Sim, Hao‐Wen

Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor isocitrate dehydrogenase (IDH) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities.

571 Background: Tumor-induced generation of splenic erythroblast- like cells (Ter-cells) has been shown to promote tumor progression. These Ter-cells produce the glial-line derived neurotropic factor, ARTN. We investigated the association of pre-operative serum ARTN and the risk of recurrence in HCC patients (pts) undergoing curative resection. Methods: Blood samples were collected prior to surgery as part of an institutional molecular epidemiologic study. Serum ARTN concentration was measured using an enzyme-linked immunosorbent assay (ELISA). Demographics, pathological variables known to be associated with outcomes and clinical outcomes were collected. Uni- and multi-variate analysis were conducted. The optimal cutpoint method was used to define high and low ARTN concentrations. Cox models (hazard ratios, HR) were used to compare progression-free (PFS, primary endpoint), and overall survival (OS) of pts with high vs low serum ARTN. Results: Pre-operative blood samples were available for 58 pts. Median age was 63 years (range: 25-85 years); 74% were male and 50% were Asian. Etiology of liver disease was hepatitis B (43%) and hepatitis C (22%); 43% of tumors were ≤5cm, and vascular invasion was seen in 62%. A baseline alpha-fetoprotein (AFP) of > 100 mcg/L was observed in 36% pts. Median follow-up was 18.9 months. Median ARTN concentration was 0.322 ng/mL. The optimal ARTN concentration cut-off was 0.206 ng/mL. Median PFS for pts with high ( > 0.206 ng/mL) vs low (≤0.206 ng/mL) ARTN was 15.7 vs 55 months (p = 0.04) respectively. Three year PFS was 34% vs 55%, and three year OS 54% vs 91% for high vs low groups. Univariate analysis found that high ARTN concentration (HR 2.44, p = 0.05) and multifocal tumors were associated with a worse PFS. In a multivariate analysis adjusted for AFP > 100mcg/L, vascular invasion, hepatitis status and multifocal tumors, high ARTN remained a negative prognostic factor for PFS, aHR 3.32 (95% CI: 1.22-9.05, p = 0.02). Conclusions: A high pre-surgery serum ARTN is associated with earlier recurrence in HCC pts undergoing curative resection. ARTN should be further studied in HCC to determine its value as a prognostic marker.