Process devised to make minimally invasive surgery more accurate
Johns Hopkins researchers have devised a computerized process that could make minimally invasive surgery more accurate and streamlined using equipment already common in the operating room.
In a report published recently in the journal Physics in Medicine and Biology, the researchers say initial testing of the algorithm shows that their image-based guidance system is potentially superior to conventional tracking systems that have been the mainstay of surgical navigation over the last decade.
“Imaging in the operating room opens new possibilities for patient safety and high-precision surgical guidance,” says Jeffrey Siewerdsen, Ph.D., a professor of biomedical engineering in the Johns Hopkins University School of Medicine. “In this work, we devised an imaging method that could overcome traditional barriers in precision and workflow. Rather than adding complicated tracking systems and special markers to the already busy surgical scene, we realized a method in which the imaging system is the tracker and the patient is the marker.”
Siewerdsen explains that current stateof- the-art surgical navigation involves an often cumbersome process in which someone – usually a surgical technician, resident or fellow – manually matches points on the patient’s body to those in a preoperative CT image. This process, called registration, enables a computer to orient the image of the patient within the geometry of the operating room. “The registration process can be error-prone, require multiple manual attempts to achieve high accuracy and tends to degrade over the course of the operation,” Siewerdsen says.
Siewerdsen’s team used a mobile C-arm to develop an alternative. They suspected that a fast, accurate registration algorithm could be devised to match two-dimensional X-ray images to the three-dimensional preoperative CT scan in a way that would be automatic and remain up to date throughout the operation. Starting with a mathematical algorithm they had previously developed to help surgeons locate specific vertebrae during spine surgery, the team adapted the method to the task of surgical navigation. When they tested the method on cadavers, they found a level of accuracy better than 2 millimetres and consistently better than a conventional surgical tracker, which has 2 to 4 millimetres of accuracy in surgical settings.
“The breakthrough came when we discovered how much geometric information could be extracted from just one or two Xray images of the patient,” says Ali Uneri, a graduate student in the Department of Computer Science in the Johns Hopkins University Whiting School of Engineering. “From just a single frame, we achieved better than 3 millimetres of accuracy, and with two frames acquired with a small angular separation, we could provide surgical navigation more accurately than a conventional tracker.”
The team investigated how small the angle between the two images could be without compromising accuracy and found that as little as 15 degrees was sufficient to provide better than 2 millimetres of accuracy. An additional advantage of the system, Uneri says, is that the two X-ray images can be acquired at extremely low dose of radiation – far below what is needed for a visually clear image, but enough for the algorithm to extract accurate geometric information.
The team is translating the method to a system suitable for clinical studies. While the system could potentially be used in a wide range of procedures, Siewerdsen expects it to be most useful in minimally invasive surgeries, such as spinal and intracranial neurosurgery.
Disorganised cortical patches suggest prenatal origin of autism
The architecture of the autistic brain is speckled with patches of abnormal neurons, according to research published in the New England Journal of Medicine on March 27, 2014.
The study suggests that brain irregularities in children with autism can be traced back to prenatal development. “While autism is generally considered a developmental brain disorder, research has not identified a consistent or causative lesion,” said Thomas R. Insel, M.D., director of US-based National Institute of Mental Health (NIMH).
“If this new report of disorganized architecture in the brains of some children with autism is replicated, we can presume this reflects a process occurring long before birth. This reinforces the importance of early identification and intervention.”
Eric Courchesne, Ph.D. and Rich Stoner, Ph.D., of the Autism Center of Excellence at the University of California, San Diego joined colleagues from the Allen Institute for Brain Science to investigate the cellular architecture of the brain’s outermost structure, the cortex, in children with autism. Courchesne recently reported an overabundance of neurons in the prefrontal cortex of children with autism.
For the current study, the researchers analyzed gene expression in postmortem brain tissue from children with and without autism, all between 2 and 15 years of age. As the prenatal brain develops, neurons in the cortex differentiate into six layers. Each is composed of particular types of brain cells with specific patterns of connections.
The research team focused on genes that serve as cellular markers for each of the cortical layers as well as genes that are associated with autism. The study found that the markers for several layers of the cortex were absent in 91% of the autistic case samples, as compared to 9% of control samples. Further, these signs of disorganization were not found all over the brain’s surface, but instead were localized in focal patches that were 5-7 millimetres in length and encompassed multiple cortical layers.
These patches were found in the frontal and temporal lobes of the cortexregions that mediate social, emotional, communication, and language functions. Considering that disturbances in these types of behaviours are hallmarks of autism, the researchers conclude that the specific locations of the patches may underlie the expression and severity of various symptoms in a child with the disorder. The patchy nature of the defects may explain why early treatments can help young infants and toddlers with autism improve.
According to the researchers, since the faulty cell layering does not occur over the entire cortex, the developing brain may have a chance to rewire its connections by sidestepping the pathological patches and recruiting cells from neighbouring brain regions to assume critical roles in social and communication functions. l doi: 10.1056/NEJMoa1307491 Youtube - Patches of Disorganization in the Neocortex of Children with Autism http://youtu.be/B3Jv16KsAwE
Recycling a patient’s blood during surgery better than using banked blood
Patients whose own red blood cells are recycled and given back to them during heart surgery have healthier blood cells better able to carry oxygen where it is most needed compared to those who get transfusions of blood stored in a blood bank, according to results of a small study at Johns Hopkins.
In a report for the June issue of the journal Anesthesia & Analgesia, the researchers say they found that the more units of banked blood a patient received, the more red cell damage they observed. The damage renders the cells less flexible and less able to squeeze through a body’s smallest capillaries and deliver oxygen to tissues.
Among patients who received five or more units of red blood cells from a hospital blood bank during the study, the damage persisted for at least three days after surgery. In the past, studies have linked transfusions to increased risk of hospital-acquired infections, longer hospital stays and increased risk of death.
“We now have more evidence that fresh blood cells are of a higher quality than what comes from a blood bank,” says study leader Steven Frank, M.D., an associate professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine.
“If banked blood, which is stored for up to six weeks, is now shown to be of a lower quality, it makes more sense to use recycled blood that has only been outside the body for one or two hours.
It’s always been the case that patients feel better about getting their own blood, and recycling is also more cost effective.” To recycle the blood, a machine known as a cell saver is used to collect what a patient loses during surgery, rinse away unneeded fat and tissue, and then centrifuge and separate the red cells, which are then returned to the patient should he or she need it.
“If something is bad for you, a little bit might be OK, but a lot of it is much worse,” Frank says. “It turns out that blood is more like milk, which has a relatively short shelf life, than a fine wine, which gets better with age.” Frank cautions that cell saver machines are not appropriate for all operations, and not all hospitals have access to round-the-clock perfusionists to run them.
For heart surgeries, however, a perfusionist is already in the operating room to run the heart-lung bypass machine. And, he adds, many operations are considered to be low risk for blood loss, in which case the cell saver is unnecessary.
But he advocates wider use of recycled blood. “In any patient where you expect to give one unit of red blood cells or more, it’s cost-effective and beneficial to recycle,” he says.
New immunotherapy could be effective against wide range of cancers
A new method for using immunotherapy to specifically attack tumour cells that have mutations unique to a patient’s cancer has been developed by scientists at the US National Cancer Institute (NCI), part of the National Institutes of Health.
The researchers demonstrated that the human immune system can mount a response against mutant proteins expressed by cancers that arise in epithelial cells which can line the internal and external surfaces (such as the skin) of the body. These cells give rise to many types of common cancers, such as those that develop in the digestive tract, lung, pancreas, bladder and other areas of the body.
The research provides evidence that this immune response can be harnessed for therapeutic benefit in patients, according to the scientists. The study was published May 9, 2014, in the journal Science.
“Our study deals with the central problem in human cancer immunotherapy, which is how to effectively attack common epithelial cancers,” said Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research.
“The method we have developed provides a blueprint for using immunotherapy to specifically attack sporadic or driver mutations, unique to a patient’s individual cancer.” All malignant tumours harbour genetic alterations, some of which may lead to the production of mutant proteins that are capable of triggering an antitumor immune response. Research led by Rosenberg and his colleagues had shown that human melanoma tumours often contain mutation- reactive immune cells called tumourinfiltrating lymphocytes, or TILs.
The presence of these cells may help explain the effectiveness of adoptive cell therapy (ACT) and other forms of immunotherapy in the treatment of melanoma. In ACT, a patient’s own TILs are collected, and those with the best antitumor activity are grown in the laboratory to produce large populations that are infused into the patient. However, prior to this work it had not been clear whether the human immune system could mount an effective response against mutant proteins produced by epithelial cell cancers.
These cells comprise more than 80% of all cancers. It was also not known whether such a response could be used to develop personalized immunotherapies for these cancers. In this study, Rosenberg and his team set out to determine whether TILs from patients with metastatic gastrointestinal cancers could recognize patient-specific mutations.
They analyzed TILs from a patient with bile duct cancer that had metastasized to the lung and liver and had not been responsive to standard chemotherapy. The patient, a 43-year-old woman, was enrolled in an NIH trial of ACT for patients with gastrointestinal cancers (Clinical trial number NCT01174121). The researchers first did whole-exome sequencing, in which the protein-coding regions of DNA are analyzed to identify mutations that the patient’s immune cells might recognize.
Further testing showed that some of the patient’s TILs recognized a mutation in a protein called ERBB2-interacting protein (ERBB2IP). The patient then underwent adoptive cell transfer of 42.4 billion TILs, approximately 25% of which were ERBB2IP mutation-reactive T lymphocytes, which are primarily responsible for activating other cells to aid cellular immunity, followed by treatment with four doses of the anticancer drug interleukin-2 to enhance T-cell proliferation and function.
Following transfer of the TILs, the patient’s metastatic lung and liver tumours stabilized. When the patient’s disease eventually progressed, after about 13 months, she was re-treated with ACT in which 95% of the transferred cells were mutation-reactive T cells, and she experienced tumour regression that was ongoing as of the last follow up (six months after the second T-cell infusion).
These results provide evidence that a T-cell response against a mutant protein can be harnessed to mediate regression of a metastatic epithelial cell cancer. “Given that a major hurdle for the success of immunotherapies for gastrointestinal and other cancers is the apparent low frequency of tumor-reactive T cells, the strategies reported here could be used to generate a Tcell adoptive cell therapy for patients with common cancers,” said Rosenberg. l doi: 10.1126/science.1251102.
Discovery of anti-appetite molecule released by fibre could help tackle obesity
New research has helped unpick a longstanding mystery about how dietary fibre supresses appetite. In a study led by Imperial College London and the Medical Research Council (MRC), an international team of researchers identified an anti-appetite molecule called acetate that is naturally released when we digest fibre in the gut.
Once released, the acetate is transported to the brain where it produces a signal to tell us to stop eating. The research, published in Nature Communications confirms the natural benefits of increasing the amount of fibre in our diets to control over-eating and could also help develop methods to reduce appetite.
The study found that acetate reduces appetite when directly applied into the bloodstream, the colon or the brain. Dietary fibre is found in most plants and vegetables but tends to be at low levels in processed food. When fibre is digested by bacteria in our colon, it ferments and releases large amounts of acetate as a waste product.
The study tracked the pathway of acetate from the colon to the brain and identified some of the mechanisms that enable it to influence appetite. “The average diet in Europe today contains about 15 g of fibre per day,” said lead author of the study Professor Gary Frost, from the Department of Medicine at Imperial College London.
“In stone-age times we ate about 100g per day but now we favour low-fibre ready-made meals over vegetables, pulses and other sources of fibre. Unfortunately our digestive system has not yet evolved to deal with this modern diet and this mismatch contributes to the current obesity epidemic.
Our research has shown that the release of acetate is central to how fibre supresses our appetite and this could help scientists to tackle overeating.” Co-author on the study Professor Jimmy Bell from the MRC Clinical Sciences Centre said: “It’s exciting that we have started to really understand what lies behind fibre’s natural ability to supress our appetite and identified acetate as essential to the process. In the context of the growing rates of obesity in western countries, the findings of the research could inform potential methods to prevent weight gain.” Professor Gary Frost added: “The major challenge is to develop an approach that will deliver the amount of acetate needed to supress appetite but in a form that is acceptable and safe for humans.” l doi: 10.1038/n-comms4611
Longer stay in ICU has detrimental effect on patient’s long term quality of life
Patients have substantial physical impairments even two years after being discharged from the hospital after a stay in an intensive care unit (ICU), new Johns Hopkins research suggests.
The scientists found that for every day of bed rest in the ICU, muscle strength was between 3% and 11% lower over the following months and years. “Even a single day of bed rest in the ICU has a lasting impact on weakness, which impacts patients’ physical functioning and quality of life,” says Dale M. Needham, M.D., Ph.D., an associate professor of medicine and of physical medicine and rehabilitation at the Johns Hopkins University School of Medicine and senior author of the study described in the April issue of Critical Care Medicine.
“We previously thought that bed rest and sedation in an ICU were helpful for patients, but we’re finding this approach to care is actually harmful to the long-term recovery of many.” For the study, the Johns Hopkins team followed up on 222 patients discharged from one of 13 ICUs at four Baltimore hospitals between October 2004 and October 2007. All patients spent time on a mechanical ventilator as part of their successful treatment for acute lung injury, a syndrome marked by inflammation and excessive fluid in the lungs and frequent multiorgan failure.
The disorder is considered an archetype disease in studying patients with critical illness. The patients underwent evaluation of muscle strength at hospital discharge and also three, six, 12 and 24 months later.
More than one-third of survivors had muscle weakness at discharge, and while many saw improvement over time, the weakness was associated with substantial impairments in physical function and quality of life at subsequent follow-up visits. The two variables most associated with a patient’s muscle weakness were age and the duration of bed rest in the ICU, a unit where patients are traditionally confined to their beds because of deep sedation, breathing tubes and life-sustaining machinery.
“Age is not a modifiable risk factor, but bed rest is,” Needham says. “We need to focus on changing bed rest to improve patients’ recovery.” Previous research has shown that during the first three days a severely ill patient spends in the ICU, he or she can expect a 9 percent decrease in muscle size.
The patients in this new study spent an average of two weeks in the ICU. The key to improving long-term physical outcomes for survivors of critical illnesses may be in rethinking how patients are treated in the ICU, the researchers say.
“The standard of care for really sick patients has been keeping them sedated and in bed,” says Eddy Fan, M.D., Ph.D., a former Johns Hopkins physician who now works at the University of Toronto and the study’s first author. “Many doctors and nurses believe that when there’s a breathing tube in place, patients need deep sedation, not rehab.
But that is a myth. We need our patients awake and moving.” Needham stresses the importance of keeping ICU patients as active as possible, even for severely ill patients who may only be able to sit up at the edge of the bed or have their arms and legs exercised by a physical or occupational therapist.
Researchers use stem cells to create light-sensitive retinal tissue in a dish
Using a type of human stem cell, Johns Hopkins researchers say they have created a three-dimensional complement of human retinal tissue in the laboratory, which notably includes functioning photoreceptor cells capable of responding to light, the first step in the process of converting it into visual images.
“We have basically created a miniature human retina in a dish that not only has the architectural organization of the retina but also has the ability to sense light,” says study leader M. Valeria Canto-Soler, Ph.D., an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine.
She says the work, reported online June 10 in the journal Nature Communications, “advances opportunities for vision-saving research and may ultimately lead to technologies that restore vision in people with retinal diseases.” Like many processes in the body, vision depends on many different types of cells working in concert, in this case to turn light into something that can be recognized by the brain as an image. Canto- Soler cautions that photoreceptors are only part of the story in the complex eye-brain process of vision, and her lab hasn’t yet recreated all of the functions of the human eye and its links to the visual cortex of the brain.
“Is our lab retina capable of producing a visual signal that the brain can interpret into an image? Probably not, but this is a good start,” she says. The achievement emerged from experiments with human induced pluripotent stem cells (iPS) and could, eventually, enable genetically engineered retinal cell transplants that halt or even reverse a patient’s march toward blindness, the researchers say.
Retinal tissue is complex, comprising seven major cell types, including six kinds of neurons, which are all organized into specific cell layers that absorb and process light, “see,” and transmit those visual signals to the brain for interpretation. The lab-grown retinas recreate the three-dimensional architecture of the human retina.
“We knew that a 3-D cellular structure was necessary if we wanted to reproduce functional characteristics of the retina,” says Canto-Soler, “but when we began this work, we didn’t think stem cells would be able to build up a retina almost on their own. In our system, somehow the cells knew what to do.” Canto-Soler says that the newly developed system gives them the ability to generate hundreds of mini-retinas at a time directly from a person affected by a particular retinal disease such as retinitis pigmentosa.
This provides a unique biological system to study the cause of retinal diseases directly in human tissue, instead of relying on animal models. The system, she says, also opens an array of possibilities for personalized medicine such as testing drugs to treat these diseases in a patientspecific way.
In the long term, the potential is also there to replace diseased or dead retinal tissue with lab-grown material to restore vision.
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