Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial.

Importance: New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma. Objective: To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC). Design, Setting, and Participants: A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. Interventions: Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab. Main Outcomes and Measures: The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS. Results: All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group. Conclusions and Relevance: Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points. Trial Registration: ClinicalTrials.gov Identifier: NCT02414165.

Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs.

BACKGROUND: Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified. RESULTS: We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types. After excluding imprinting, the data pinpoint 15,112 high-confidence ASM differentially methylated regions, of which 1838 contain SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies are increased in cancers versus matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancer cells show increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor binding motifs are similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes track with de novo ASM. Allele-specific transcription factor binding from ChIP-seq is enriched among ASM loci, but most ASM differentially methylated regions lack such annotations, and some are found in otherwise uninformative "chromatin deserts." CONCLUSIONS: ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and transcription factor binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, cardiometabolic, neuropsychiatric, and neoplastic diseases.

Management and implications of intraoperative cerebrospinal fluid leak in transnasoseptal transsphenoidal microsurgery.

BACKGROUND: Nonvascularized autologous grafts used for sellar reconstruction in transseptal transsphenoidal surgery are commonly applied in the setting of intraoperative cerebrospinal fluid (CSF) leak and have been shown to be effective in preventing postoperative complications. OBJECTIVE: To assess the clinical implications of intraoperative CSF leak, to evaluate the efficacy of repair techniques using autologous nonvascularized materials, and to analyze the nature and timing of failures. These data may serve as a basis for assessing the utility of innovations in techniques and implant technologies. METHODS: A review was conducted of 257 consecutive patients who underwent transsphenoidal surgery that was complicated by intraoperative CSF leak from 1995 to 2001. Sellar reconstruction was performed with autologous materials except in reoperations in which septal materials were not available; lumbar drain catheters were used selectively. RESULTS: Six of the 257 patients (2.3%) developed postoperative CSF rhinorrhea occurring an average of 6.6 days after surgery. All 6 underwent reoperation, with 5 of 6 managed with operative lumbar drainage. Bacterial meningitis developed in 3 of 257 (1.2%). Worsening in visual function occurred in 8 of 257 (3.1%), with 1 of 257 (0.3%) suffering from permanent worsening of visual function. Additional surgery was performed in 2 of these patients, resulting in successful reversal of visual loss. Ten of 257 patients (3.9%) developed a subcutaneous hematoma at the fat graft harvest site, with 1 patient requiring surgical re-exploration. CONCLUSIONS: Watertight closure of the sella with autologous materials is effective in preventing postoperative rhinorrhea. Complications specific to the technique include graft site hematoma (4%) and rare instances of visual loss caused by optic nerve compression.

Gamma knife radiosurgery for dural arteriovenous fistulas.

BACKGROUND: The current management of intracranial dural arteriovenous fistulas (dAVFs) incorporates a multimodal approach involving microneurosurgery, endovascular embolization, and radiosurgery. OBJECTIVE: To explore the role of Gamma Knife radiosurgery for dAVFs. METHODS: The series includes patients with dAVFs who had Gamma Knife radiosurgery at the University of Virginia Medical Center between 1989 and 2005 with clinical follow-up through 2008. Medical records were reviewed to obtain clinical history, demographic data, and dosimetry. Radiographic records provided the location and anatomy of the dAVFs. Follow-up angiography was performed 2 to 3 years after treatment, with cure defined as complete obliteration of fistulous flow. Follow-up for clinical symptomology and quality of life was obtained from direct patient and primary physician questionnaires. RESULTS: Fifty-five patients underwent Gamma Knife radiosurgery for dAVFs during the study period. Twenty patients (36%) presented with intracranial hemorrhage before radiosurgery. Gamma Knife radiosurgery was preceded by craniotomy for microneurosurgical ablation in 11 patients (20%) or endovascular embolization in 36 patients (65%). Follow-up angiography was performed on 46 patients (83%) with documented obliteration in 30 patients (65%). Patients lost to follow-up were classified as treatment failures, adjusting the range of efficacy from 65% to 54%. Three patients (5%) suffered a posttreatment hemorrhage during the follow-up period, but no new permanent neurological deficits resulted from these events. CONCLUSION: Gamma Knife radiosurgery is an effective adjunct therapy for dAVFs with persistence of flow after open neurosurgical resection or endovascular treatment while still maintaining a role in nonaggressive dAVFs not amenable to either surgery or embolization.

Transsphenoidal approaches for the extracapsular resection of midline suprasellar and anterior cranial base lesions.

OBJECTIVE: The transsphenoidal approach is an effective method for treating tumors contained within the sella or extending into the suprasellar cistern. The technique of tumor dissection is predicated on preservation of the integrity of the diaphragma, i.e., intracapsular removal. Gross total extracapsular dissection may, however, be accomplished either by using a standard approach to the pituitary fossa or by extending the exposure to include removal of a portion of the planum sphenoidale and division of the superior intercavernous sinus. METHODS: Included in this series were 14 patients with parasellar or sellar tumors with extension into the anterior fossa and/or suprasellar cistern. For 4 of 14 patients (29%), extracapsular access was gained by broaching the tumor capsule from within the pituitary fossa. For the remaining 10 of 14 patients (71%), the dura of the floor of the sella and the planum sphenoidale was exposed, using neuronavigation to verify the limits of bony dissection; extracapsular tumor resection was performed using the operating microscope and endoscopy as indicated. The dural defect was repaired with abdominal fat, the sellar floor and planum sphenoidale were reconstructed, and in selected cases a lumbar drain was placed. RESULTS: Seven of 14 tumors (50%) were craniopharyngiomas, 3 of 14 (21%) were pituitary adenomas, and 2 of 14 (14%) were meningiomas. There was one case of lymphocytic hypophysitis and one yolk sac tumor. Gross total resection was possible in 11 of 14 cases (79%). Immediate postoperative visual function worsened in 2 of 14 cases (14%), improved in 3 of 14 cases (21%), and was stable in the remainder of cases. Postoperatively, 2 of 14 patients (14%) developed bacterial meningitis. Overt postoperative cerebrospinal fluid rhinorrhea was not observed. CONCLUSION: Gross total extracapsular resection of midline suprasellar tumors via a transsphenoidal approach is possible but is associated with a higher risk of complications than is standard transsphenoidal surgery.

Early antiepileptic drug reduction following anterior temporal lobectomy for medically intractable complex partial epilepsy.

PURPOSE: To determine the safety, in our practice, of allowing patient preference to influence the timing of antiepileptic drug (AED) reduction, once they became seizure-free after anterior temporal lobectomy (ATL). METHODS: Thirty patients underwent anterior temporal lobectomy for medically intractable complex partial epilepsy at Loma Linda University Medical Center between December 1st 1991 and November 30th 2001. Timing of AED reduction in seizure-free patients was based on patient request. A review of patient records noted seizure status, duration from surgery to AED reduction, AED side effects, seizure recurrence and whether control was regained. RESULTS: Twenty-four (80%) of the 30 patients became seizure-free on their preoperative AEDs after initial ATL; three additional patients after a second operation. AEDs were not reduced in the reoperated patients, the three patients who did not become seizure-free, and in two patients who asked to increase AEDs to control auras. Thus, AEDs were reduced in 22 of the 27 seizure-free patients. Patients were followed an average of 3.4 +/- 2.7 (mean +/- standard deviation) years. AED reduction was initiated 4.6 +/- 7.2 months (range 0-27 months) after surgery. Polytherapy use decreased from 54% preoperatively to 18% at last follow up. Seizures recurred in six patients (27% of 22); three became seizure-free after AED adjustments. CONCLUSIONS: In our practice, using an individualized approach to AED reduction following successful epilepsy surgery resulted in early reduction in AEDs. Our data suggest that early AED reduction can be performed safely and without undue risk of seizure recurrence.

Pituitary surgery: transsphenoidal approach.

THE TRANSSPHENOIDAL APPROACH for sellar tumors has evolved significantly since it was described initially during the first decade of the 20th century. The approach currently incorporates technological advancements and refinements in patient selection, operative technique, and postoperative care. Although many of these innovations are considered indispensable, the operative technique, as performed by contemporary neurosurgeons, is not standardized. This variability is a reflection of surgeon's preference, the lessons of experience, and the bias inherent in neurosurgical training. The methods and preferences described herein embody the distillation of an experience gained from 3900 transsphenoidal operations.

Depiction of a postoperative pseudomeningocele with digital subtraction myelography.

Digital subtraction myelography is described for its utility in the detection of dural leaks associated with pseudomeningoceles. Although myelography, CT, and MR imaging have been described as effective means for diagnosing pseudomeningocele, this complicated entity can be difficult to diagnose.

Pediculotomy as an adjunct to posterior cervical hemilaminectomy, foraminotomy, and discectomy.

Currently the posterior approach undertaken to perform cervical hemilaminectomy and foraminotomy provides sufficient exposure to treat the majority of lateral soft-disc herniations or osteophytes causing radiculopathy. Limitations imposed by the surgical field, however, often necessitate excessive retraction of the nerve root and epidural venous plexus, which may potentially exacerbate a preexisting radiculopathy or increase intraoperative blood loss. Partial resection of the inferior pedicle augments exposure and enlarges the neural foramen, thus facilitating decompression while minimizing manipulation of the nerve root and epidural venous plexus. With the patient in the prone position, partial hemilaminectomy and foraminotomy are performed using a highspeed 3-mm diamond burr with continuous irrigation. The thecal sac and nerve root are exposed, and the overlying fibroareolar layer is coagulated and incised. With the nerve root protected and under direct vision, the superomedial portion of the inferior pedicle is removed. Nerve root decompression is then performed through this augmented exposure. Partial excision of the pedicle allows for more expeditious removal of the pathological elements causing cervical radiculopathy and requires minimal manipulation of the nerve root and epidural venous plexus. This procedure results in a potential decrease in transient postoperative radiculopathy and minimization of intraoperative blood loss. In addition, the resulting foraminal enlargement enhances the decompression provided by traditional foraminotomy, even if discectomy is not performed.