A case study of a long-term glioblastoma survivor with unmethylated MGMT and hypermutated genotype.

Effective treatments that extend survival of malignant brain tumor glioblastoma (GBM) have not changed in more than a decade; however, there exists a minority patient group (<5%) whose survival is longer than 3 yr. We herein present a case report of a long-term surviving 51-yr-old female diagnosed with a MGMT unmethylated GBM. The patient was progression-free for 23 mo. Fresh primary and recurrent tumor samples were collected and processed for patient-derived model development. Whole-genome sequencing (WGS) was performed concurrently with additional standard of care diagnostics. WGS revealed a hypermutated genotype in the germline tissue and in both the primary and recurrent tumor samples. Specific to the matched tumors, an average of 30 cancer driver genes were mutated. Noteworthy was the identification of a nonsynonymous mutation in the POLE gene. As a possible instigator of the hypermutational genotype observed in the tumors, we identified nonsynonymous germline mutations within the mismatch repair genes, MLH1 and PMS2 Mutations within these genes are often indicative of the pan-cancer phenotype known as Lynch syndrome; however, their pathogenicity remains unreported. We performed a drug screen of 165 compounds, which identified one compound, YM155, an experimental survivin inhibitor, that showed effectivity to the patient-derived cell lines of both tumors. Treatment selection based on a patient's genome to individualize treatment for GBM patients could potentially be useful in the clinic. This is a promising avenue for further translational research, with larger databases and integrated platforms to increase the efficiency of analyzing and interpreting the individual genomic data of GBM.

Minimally invasive percutaneous fixation techniques for metastatic spinal disease.

OBJECTIVE: Surgical treatment of spinal metastasis is generally a palliative procedure. Although minimally invasive surgical (MIS) techniques are supposedly less morbid than open techniques, there is a lack of stratification of MIS techniques based on anticipated longevity. A simple stratification into three percutaneous surgical techniques based on modified Tokuhashi score is here proposed. METHODS: Patients recommended for spinal surgery for metastatic spinal disease between 2009 and 2012 and operated on by the senior author (RJM) were retrospectively reviewed. One of three MIS techniques was offered based on estimated survival using a modified Tokuhashi score. Technique #1 is suitable for patients with predicted short longevity (<6 months). Using a mini-open midline or paramedian decompression and percutaneous screw fixation, the goal here is for rapid mobilization and minimization of hospitalization. Technique #2 is suitable for patients with predicted medium longevity (6-12 months). They are suitable for decompression and/or cement vertebral body replacement and a two levels stabilization. Technique #3 is suitable for patients with predicted long term survival survival (>12 months). In these patients, the primary goal of surgery is a wide local or marginal resection of tumor, decompression of the neurological elements and a robust stabilization construct. They are suitable for an open 360°decompression, vertebral body reconstruction and a multilevel stabilization. RESULTS: The study included eight patients with a mean age of 59 years (range, 36-72 years). Mean modified Tokuhashi score was 10 (range, 7-13) with three patients in the short term, two in the medium term and three in the long term survival category. Mean blood loss was 700 mL (range, 100-1200 mL), mean operating time 280 min (range, 120-360 min) and length of stay in the hospital was on average 13 days (range, 3-30 days). CONCLUSION: The authors present three minimally invasive technique options for the management of spinal metastatic disease corresponding to three clinical prognostic categories. In this small series, MIS techniques resulted in speedy recovery, minimal morbidity and no mortality.

Durable thrombosis in a rat model of arteriovenous malformation treated with radiosurgery and vascular targeting.

OBJECT: Radiosurgical treatment of brain arteriovenous malformations (AVMs) has the significant shortcomings of being limited to lesions smaller than 3 cm in diameter and of a latency-to-cure time of up to 3 years. A possible method of overcoming these limitations is stimulation of thrombosis by using vascular targeting. Using an animal model of AVM, the authors examined the durability of the thrombosis induced by the vascular-targeting agents lipopolysaccharide and soluble tissue factor conjugate (LPS/sTF). METHODS: Stereotactic radiosurgery or sham radiation was administered to 32 male Sprague-Dawley rats serving as an animal model of AVM; 24 hours after this intervention, the rats received an intravenous injection of LPS/sTF or normal saline. The animals were killed at 1, 7, 30, or 90 days after treatment. Immediately beforehand, angiography was performed, and model AVM tissue was harvested for histological analysis to assess rates of vessel thrombosis. RESULTS: Among rats that received radiosurgery and LPS/sTF, induced thrombosis occurred in 58% of small AVM vessels; among those that received radiosurgery and saline, thrombosis occurred in 12% of small AVM vessels (diameter < 200 µm); and among those that received LPS/sTF but no radiosurgery, thrombosis occurred at an intermediate rate of 43%. No systemic toxicity or intravascular thrombosis remote from the target region was detected in any of the animals. CONCLUSIONS: Vascular targeting can increase intravascular thrombosis after radiosurgery, and the vessel occlusion is durable. Further work is needed to refine this approach to AVM treatment, which shows promise as a way to overcome the limitations of radiosurgery.

Successful endovascular and surgical treatment of spinal extradural metameric arteriovenous malformation. Case report.

A report of successful combined endovascular and surgical management of an unusual case of metameric (juvenile) spinal arteriovenous malformation (AVM) is presented. The malformation had extradural and paraspinal components, but no intradural elements. It had caused rapid neurological deterioration to near-complete paraplegia prior to treatment (American Spinal Injury Association [ASIA] Grade C). A combination of endovascular occlusion of major feeding vessels and excision of the malformation resulted in a complete neurological recovery (ASIA Grade E). The authors conclude that selected metameric AVMs can be successfully treated with multimodal therapy. This case further illustrates the fact that not all spinal vascular malformations are easily categorized.

Intracranial haemorrhage in pregnancy.

Intracranial haemorrhage (ICH) is a rare, yet potentially devastating event in pregnancy. There is a risk of maternal mortality or morbidity and a significant risk to the unborn child. The risk of haemorrhage increases during the third trimester and is greatest during parturition and the puerperium. ICH can be extradural, subdural, subarachnoid or intraparenchymal. Causes of bleeding include trauma, arteriovenous malformations, aneurysms, preeclampsia/eclampsia and venous thrombosis. Urgent neurosurgical conditions generally outweigh obstetric considerations in management decisions, although anaesthetic and surgical modifications can be made to minimize adverse effects to the fetus.