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zika virus

Neuroimaging essential for Zika cases

zika virus

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero.

Seventy-one of 110 Brazilian infants at the highest risk for experiencing problems due to exposure to the Zika virus in the womb experienced a wide spectrum of brain abnormalities, including calcifications and malformations in cortical development, according to a study published July 31, 2019 in JAMA Network Open.

The infants were born at the height of Brazil’s Zika epidemic, a few months after the nation declared a national public health emergency. Already, many of the infants had been classified as having the severe form of congenital Zika syndrome, and many had microcephaly, fetal brain disruption sequence, arthrogryposis and abnormal neurologic exams at birth.

These 110 infants “represented a group of ZIKV-exposed infants who would be expected to have a high burden of neuroimaging abnormalities, which is a difference from other reported cohorts,” Sarah B. Mulkey, M.D., Ph.D., writes in an invited commentary published in JAMA Network Open that accompanies the Rio de Janeiro study. “Fortunately, many ZIKV-exposed infants do not have abnormal brain findings or a clinical phenotype associated with congenital Zika syndrome,” adds Dr. Mulkey, a fetalneonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National in Washington, D.C.

Indeed, a retrospective cohort of 82 women exposed to Zika during their pregnancies led by a research team at Children’s National found only three pregnancies were complicated by severe fetal brain abnormalities. Compared with the 65% abnormal computed tomography (CT) or magnetic resonance imaging (MRI) findings in the new Brazilian study, about 1 in 10 (10%) of babies born to women living in the continental U.S. with confirmed Zika infections during pregnancy had Zika-associated birth defects, according to the Centers for Disease Control and Prevention.

“There appears to be a spectrum of brain imaging abnormalities in ZIKV-exposed infants, including mild, nonspecific changes seen at cranial US [ultrasound], such as lenticulostriate vasculopathy and germinolytic cysts, to more significant brain abnormalities, such as subcortical calcifications, ventriculomegaly and, in its most severe form, thin cortical mantle and fetal brain disruption sequence,” Dr. Mulkey writes.

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero. Unlike congenital cytomegalovirus infection, cerebral calcifications associated with Zika are typically subcortical, Dr. Mulkey indicates. What’s more, fetal brain disruption sequence seen in Zika-exposed infants is unusual for other infections that can cause microcephaly.

“Centered on the findings of Pool, et al, and others, early neuroimaging remains one of the most valuable investigations of the Zika-exposed infant,” Dr. Mulkey writes, including infants who are not diagnosed with congenital Zika syndrome.  She recommends:

  • Cranial ultrasound as the first-line imaging option for infants, if available, combined with neurologic and ophthalmologic exams, and brainstem auditory evoked potentials
  • Zika-exposed infants with normal cranial ultrasounds do not need additional imaging unless they experience a developmental disturbance
  • Zika-exposed infants with abnormal cranial ultrasounds should undergo further neuroimaging with low-dose cranial CT or brain MRI.
Jeffrey Dome

The impact of surveillance imaging to detect relapse in Wilms tumor patients

Jeffrey Dome

Dr. Jeffrey Dome, M.D., Ph.D., vice president, Center for Cancer and Blood Disorders.

The Children’s Oncology Group published an article in the Journal of Clinical Oncology looking at the impact that surveillance imaging has on patients with Wilms tumor (WT), the most common kidney cancer in children.

Despite the risks and costs, the use of computed tomography (CT) for routine surveillance to detect recurrence in patients with WT has increased in recent years. The rationale for using CT scans rather than chest x-rays (CXR) and abdominal ultrasounds (US) is that CT scans are more sensitive, thereby enabling recurrences to be detected earlier.

In this study, led by Jeffrey S. Dome, M.D., Ph.D, vice president of the Center for Cancer and Blood Disorders at Children’s National Health System, researchers conducted a retrospective analysis of patients enrolled in the fifth National Wilms Tumor Study (NWTS-5) who experienced relapse to determine if relapse detection with CT scan correlates with improved overall survival compared with relapse detection by CXR or abdominal US.

A total of 281 patients with favorable-histology WT (FHWT) were included in the analysis. The key findings of the study were that:

  • Among patients with relapse after completion of therapy, outcome was improved in patients whose relapse was detected by surveillance imaging rather after signs and symptoms developed.
  • A higher disease burden at relapse, defined by the diameter of the relapsed tumor and the number of sites of relapse, was associated with inferior survival.
  • Relapses detected by CT scan were detected earlier and were smaller on average than relapses detected by CXR or US.
  • However, there was no difference in survival between patients whose relapse was detected by CT versus CXR or US.

An analysis of radiation exposure levels showed that surveillance regimes including CT scans have about seven times the radiation exposure compared to regimens including only CXR and US. Moreover, the cost to detect each recurrence reduced by 50 percent when CXR and US are used for surveillance.

“The results of this study will be practice changing,” said Dr. Dome, one of the doctors leading the clinical trial. “The extra sensitivity that CT scans provide compared to CXR and US do not translate to improved survival and are associated with the downsides of extra radiation exposure, cost and false-positive results that can lead to unnecessary stress and medical interventions,” he added. “Although counter-intuitive, the more sensitive technology is not necessarily better for patients.”

In conclusion, the doctors found that the elimination of CT scans from surveillance programs for unilateral favorable histology Wilms tumor is unlikely to compromise survival. However, it could result in substantially less radiation exposure and lower health care costs. Overall, the risk-benefit ratio associated with imaging modalities should be considered and formally studied for all pediatric cancers.

Learn more about this research in a podcast from the Journal of Clinical Oncology.

Affiliations

Elizabeth A. Mullen, Dana-Farber Cancer Institute/Boston Children’s Cancer and Blood Disorders Center, Boston, MA; Yueh-Yun Chi and Emily Hibbitts, University of Florida, Gainesville, FL; James R. Anderson, Merck Research Laboratories, North Wales, PA; Katarina J. Steacy, University of Maryland Medical Center, Baltimore, MD; James I. Geller, Cincinnati Children’s Hospital Medical Centre, Cincinnati, OH; Daniel M. Green, St Jude Children’s Research Hospital, Memphis, TN; Geetika Khanna, Washington University School of Medicine, St Louis, MO; Marcio H. Malogolowkin, University of California at Davis Comprehensive Cancer Center, Sacramento, CA; Paul E. Grundy, Stollery Children’s Hospital, University of Alberta, Alberta; Conrad V. Fernandez, University, Halifax, Nova Scotia, Canada; and Jeffrey S. Dome, Children’s National Health System, George Washington University School of Medicine and Health Sciences, Washington, D.C.

Kirsten-M.-Williams

Helpful, hopeful news for bone marrow transplant patients

Kirsten-M.-Williams

Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Kirsten M. Williams, M.D., suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

Leukemia can be a terrifying diagnosis for the more than 60,000 U.S. patients who are told they have this blood cancer every year. But the treatment for this disease can be just as frightening. For patients with certain forms of leukemia, the only chance they have for a cure is to receive a massive dose of radiation and chemotherapy that kills their hematopoietic stem cells (HSCs), the cells responsible for making new blood, and then receive new HSCs from a healthy donor.

While patients are waiting for these new cells to go to the bone marrow factory and begin churning out new blood cells, patients are left without an immune system. Devoid of working HSCs for two to four weeks – or longer, if a first transplant doesn’t take – patients are vulnerable to infections that can be just as deadly as their original cancer diagnosis.

As they wait in the protected confines of a hospital, patients who undergo HSC transplants receive blood tests every day to gauge successful engraftment, searching for the presence of immune cells called neutrophils, explains Kirsten M. Williams, M.D., blood and bone marrow transplant specialist at Children’s National Health System.

“As you head into week three post-transplant and a patient’s cell counts remain at zero, everyone starts to get nervous,” Dr. Williams says. The longer a patient goes without an immune system, the higher the chance that they’ll develop a life-threatening infection. Until recently, Dr. Williams says, there has been no way beyond those daily blood tests to assess whether the newly infused cells have survived and started to grow early healthy cells in the bone marrow, a process called engraftment.

A new study could change that paradigm. Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Dr. Williams suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

The study evaluated an investigational imaging test called 18F-fluorothymidine (18F-FLT). It’s a radio-labeled analogue of thymidine, a natural component of DNA. Studies have shown that this compound is incorporated into just three white blood cell types, including HSCs. Because it’s radioactive, it can be seen on various types of common clinical imaging exams, such as positron emission tomography (PET) and computed tomography (CT) scans. Thus, after infusion, the newly infused developing immune system and marrow is readily visible.

To see whether this compound can readily and safely visualize transplanted HSCs, Dr. Williams and colleagues tested it on 23 patients with various forms of high-risk leukemia.

After these patients received total-body irradiation to destroy their own HSCs, they received donor HSCs from relatives or strangers. One day before they were infused with these donor cells, and then at five or nine days, 28 days, and one year after transplantation, the patients underwent imaging with the novel PET/and CT scan imaging platform.

Each of these patients had successful engraftment, reflected in blood tests two to four weeks after their HSC transplants. However, the results of the imaging exams revealed a far more complicated and robust story.

With 18F-FLT clearly visible in the scans, the researchers saw that the cells took a complex journey as they engrafted. First, they migrated to the patients’ livers and spleens. Next, they went to the thoracic spine, the axial spine, the sternum, and the arms and legs. By one year, most of the new HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.

Interestingly, notes Dr. Williams, this pathway is the same one that HSCs take in the fetus when they first form. Although experimental model research had previously suggested that transplanted HSCs travel the same route, little was known about whether HSCs in human patients followed suit.

The study also demonstrated that the radiation in 18F-FLT did not adversely affect engraftment. Additionally, images could identify success of their engraftments potentially weeks faster than they would have through traditional blood tests – a definite advantage to this technique.

“Through the images we took, these patients could see the new cells growing in their bodies,” Dr. Williams says. “They loved that.”

Besides providing an early heads up about engraftment status, she adds, this technique also could help patients avoid painful bone marrow biopsies to make sure donor cells have taken residence in the bones or at the very least help target those biopsies. It also could be helpful for taking stock of HSCs in other conditions, such as aplastic anemia, in which the body’s own HSCs fade away. And importantly, if the new healthy cells don’t grow, this test could signal this failure to doctors, enabling rapid mobilization of new cells to avert life-threatening infections and help us save lives after transplants at high risk of graft failure.

“What happens with HSCs always has been a mystery,” Dr. Williams says. “Now we can start to open that black box.”

Dr. Williams’ co-authors include co-lead author Jennifer Holter-Chakrabarty, M.D., Quyen Duong, M.S., Sara K. Vesely, Ph.D., Chuong T. Nguyen, Ph.D., Joseph P. Havlicek, Ph.D., George Selby, M.D., Shibo Li, M.D., and Teresa Scordino, M.D., University of Oklahoma; Liza Lindenberg, M.D., Karen Kurdziel, M.D., Frank I. Lin, M.D., Daniele N. Avila, N.P., Christopher G. Kanakry, M.D., Stephen Adler, Ph.D., Peter Choyke, M.D., and senior author Ronald E. Gress, M.D., National Cancer Institute; Juan Gea-Banacloche, M.D., Mayo Clinic Arizona; and Catherine “Cath” M. Bollard, M.D., MB.Ch.B., Children’s National.

Research reported in this story was supported by the National Institutes of Health, Ben’s Run/Ben’s Gift, Albert and Elizabeth Tucker Foundation, Mex Frates Leukemia Fund, Jones Family fund and Oklahoma Center for Adult Stem Cell Research.