When Exercise Can Kill — The Rare Risk of Rhabdomyolysis


Story at-a-glance

  • Muscle trauma due to overexercise can lead to rhabdomyolysis (rhabdo), a serious condition that can lead to kidney damage, renal failure and death
  • When muscle is damaged, it dumps myoglobin, an iron- and oxygen-binding muscle protein, into your bloodstream. Excessive myoglobin obstructs your kidney’s filtration system, which can lead to acute renal damage
  • Classic symptoms of rhabdo include muscle swelling, pain, muscle weakness and dark, scant urine output. Other possible symptoms include nausea, vomiting, fever, intense shivering, confusion and possibly fainting
  • Aside from overexercise, other circumstances that can trigger rhabdo include accidents and blunt trauma, prolonged immobilization, drug side effects and metabolic and genetic disorders
  • Rhabdo can happen with any intense, repetitive motion exercise. Spin classes have produced dozens of cases, typically among newcomers who work above capacity. But even professional athletes and military personnel are affected

By Dr. Mercola

A recent WebMD article1 addresses a rare but potentially fatal muscle disorder called rhabdomyolysis, or rhabdo for short. Estimates suggest it may affect 22 people out of 100,000, and muscle trauma due to overexertion is a common cause. Your skeletal muscles are under your volitional control, which is why they’re also known as voluntary muscles.

You engage them when walking and moving. When skeletal muscle is damaged through overexertion injury, the muscle starts dumping myoglobin, an iron- and oxygen-binding muscle protein, into your bloodstream. Excessive myoglobin obstructs your kidney’s filtration system, which can lead to acute renal damage.

Rhabdo causes kidney failure in up to 40 percent of cases, so early diagnosis and rapid medical intervention is crucial. Liberated potassium leading to hyperkalemia (high potassium in your blood), which can occur within hours after muscle injury, can also be life threatening.

Signs and Symptoms of Rhabdo

The following symptoms are considered “classic” rhabdo symptoms, although all may not necessarily be present in all cases:

  • Muscle swelling
  • Pain in the affected muscle group
  • Muscle weakness or trouble moving your limbs
  • Dark and scant urine output

Other possible symptoms include nausea, vomiting, fever, intense shivering, confusion, dehydration and possibly fainting. While it is clear that rhabdomyolysis occurs due to the breakdown of damaged muscle tissue, there are many situations or circumstances that can trigger it. Some of the most prominent examples include:2

Overexercising

Pushing yourself while exercising, such as running too far or lifting weights beyond your limit, can damage your muscles. While muscle soreness is normal following a workout, suspect rhabdo if the pain is extreme and seems disproportionate to your exertion. Another tipoff is if symptoms trend toward getting worse rather than better over the next couple of days. Untreated, rhabdo will progressively get worse.

Accidents and blunt trauma

Patients who survive major accidents typically develop extensive muscular damage. Nonaccidental injury can also cause muscle trauma that can lead to rhabdo.

Prolonged immobilization

Being bedridden for long periods of time, such as when you suffer a stroke, can put pressure on the muscles pressing against the bed, cutting off blood flow and causing tissue death.

Drug side effects

Cholesterol-lowering medications such as statins or fibrates usually produce muscle weakness as a side effect. Abuse of illicit drugs such as cocaine and heroin can cause weakness as well.

Metabolic disorders

Certain metabolic disorders can raise your risk of rhabdo. This includes problems with metabolism of lipids (fats), carbohydrates or purines, hypothyroidism, diabetic ketoacidosis and electrolyte imbalances.

Genetic disorders

Genetic conditions that can raise your risk includes carnitine deficiency, McArdle’s disease, lactate dehydrogenase deficiency and Duchenne muscular dystrophy.

High-Intensity Repetitive Movement Is a Major Risk Factor

According to Dr. Maureen Brogan, associate professor of medicine at New York Medical College and author of a 2017 paper3 on the condition, rhabdo can happen with any intense, repetitive motion exercise. Spin classes (high-intensity cycling), for example, have produced dozens of cases, typically among newbies who are just starting out and are working above capacity.

One New York City hospital reports seeing 29 rhabdo cases within a four-year span, 14 of which were related to high-intensity cycling.4 According to Brogan, “The high-intensity exercise associated with spin class comes with significant risks to newcomers.” She even goes so far as to call spinning-induced rhabo a “public health concern.” WebMD reports:5

“She says she came to see it as that after six patients came to her hospital’s ER, and all involved people trying a cycling class for the first time … When she searched medical literature, 42 of the 46 cases she found also involved people going to cycling class for the first time.

‘Those are the patients that were most at risk because they may not be conditioned and are using and engaging new muscle groups for the first time at an intense rate,’ she says. ‘So even if you were a different type of athlete like a runner, and then you switch to biking and use quadriceps and gluteus maximus muscles at an intense rate — that first time, you may be at risk of getting rhabdo’ …

[P]eople who stop cycling for some time and then go back at the same rate are at risk, too. ‘[Cycling] is great exercise if you are conditioned for it,’ she says. ‘But you burn 600 to 900 calories in one class. You wouldn’t go out and run 6 to 9 miles on your first day of running. If you did that, you wouldn’t be able to walk either.’”

Dehydration and Extreme Temperatures Raises Your Risk

Inadequate physical conditioning in combination with severe dehydration and/or extreme body temperatures raise your risk of rhabdo, regardless of the exercise you’re doing. Always make sure to stay well-hydrated before, during and after exercise, and take a break if you start feeling excessively hot. If you’re not conditioned to exercise in hot conditions, avoid starting a new type of exercise in a heated exercise room.

When starting a new exercise, even if you’re fit, listen to your body, start slow, take breaks, and work your way up to greater intensity over time. It’s important to recognize that you don’t have to be in poor physical condition for rhabdo to occur, or that you have to work out for an extended period of time. One of Brogan’s patients developed rhabdo after just 15 minutes of cycling.

In fact, many rhabdo patients exercise regularly and express surprise when getting their diagnosis. The key to remember is that there’s a fine line between exercising to capacity and overexerting yourself. Approximately 7 to 8 out of 100,000 military recruits, for example, are affected each year, and even professional athletes — especially marathoners and ultramarathoners — have suffered its consequences.

No One Is Immune to Rhabdo

Professional snowboarder Amy Purdy was hospitalized in 2016 after participating in a CrossFit class for the first time. While generally well-conditioned, she had not done pullups for a few months and the high-intensity, repetitive pullups done during class did her in. She told WebMD:

“It wasn’t until 72 hours later, I was back in my hometown with friends at a restaurant around 11 at night. I told them I worked out too hard a few days ago, and my arms wouldn’t straighten all the way. I then took my jacket off and instantly noticed swelling around my elbows on both arms. The doctors were convinced I didn’t have it because my arms were only slightly swollen. They decided to test me anyway.

That whole experience was one of that [sic] hardest experiences of my life! If you push your body to failure and keep going, you are at risk. Listen to your body. It knows best. And if you find yourself going on days with overly stiff and sore muscles and you notice swelling, get to the hospital ASAP. It may not be rhabdo, but a simple blood test can tell.”

Diagnosis and Treatment

Diagnosis usually begins with a review of your medical history and the events that led up to your medical visit. A variety of blood and urine tests can help diagnose rhabdo. The following tests are typically recommended:6

  • Complete blood count, including hemoglobin, hematocrit and platelets
  • Serum chemistries, including blood urea nitrogen, creatinine, glucose, calcium, potassium, phosphate, uric acid and liver function tests
  • Prothrombin time and activated partial thromboplastin time
  • Serum aldolase
  • Lactate dehydrogenase

In mild cases of rhabdo, simple lifestyle changes are typically sufficient for a full recovery. This includes:

Hydration: Keeping your body properly hydrated helps flush out toxins and ease the workload of your kidneys. Drink clean, filtered water until your urine turns to a light-colored yellow.

Reduce exercise: Cut back on your workout until your muscles recover and your urine normalizes. This can help lower the amount of toxins entering your kidneys until you get better.

Increase circulation: Improving blood circulation is vital to helping your muscles heal and lowering your risk of tissue death. Gentle full-body massages and gentle movements can be helpful. Certain foods can also help improve blood circulation. This includes oranges, goji berries, dark chocolate, sunflower seeds, garlic, ginger and cayenne pepper.

Eat a nutritious diet: Optimizing your diet will also increase your chances of a full recovery. By focusing on eating organic, whole foods that are rich in nutrients, you are nourishing your muscles to recover better and improve your overall well-being.

While protein is important for muscle recovery, avoid protein loading as excessive protein consumption can stimulate your mTOR (mammalian target of rapamycin) for growth rather than regeneration, which is not what you need. To avoid this, limit your intake to 0.5 gram of protein per pound of lean body mass, and focus instead on eating the highest quality protein you can get. This includes grass fed meats, raw seeds and nuts and pasture-raised eggs.

For more serious cases of rhabdo, additional measures may be required. An intravenous solution of special minerals may be used to counteract the potential harms caused by severe muscle damage. Electrolyte imbalances will need to be monitored and promptly treated as well, and in severe cases you may need hemofiltration to address kidney damage.

Rehabbing and Long-Term Prognosis

Overall, the prognosis of rhabdo is good as long as your blood, electrolytes and urine are closely monitored following muscle failure. The mortality rate for rhabdo is only 5 percent, but your risk can significantly increase if kidney failure occurs. If you take good care of yourself by moderating exercise, drinking enough water and getting enough rest, you will be on your way to a successful recovery. It can take time though. Purdy spent months in rehab before being able to lift even the lightest of weights.

While rhabdo is a serious condition, and can happen to anyone, you shouldn’t be scared away from exercise. The take-home message is to always listen to your body. Go easy when you first start something new or different from your regular fitness routine. Give your body some time to adapt and don’t go all-out during the initial sessions.

Also, if you just don’t feel right following a strenuous exercise, keep close watch on your symptoms. Check the color of your urine and pay attention to pain, swelling and weakness. If you’re trending downward when you know you should be recovering, seek medical attention. Blood tests can help diagnose the problem and with proper treatment, kidney damage can be avoided.

Smallest sized replacement heart valve approved in the world


https://speciality.medicaldialogues.in/smallest-sized-replacement-heart-valve-approved-in-the-world/

4 weeks tuberculosis chemoprophylaxis as effective as 9 months course : New Study


https://speciality.medicaldialogues.in/4-weeks-tuberculosis-chemoprophylaxis-as-effective-as-9-months-course-new-study/

Does a Quantum Equation Govern Some of the Universe’s Large Structures?


A new paper uses the Schrödinger equation to describe debris disks around stars and black holes—and provides an object lesson about what “quantum” really means

Does a Quantum Equation Govern Some of the Universe's Large Structures?
This artist’s concept shows a swirling debris disk of gas and dust surrounding a young protostar.

Researchers who want to predict the behavior of systems governed by quantum mechanics—an electron in an atom, say, or a photon of light traveling through space—typically turn to the Schrödinger equation. Devised by Austrian physicist Erwin Schrödinger in 1925, it describes subatomic particles and how they may display wavelike properties such as interference. It contains the essence of all that appears strange and counterintuitive about the quantum world.

But it seems the Schrödinger equation is not confined to that realm. In a paper just published in Monthly Notices of the Royal Astronomical Society, planetary scientist Konstantin Batygin of the California Institute of Technology claims this equation can also be used to understand the emergence and behavior of self-gravitating astrophysical disks. That is, objects such as the rings of the worlds Saturn and Uranus or the halos of dust and gas that surround young stars and supply the raw material for the formation of a planetary system or even the accretion disks of debris spiraling into a black hole.

And yet there’s nothing “quantum” about these things at all. They could be anything from tiny dust grains to big chunks of rock the size of asteroids or planets. Nevertheless, Batygin says, the Schrödinger equation supplies a convenient way of calculating what shape such a disk will have, and how stable it will be against buckling or distorting. “This a fascinating approach, synthesizing very old techniques to make a brand-new analysis of a challenging problem,” says astrophysicist Duncan Forgan of the University of Saint Andrews in Scotland, who was not part of the research. “The Schrödinger equation has been so well studied for almost a century that this connection is clearly handy.”

From Classical to Quantum

This equation is so often regarded as the distilled essence of “quantumness” that it is easy to forget what it really represents. In some ways Schrödinger pulled it out of a hat when challenged to come up with a mathematical formula for French physicist Louis de Broglie’s hypothesis that quantum particles could behave like waves. Schrödinger drew on his deep knowledge of classical mechanics, and his equation in many ways resembles those used for ordinary waves. One difference is that in quantum mechanics the energies of “particle–waves” are quantized: confined to discrete values that are multiples of the so-called Planck’s constant h, first introduced by German physicist Max Planck in 1900.

This relation of the Schrödinger equation to classical waves is already revealed in the way that a variant called the nonlinear Schrödinger equation is commonly used to describe other classical wave systems—for example in optics and even in ocean waves, where it provides a mathematical picture of unusually large and robust “rogue waves.”

But the normal “quantum” version—the linear Schrödinger equation—has not previously turned up in a classical context. Batygin says it does so here because the way he sets up the problem of self-gravitating disks creates a quantity that sets a particular “scale” in the problem, much as h does in quantum systems.

Loopy Physics

Whether around a young star or a supermassive black hole, the many mutually interacting objects in a self-gravitating debris disk are complicated to describe mathematically. But Batygin uses a simplified model in which the disk’s constituents are smeared and stretched into thin “wires” that loop in concentric ellipses right around the disk. Because the wires interact with one another through gravity, they can exchange orbital angular momentum between them, rather like the transfer of movement between the gear bearings and the axle of a bicycle.

This approach uses ideas developed in the 18th century by the mathematicians Pierre-Simon Laplace and Joseph-Louis Lagrange. Laplace was one of the first to study how a rotating clump of objects can collapse into a disklike shape. In 1796 he proposed our solar system formed from a great cloud of gas and dust spinning around the young sun.

Batygin and others had used this “wire” approximation before, but he decided to look at the extreme case in which the looped wires are made thinner and thinner until they merge into a continuous disk. In that limit he found the equation describing the system is the same as Schrödinger’s, with the disk itself being described by the analog of the wave function that defines the distribution of possible positions of a quantum particle. In effect, the shape of the disk is like the wave function of a quantum particle bouncing around in a cavity with walls at the disk’s inner and outer edges.

The resulting disk has a series of vibrational “modes,” rather like resonances in a tuning fork, that might be excited by small disturbances—think of a planet-forming stellar disk nudged by a passing star or of a black hole accretion disk in which material is falling into the center unevenly. Batygin deduces the conditions under which a disk will warp in response or, conversely, will behave like a rigid body held fast by its own mutual gravity. This comes down to a matter of timescales, he says. If the angular momentum of the objects orbiting in the disk is transferred from one to another much more rapidly than the perturbation’s duration, the disk will remain rigid. “If on the other hand the self-interaction timescale is long compared with the perturbation timescale, the disk will warp,” he says.

Is “Quantumness” Really So Weird?

When he first saw the Schrödinger equation materialize out of his theoretical analysis, Batygin says he was stunned. “But in retrospect it almost seems obvious to me that it must emerge in this problem,” he adds.

What this means, though, is the Schrödinger equation can itself be derived from classical physics known since the 18th century. It doesn’t depend on “quantumness” at all—although it turns out to be applicable to that case.

That’s not as strange as it might seem. For one thing, science is full of examples of equations devised for one phenomenon turning out to apply to a totally different one, too. Equations concocted to describe a kind of chemical reaction have been applied to the modeling of crime, for example, and very recently a mathematical description of magnets was shown also to describe the fruiting patterns of trees in pistachio orchards.

But doesn’t quantum physics involve a rather uniquely odd sort of behavior? Not really. The Schrödinger equation does not so much describe what quantum particles are actually “doing,” rather it supplies a way of predicting what might be observed for systems governed by particular wavelike probability laws. In fact, other researchers have already shown the key phenomena of quantum theory emerge from a generalization of probability theory that could, too, have been in principle devised in the 18th century, before there was any inkling that tiny particles behave this way.

The advantage of his approach is its simplicity, Batygin notes. Instead of having to track all the movements of every particle in the disk using complicated computer models (so-called N-body simulations), the disk can be treated as a kind of smooth sheet that evolves over time and oscillates like a drumskin. That makes it, Batygin says, ideal for systems in which the central object is much more massive than the disk, such as protoplanetary disks and the rings of stars orbiting supermassive black holes. It will not work for galactic disks, however, like the spiral that forms our Milky Way.

But Ken Rice of The Royal Observatory in Scotland, who was not involved with the work says that in the scenario in which the central object is much more massive than the disk, the dominant gravitational influence is the central object. “It’s then not entirely clear how including the disk self-gravity would influence the evolution” he says. “My simple guess would be that it wouldn’t have much influence, but I might be wrong.” Which suggests the chief application of Batygin’s formalism may not be to model a wide range of systems but rather to make models for a narrow range of systems far less computationally expensive than N-body simulations.

Astrophysicist Scott Tremaine of the Institute for Advanced Study in Princeton, N.J., also not part of the study, agrees these equations might be easier to solve than those that describe the self-gravitating rings more precisely. But he says this simplification comes at the cost of neglecting the long reach of gravitational forces, because in the Schrödinger version only interactions between adjacent “wire” rings are taken into account. “It’s a rather drastic simplification of the system that only works for certain cases”, he says, “and won’t provide new insights into these disks for experts.” But he thinks the approach could have useful pedagogical value, not least in showing that the Schrödinger equation “isn’t some magic result just for quantum mechanics, but describes a variety of physical systems.”

But Saint Andrews’s Forgan thinks Batygin’s approach could be particularly useful for modeling black hole accretion disks that are warped by companion stars. “There are a lot of interesting results about binary supermassive black holes with ‘torn’ disks that this may be applicable to,” he says.

Ageing and inflammation in patients with HIV infection


Summary

Nowadays, HIV+ patients have an expected lifespan that is only slightly shorter than healthy individuals. For this reason, along with the fact that infection can be acquired at a relatively advanced age, the effects of ageing on HIV+ people have begun to be evident. Successful anti-viral treatment is, on one hand, responsible for the development of side effects related to drug toxicity; on the other hand, it is not able to inhibit the onset of several complications caused by persistent immune activation and chronic inflammation. Therefore, patients with a relatively advanced age, i.e. aged more than 50 years, can experience pathologies that affect much older citizens. HIV+ individuals with non-AIDS-related complications can thus come to the attention of clinicians because of the presence of neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities and non-HIV-associated cancers. Chronic inflammation and immune activation, observed typically in elderly people and defined as ‘inflammaging’, can be present in HIV+ patients who experience a type of premature ageing, which affects the quality of life significantly. This relatively new condition is extremely complex, and important factors have been identified as well as the traditional behavioural risk factors, e.g. the toxicity of anti-retroviral treatments and the above-mentioned chronic inflammation leading to a functional decline and a vulnerability to injury or pathologies. Here, we discuss the role of inflammation and immune activation on the most important non-AIDS-related complications of chronic HIV infection, and the contribution of aging per se to this scenario

Turning Stressed Immune Cells Back Into Fierce Cancer Fighters


immune cells; oncology

Juan R. Cubillos-Ruiz, PhD, “fell in love” with immunology and has translated that passion into award-winning research. Specifically, he is trying to understand how immune cells see and attack cancer cells, and how tumors can influence the function of immune cells and suppress the action of the immune system.

His fascination all began with Dolly the Sheep. As a boy in Bogota, Colombia, Cubillos-Ruiz, now Assistant Professor of Microbiology and Immunology at Weill Cornell Medicine, New York City, he was charmed by the wooly cloned beauty who took the world by storm.

“I knew I wanted to do something related to genetic engineering, but back home that was impossible—we didn’t have any programs like that specifically. The next closest undergrad program was microbiology, so I started studying microbes and how bacteria cause infections, regulate their gene expression, and form biofilms—structures that promote antibiotic resistance.”

To go further, he knew he would need to leave Colombia. “I had a unique experience during my senior year in undergrad—an opportunity to go to the U.S., to Harvard, for a research internship. I was extremely blessed, especially being from South America, to have the chance. I wanted to experience how doing research abroad would be. I worked in the lab of one of the best microbiologists in the world—Roberto Kolter, PhD. Incredible. I was exposed to real scientific research, had conversations every day with post-doctoral fellows, and I was able to attend all the seminars. It was exciting, exhilarating. It was an experience I couldn’t let go of. So I did my best to learn and grab every single tiny bit of it. I decided I would go back home, finish my undergraduate degree, then apply for graduate school in the U.S.”

In 2005, Cubillos-Ruiz received a scholarship to earn his PhD at Dartmouth Medical School in Hanover, N.H. “I left my country, started my doctoral studies, and fell in love with immunology—particularly tumor immunology,” he declared. While he originally had planned to earn a PhD in microbiology, a rotation into a tumor immunology lab redirected his path. “The first week my first project was isolating immune cells from ovarian tumors and expanding them in the lab to make a lot of them, then use genetic engineering to modify them. Bingo! In 2 weeks, I saw what I could do and how thrilling and exciting that research was.”

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Emergence of Immunology

At that time, 2005, cancer immunology was not prominent as it is today. “Many other investigators did not believe that the immune system could actually control cancer growth; there were very few strategies to harness the activities of the immune system,” Cubillos-Ruiz recalled.

But the times, they were a-changing, and the exploitation of the function of the immune system to control cancer moved stridently forward.

Having found his research direction under the guidance of his grad school mentor, Jose Conejo, MD, PhD, to whom he gives great credit, Cubillos-Ruiz said, “I strive to understand why immune cells don’t work well inside the tumor. Immune cells are able to recognize cancer cells, and their job is to kill them. But when they get into the tumor they become suppressed. They become inhibited by all of the environmental conditions that the tumor creates. It is a hostile microenvironment—a place where immune cells simply cannot work. So, for example, within the tumor there is no glucose or other nutrients for the immune cell. There is no oxygen. There are no amino acids that are essential for the proper action of immune cells. This is because cancer cells steal all those essential nutrients from the immune cells.”

Cubillos-Ruiz further detailed that because cancer cells divide more rapidly they have become more efficient at “grabbing” glucose, amino acids, nucleic acids, and all the other building blocks in biology required for cell division. In response, the researcher said his task now is to learn how to make the immune system resistant to that environment, “… how to rewire the metabolism and the molecular biology of the immune cell to actually do well in that microenvironment. We want to enhance their function, make them stronger to resist that tumor environment.”

He explained that the hostile environmental situations—like nutrient deprivation—negatively impact immune cells. “They are literally stressed out,” he said. “Not only are they weakened, but they ‘sense’ (via proteins that detect the stress created by the tumor) that the environment is unfavorable and they initiate a cellular program—the stress response. The stress response pathways are supposed to be activated very transiently, very rapidly, and then shut down. This is an adaptation mechanism. But the problem is that within the tumor that pathway is persistently activated. Having that pathway ‘on’ all the time is what causes immune cell dysfunction. It is a constant, chronic state of stress. And that is not good for any cell.”

Always eager to pay homage to those who have directed his scientific career, Cubillos-Ruiz credits his post-doc mentor Laurie Glimcher, MD, who he trained with first at Harvard and then at Weill Cornell. “It was under her guidance that I gained my understanding of cellular stress responses and basic immunology,” he said humbly.

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De-Stressing Immune Cells

The question, then, becomes how do we turn off that stress response? Cubillos-Ruiz claimed there are three approaches explored both in his lab and with collaborators at Weill Cornell. The first is the creation of a novel, small molecule inhibitor that binds to the active site of the stress sensor and inhibits its function. This means that while the immune cell is still in an adverse microenvironment—there is still stress—they do not undergo the stress response.

“They don’t sense that they are stressed, molecularly speaking,” explained Cubillos-Ruiz. “This approach requires incredible chemistry research and expertise. We are screening thousands of compounds that show inhibitory activity against these sensors. We are exploiting the opportunities that we have here at Weill Cornell—it’s an entrepreneurial ecosystem. We have created a biotechnology company with the goal of generating these novel small molecule inhibitors to inhibit the stress sensors.”

Cubillos-Ruiz, who also serves as Scientific Co-Founder in that biotechnology company, explained that all of the chemistry efforts, drug optimization, and development happens within the company, not in his lab. “The hope is to try to be in clinic by early 2019. That requires many, many experimental tests, optimization, making sure there are no toxicities, etc. This builds upon our first-in-class inhibitory compounds specific for stress sensors—something no one has contemplated as an immunotherapy for cancer. Our approach of using those compounds to reactivate the immune system is innovative and very exciting.”

Juan R

Juan R

The second approach under exploration uses nanotechnology—tiny particles 10-100 nanometers in size (which is 1 million times smaller than a meter). “These small spheres actually encapsulate some drugs that can shut down that pathway. It is called silencing RNA (siRNA), which is commonly used to shut down the expression of genes,” he told OncologyTimes. “By using these nanoparticles, we can deliver the silencing molecules to immune cells in the tumor and silence specific stress sensors. When we shut down the pathway, either genetically or by using pharmacological inhibitors as in the first approach, we can actually reactivate the function of that immune cell. We can reprogram that immune cell so that it now works in the tumor microenvironment.

“This approach was developed when I was a PhD student at Dartmouth. Now they are a tool we have to generate proof-of-principle data as to whether targeting a particular pathway in vivo can elicit some therapeutic effects.”

However, the researcher said the approach will not be prioritized for clinical application now, because the regulatory hurdles of using those nanoparticles are significantly more complicated and lengthy.

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A New Therapeutic Vaccine Type

The third approach revolves around an attempt to generate a new type of vaccine. “Taking advantage of this knowledge, we try to create modified vaccines using innate immune cells that lack stress sensors. If they don’t react to the stress, they can then mount an immune response against the cancer. These are called ‘therapeutic vaccines’ and the goal is to give them to the patient after surgery and chemotherapy to prevent the recurrence of ovarian cancer,” Cubillos-Ruiz explained.

While there have already been many attempts by others to generate vaccines, they have shown very limited efficacy in the clinic in prostate, ovarian, and other cancer types. “They have not worked well in the context of therapeutic vaccines. But our approach is a little bit different,” he stated. “What we want to do is actually modify the immune cells that we use for this vaccination approach and again make them resistant to the tumor microenvironment, allowing it to function better and elicit protective immune response that prevents cancer recurrence.”

This approach is still in a preclinical phase and is being optimized in animal models. However, Cubillos-Ruiz believes this could be the fastest of the three methods to move to the clinic because it will use the patients’ own immune cells, isolated from their blood.

“The idea is to isolate a specific type of immune cell called dendritic cells. They are a very specialized cell type in the immune system involved in presenting tumor antigens,” said Cubillos-Ruiz, adding that the other immune cells, called T cells, can kill the cancer. However T cells will not undertake the killing of cancer if they are not activated by dendritic cells.

“The dendritic cells are absolutely fundamental for licensing anti-tumor T cells. Our approach is to modify the patient’s dendritic cells in the lab, then put them back into the patient. This is somewhat similar to CAR T-cell therapy,” he explained. “But in this case we are not modifying T cells, but instead the dendritic cells so that they empower the T cells to kill. We have seen that, by disabling some factors of the stress response in dendritic cells, they can activate anti-tumor T cells more robustly.”

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Hope Requires Hard Work

It all spells cause for hope for the scientist. “It is very exciting and we are very hopeful. Ovarian cancer is how we started this work, but we see that the same findings are also relevant to bladder, lung, and pancreatic cancers. When the immune response is allowed to do its work, it is strong enough to delay cancer progression in some cases to actually extend the survival of animals with cancer,” said Cubillos-Ruiz.

“When the response is extremely efficient, some animals can actually get rid of tumors and experience tumor regression. But this is all very challenging work,” he reminded. “Tumors are very aggressive; they have evolved multiple mechanisms to evade the immune system.”

Cubillos-Ruiz has come a long way since his days as a boy in Bogota where he was a goalkeeper for his soccer team, played classical guitar, and trained in martial arts. Today, in addition to his career persona, he is husband to a fellow scientist—a microbiologist—and together they hope to have children one day. Until then, he lavishes affection on two small poodles—Mango and Iggy (“… they are fantastic therapy for a crazy scientist like me.”) He also takes advantage of the cultural offerings of New York City, especially concerts, and he enjoys cooking. “A good scientist must be a good cook. If you ever find a scientist who doesn’t know how to cook, that’s a bad sign. Watch out,” he warned through a laugh. Other favored pursuits include travel and writing—in English. “It is a beautiful language, and writing well in English is a crucial skill for scientists to have.”

Asked when he will consider his work a success, he responded, “When we see in the clinic that our new approaches can extend the survival of patients with cancer, and when we can delay or completely eliminate the recurrence of cancer. When tumors recur, they become more aggressive and there is little we can do to stop them. I am convinced that the only way we can prevent or control cancer recurrence is by harnessing the power of the immune system.”

Toward that end, he hopes that all professionals in the field of oncology will recognize the absolute importance of understanding the molecular biology of immune cells, and continue the push to find ways to enhance their function. He also noted that the mechanisms that control immune cell function in cancer are really tumor-specific. “One of the mistakes clinicians make is assuming that immunotherapy is one-size-fits-all. Checkpoint blockade immunotherapy, for example, works remarkably well for melanoma and lung cancers, but unfortunately shows marginal efficacy in ovarian, brain, or pancreatic cancer patients,” he noted.

When presented with the suggestion that he must feel a sense of pride in having reached his current level of understanding and research, Cubillos-Ruiz forcefully disagreed. “Satisfaction? Pride? No, it is just the opposite. I am not satisfied. I feel my responsibility has grown even larger. We need a lot of patients, a lot of resources, a lot of collaboration, a lot of deep mechanistic understanding to keep this work moving forward. This is just the beginning. I have not achieved anything significant—yet.” A three-letter word is the cause for hope.

Combined treatment with mycophenolate improves response in Graves’ orbitopathy


In patients with Graves’ orbitopathy, adding the immunosuppressant drug mycophenolate to glucocorticoid therapy appeared to improve treatment response compared with methylprednisolone alone, according to results of a randomized clinical trial.

“The 2016 European Thyroid Association guidelines recommend intravenous methylprednisolone pulse therapy as first-line treatment for active and severe Graves’ orbitopathy,” George J. Kahaly, MD, PhD, of Johannes Gutenberg University Medical Center, Mainz, Germany, and colleagues wrote. “However, some patients do not respond or relapse after completion of steroid treatment. There is therefore a need to identify new therapeutic strategies, including combination therapies.”

Kahaly and colleagues performed an observer-masked, block-randomized, center-stratified trial of 164 patients with moderate to severe Graves’ orbitopathy at two centers in Germany and two in Italy. Patients were randomly assigned to a course of methylprednisolone (500 mg per week for 6 weeks followed by 250 mg per week for another 6 weeks) alone (n = 81) or with 360 mg of oral mycophenolate twice daily for 24 weeks (n = 83). The main outcomes were rate of response at 12 weeks and rate of relapse at 24 and 36 weeks. The researchers evaluated response at weeks 24 and 36 in post-hoc analyses.

At 12 weeks, 36 of 73 (49%) patients in the monotherapy group showed a response to treatment, compared with 48 of 76 (63%) in the combination therapy group, Kahaly and colleagues reported (OR = 1.76; 95% CI, 0.92-3.39). At 24 weeks, more than half of the monotherapy group responded to treatment (53%; n = 38 of 72 remaining patients), along with nearly three-quarters of the combination therapy group (71%; n = 53 of 75 remaining patients).

However, four patients in the monotherapy group (11%) and four in the combination therapy group (8%) relapsed at 24 weeks (OR = 0. 71; 95% CI, 0.17-3.03). Further, another three patients in the monotherapy group (8%) and two in the combination group (4%) relapsed at week 36 (OR = 0.65; 95% CI, 0.12-3.44).

More than 40% of patients assigned to monotherapy (n = 31 of 68 remaining patients; 46%) and more than half in the combination group (n = 49 of 73 remaining patients; 67%) demonstrated a sustained response at week 36 (OR = 2.44; 95% CI, 1.23-4.82).

The researchers reported 24 serious adverse events in 23 different patients. Of these, 11 occurred among 10 patients assigned to combination therapy and 13 events among 13 patients assigned to monotherapy. Twenty percent of patients in the monotherapy group experienced mild to moderate adverse events, compared with 25% in the combination therapy group.

“The addition of a moderate daily oral dose of mycophenolate to an established moderate dose of intravenous methylprednisolone did not significantly affect the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks,” the researchers wrote. “However, this add-on mycophenolate did lead to significant improvements in patients’ quality of life and, in our post-hoc analysis, ophthalmic symptoms and signs.”

First trimester thyroid hormone levels linked to adverse neonatal outcomes


Pregnant women with first trimester thyroid-stimulating hormone levels of 2.5 mIU/L to 5 mIU/L had increased risks for perinatal loss, miscarriage and premature birth compared with women with lower levels of the hormone, study data show.

Marta Hernández, MD, of the endocrinology and nutrition department at the Hospital Universitari Arnau de Vilanova in Spain, and colleagues evaluated data on 1,981 women (mean age, 30.12 years) who underwent screening for thyroid function at the hospital to determine associations between fetal and maternal complications with first trimester maternal TSH values. Screening was performed between weeks 9 and 12 of gestation.

Median TSH level was 1.72 mIU/L; 26.9% had TSH levels greater than 2.5 mIU/L and 3.2% had levels greater than 5 mIU/L.

Median TSH levels were higher in participants with a miscarriage compared with those without a miscarriage (1.97 mIU/L vs. 1.71 mIU/L; P = .009). Participants with preeclampsia also had higher median TSH levels compared with those without preeclampsia (2.19 mIU/L vs. 1.71 mIU/L; P = .027). First trimester maternal TSH levels were not correlated with infant weight.

Compared with participants with TSH levels less than 2.5 mIU/L, those with levels of 2.5 mIU/L to 5 mIU/L had a higher risk for perinatal loss (OR = 1.519; 95% CI, 1.04-2.219). After adjustment for mother’s age, compared with participants with TSH levels less than 2.5 mIU/L, those with levels of 2.5 mIU/L to 5 mIU/L had greater risks for perinatal loss (OR = 1.589; 95% CI, 1.085-2.329), miscarriage (OR = 1.702; 95% CI, 1.126-2.572) and premature birth (OR = 1.39; 95% CI, 1.013-1.876).

“Our results are in agreement with previous studies that have demonstrated an association between the value of TSH during the first trimester of pregnancy and the incidence of maternal and fetal complications,” the authors wrote. “Our data support that higher levels of TSH within the reference normal concentrations during the first trimester are associated with higher risk of adverse obstetric outcomes, but the single measurement of crude TSH has no individual predictive value.”

Radioactive iodine treatment for thyroid cancer may adversely affect ovarian reserve


Women with differentiated thyroid cancer treated with radioactive iodine ablation experienced decreased anti-Müllerian hormone levels 3 months after treatment with only partial recovery at 1 year after treatment, which may suggest an adverse effect of radioactive iodine in women of reproductive age, according to study findings.

“Many of the subjects treated for differentiated thyroid cancer are women in their reproductive years, often before having given birth for the first time,” Karen M. Tordjman, MD, director of the endocrine clinics at the Institute of Endocrinology at the Tel Aviv Sourasky Medical Center in Israel, told Endocrine Today. “The findings of this study suggest that radioiodine, given as part of the initial treatment for this cancer, could have a negative impact on the future reproductive potential of some of these women. The concerns raised by this study support the current approach that radioactive iodine ablative treatment be reserved to subjects in whom it offers a clear survival or disease-free advantage.”

Tordjman and colleagues evaluated data on 24 women (mean age, 34.3 years) with differentiated thyroid cancer who underwent radioactive iodine (RAI) ablation to determine the effect of RAI treatment on ovarian reserve by measuring the concentration of anti-Müllerian hormone (AMH) 1 year after treatment. A subgroup of five women (mean age, 33.6 years) who underwent RAI ablation for Graves’ disease were also evaluated. AMH levels were measured at baseline and 3, 6 and 12 months after RAI. Baseline AMH levels were 3.2 ng/mL in the differentiated thyroid cancer group and 2.6 ng/mL in the Graves’ disease subgroup.

In participants with differentiated thyroid cancer, baseline AMH level decreased by 49% at 3 months after RAI treatment from 3.25 ng/mL to 1.9 ng/mL (P = .001). In the entire cohort, some recovery in AMH levels was observed, but plateaued at 9 months; at 1-year, AMH concentrations were 32% lower compared with baseline (P = .016).

When the median age of 35 years was used as a cutoff, participants aged at least 35 years were more likely to experience a reduction in AMH at 3 months compared with younger participants (P = .007).

In participants with Graves’ disease, RAI ablation had no treatment effect on AMH levels.

Amenorrhea lasting up to 4 months was reported by two participants, and three reported irregular periods for at least 1 year after treatment. Menstrual irregularities were reported by 19.2% of participants with differentiated thyroid cancer.

“As this is a pilot study that followed a limited number of subjects for only a year, a larger and more prolonged prospective study is needed to confirm these preliminary data, and using fertility outcomes as hard endpoints, to determine if this effect on anti-Müllerian hormone translates into decreased fertility,” Tordjman said. “In the meantime, the authors suggest that serum levels of anti-Müllerian hormone could serve as an ancillary tool when planning radioiodine ablative therapy for women over the age of 35 who desire pregnancy.”

Extra-thyroid extension increases recurrence rates in differentiated thyroid cancer


Extra-thyroid extension increases the risk for disease recurrence in adults with differentiated thyroid cancer compared with those without extension, but overall mortality is higher in those without extension, study data show.

Eyal Robenshtok, MD, of the Endocrine Institute at Rabin Medical Center-Beilinson Hospital and the Sackler Faculty of Medicine at Tel Aviv University in Israel, Talia Diker-Cohen, MD, PhD, of the Institute of Endocrinology, Diabetes and Metabolism at Rabin Medical Center-Beilinson Hospital in Israel, and colleagues conducted a systematic review and meta-analysis of 13 studies published between 1966 and June 2017 with a median follow-up of 86 months that included 23,816 adults with differentiated thyroid cancer to determine the effect of minimal extra-thyroid extension on disease outcome. Participants with and without lymph node metastases were included. Recurrent or persistent disease at the end of follow-up, disease-related mortality and overall mortality were the primary outcomes.

Among participants without lymph node metastases, the risk for recurrence was increased among those with minimal extra-thyroid extension compared with those without extension (OR = 1.73; 95% CI, 1.03-2.92). Participants with tumor extension had a higher absolute risk for recurrence compared with those without extension (3.5% vs. 2.2%; P = .04). Further, the risk for recurrence was higher in participants with extension who underwent lobectomy alone compared with those without extension who underwent lobectomy alone (6.9% vs. 4.2%; P = .3).

Among a combination of participants with and without lymph node metastases, the risk for recurrence was higher among those with extension compared with those without extension (OR = 1.82; 95% CI, 1.14-2.91). The absolute risk for recurrence was also higher in those with extension compared with those without extension (7% vs. 6.2%; P = .01). In participants with or without lymph node metastases who underwent total thyroidectomy or radioactive iodine ablation, the risk for recurrence was higher in those with extension compared with those without extension (4.8% vs. 2.3%; P = .06).

Among participants with micropapillary thyroid carcinoma, minimal extra-thyroid extension had no significant effect on recurrence rates.

Participants with extension had lower overall mortality compared with those without extension (8.7% vs. 9.8%).

“For many years, minimal extra-thyroid extension was regarded as an indication for total thyroidectomy and radioiodine ablation, due to fear of high risk for recurrence,” Robenshtok told Endocrine Today. “Our study strongly demonstrates that though the risk is slightly higher, it is still within the low-risk category. This implies that patients with minimal extra-thyroid extension with lymph node involvement may be treated less aggressively — either without radioiodine or with lobectomy alone. This approach is in line with the current paradigm of less-aggressive treatment in patients with low-risk thyroid cancer, balancing the benefit of treatment with treatment-related morbidity. We need to look at the patient as a whole, looking to cure disease while preserving optimal quality of life. Given how common minimal extra-thyroid extension is, this data may have a substantial effect on treatment recommendations.”

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