Chronic Conditions Found in Nearly All Childhood Cancer Survivors.

Nearly all survivors of childhood cancer have chronic health conditions in adulthood, according to a JAMA study.

Researchers systematically screened 1700 adults (median age, 32) who were diagnosed with cancer as children. Roughly 25 years after diagnosis, 98% had a chronic health problem. Two thirds had a disabling or life-threatening condition. The most prevalent impairments were pulmonary abnormalities, cardiac problems, endocrine disorders, hearing loss, and neurocognitive impairment. Hematopoietic, hepatic, skeletal, and urinary tract dysfunction were less common.

The authors conclude, “These data underscore the need for clinically focused monitoring, both for conditions that have significant morbidity if not detected and treated early, such as second malignancies and heart disease, and also for those that if remediated can improve quality of life, such as hearing loss and vision deficits.”

Source: JAMA 

Scientists create hybrid flu that can go airborne.


H5N1 virus with genes from H1N1 can spread through the air between mammals.

As the world is transfixed by a new H7N9 bird flu virus spreading through China, a study reminds us that a different avian influenza — H5N1 — still poses a pandemic threat.

A team of scientists in China has created hybrid viruses by mixing genes from H5N1 and the H1N1 strain behind the 2009 swine flu pandemic, and showed that some of the hybrids can spread through the air between guinea pigs. The results are published in Science1.

Flu hybrids can arise naturally when two viral strains infect the same cell and exchange genes. This process, known as reassortment, produced the strains responsible for at least three past flu pandemics, including the one in 2009.

There is no evidence that H5N1 and H1N1 have reassorted naturally yet, but they have many opportunities to do so. The viruses overlap both in their geographical range and in the species they infect, and although H5N1 tends mostly to swap genes in its own lineage, the pandemic H1N1 strain seems to be particularly prone to reassortment.

“If these mammalian-transmissible H5N1 viruses are generated in nature, a pandemic will be highly likely,” says Hualan Chen, a virologist at the Harbin Veterinary Research Institute of the Chinese Academy of Sciences, who led the study.

“It’s remarkable work and clearly shows how the continued circulation of H5N1 strains in Asia and Egypt continues to pose a very real threat for human and animal health,” says Jeremy Farrar, director of the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam.

Flu fears

Chen’s results are likely to reignite the controversy that plagued the flu community last year, when two groups found that H5N1 could go airborne if it carried certain mutations in a gene that produced a protein called haemagglutinin (HA)2, 3. Following heated debate over biosecurity issues raised by the work, the flu community instigated a voluntary year-long moratorium on research that would produce further transmissible strains. Chen’s experiments were all finished before the hiatus came into effect, but more work of this nature can be expected now that the moratorium has been lifted.

“I do believe such research is critical to our understanding of influenza,” says Farrar. “But such work, anywhere in the world, needs to be tightly regulated and conducted in the most secure facilities, which are registered and certified to a common international standard.”

Virologists have created H5N1 reassortants before. One study found that H5N1 did not produce transmissible hybrids when it reassorts with a flu strain called H3N24. But in 2011, Stacey Schultz-Cherry, a virologist at St. Jude Children’s Research Hospital in Memphis, Tennessee, showed that pandemic H1N1 becomes more virulent if it carries the HA gene from H5N15.

Chen’s team mixed and matched seven gene segments from H5N1 and H1N1 in every possible combination, to create 127 reassortant viruses, all with H5N1’s HA gene. Some of these hybrids could spread through the air between guinea pigs in adjacent cages, as long as they carried either or both of two genes from H1N1 called PA and NS. Two further genes from H1N1, NA and M, promoted airborne transmission to a lesser extent, and another, the NP gene, did so in combination with PA.

“It’s a very extensive paper,” says Schultz-Cherry. “It really shows that it’s more than just the HA. The other proteins are just as important and can drive transmission.” Chen says that health organisations should monitor wild viruses for the gene combinations that her team identified in the latest study. “If those kinds of reassortants are found, we’d need to pay high attention.”

Knowledge gap

It is unclear how the results apply to humans. Guinea pigs have bird-like receptor proteins in their upper airways in addition to mammalian ones, so reassortant viruses might bind in them more easily than they would in humans.

And scientists do not know whether the hybrid viruses are as deadly as the parent H5N1. The hybrids did not kill any of the guinea pigs they spread to, but Chen says that these rodents are not good models for pathogenicity in humans.

There is also a chance that worldwide exposure that already occurred to the pandemic H1N1 strain might actually mitigate the risk of a future pandemic by providing people with some immunity against reassortants with H5N1. In an earlier study, Chen and her colleagues showed that a vaccine made from pandemic H1N1 provided some protection against H5N1 infections in mice6.

“If you take [antibodies] from people who have been vaccinated or naturally infected, will they cross-react with these viruses?” asks Schultz-Cherry. “That’s an important study that would need to be done.”

Ironically, Chen’s team is now too busy reacting to the emerging threat of a different bird flu — H7N9. Research on H5N1 will have to wait.

Source: Nature


Beam of Hope.



Beth colorfully compares her first proton therapy treatment session to watching a scene from a science fiction movie unfold around her. Although the pristine white walls and state-of-the-art equipment conjure up images from the future, the technology will soon be a reality on the St. Jude Children’s Research Hospital campus. The hospital is currently building the world’s only proton center dedicated solely to the treatment of children.

Part of a $198 million project to enhance the hospital’s clinical and laboratory facilities, the St. Jude Red Frog Events Proton Therapy Center is slated to open in 2015.

The new center will greatly enhance the hospital’s ability to conduct research optimizing the use of proton therapy in children.

“This facility will enable us to complete important trials while providing the support that only St. Jude can provide to patients,” says Larry Kun, MD, chair of St. Jude Radiological Sciences.

What is proton therapy?

Proton therapy offers tremendous advantages compared to X-ray technology because it is more precise and may be used to deliver a potentially higher dose of radiation to the tumor with fewer side effects. By confining radiation exposure to the tumor itself, the pinpointed therapy reduces a person’s risk of experiencing toxic effects on major organs and of developing secondary cancers later in life.

“It’s exciting to hear that St. Jude is building its own proton therapy center,” adds Beth, who participated in a St. Jude protocol that involved traveling to Florida for treatment.

Beth was found to have a rare brain tumor known as craniopharyngioma when she was a college sophomore. After six weeks of daily proton therapy, which lasted from one to two hours each, Beth’s tumor is now smaller.

“St. Jude has given Beth hope, and that was more than any other therapy could offer,” says Beth’s mom.

Precise treatment

Beth’s doctor, Thomas Merchant, DO, PhD, division chief
of St. Jude Radiation Oncology, says proton therapy represents the next logical step for the hospital as it remains a world leader in the research and treatment of brain tumors and radiation therapy. Proton therapy can deliver high radiation doses directly to tumors while sparing normal tissues and reducing the side effects of traditional X-ray therapy. Proton therapy’s chief advantage is the ability to control its depth and intensity in tissue. The more precise the beam, the more targeted the therapy.

“It’s very important that we deliver precise treatment to children, and we’ve designed our facility in such a way that when it opens in 2015, it will have one of the narrowest beams in the United States,” says Merchant, who toured leading proton centers throughout the world in researching the project.

In addition to treating brain tumors, the new technology will also be used to treat Hodgkin lymphoma and other solid tumors such as Ewing sarcoma, neuroblastoma and retinoblastoma. Treatment sessions may range from 20 minutes to an hour.

“It’s been wonderful to be able to offer the treatment to our patients at the facility in Florida, but it’s a huge challenge for the families to have to uproot again,” says St. Jude social worker Melanie Russell. “When we have our own treatment facility here, it will be so much easier for our families.”

The new tower housing the facility will also include expanded surgical suites, an advanced Intensive Care Unit, the new Computational Biology department and a global education and collaboration center.


Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia.

Using genomic tools, researchers have uncovered genetic changes associated with a form of leukemia that recurs in some children. The findings, reported last month in Cancer Cell, suggest that some of these young patients may benefit from targeted drugs that are available but currently not used to treat this particular form of the disease.

The study focused on a subtype of acute lymphoblastic leukemia (ALL) known as Philadelphia chromosome-like ALL. Children with this subtype have a higher risk of a recurrence after standard chemotherapy and lower rates of long-term survival than other children with high-risk ALL.

Since the subtype was first described in 2009 (here and here), researchers have identified genetic changes that could explain about half of these cases. Building on this work, a team led by Dr. Charles Mullighan of the St. Jude Children’s Research Hospital analyzed RNA from 15 patients with the subtype and sequenced the genomes of two of these patients.

The results, Dr. Mullighan said, were “striking.” His team found a diverse set of genetic abnormalities linked to cancer, including DNA mutations and chromosomal rearrangements. The biological effects of these changes, however, appeared to be concentrated primarily on two signaling pathways involved in cell growth and proliferation.

Making Use of Available Drugs 

“We found a wide range of gene fusions, but they converged on a limited number of pathways,” said Dr. Kathryn Roberts of St. Jude, a study author. These pathways included the proteins ABL1, PDGFRB, and JAK2, which all play a role in cell growth.

In the lab, several drugs that inhibit growth-promoting signals through these pathways—including imatinib (Gleevec), dasatinib (Sprycel), and ruxolitinib (Jakafi)—showed anticancer effects against models of Philadelphia chromosome-like ALL.

“These findings are important because these children frequently have very poor outcomes,” Dr. Mullighan said. Future studies could test whether patients with mutations affecting these pathways could be candidates to receive targeted drugs along with chemotherapy, he added.

Overall, children with high-risk ALL have a greater than 80 percent chance of being cured by standard treatments, but only about 60 percent of children with Philadelphia chromosome-like ALL are alive and free of cancer after 5 years. This subtype, which accounts for about 15 percent of childhood ALL cases, shows similar patterns of gene activity as Philadelphia chromosome-positive ALL, but the BCR-ABL1 fusion gene is absent.

Better Diagnostic Tests Needed

The new results are from the TARGET initiative, an NCI-supported project that brings together experts on childhood cancers and genome analysis to identify genetic alterations that could be targeted by new or existing therapies.

“These are exactly the kind of results this initiative was created to generate,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program and an NCI leader of the TARGET initiative.

“At this point there are anecdotal examples of how these findings could be translated for broader application,” Dr. Smith continued. Future challenges include improving diagnostic tests to detect the specific molecular alterations and developing treatments appropriate for each alteration, he noted.

At St. Jude, Dr. Roberts is investigating two approaches for detecting this subtype of ALL at the time of diagnosis. One strategy is to profile the active pathways in the leukemia cells, and the other is to look for signature patterns of gene activity.

These tests could serve as an initial screen for Philadelphia chromosome-like ALL, followed by testing for specific genetic alterations associated with the disease, according to Dr. Christine Harrison of Newcastle University in the United Kingdom, who wrote an accompanying editorial.

She praised the study for providing “a comprehensive genomic definition” of Philadelphia chromosome-like ALL, showing it to be a disease with distinctive genetic alterations that affect a range of proteins involved in cell growth.

The work also illustrates one way that cancer researchers are increasingly using genomic tools, noted co-author Dr. Stephen Hunger of the University of Colorado, who is also chair of the Children’s Oncology Group ALL Disease Committee.

“The first step is to identify the abnormalities driving the development of a particular cancer,” he explained. “Then, you use therapies directed against those abnormalities—either alone or with chemotherapy—to improve the outcomes of patients with the least possible side effects.”

Dr. Smith added, “Targeted agents are already known for some of the molecular alterations in Philadelphia chromosome-like ALL, but for others they will need to be identified.”

Dr. Mullighan agreed that a more complete understanding of the Philadelphia chromosome-like ALL subtype is needed. When his team expanded their analysis to include samples from more than 400 patients, the critical lesions in about 20 percent of the cases were unknown.

“We need to know what the changes are, and no single method of analysis is going to pick up every genetic alteration,” he said.

Knowledge gained from studying Philadelphia chromosome-like ALL in children could prove useful for adolescents and young adults as well. This subtype is thought to be more common with advancing age, and the prognosis may also worsen with age.

Since the study was published, Dr. Mullighan has received inquiries from doctors who want to know whether their patients with ALL might be candidates for the new approach. For the study authors, this has underscored the importance of developing clinically accredited tests.

“We really need to develop the diagnostic tests so that we can identify these patients at the time of diagnosis and direct them to the most appropriate targeted therapy,” Dr. Roberts said.

Source: NCI.