The incidence of brain metastasis from hepatocellular carcinoma (HCC) is expected to increase as a result of prolonged survival due to the recent advances in HCC treatment. However, there is no definite treatment strategy for brain metastasis from HCC mainly due to its rarity and dismal prognosis. To provide helpful recommendations in treatment of brain metastasis from HCC, the authors aimed to identify prognostic factors that influence survival rates with a review of the recently published data.

Gamma knife radiosurgery (GKRS) has been increasingly employed for the treatment of elderly patients with brain metastases, mainly due to its demonstrated effectiveness and low complication rate. However, only a few studies have investigated the prognostic factors that influence the survival of elderly patients after GKRS. The purpose of this study was to identify a scoring system that is able to predict the survival of elderly patients undergoing GKRS using data obtained at the time of diagnosis for brain metastases. Between 2004 and 2011, death was confirmed in 147 patients aged 70 years and older who had been treated with GKRS for brain metastases. Median age at the time of GKRS was 75.7 years (range, 70–86 years). The median tumor volume was 5.1 cm3 (range, 0.05–59.9 cm3). The median marginal prescription dose was 21.4 Gy (range, 14–25 Gy). The median survival was 167 days. Overall survival rates at 6 months and 1 year were 60.4% and 29.4%, respectively. Among the patient characteristics pertaining to systemic cancer and brain metastasis for which data were obtained preoperatively, a multivariate analysis showed that low Karnofsky performance status (KPS ≤ 80, P = 0.047) and the presence of extracranial metastases (P = 0.014) detected at the time of brain metastasis diagnosis were independent prognostic factors for short survival. A high score index for radiosurgery (SIR score ≥ 4, P = 0.024) and a high graded prognostic assessment (GPA score ≥ 2, P = 0.004) were associated with longer survival. A multivariate analysis of the important characteristics of systemic cancer, and the scoring system evaluating survival duration showed that a low GPA score was the most powerful independent factor for predicting short survival (hazard ratio 1.756, 95% confidence interval 1.252–2.456, P = 0.001). GKRS is a safe approach to treat brain metastases in patients age 70 years and older. In this group, our study identified GPA score at the time of GKRS as a powerful prognostic factor for survival.

The main purpose of this study is to synthesize novel types of nanophotosensitizers that are based on hyperbranched chlorin e6 (Ce6) via disulfide linkages. Moreover, hyperbranched Ce6 was conjugated with hyaluronic acid (HA) for CD44-receptor mediated delivery and redox-sensitive photodynamic therapy (PDT) against cancer cells. Hyperbranched Ce6 was considered to make novel types of macromolecular photosensitizer since most of the previous studies regarding nanophotosensizers are concerned with simple conjugation between monomeric units of photosensitizer and polymer materials. Hyperbranched Ce6 was synthesized by conjugation of Ce6 each other while using disulfide linkage. To synthesize Ce6 tetramer, carboxyl groups of Ce6 were conjugated with cystamine and three equivalents of Ce6 were then conjugated again with the end of amine groups of Ce6-cystamine. To synthesize Ce6 decamer as a hyperbranched Ce6, six equivalents of Ce6 was conjugated with the end of Ce6 tetramer via cystamine linkage. Furthermore, HA-cystamine was attached with Ce6 tetramer or Ce6 decamer to synthesize HA-Ce6 tetramer (Ce6tetraHA) or HA-Ce6 decamer (Ce6decaHA) conjugates. Ce6tetraHA and Ce6decaHA nanophotosensitizers showed small diameters of less than 200 nm. The addition of dithiothreitol (DTT) and hyaluronidase (HAse) induced a faster Ce6 release rate in vitro drug release study, which indicated that Ce6tetraHA nanophotosensitizers possess redox-sensitive and HAse-sensitive release properties. Ce6tetraHA nanophotosensitizers showed higher intracellular Ce6 accumulation, higher ROS generation, and higher PDT efficacy than that of Ce6 alone. Ce6tetraHA nanophotosensitizers responded to the CD44 receptor of cancer cell surface, i.e., the pre-treatment of HA blocked CD44 receptor of U87MG or HCT116 cells and then inhibited delivery of nanophotosensitizers in vitro cell culture study. Furthermore, in vivo tumorxenograft study showed that fluorescence intensity in the tumor tissues was stronger than those of other organs, while CD44 receptor blocking by HA pretreatment induced a decrease of fluorescence intensity in tumor tissues when compared to liver. These results indicated that Ce6tetraHA nanophotosensitizers delivered to tumors by redox-sensitive and CD44-sensitive manner.