Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC.

Background: Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods: In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results: Among 56 patients, durable complete responses were observed. A subgroup was identified based on Toca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions: Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma.

Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).

Reliability of S100B in predicting severity of central nervous system injury.

S100B is a protein biomarker that reflects CNS injury. It can be measured in the CSF or serum with readily available immunoassay kits. The excellent sensitivity of S100B has enabled it to confirm the existence of subtle brain injury in patients with mild head trauma, strokes, and after successful resuscitation from cardiopulmonary arrest. The extent of S100B elevation has been found to be useful in predicting clinical outcome after brain injury. Elevations of S100B above certain threshold levels might be able to reliably predict brain death or mortality. A normal S100B level reliably predicts the absence of significant CNS injury. The specificity of S100B levels as a reflection of CNS injury is compromised by the findings that extra-cranial injuries can lead to elevations in the absence of brain injury. This potential problem can most likely be avoided by measuring serial S100B levels along with other biomarkers and carefully noting peripheral injuries. Serum markers GFAP and NSE are both more specific for CNS injury and have little to no extra-cranial sources. Sustained elevations of S100B over 24 h along with elevations of GFAP and NSE can more reliably predict the extent of brain injury and clinical outcomes. In the future, S100B measurements might reliably predict secondary brain injury and enable physicians to initiate therapeutic interventions in a timelier manner. S100B levels have been shown to rise hours to days before changes in ICP, neurological examinations, and neuroimaging tests. S100B levels may also be used to monitor the efficacy of treatments.

A review of intrathecal morphine therapy related granulomas.

The development of catheter associated granulomatous masses in intrathecal morphine therapy is an uncommon, but potentially serious problem. While these systems have historically been used in patients with short life expectancies, more recently patients with pain from a benign source have benefited from this therapy, and new complications are being encountered secondary to the patients' longer life spans. Morphine is the most commonly used intrathecal opioid and evidence exists that the formation of granulomatous masses are related to the use of higher doses. When the patients' requirement of morphine increases significantly, the physician should be alert for signs of spinal cord compression, such as new neurological deficits, myelopathy, or radiculopathy. Patients that require these higher doses should be properly informed of the association with granulomas and their associated risks. Indolent infection may also be the etiology of granulomatous masses, and the presence of organisms, both aerobic and anaerobic, should be routinely investigated. Patients with catheter-associated granulomas appear to share several features. They exhibit the onset of symptoms several months following the initiation of intraspinal opioids and commonly present with an increase in pain that precedes signs and symptoms of neurological deterioration. While MRI might be the preferred method of detection of intrathecal granulomas, its cost and availability are prohibitive for routine screening. CT myelogram via pump side port injection of contrast can also be performed to detect catheter tip related granulomas/obstructions. Serial neurological examinations for new deficits may be performed and recorded during pump refill visits to recognize a granulomatous mass in its early stages. If an abnormality is identified, imaging studies are appropriate. Awareness of the condition and vigilance are the keys to successful management of this complication.

Intrathecal morphine therapy related granulomas: two case reports.

Intrathecal morphine infusions have historically been used in patients with short life expectancies. More recently, patients with pain from a benign source have benefited from this therapy. While use in this population has been well documented and found to be relatively safe, new complications are being encountered secondary to the patients' longer life spans. The development of granulomatous masses from catheter use in intrathecal morphine therapy is an uncommon, but potentially serious problem. At West Virginia University Hospital, we have implanted more than 700 intrathecal drug delivery systems (IT-DDS) since 1989, and have encountered two cases of granulomatous masses developing at the tip of the intrathecal catheter. This report describes these illustrative cases and provides a review of the literature.

Diagnostic pitfall of computed tomography in patients with superficial siderosis of the central nervous system.

Superficial siderosis of the central nervous system (SSCN) is a well-described entity with distinct clinical presentation as well as computed tomography (CT) and magnetic resonance imaging (MRI) findings. However, it is critical that when a patient previously diagnosed with SSCN undergoes CT on the brain at a later date, that this scan not be misinterpreted as a new subarachnoid hemorrhage (SAH) so unecessary repeated angiograms are not performed. This report describes such a situation and discusses unique CT findings in SSCN that have been under-recognized and under-emphasized. While conditions such as SAH should not be ruled out, they would be considered atypical. Combined with an adequate prior diagnostic testing history, physicians should proceed to MRI without subjecting the patient to repeat angiography.

The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine.

OBJECTIVE: The objective of the Brain Tumor Cooperative Group NIH Trial 87-01 trial was to investigate the effect of additional implanted radiation therapy in newly diagnosed patients with pathologically confirmed malignant gliomas. METHODS: The study involved a randomized comparison of surgery, external beam radiotherapy, and carmustine (BCNU) versus surgery, external beam therapy, interstitial radiotherapy boost, and BCNU in newly diagnosed malignant gliomas. (125)I was chosen as best suited for this effort because it allowed preimplantation planning and postimplantation quality assurance review. Two hundred ninety-nine patients met the eligibility criteria and were randomized into the two arms of the study between December 1987 and April 1994. Follow-up continued for an additional 3 years. Twenty-nine patients were identified as having committed protocol violations and were excluded, resulting in 270 subjects in the Valid Study Group. One hundred thirty-seven patients received external beam radiation and BCNU, and 133 underwent the (125)I implantation plus external beam radiation and BCNU therapy. RESULTS: The overall median survival for the Valid Study Group was 64.3 weeks. The median survival for patients receiving additional therapy of (125)I was 68.1 weeks, and median survival for those receiving only external beam radiation and BCNU was 58.8 weeks. The cumulative proportion surviving between the two treatment groups was not statistically significantly different (log-rank test, P = 0.101). As in other studies in the literature, age, Karnofsky score, and pathology were predictors of mortality. Additional analyses incorporating an adjustment for these prognostic variables, either in a stratified analysis or Cox proportional hazards model, did not result in statistically significant differences in the cumulative proportion of patients surviving between the two treatment groups. CONCLUSION: We conclude that there is no long-term survival advantage of increased radiation dose with (125)I seeds in newly diagnosed glioma patients.