The study of endometrial cancer — the cancer of the uterine lining — and another of acute myeloid leukemia, published simultaneously on Wednesday by Nature and The New England Journal of Medicine, are part of a sprawling, ambitious project by the National Institutes of Health to scrutinize DNA aberrations in common cancers.

Over the past year, as part of this project, researchers have reported striking genetic changes in breast, colon and lung cancers that link them to other cancers. One kind of breast cancer was closely related to ovarian cancer. Colon cancers often had a genetic change found in breast cancer. And about half of squamous cell lung cancers might be attacked by drugs being developed for other cancers.

The endometrial cancer and leukemia efforts alone involved more than 100 researchers who studied close to 400 endometrial tumors and 200 leukemias. Endometrial cancer is the most common gynecological cancer in American women and strikes nearly 50,000 of them a year, killing about 8,000. Acute myeloid leukemia, the most prevalent acute adult leukemia, is diagnosed in about 14,000 Americans a year and kills about 10,000.

“This is exploring the landscape of cancer genomics,” said Dr. David P. Steensma, a leukemia researcher at the Dana-Farber Cancer Institute who was not involved with the studies. “Many developments in medicine are about treatments or tests that are only useful for a certain period of time until something better comes by. But this is something that will be useful 200 years from now. This is a landmark that will stand the test of time.”

Dr. Douglas Levine of Memorial Sloan Kettering Cancer Center, the principal investigator on the endometrial cancer study, said the group scoured the country for samples of this cancer.

The cancer has long been evaluated by pathologists who examine thin slices of endometrial tumors under a microscope and put them in one of two broad categories. But the method is not ideal. In general, one category predicts a good prognosis and tumors that could be treated with surgery and radiation, while the other holds a poorer prognosis and requires chemotherapy after surgery. But pathologists often disagree about how to classify the tumors and can find it difficult to distinguish between the two types, Dr. Levine said. 

The new genetic analysis of hundreds of tumors found patterns of genetic aberrations that more precisely classify the tumors, dividing them into four distinct groups. About 10 percent of tumors that had seemed easily treated with the old type of exam now appear to be more deadly according to the genetic analysis and would require chemotherapy.

Another finding was that many endometrial cancers had a mutation in a gene that had been seen before only in colon cancers. The mutation disables a system for repairing DNA damage, resulting in 100 times more mutations than typically occur in cancer cells.

“That was a complete surprise,” Dr. Levine said.

It turned out to be good news. Endometrial cancers with the mutation had better outcomes, perhaps because the accumulating DNA damage is devastating to cancer cells.

Another surprise was that the worst endometrial tumors were so similar to the most lethal ovarian and breast cancers, raising the tantalizing possibility that the three deadly cancers might respond to the same drugs.

Jeff Boyd, executive director of the Cancer Genome Institute at Fox Chase Cancer Center, who was not involved with the new research, said the similarity among breast, ovarian and endometrial tumors was the best example yet of the idea that cancers are more usefully classified by their gene mutations than by where they originate. Though many scientists believe this view is correct, Dr. Boyd said, “It is very rewarding — I can’t overstate it” to see it validated with real data.

While the genetics of endometrial cancer had gone largely unstudied until now, acute myeloid leukemia has been investigated for decades, in part because leukemia cells are so accessible. They are in the blood and bone marrow.

Using microscopes and special staining methods, researchers had already discovered, for example, that chromosomes in these leukemia cells are often broken or hooked together in strange ways. They also knew that some chromosomal alterations were associated with a good prognosis, and others with a bad one. Patients with a good prognosis can usually be treated with chemotherapy alone while those with a worse prognosis need the expensive, difficult and risky treatment of last resort: a bone marrow transplant. It comes with a 10 percent mortality rate.

The problem was that the traditional methods for categorizing the leukemia were imprecise, said Dr. Timothy Ley of Washington University in St. Louis, who led the study with Richard Wilson, also of Washington University. Nearly half the acute myeloid leukemias had normal chromosomes. There was no good way to decide which treatment these patients needed. Some did well with chemotherapy; some did poorly.

“It was a huge conundrum,” Dr. Ley said. “For patients who cannot be cured with chemotherapy, we have a potentially curative therapy. But picking the right patients for a transplant was very difficult.”

The new study of 200 acute myeloid leukemias identified at least 260 genes that were mutated in at least 2 of the 200 leukemia samples, finding virtually all of the common genetic malfunctions that occur in it. Now researchers have a new foundation for assessing which cancers will be lethal unless the patient gets a risky bone marrow transplant and which can be treated with chemotherapy alone.

“We have the basic playbook,” Dr. Ley said. “We finally know what the major pathways are and what all the major mutations look like.” And knowing which genes are mutated also allows researchers to investigate drugs that target those genes.

The next step will be for investigators to determine which mutations lead to good or bad outcomes.

“Within two or three years, risk assessment may be dramatically better,” Dr. Ley said. “It certainly sets the stage for the next era of therapy.”

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A sudden stop, a blow to the body, or a sharp twist of the head may make an athlete feel momentarily dazed, dizzy or nauseated. Typically, the athlete would play through these symptoms or return to play as soon as he or she felt better. Yet, days and months later, that same athlete could be plagued by headaches, difficulty concentrating and mood swings. 

Mental exertion or a return too early to physical activity before a brain injury is resolved can worsen symptoms, and puts athletes at increased risk of repeat injury with potentially permanent neurologic consequences. Until fully recovered, the brain is in crisis. Injured again, the crisis could turn life-threatening.

Second-impact syndrome, a rare but usually fatal syndrome predominantly affecting young male athletes under the age of 18 years, is a devastating consequence of returning athletes to play before complete recovery. 

Determining when the brain has fully recovered is critical to the long-term health and even survival of someone who has sustained an initial concussion. The Department of Neurology at Mayo Clinic in Arizona is addressing this and other issues surrounding concussion by offering complimentary baseline and after-injury computerized cognitive testing to all athletes of high school and middle school age in the state.

In addition, the department has founded a new comprehensive concussion program and is working to develop a sports neurology subspecialty for neurologists nationwide. 

In the face of heightened public concern about concussion, several states have mandated through legislation that athletes recognized as experiencing a concussion be immediately removed from play and not allowed to return to play until evaluated and cleared by a licensed health care provider.

However, without an objective measure, such diagnostic decisions are difficult even for those providers with expertise in dealing with brain injury. Results of the neurologic examination may be normal. Standard imaging, such as CT and MRI of the brain, lacks the resolution to show microscopic structural and metabolic changes in the recovering brain. And the subjective assessment of athletes, many of whom do not recognize the connection between their symptoms and a concussion or fail to report their symptoms in the interest of returning to their sport, can be unreliable.

Cognitive testing is often the only viable and objective measure of impairment and recovery, but to be effective, it must be measured against an individual's pre-injury baseline. Administered online, the cognitive baseline and after-injury test takes about 10 minutes to complete. It assesses skills such as memory, attention, learning, reaction time and processing speed. Students can share the results with coaches, athletic trainers, and the health care provider of their choosing.

In its first month of distribution, more than 25,000 athletes completed the testing. "While advances in helmets and protective equipment are important, there is a limit in their capacity to prevent concussion, and we may be nearing that limit," says David W. Dodick, M.D., a neurologist at Mayo Clinic in Arizona, director of the comprehensive concussion program, and president of the American Headache Society.

"Educating athletes, coaches, parents and athletic trainers about the symptoms, signs and potential long-term effects of concussion and repeated concussion is critically important," says Dr. Dodick. "Preventing concussion is as important as detecting it. Emphasizing the importance of mutual respect among players, eliminating head hits and fighting, and teaching young athletes who are involved in collision sports how to deliver and absorb a body check or tackle will go a long way to minimizing the frequency of concussion."

He also notes that it is important to be aware that children are particularly vulnerable to concussion.

The developmental and maturational changes that occur in the brains of children appear to render them vulnerable to concussion, with symptoms that may take longer to resolve. In addition, concussions are more frequent in female athletes than male athletes, possibly because of their smaller neck girth, which does not provide the stability required to prevent the angular or rotational acceleration of the head that is a common mechanism of concussion.

As Dr. Dodick puts it, "Injured brains need rest — both cognitive and physical." He notes that recovery typically takes more time in a child than an adult. He goes on to say, "Not only is the developing brain more susceptible to injury, but an injury of similar magnitude will have a greater impact on a 12-year-old child than a 28-year-old adult. Repeated concussive injury can affect cognitive development, with consequences for learning and future employment. The concussed brain is a brain in crisis, and even a return to cognitive activities at school can stress the brain, amplify symptoms and prolong recovery."

As part of its commitment to patients with concussion, Mayo Clinic in Arizona has established the comprehensive concussion program, led by Dr. Dodick. Reflecting the three shields of Mayo Clinic, it focuses on patient care, education and research.

The care of patients treated through the program will be managed by an interdisciplinary team that includes 13 subspecialties.

This past August, in conjunction with Arizona State University and Phoenix Children's Hospital, Mayo Clinic in Arizona held a concussion education and awareness summit designed to educate the general public, athletes, athletic trainers and directors, coaches, and health care providers about concussion. The day the concussion summit was held was proclaimed "Arizona Concussion Awareness Day" by the governor of Arizona.

The comprehensive concussion program will also conduct research. Working with clinical researchers at Mayo Clinic in Rochester, Minn., Dr. Dodick and colleagues are beginning a prospective study in Junior A League hockey players to evaluate the correlation between clinical, imaging, and serum biomarkers and in-helmet g-force measurements and outcomes following concussion.

Dr. Dodick is also working with his colleagues in Arizona on developing research protocols to:

In the future, for example, there may be an imaging signature on proton MR spectroscopy that indicates when an individual's brain has actually recovered from concussion, rather than relying on subjective reporting of symptoms or on subtle or absent findings on the physical examination.

Dr. Dodick points out that evidence in the experimental and imaging literature shows that it takes much longer for the brain to recover from concussion than outward symptoms might suggest. "Right now, we're dependent on measures that require us to infer recovery. I want to know not only when athletes tell me they're back to baseline, but when their brain has returned to its metabolic baseline. It's all about when the athlete's brain is safe to return to play."

Dr. Dodick and his colleagues are collaborating with four other institutions to become among the first programs to offer accredited fellowships in sports neurology. Currently, most sports medicine programs are part of a physical medicine and rehabilitation or orthopedic practice and focus on the physical aspects of recovery.

A sports neurology program would bring neurologic expertise to the practice of managing athletic injuries related to concussive brain injury, among other neurologic aspects of athletic participation, such as peripheral nerve injury and neuromuscular and movement disorders.

Until my next article, keep learning, and stay healthy.

Dr. Counce

Every October, I write an article about breast cancer. However, it seems that everyone becomes a little overwhelmed with "pink" and the constant barrage of "National Breast Cancer Month". So this year we have gone directly to The National Cancer Institute to bring you links to the latest information on the fight against breast cancer. Just click on the images, and find the information you are looking for. 

                                                      Dr. Counce

Typically affecting the elderly, normal pressure hydrocephalus (NPH) is one of the more difficult conditions to diagnose. In addition to a wide based gait, ataxia, and incontinence, the signs and symptoms include cognitive impairment, which is often characterized as progressive memory loss. 

The cause of enlarged ventricles, found on CT scans or MRI, is uncertain. However, NPH has been shown experimentally to be associated with decreased absorption of spinal fluid, increased systolic blood pressure, and brain atrophy.

After other causes of gait disturbance have been ruled out, patients have a test that mimics a temporary shunt to determine whether decreasing cerebrospinal fluid volume improves gait. Typically, 30 cubic centimeters of fluid is removed during a spinal tap, and pre- and post-procedure videos of the patient walking are compared.

Separately, tests for cognitive function are conducted to help determine if memory problems are isolated or are accompanied by other impairments. The presence of aphasia, for example, suggests an additional degenerative pathology that likely will not improve with shunting. 

Treatment consists of a neurosurgically placed shunt that drains cerebrospinal fluid into the peritoneal cavity. One of the known complications in the past has been over-drainage, which can cause the brain to shrink and may result in subdural hemorrhage or subdural hygroma.

The recent introduction of programmable shunt valves, however, has improved outcomes and reduced the need for additional surgical procedures to adjust the rate of drainage. It should be noted that NPH may have a degenerative component. Even in patients with initial success, it may be necessary to adjust the rate of drainage six months to several years later. The programmable valve readily enables such adjustments and has made surgery more viable for patients.

Not all symptoms improve with treatment. Often, gait and incontinence improve, but memory and cognition may not. Overlapping conditions may be important to the cognitive decline associated with NPH. The presence of aphasia or even mild naming deficits may signal coexisting pathology, such as vascular disease or Alzheimer's disease (AD). Studies have shown that among people older than 74 years, the brains of more than 30 percent of patients show evidence of AD pathology on autopsy. Cerebrovascular disease is also frequent in this age group because hypertension is common.

Several studies show that hypertension is associated with hydrocephalus in animal models and with hydrocephalus in humans. The Atherosclerosis Risk in Communities (ARIC) Study, a prospective epidemiologic study sponsored by the National Heart, Lung, and Blood Institute (NHLBI), looked at the MRI scans of study participants taken 10 years apart. The investigators found that both increased systolic blood pressure and increased pulse pressure correlated with increased ventricle size.

In earlier research, it was found that head size also correlates with increased risk of NPH. Approximately 10 to 20 percent of people with NPH have a head size at or above the 98th percentile. Thus, it may be that people born with a large head have congenital hydrocephalus that becomes symptomatic as they age. The question of the contribution of head size, vascular disease and underlying AD pathological factors is important to predicting outcomes for surgical shunting.

To address these issues, Drs. Graff-Radford and Wharen at the Mayo Clinic, are initiating a prospective study in which 25 NPH patients who have agreed to shunt surgery will be given a battery of neuropsychological tests and PET imaging to screen for amyloid plaque buildup before surgery. They will also have gait evaluation and neuropsychological testing at one-year follow-up. The goal of the study is to determine whether the presence of amyloid in the brain influences cognitive outcomes from shunt surgery in NPH. The investigators hope their findings will help physicians in counseling patients about which symptoms may improve with a shunt and whether shunting is a good option.

Dr. Counce

The search for a solution to this dilemma led researchers to look back in history. A 1931 publication documented that surgically disrupting the sympathetic nerves connecting the kidneys with the central nervous system, via a procedure called splanchnicectomy, helped reduce blood pressure. The use of surgical procedures (splanchnicectomy and even nephrectomy) to treat severe hypertension continued through the early 1950s, until medical therapies became widely available. Decades later, with the incidence of drug resistant hypertension rising and the availability of less invasive techniques, researchers began looking at interventions with renewed interest. With catheter-delivered radiofrequency ablation already in use for the treatment of complex ventricular arrhythmias, certain cancers, and other disorders, this option is now being studied as a possible intervention for resistant hypertension.   

Points to Remember:  

 

• Mayo Clinic is enrolling patients in the Symplicity HTN-3 trial, a multicenter study of the safety and effectiveness of renal denervation in subjects with uncontrolled hypertension. 

Figure. During denervation, a catheter is introduced via thefemoral artery and positioned in the renal artery under fluoroscopicguidance. The device design allows for continuous bloodflow throughout the treatment, which provides cooling of theartery wall. The catheter is torquable, allowing the user to easilyrotate the device to treat different segments of the vessel.