Clinical significance of polyglutamylation in primary central nervous system lymphoma.

The therapeutic response to high-dose methotrexate (HD-MTX) therapy for primary central nervous system lymphoma (PCNSL) varies. Polyglutamylation is a reversible protein modification with a high occurrence rate in tumor cells. MTX incorporated into cells is polyglutamylated and strongly binds to dihydrofolate reductase without competitive inhibition by leucovorin (LV). Tumor cells with high polyglutamylation levels are selectively killed, whereas normal cells with lower polyglutamylation are rescued by LV. We hypothesized that the extent of polyglutamylation in tumor cells determines treatment resistance. Here, we investigated the therapeutic response of PCNSL to HD-MTX therapy with LV rescue based on polyglutamylation status. Among 113 consecutive PCNSL patients who underwent HD-MTX therapy in our department between 2001 and 2014, polyglutamylation was evaluated by immunostaining in 82 cases, with relationships between polyglutamylation and therapeutic response retrospectively examined. Human malignant lymphoma lines were used for in vitro experiments, and folpolyglutamate synthetase (FPGS), which induces polyglutamylation, was knocked down with short-hairpin RNA, and a stable cell line with a low rate of polyglutamylation was established. Cell viability after MTX treatment with LV rescue was evaluated using sodium butyrate (NaBu), a histone-deacetylase inhibitor that induces polyglutamylation by elevating FPGS expression. The complete response rate was significantly higher in the group with polyglutamylation than in the non-polyglutamylation group [58.1% (25/43) and 33.3% (13/39), respectively] (p < 0.05), and progression-free survival was also significantly increased in the group with polyglutamylation (p < 0.01). In vitro, the relief effect of LV after MTX administration was significantly enhanced after FPGS knockdown in al cell lines, whereas enhancement of FPGS expression by NaBu treatment significantly reduced this relief effect. These findings suggested that polyglutamylation could be a predictor of therapeutic response to HD-MTX therapy with LV rescue in PCNSL. Combination therapy with HD-MTX and polyglutamylation-inducing agents might represent a promising strategy for PCNSL treatment.

Surgical Outcomes of Endoscopic Endonasal Skull Base Surgery of Craniopharyngiomas Evaluated According to the Degree of Hypothalamic Extension.

OBJECTIVE: Sparing the hypothalamus after craniopharyngioma treatment is a prerequisite to ensure a good quality of life. In this study, the functional prognosis of craniopharyngioma after endoscopic endonasal skull base surgery (EES) was examined in function of the degree of hypothalamic extension. METHODS: Twenty cases of craniopharyngioma treated by EES were categorized according to the Puget classification using preoperative and postoperative magnetic resonance imaging. The degree of resection rates, amelioration of symptoms, and endocrinologic and hypothalamic functions were evaluated during the postoperative follow-up period. RESULTS: All cases were preoperatively classified into grades 0 (n = 8), 1 (n = 7), and 2 (n = 5). Near total resection was achieved in half of the cases. Moreover, visual improvement was observed in 75% of the cases. The incidence rate of additional endocrinologic dysfunction was not related to the preoperative grade or intraoperative stalk preservation. Postoperative magnetic resonance imaging indicated hypothalamic preservation for all grades. After an average of 60 months follow-up of 11 patients with primary tumors, 4 patients showed tumor regrowth controlled by stereotactic radiation therapy. All patients recorded more than 80% on the Karnofsky Performance Scale and showed no additional obesity at follow-up. CONCLUSIONS: EES provides optimal resection rate and limited complications because of the preservation of the hypothalamus, regardless of the degree of preoperative hypothalamic involvement. Consequently, the rate of obesity occurrence is also decreased. This study indicates that EES protects hypothalamus function and improves tumor removal rate, and that it will become the first choice of surgical procedure for managing craniopharyngiomas.