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    Targeted vitreoretinal lymphoma therapies mimic other approaches

    Genetic sequencing for non-ocular cancers provide insight for identifying new mutations

    Vitreoretinal lymphomas are both deceptive and deadly. While there are only about 350 cases reported annually in the United States, median survival is less than 5 years, said Rajesh C. Rao, MD.

    “Vitreoretinal lymphoma is often difficult to diagnose,” said Dr. Rao, assistant professor of ophthalmology and visual sciences and pathology, University of Michigan, Ann Arbor. “There are no standardized therapies.

    “While current intravitreous therapies—such as methotrexate and rituximab—can control intraocular disease, survival rates remain dismal due to central nervous system involvement,” he said.

    Dr. Rao described a genetic approach based on precision-medicine strategies that have been used successfully in other cancers. His lab has identified genetic alterations that both identify vitreoretinal lymphomas and invite the kind of targeted therapies transforming treatments for other types of cancers.

    Vitreoretinal lymphoma mimics forms of posterior uveitis, which are much more common than lymphoma. The gold standard for diagnosis is pathological confirmation of lymphoma cells, though this requires undiluted vitreous samples, and large-volume biopsies are seldom possible.

    Vitreous is more viscous and difficult to process than serum and other liquid tissue biopsies. Diluted samples provide more material but make it harder to identify rare lymphoma cells. Adjunctive modalities, such as flow cytometry and interleukin-6/10 ratio testing, are of limited value without pathologic confirmation.

    Genetic sequencing has identified multiple treatment targets in other cancer types. Breast cancers with ERBB2 amplifications are susceptible to trastuzumab. Non-small cell lung cancers with ALK translocations are sensitive to crizotinib, and chronic myeloid leukemias with BCR-ABL fusions respond well to imatinib.

    Earlier research used polymerase chain reaction-based assays to probe the vitreoretinal lymphoma genome for IgH rearrangements and a single point mutation in the MYD88 oncogene.

    Dr. Rao brought next-generation sequencing to the problem. Working with Scott Tomlins, MD, PhD, assistant professor of pathology and urology, University of Michigan, Dr. Rao analyzed vitreal samples from four patients with confirmed vitreoretinal lymphoma using a modified version of a panel currently used in the National Cancer Institute NCI-MATCH trial.

    “We didn’t search for everything. We searched for actionable alterations,” Dr. Rao said. “Nearly every variant on this panel is linked to an agent that is either approved for other cancers or in development. The sensitivity of this assay is so high we could use as little as five nanograms of DNA in a 500 microliter sample.”

    Initial results promising

    Fred Gebhart
    The author is a correspondent for Urology Times, a sister publication.

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