Ultra-High-Molecular-Weight Polyethylene Merlon Shape: Novel Fixation of Artificial Bone for Cranioplasty.

BACKGROUND: Cranioplasty is a surgical procedure widely performed for repairing cranial defects caused by external decompression surgery for cerebrovascular disease or traumatic brain injury. We devised a new cranioplasty method using artificial bone made up of ultra-high molecular-weight polyethylene, with serrated wings on the edge. We named this newly designed artificial bone as Merlon shape. OBJECTIVE: To describe our initial experience with the Merlon shape and evaluate its usefulness and safety in cranioplasty. METHODS: The serrated wings of the Merlon shape were preoperatively designed for solid fixation and improving cosmetic results by reducing the thickness of the artificial bone. We evaluated 25 patients who underwent cranioplasty with the Merlon shape between December 2018 and December 2021. The causes of bone defects in these patients (male: 9, female: 16; median age: 62 years) were subarachnoid hemorrhage (n = 14), cerebral infarction (n = 8), and traumatic brain injury (n = 3). RESULTS: There were no postoperative adverse events such as infection, bone resorption, implant exposure, or graft sinking in 24 patients during an average follow-up period of 19 months. One patient experienced acute epidural hemorrhage and required reoperation. CONCLUSION: This is the first report on the use of the ultra-high molecular-weight polyethylene Merlon shape. Our initial 4-year case series showed good outcomes with this method.

Safety and feasibility of convection-enhanced delivery of nimustine hydrochloride co-infused with free gadolinium for real-time monitoring in the primate brain.

OBJECTIVES: Convection-enhanced delivery (CED) has been developed as an effective drug-delivery strategy for brain tumors. Ideally, direct visualization of the tissue distribution of drugs infused by CED would assure successful delivery of therapeutic agents to the brain tumor while minimizing exposure of the normal brain tissue. We previously showed the anti-tumor efficacy of nimustine hydrochloride (ACNU) delivered via CED against a rodent intracranial xenografted tumor model. Here, we developed a method to monitor the drug distribution using a non-human primate brain. METHODS: CED of a mixture of ACNU with gadodiamide was performed using three non-human primates under real-time magnetic resonance imaging monitoring. Animals were clinically observed for any toxicity after infusion. Two months later, their brains were subjected to histological examination for the evaluation of local toxicity. Another one animal was euthanized immediately after CED of a mixture of ACNU, gadodiamide, and Evans blue dye to evaluate the concordance between ACNU and gadodiamide distributions. The harvested brain was cut into blocks and the ACNU content was measured. RESULTS AND DISCUSSION: Real-time magnetic resonance imaging monitoring of co-infused gadodiamide confirmed the success of the infusion maneuver. In the monkey that also received Evans blue, the distribution of Evans blue was similar to that of gadodiamide and paralleled the measured ACNU content, suggesting concordance between ACNU and gadodiamide distributions. Histological examination revealed minimum tissue damage with the infusion of ACNU at 1 mg/ml, determined as a safe dose in our previous rodent study. CED of ACNU can be co-administered with gadodiamide to ensure successful infusion and monitor the distribution volume.

Convection-enhanced delivery of a synthetic retinoid Am80, loaded into polymeric micelles, prolongs the survival of rats bearing intracranial glioblastoma xenografts.

Prognosis for the patients with glioblastoma, the most common malignant brain tumor, remains dismal. A major barrier to progress in treatment of glioblastoma is the relative inaccessibility of tumors to chemotherapeutic agents. Convection-enhanced delivery (CED) is a direct intracranial drug infusion technique to deliver chemotherapeutic agents to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED can provide wider distribution of infused agents compared to simple diffusion. We have reported that CED of a polymeric micelle carrier system could yield a clinically relevant distribution of encapsulated agents in the rat brain. Our aim was to evaluate the efficacy of CED of polymeric micellar Am80, a synthetic agonist with high affinity to nuclear retinoic acid receptor, in a rat model of glioblastoma xenografts. We also used systemic administration of temozolomide, a DNA-alkylating agent, which has been established as the standard of care for newly diagnosed malignant glioma. U87MG human glioma cells were injected into the cerebral hemisphere of nude rats. Rats bearing U87MG xenografts were treated with CED of micellar Am80 (2.4 mg/m(2)) on day 7 after tumor implantation. Temozolomide (200 mg/m(2)/day) was intraperitoneally administered daily for 5 days, starting on day 7 after tumor implantation. CED of micellar Am80 provided significantly longer survival than the control. The combination of CED of micellar Am80 and systemic administration of temozolomide provided significantly longer survival than single treatment. In conclusion, temozolomide combined with CED of micellar Am80 may be a promising method for the treatment of malignant gliomas.

O(6)-Methylguanine DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression is correlated with progression-free survival in patients with glioblastoma.

OBJECTIVE: The prognostic significance of O(6)-methylguanine DNA methyltransferase (MGMT) was evaluated by analysis of both MGMT promoter methylation and protein expression in a series of patients with newly diagnosed glioblastoma. METHODS: Seventy-three patients with glioblastomas treated with alkylating agents were analyzed for MGMT expression by immunohistochemistry. Genomic DNA was isolated from frozen surgical specimens obtained from 62 of 73 patients. MGMT promoter methylation was determined by methylation-specific polymerase chain reaction. The prognostic significance of MGMT was evaluated together with other well-known prognostic factors. RESULTS: MGMT promoter hypermethylation was detected in 35 of 62 patients (56.4%). MGMT immunoreactivity was low in 26 (35.6%) tumors, moderate in 24 (32.9%), and high in 23 (31.5%). Significant correlation was observed between MGMT expression and MGMT promoter methylation (P < 0.001). Both MGMT promoter methylation and low MGMT expression were independently associated with better progression-free survival but not with longer overall survival. However, in the subgroup analysis, MGMT promoter hypermethylation was significantly associated with longer overall survival in patients treated with temozolomide (TMZ) after nimustine hydrochloride (ACNU) treatment. CONCLUSIONS: Low MGMT expression and MGMT promoter methylation are both predictive markers for slower tumor progression in patients with glioblastoma.