Urine cell-free DNA multi-omics to detect MRD and predict survival in bladder cancer patients.

Circulating tumor DNA (ctDNA) sensitivity remains subpar for molecular residual disease (MRD) detection in bladder cancer patients. To remedy this problem, we focused on the biofluid most proximal to the disease, urine, and analyzed urine tumor DNA in 74 localized bladder cancer patients. We integrated ultra-low-pass whole genome sequencing (ULP-WGS) with urine cancer personalized profiling by deep sequencing (uCAPP-Seq) to achieve sensitive MRD detection and predict overall survival. Variant allele frequency, inferred tumor mutational burden, and copy number-derived tumor fraction levels in urine cell-free DNA (cfDNA) significantly predicted pathologic complete response status, far better than plasma ctDNA was able to. A random forest model incorporating these urine cfDNA-derived factors with leave-one-out cross-validation was 87% sensitive for predicting residual disease in reference to gold-standard surgical pathology. Both progression-free survival (HR = 3.00, p = 0.01) and overall survival (HR = 4.81, p = 0.009) were dramatically worse by Kaplan-Meier analysis for patients predicted by the model to have MRD, which was corroborated by Cox regression analysis. Additional survival analyses performed on muscle-invasive, neoadjuvant chemotherapy, and held-out validation subgroups corroborated these findings. In summary, we profiled urine samples from 74 patients with localized bladder cancer and used urine cfDNA multi-omics to detect MRD sensitively and predict survival accurately.

Leptomeningeal spread of gestational trophoblastic neoplasia in a 19-year old woman.

Gestational trophoblastic neoplasia (GTN) with brain metastasis is usually seen in patients with advanced disease. Ten percent of metastatic gestational trophoblastic disease involves the brain and spinal cord, most often manifesting as an intracerebral mass or subdural hematoma, and are generally known to be a poor prognostic factor (Dadlani et al., 2010). Leptomeningeal metastases are tremendously rare and not well documented in the literature. A standardized treatment regimen for patients with brain metastases has not been established and is controversial due to a number of multimodal treatments that have been published in the literature without a prospective trial having been completed. We report a case of a patient with gestational trophoblastic disease that metastasized to the lung and leptomeninges, who after treatment with induction chemotherapy using etoposide (E) and cisplatin (P) followed by etoposide, methotrexate and dactinomycin (EMA) chemotherapy achieved a complete response without brain radiation (Han et al., 2012).