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Moderate/severe and penetrating traumatic brain injuries (TBIs) were linked with subsequent brain cancer, a retrospective study of U.S. veterans of the Iraq and Afghanistan wars showed.

Of 1.9 million veterans in the study, 450,000 experienced TBI. Over a median follow-up of 7.2 years, brain cancer occurred in 318 veterans without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (0.06% or less), reported Ian Stewart, MD, of the Uniformed Services University of Health Sciences in Bethesda, Maryland, and co-authors.

Brain cancer was associated with moderate/severe TBI (adjusted hazard ratio [HR] 1.90, 95% CI 1.16-3.12) and penetrating TBI (HR 3.33, 95% CI 1.71-6.49), but not with mild TBI (HR 1.14, 95% CI 0.88-1.47).

"While brain cancer is an uncommon diagnosis, it is a devastating one, with very few known risk factors," Stewart and colleagues wrote in . "Given that TBI is a common injury incurred in the course of military service, further research of this rare but devastating condition is needed to better identify those at risk and develop screening protocols."

Identifying contributors to brain cancer in veterans is critical, observed Elie Massaad, MD, MSc, and Ali Kiapour, PhD, MMSc, both of Harvard Medical School in Boston, in an .

"According to recent VA and National Institutes of Health data, glioblastoma, the most aggressive malignant brain tumor, is the third leading cause of cancer-related death among active-duty personnel," Massaad and Kiapour wrote. "Post-9/11 veterans deployed to Iraq, Afghanistan, and elsewhere face a 26% higher glioblastoma rate versus the general public, with average age of onset decades earlier than in broader populations."

Previous research about TBI and subsequent brain cancer has produced mixed results, Stewart and colleagues pointed out. "Some studies have suggested that brain cancer is associated with prior TBI, while other studies have not observed such an association," the researchers wrote. Studies in rats and stem cells have suggested biologically plausible mechanisms that may play a role, including inflammation.

The team evaluated veterans from the , which consolidates data from Veterans Affairs (VA) and Department of Defense (DoD) sources and the National Death Index. The study was conducted from October 2004 to September 2019.

The primary outcome was brain cancer based on diagnosis codes or death from brain cancer. To reduce possible reverse causality, people who developed brain cancer within 1 year of brain injury were excluded from the study. Veterans also were excluded if they had no encounters within the study period.

The cohort included 1,919,740 veterans with a median age of 31 at index date. Most were men (80.25%) and white (63.11%). A total of 385,848 veterans experienced mild TBI, 46,859 had moderate/severe TBI, and 17,173 had penetrating TBI.

Per 100,000 person-years, crude incidence rates for brain cancer were 3.06 for no TBI, 2.85 for mild TBI, 4.88 for moderate/severe TBI, and 10.34 for penetrating TBI (P<0.001). Follow-up times were similar for no TBI (7.2 years), mild (7.4 years), and moderate/severe TBI (7.4 years), but were less for penetrating TBI (3.9 years).

TBIs diagnosed and treated outside the VA or DoD systems were not captured in this analysis, the researchers acknowledged. Other confounders, including potential toxic exposures, may have influenced results. The findings from this "predominantly young, male military population may not be generalizable to the U.S. population as a whole," Stewart and colleagues noted.

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