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Urine test may help monitor disfiguring birthmarks

Vascular anomalies—birthmarks caused by abnormal development of lymph or blood vessels—are usually relatively stable. But sometimes they progress rapidly, requiring aggressive treatment to save the child's health or vision. Now, a study in the July Pediatrics suggests that urine testing can help predict when an anomaly is about to become a serious threat, and raises the possibility of new drug treatments.

Children's Hospital Boston's Vascular Biology research program, headed by Judah Folkman, MD, and the clinical Vascular Anomalies Center, the busiest and most experienced center in the world for the treatment of vascular anomalies, collaborated for the study.

Vascular Biology researcher Marsha Moses, PhD, had been studying the matrix metalloproteinases (MMPs), enzymes that are required for angiogenesis, or growth of blood vessels. Angiogenesis is critical to a cancer's expansion, and Dr. Moses' lab was the first to show that inhibitors of MMPs can block vessel growth. More recently, Dr. Moses' lab demonstrated that cancer patients have elevated levels of MMPs in their urine.

Learning of this, Jennifer Marler, MD, a fellow in Folkman's lab and a clinical fellow in the Vascular Anomalies Center, approached Dr. Moses about doing a study. (Dr. Marler is now at Cincinnati Children's Hospital). Together, they tested urine samples from 217 patients with vascular anomalies and 74 healthy, age-matched controls, and found elevated levels of certain MMPs in 53 percent of patients with vascular tumors and 41 percent of patients with vascular malformations, but just 22 percent of controls. Increased urinary MMPs correlated with both the extent and progression of vascular anomalies.

If these findings bear out, urine testing for MMPs may help physicians know when a vascular anomaly needs intervention. The study also suggests, for the first time, that angiogenesis may play a role in the progression of vascular malformations. Angiogenesis is already known to be important in hemangiomas, and they are treated with anti-angiogenic regimens. But until now, it hadn't been thought that vascular malformations might respond to drugs. Instead, treatment consists of surgery, embolization or sclerotherapy, which can be dangerous, deforming or produce unsatisfactory results.

"This study gives us hope that we'll be able to develop drug treatments," says surgeon Steven Fishman, MD, who is conducting a Phase I trial of MMP inhibitors in nine patients with vascular malformations that have failed current treatments or aren't candidates for them. Giannoula Klement, MD, PhD, a new hematologist/oncologist at the Vascular Anomalies Center and researcher in Folkman's lab, is developing additional drug protocols for difficult-to-treat vascular malformations.

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