candidates, it is important that standardised, quantifiable endpoints are applied to clinical trials of COVID-19 vaccines, and that their limitations and potential for bias are understood.

The authors also highlight a further challenge: evaluating the efficacy of candidate vaccines to protect against severe disease and death from SARS-COV-2 infection. They argue that long-term follow-up of recipients of candidate COVID-19 vaccines will be important, both to evaluate efficacy against severe disease and mortality, and to ensure the ongoing evaluation of vaccine safety.

Co-author, Dr Kate Emary, University of Oxford, UK says: "To determine whether a vaccine protects against severe COVID-19 disease, a clinical trial needs to show that there are significantly fewer cases of severe disease in individuals vaccinated with a COVID-19 vaccine, compared with individuals who were not. However, only a small proportion of individuals infected with SARS-CoV-2 develop severe disease, which means an extremely large number of volunteers is needed in a clinical trial for there to be enough cases to get a reliable measure of vaccine efficacy. This means that it is likely that we will only know if a vaccine protects against severe disease once it has been deployed and given to a large population." [1]

The authors also discuss controlled infection studies in humans (challenge trials) as they may offer a way to measure vaccine efficacy as SARS-CoV-2 transmission declines in the community. They argue that while these studies may provide the only means of rapidly assessing a vaccine's efficacy, the relationship between efficacy in younger individuals in challenge trials and in older and at-risk populations after vaccine deployment remains unclear.

They conclude that in keeping with the development of any novel medical intervention, but particularly so in this context, it is imperative that efficacy outcomes for a SARS-CoV-2 vaccine are critically appraised with scientific rigour to understand their generalisability and clinical significance. They note that although some countries might deploy COVID-19 vaccines on the strength of safety and immunogenicity data alone, the goal of vaccine development is to gain direct evidence of vaccine efficacy in protecting humans against SARS-CoV-2 infection and disease so that manufacture of efficacious vaccines can be selectively upscaled.

(LOS ANGELES) - Breast cancer is the most commonly occurring cancer for women around the world, and much effort has been spent in the development of therapies to treat this disease. Among these treatments, chemotherapy has been shown to be among the most effective methods; however, the drugs used in these therapies can have adverse side effects, the most serious of which is toxicity to the heart. In addition to tissue damage to the heart, chemotherapeutic breast cancer drugs can also affect the heart's pumping ability or result in clinical heart failure.

In order to avoid these problems, efforts are made to monitor the heart of patients who are undergoing chemotherapeutic treatment for breast cancer and to adjust their treatment levels accordingly. Current methods to monitor the heart include the use of echocardiograms and other imaging procedures, as well as taking biopsies of the heart. But the imaging methods only detect late-stage, irreversible cardiac failure and biopsies are highly invasive and are physically painful for the patient.

There are alternative monitoring systems that can be created in the laboratory to mimic what is happening in the body. These organs-on-a-chip models consist of a silicone chip with compartments for culturing specific types of live human tissues. The compartments are connected to microfluidic channels through which oxygen and nutrient media are pumped and circulated. The tissue cells normally secrete molecules called biomarkers into the surrounding medium, which are good indicators of their health and function. The levels of these biomarkers can then be measured in order to determine the condition of the tissues.

Recently, methods have been successful in creating simple systems to monitor heart toxicity from breast cancer drugs in selected patients, but, to date, there have been few attempts to produce such a system in a larger, more comprehensive and reliable model.

A collaborative team, which includes a group from the Terasaki Institute for Biomedical Innovation, has developed an organs-on-a-chip system that more widely examines the responses of breast cancer and heart tissues to therapeutic breast cancer drugs. For their system, they chose to measure two cardiac biomarkers which are produced by healthy heart cells and one biomarker that is produced by actively growing breast cancer cells. Included in the study were tests of both healthy and artificially-induced damaged heart tissues, to mirror the possible heart conditions of breast cancer patients prior to chemotherapy. They also devised added features to the system to enhance its capabilities.

The team designed a chip system with two separate compartments for tissue cultures of breast cancer and either healthy or artificially-induced damaged heart tissues; these compartments were connected by channels which allowed the free flow of fluid between them. To more closely reproduce the mechanical properties of native body tissues, the tissue cultures were prepared by enclosing tiny spheroids of either heart or breast cancer cells in a gelatinous substance. Pre-determined controls for the chip's circulatory fluidic system ensured that the tissues received oxygen, nutrient media and chemotherapeutic drug delivery.

"This work establishes an important model for monitoring cardiac toxicity from breast cancer chemotherapy," said first author Junmin Lee, Ph.D., part of the Terasaki Institute's research team. "We successfully created cardiac and breast cancer tissues that closely mimic bodily tissues, and we developed an improved sensing device and drug delivery system; these are milestones in organs-on-a-chip technology."

In comparison with single-compartment models with either heart or breast cancer tissues, it was found that actively growing breast cancer tissues in communication with heart tissues decreased the levels of healthy heart biomarkers than those found in the single-chip systems. Moreover, the dual-chip system provided evidence that the breast cancer cells' biomarker secretion was affected not only by drug treatment, but by their interaction with cardiac tissues with different levels of damage. This showed that the interplay between the heart and breast cancer tissues had an important influence on indicators of cell function and disease progression.

Although no definitive conclusions could be made on whether pre-damaged heart tissues were more susceptible to cardiac injury when exposed to breast cancer drugs, the results showed that in healthy cardiac tissues, delivery of the breast cancer drug resulted in decreased cellular growth and secretion of healthy heart biomarkers than without the drug.

Further tests may be conducted to explore the use of this model for detecting and predicting cardiac toxicity from chemotherapeutic drugs. The model may be expanded to include observations of tissues cultured on a long-term basis, examination of additional biomarkers, testing the model using tissues derived from several patients and measurements of other, non-biomarker indicators of cardiac damage (electrical and contractive functions, for example). Future possibilities could be the addition of a liver tissue component onto the chip and considerations of the system's scalability to correlate with bodily systems.

"These efforts lay important groundwork that can pave the way to future applications in disease modeling," said Ali Khademhosseini, Ph.D., director and CEO for the Terasaki Institute. "The Personalized Physiological platform that we have at our Institute is one of the many vehicles that we have for bringing personalized medicine to the real world."

Professor Adrian Linacre at Flinders University is part of a team that focuses on developing forensic DNA technology to thwart a thriving global black market in exotic animals - and the significance of this new test working so effectively on such a difficult substance as ivory is especially significant, showing the power and accuracy of this investigation technique.

Ivory, which is essentially a form of tooth structure, has only tiny amounts of DNA contained within it, yet Professor Linacre says the new test procedure can work with only a tiny amount of connected DNA to return results of perfect accuracy.

Elephant populations have been greatly reduced, mainly due to illegal poaching for their ivory. While the trade in elephant products is protected by national laws and CITES agreements to prevent further population declines, ivory poaching and illegal trade in ivory persists. For instance, in Thailand, it is illegal to trade ivory from African elephants; however, the law allows possession of ivory from Asian elephants if permission has been obtained from the authorities. It has been difficult to determine the necessary differences by tests alone.

"This means the enforcement of legislation needs to classify the legal status of seized ivory products," explains Professor Linacre. "Many DNA-based techniques have been previously reported for this purpose, although these have a limit of detection not suitable for extremely degraded samples. Now, this new technique has made a great leap forward."

Historically, the tiny amounts of DNA contained in tusks has made tracking the origins of ivory goods very difficult - and why much of the poached ivory is shipped to Asia and swiftly broken down into tiny pieces, primarily for jewellery and trinkets that can be easily resold and does not allow easy or accurate DNA tracing.

However, the new process can confirm the legal or illegal status of seized ivory samples, even where it is assumed that the DNA will be highly degraded.

The results of the testing - "Discrimination of highly degraded, aged Asian and African elephant ivory using denaturing gradient gel electrophoresis (DGGE)," by Nitchakamon Suwanchatree, Phuvadol Thanakiatkrai, Adrian Linacre and Thitika Kitpipit - have been published in the International Journal of Legal Medicine (DOI: 10.1007/s00414-020-02414-w)

In these tests, DNA from aged ivory was tested for reproducibility, specificity, and, importantly, sensitivity. Blind testing of 304 samples resulted in 100% identification accuracy. It also resulted in correct assignment in the legal status of 227 highly degraded, aged ivories within the test cohort, thus underlining the high sensitivity of the process.

The result of these successful tests will have international implications for the illegal trafficking and poaching of ivory, says Professor Linacre.

"This research output - which is part of our continuing analysis of forensic DNA technology to accurately analyse smaller amount of DNA - will be beneficial to help analyse ivory casework samples in wildlife forensic laboratories, and ultimately help to identify ivory poaching hotspots."

Tsukuba, Japan - Using the body's immune system to fight cancer has great potential, but can also bring serious side effects, including itchy and painful skin reactions. But now, researchers from Japan have found how these skin reactions happen, potentially leading to a way to prevent them.

In a study published this month in Communications Biology, researchers from the University of Tsukuba have determined that one unpleasant side effect of immunotherapy with PD-1 inhibitors, called "anti-PD-1 antibody-induced psoriasis-like dermatitis," is caused by inflammation resulting from high levels of a specific protein. Cancer immunotherapies work through a process that allows the body's T cells to recognize and attack cancers. But because these same processes regulate inflammation, things can get out of balance.

Therapies targeting PD-1 often lead to side effects called immune-related adverse events (irAEs), which happen in more than 70% of patients who take them. The most common of these is a skin reaction, and while some of these are mild and can be easily treated with steroid creams, other patients have itchy, painful, or scaly rashes requiring more intensive treatment. Nearly a fifth of patients receiving immunotherapy stop taking the treatment because of irAEs--even though the treatment may be working well against their cancer.

"Inhibition of the PD-1 pathway is becoming front-line treatment for more and more cancers," says senior author Professor Naoko Okiyama. "But it can't work if patients experience adverse events and discontinue treatment because of them. We hoped that by finding out exactly how PD-1 inhibitors cause dermatitis, we could also find a way to stop it."

The new study builds on earlier research from the same team, who examined blood samples from cancer patients with this side effect, finding high levels of a cell signaling protein called IL-6. Testing this theoretical connection in mice, they found that PD-1 deficiency increased numbers of a specific type of white blood cells (called CD8 T cells) infiltrating the epidermis. CD8 T cells help the immune system kill viruses and bacteria as well as cancer cells. But when activated in large numbers, they can cause an excessive immune response leading to irAEs.

The experiments in mice showed that PD-1 expressed on CD8 T cells regulates skin inflammation. The mice with PD-1 deficiency had high levels of IL-6 expression and subsequently developed dermatitis. As a final step, the researchers used an antibody to block IL-6 signaling in some of these mice--and those mice developed significantly less dermatitis than the control group.

"Altogether, the results clearly show the efficacy of targeting IL-6 in mice," explains Professor Okiyama. "With further study in humans, we may have a potential approach to resolving PD-1-related dermatitis."

On the basis of these results, the researchers also propose that blockade of both IL-6 and PD-1 together could have an even better combined anti-cancer effect, though this has not yet been systematically studied. It's also unknown whether the approach will work as well in people as it does in mice.

"Our most striking finding is the importance of PD-1 expression on CD8 T cells in the development of dermatitis, showing real potential of IL-6 as a target for therapeutic intervention," says Professor Okiyama. "But the hope is that we can implement this combined strategy without compromising the anti-tumor effects of the anti-PD-1 therapy."

Immunotherapies for cancer treatment are still relatively new; therefore, limited information is available on their long-term side effects in comparison with older chemotherapy treatments. As increasing numbers of cancer patients are treated with anti-PD-1 immunotherapy, it will be ever more important to identify strategies to prevent or lessen these adverse events.

ARLINGTON, Va., October 26, 2020 -- A new study, conducted across 13 medical centers in Australia and New Zealand, strengthens the case for radiation therapy as a treatment for cancer that has begun to spread throughout the body. In the randomized phase II trial, patients with up to three lung metastases who were treated with stereotactic ablative radiotherapy (SABR, also known as stereotactic body radiation therapy, or SBRT) fared equally well whether their radiation was delivered in one or four treatment sessions. Findings of the SAFRON II trial (NCT01965223) will be presented today at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

"I think the future of radiation oncology could be these ultra-short treatments," said lead investigator Shankar Siva, PhD, an associate professor of radiation oncology and head of the SBRT program at the Peter MacCallum Cancer Centre in Melbourne, Australia. "Our results indicate that SBRT can be a safe and effective treatment for patients whose cancer has spread to their lungs, even when it's delivered in a single session."

Up to half of all cancers that start elsewhere in the body spread to the lungs, the second most common site for metastases to occur. These types of tumors are typically treated with drug therapy, but typically the tumors become resistant and come back. In recent years, research has shown that SBRT can help these patients to live longer without their cancer returning.

"For patients with a limited number of metastases, recent studies have shown that there can be long-term survivors with the use of SBRT," said Dr. Siva. "These studies tend to be smaller institutional series with a wide variety of SBRT regimens, so we designed our trial to test the safety and effectiveness of SBRT in a more robust fashion."

In this phase II TROG Cancer Research trial, Dr. Siva and his team randomized 90 patients into two treatment arms: half received a single fraction of 28Gy and the other half received a biologically-equivalent regimen of four fractions of 12Gy each. Each patient had up to three lung metastases from primary tumors in other sites, most commonly colorectal cancer (47%).

A total of 37 patients in each treatment group were eligible for safety analyses at one year after treatment. In the cohort who received a single treatment, two patients had grade three side effects, including fatigue, loss of breath and chest pain; no patients experienced grade four or five side effects (i.e., hospitalization or death). In the cohort who received four SBRT treatments, one patient died after experiencing pneumonitis within three months of treatment; there were no grade three or four events. Dr. Siva explained that the events on the single-fraction arm lasted less than three months and that his team found undiagnosed interstitial lung disease in the patient who died on the four-fraction arm.

The researchers also compared survival rates between the groups a year after treatment and found them to be nearly identical across both regimens. Local control rates were 93% for patients who received a single SBRT treatment, compared to 95% for those who received four treatments; overall survival rates were 95% and 93%; and disease-free survival rates were 59% and 60%. Dr. Siva said the team will continue to analyze these secondary endpoints up to three years after treatment, as well as quality of life and cost effectiveness.

If proven safe and effective over the long-term, single-fraction SBRT can be an appealing treatment for patients with oligometastatic cancer to the lungs, said Dr. Siva. In addition to clinical benefits, SBRT has practical benefits for patients, such as fewer trips to a clinic, less time off work and lower treatment costs. "The alternative treatments for oligometastatic cancer are ongoing drug therapies with little expectation for long-term control or surgery, which can have difficult side effects. Radiation is non-invasive, and treatment can be delivered in a relatively short time," said Dr. Siva.

The COVID-19 pandemic has encouraged greater consideration of shorter-course therapies, as medical institutions look for ways to reduce potential exposure, especially among vulnerable patients with cancer. "In a pandemic, the idea of a single, non-invasive outpatient treatment that doesn't require anesthesia is appealing in the sense of reducing patient time and transmission risk in the clinic," he said.

SBRT is typically spread out over up to five treatment sessions. "When we compress a multi-treatment course into a single treatment, there is a potential risk of higher toxicity. Based on our own anecdotal experience, we are quite comfortable using the single treatment approach, but globally, it's used less often," explained Dr. Siva. "There also are concerns that a single treatment might not have the same kind of effectiveness as multiple treatments. Thankfully, in this study, at least a year out we are seeing similar efficacy, where 93-95% of the tumors were controlled in both arms. Our final analysis will show if this holds for the long-term, but these early results indicate that single fraction radiation could be carried out equally effectively across multiple institutions."

That the study was conducted across 13 institutions speaks to the general applicability of its findings and the SBRT approach, said Dr. Siva. He also stressed the importance of incorporating quality assurance into its rollout, however. "The safe delivery of SBRT, particularly in a single session, requires a multi-faceted system of quality assurance, peer review and treatment planning. You need to be absolutely certain of the accuracy of your treatment delivery, and I think it's very important that treatment teams achieve the same high levels of quality control, to make sure we are achieving the best in cancer care."

ARLINGTON, Va., October 26, 2020 -- A new study shows using fewer and higher doses of high-precision radiation therapy is a more effective approach for treating painful spinal tumors than conventional radiation therapy. More than twice as many patients treated with stereotactic body radiation therapy (SBRT) reported an enduring, complete reduction in pain, compared to those treated with conventional radiation. Findings from the Canadian phase II/III trial (NCT02512965) will be presented today at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

"This is the first phase III randomized trial that has shown an improvement with dose escalation for painful spinal lesions," said lead author Arjun Sahgal, MD, a professor and deputy chief of radiation oncology at the Sunnybrook Health Sciences Centre of the University of Toronto. "Pain deteriorates a patient's quality of life and nobody with advanced cancer should have to endure this kind of pain. Patients with painful spinal metastases who meet the eligibility criteria should be offered this treatment."

Spinal metastases are lesions on the spine that have spread from cancer that first occurred elsewhere in the body. While cancer can spread to any part of the body, two-thirds of patients with cancer will experience bone metastases, most commonly in the spine; in fact, research has shown that 70% of patients with terminal cancer develop spinal metastases before they die. Tumors that grow in the spine can cause pain, bone instability and neurologic symptoms, such as weakness, difficulty walking and bowel and bladder problems. Once cancer has spread to the spine, it is rarely considered curable, though there are treatment options to help patients live longer with less pain.

Radiation therapy is commonly used to relieve the pain of spinal metastases, by shrinking the tumors and reducing inflammatory cells. It is delivered through multiple fractions of lower-dose, conventional radiation (CRT), or though SBRT, which allows radiation oncologists to target tumors precisely with very high doses of radiation in fewer fractions. No definitive standard-of-care dose has yet been established for radiation therapy to treat painful spinal metastases.

In this phase II/III study from the Canadian Cancer Trials Group, researchers randomized patients whose primary tumors (mainly in the breast, urinary tract or lung) had metastasized to painful spinal lesions. Patients were treated with either two SBRT fractions for a total dose of 24Gy (n=114), or five CRT fractions for a total dose 20Gy (n=115). Eligible patients reported initial pain scores of greater than two on a scale of 1-10 (with a median score of five) using the Brief Pain Inventory. Pain scores were measured again at three and six months.

Patients in both treatment groups experienced reductions in pain from spinal metastases. After three months, 35% of patients in the SBRT arm of the trial, compared to 14% of those in the CRT arm, reported a complete response rate, or no remaining pain from their lesions (p"This was not just, 'Oh, I feel a little bit better,'" said Dr. Sahgal, adding that patients experienced the reduction in pain without increasing the use of pain medications. Multivariable analyses confirmed that the type of radiation was the independent factor driving pain response, not characteristics such as the patient's age, performance status or type of primary cancer. "We applied a very stringent trial design to focus on the impact of radiation," said Dr. Sahgal. "It was the radiation treatment that led to the improvement."

There was no difference between the study arms in radiation site-specific progression-free survival or overall survival. After three months, 92% of patients in the SBRT arm and 86% of those in the CRT arm were cancer-free at the treated site (p=0.4); the rates at six months were 75% and 69% (p=0.4).

In terms of adverse events, both treatments were safe with respect to fractures and there was no radiation damage to the spinal cord observed in either cohort. Overall, both arms had low rates of serious adverse events and there were no fatal events.

The study also found higher satisfaction from patients in the SBRT arm with quality-of-life measures related to financial considerations, although other quality of life measures did not differ between the two groups. "Patients felt they were in a financially better position coming to the hospital and getting two treatments, rather than five," Dr. Sahgal said. "Even though the complexity of the treatment was greater, it was better for the patient."

A different study reported at ASTRO's 2019 Annual Meeting (RTOG 0631) found no difference in pain reduction between patients treated for spinal metastases with SBRT and those treated with conventional radiation. In Dr. Sahgal's study, however, patients were given a higher dose of radiation, an SBRT dose of 24Gy in two fractions, compared to the earlier trial's dose of 16/18Gy in a single fraction.

Dr. Sahgal said he was motivated to conduct this research out of frustration over the years with being unable to adequately relieve the suffering of patients with advanced stage cancer. "We saw we were getting improvements in pain, but our patients were not pain-free. With the development of SBRT, and spinal SBRT in particular, we started to wonder if we could do better. With these new research results, we think we can."

ARLINGTON, Va., October 26, 2020 -- Results of a new randomized phase III trial suggest that stereotactic radiosurgery (SRS) should replace whole brain radiation therapy (WBRT) as the standard of care for patients with four or more brain metastases. Compared with whole-brain treatment, highly focused radiation therapy led to less cognitive decline with equivalent overall survival. Results from the clinical trial (NCT01592968) will be presented today at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

"This study provides strong evidence to support replacing whole brain radiation with more focal radiation for patients with multiple brain metastases," said lead author Jing Li, MD, PhD, an associate professor of radiation oncology and co-director of the Brain Metastasis Clinic at The University of Texas MD Anderson Cancer Center in Houston.

The trial builds on previous research that established SRS as the standard of care for patients with one to three brain metastases. "Whole brain radiation was the backbone of treatment for brain metastases for a very long time. When stereotactic radiosurgery became available, however, we saw its potential to reduce the cognitive deterioration associated with whole-brain treatment and improve patients' quality of life," said Dr. Li. SRS is more convenient for patients and minimizes interruption of systemic therapy, as well; while WBRT typically is given in 10 treatment sessions over a period of two weeks, radiosurgery generally is completed in one single-day session.

An estimated 1 in 5 patients with cancer will develop brain metastases when primary cancers, most commonly breast cancer, lung cancer or melanoma, spread to the brain. Brain metastases are diagnosed in an estimated 150,000-200,000 people each year, with rising incidence as improved treatments help patients live longer.

In this randomized phase III trial, radiation oncologists at MD Anderson treated 72 adult patients who had 4-15 untreated, non-melanoma brain metastases with either SRS (n=36) or WBRT (n=36). Patients in the WBRT arm were also recommended memantine, a prescription drug used to treat dementia, after a different phase III trial found that it helped delay cognitive decline in patients receiving WBRT for brain metastases. Researchers tracked cognitive function through standard tests of learning and memory, attention span, executive function, verbal fluency, processing speed and motor dexterity.

Cognitive function was better preserved for patients who received SRS, compared to those who received WBRT. Four months after radiation therapy, patients in the SRS group scored higher on a memory function test than they did at baseline (average z-score change from patient's own baseline, +0.21). Patients in the WBRT group arm scored worse on the memory function test compared to baseline (average z-score change, -0.74; p=0.04). Four months after treatment, 6% of the patients in the SRS arm experienced a clinically meaningful decline in cognitive function, compared to 50% of patients in the WBRT arm (p=0.018).

"Cognitive decline is one of the most debilitating effects of brain metastases and treatment, and a key goal of treatment is to improve functioning in the brain for patients with these tumors," explained Dr. Li. Previous trials have indicated that upwards of 90% of patients with brain metastases experience cognitive impairment before treatment, most commonly trouble with attention, memory or information processing.

Overall survival did not differ between the groups (SRS median 7.8 months, WBRT median 8.9 months, p=0.59). Local control rates favored SRS, but the difference did not reach statistical significance (95% at four months with SRS and 86.7% with WBRT (p=0.09). The median time to distant brain failure was 10.5 months for WBRT and 6.3 months for SRS (p=0.37).

Radiosurgery, compared to WBRT, was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS 1.7 weeks, WBRT 4.1 weeks, p=0.001). This finding is particularly important for patients with metastatic disease, explained Dr. Li, as they benefit from systemic therapy to control cancer outside of the brain.

Four patients who received WBRT (15%) and two who received SRS developed (8%) grade 3 or higher toxicities. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients on the SRS arm of the trial (4% of all treated lesions).

Next steps for the research team include comparing SRS with a newer form of WBRT designed specifically to avoid the hippocampus, a brain structure that is central to learning and memory. While a recently published trial (NRG Oncology CC 001) found an advantage of hippocampal-avoidance over standard whole-brain treatment, no trial has compared it with SRS. "Both options are currently considered standard treatment, and both options have pros and cons. We need randomized data to understand which patients will benefit most from each of these treatments," said Dr. Li.

People with cancer who exercise generally have a better prognosis than inactive patients. Now, researchers at Karolinska Institutet in Sweden have found a likely explanation of why exercise helps slow down cancer growth in mice: Physical activity changes the metabolism of the immune system's cytotoxic T cells and thereby improves their ability to attack cancer cells. The study is published in the journal eLife.

"The biology behind the positive effects of exercise can provide new insights into how the body maintains health as well as help us design and improve treatments against cancer," says Randall Johnson, professor at the Department of Cell and Molecular Biology, Karolinska Institutet, and the study's corresponding author.

Prior research has shown that physical activity can prevent unhealth as well as improve the prognosis of several diseases including various forms of cancer. Exactly how exercise exerts its protective effects against cancer is, however, still unknown, especially when it comes to the biological mechanisms. One plausible explanation is that physical activity activates the immune system and thereby bolsters the body's ability to prevent and inhibit cancer growth.

In this study, researchers at Karolinska Institutet expanded on this hypothesis by examining how the immune system's cytotoxic T cells, that is white blood cells specialized in killing cancer cells, respond to exercise.

They divided mice with cancer into two groups and let one group exercise regularly in a spinning wheel while the other remained inactive. The result showed that cancer growth slowed and mortality decreased in the trained animals compared with the untrained.

Next, the researchers examined the importance of cytotoxic T cells by injecting antibodies that remove these T cells in both trained and untrained mice. The antibodies knocked out the positive effect of exercise on both cancer growth and survival, which according to the researchers demonstrates the significance of these T cells for exercise-induced suppression of cancer.

The researchers also transferred cytotoxic T cells from trained to untrained mice with tumors, which improved their prospects compared with those who got cells from untrained animals.

To examine how exercise influenced cancer growth, the researchers isolated T cells, blood and tissue samples after a training sessions and measured levels of common metabolites that are produced in muscle and excreted into plasma at high levels during exertion. Some of these metabolites, such as lactate, altered the metabolism of the T cells and increased their activity. The researchers also found that T cells isolated from an exercised animal showed an altered metabolism compared to T cells from resting animals.

In addition, the researchers examined how these metabolites change in response to exercise in humans. They took blood samples from eight healthy men after 30 minutes of intense cycling and noticed that the same training-induced metabolites were released in humans.

"Our research shows that exercise affects the production of several molecules and metabolites that activate cancer-fighting immune cells and thereby inhibit cancer growth," says Helene Rundqvist, senior researcher at the Department of Laboratory Medicine, Karolinska Institutet, and the study's first author. "We hope these results may contribute to a deeper understanding of how our lifestyle impacts our immune system and inform the development of new immunotherapies against cancer."