Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

5-Aminolevulinic acid for enhanced surgical visualization of high-grade gliomas: a prospective, multicenter study.

OBJECTIVE: Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors' knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA-induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity. METHODS: This single-arm, multicenter, prospective study included adults aged 18-80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3-5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables. RESULTS: Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume. CONCLUSIONS: PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.

Local disease control after decompressive surgery and adjuvant high-dose single-fraction radiosurgery for spine metastases.

OBJECT Adjuvant radiation following epidural spinal cord decompression for tumor is a powerful tool used to achieve local disease control and preserve neurological function. To the authors' knowledge, only 1 published report addresses adjuvant stereotactic radiosurgery after this procedure, but that study used significantly lower doses than are currently prescribed. The authors review their experience using high-dose single-fraction radiosurgery as a postoperative adjuvant following surgical decompression and instrumentation to assess long-term local tumor control, morbidity, and survival. METHODS A retrospective chart review identified 21 patients treated with surgical decompression and instrumentation for high-grade, epidural, spinal cord compression from tumor, followed by single-fraction high-dose spinal radiosurgery (dose range 18-24 Gy, median 24 Gy). Spinal cord dose was limited to a cord maximal dose of 14 Gy. Tumor histologies, time between surgery and radiosurgery, time to local recurrence after radiosurgery as assessed by serial MR imaging, and time to death were determined. Competing risk analysis was used to evaluate these end points. RESULTS In this series, 20 tumors treated (95%) were considered highly radioresistant to conventional external beam radiation. The planning target volume received a high dose (24 Gy) in 16 patients (76.2%), and a low dose (18 or 21 Gy) in 5 patients (23.8%). During the study, 15 (72%) of 21 patients died, and in all cases death was due to systemic progression as opposed to local failure. The median overall survival after radiosurgery was 310 days (range 37 days to not reached). One patient (4.8%) underwent repeat surgery for local failure and 2 patients (9.5%) underwent spine surgery for other reasons. Local control was maintained after radiosurgery in 17 (81%) of 21 patients until death or most recent follow-up, with an estimated 1-year local failure risk of 9.5%. Of the failures, 3 of 4 were noted in patients receiving low-dose radiosurgery, equaling an overall failure rate of 60% (3 of 5 patients) and a 1-year local failure estimated risk of 20%. Those patients receiving adjuvant stereotactic radiosurgery with a high dose had a 93.8% overall local control rate (15 of 16 patients), with a 1-year estimated failure risk of 6.3%. Competing risk analysis showed this to be a significant difference between radiosurgical doses. One patient experienced a significant radiation-related complication; there were no wound-related issues after radiosurgery. CONCLUSIONS Spine radiosurgery after surgical decompression and instrumentation for tumor is a safe and effective technique that can achieve local tumor control until death in the vast majority of patients. In this series, those patients who received a higher radiosurgical dose had a significantly better local control rate.

Metastases to the craniovertebral junction.

OBJECTIVE: This study reviews the relevant literature regarding the management of craniovertebral junction (CVJ) metastases. These rare tumors present significant diagnostic and treatment challenges. METHODS: A PubMed search of cervical spine, cervical spine metastasis, craniovertebral junction, atlantoaxial spine, and metastasis radiation was conducted to define the epidemiology, imaging, and treatment protocols in the management of metastatic CVJ tumors. RESULTS: CVJ tumors represent less than 1% of spinal metastases, and the literature is limited to small case series. CVJ tumors present with flexion, extension, and rotational pain, often associated with occipital neuralgia. Magnetic resonance imaging is the most sensitive imaging modality for the detection of spinal metastases, but plain x-rays, computed tomography, and [18F]2-fluoro-2-deoxy-D-glucose play a role in diagnosis and management. Conventional external beam radiation therapy or stereotactic radiosurgery effectively treat the majority of patients with normal spinal alignment or minimal fracture subluxations. Surgery should be considered in patients with fracture subluxations greater than 5 mm, or 3.5 mm subluxation with 11-degree angulation. The palliative goals for surgery favor posterior approaches only including laminectomy for decompression, without the need for anterior approaches with the associated morbidity. Occipitocervical instrumentation using screw-rod systems are effective for irreducible subluxations, but posterior strategies using C1-C2 or C1-C3 can be used for patients with reducible subluxations. CONCLUSION: Effective management of CVJ tumors using radiation and/or surgery results in significant pain and functional improvement in properly selected patients. Advanced surgical techniques and stereotactic radiation may improve outcomes with less morbidity.

Revisiting anaplastic astrocytomas I: an expansive growth pattern is associated with a better prognosis.

PURPOSE: To study whether anaplastic astrocytomas that are nonenhancing and/or well-circumscribed (expansive) are associated with a better prognosis. MATERIALS AND METHODS: We retrospectively identified 59 patients with pathologically confirmed World Health Organizaiton (WHO) grade III anaplastic astrocytoma who underwent craniotomy at our institution from 1995 through 2006. We assessed prognostic variables including age, enhancement (EAA-34 patients) vs. nonenhancement (NEAA-25 patients), MR growth patterns (expansive [28 patients] vs. mixed/infiltrative [31 patients]), recursive partitioning analysis (RPA) class, resection extent, and addition of chemotherapy. Primary outcome measure was survival. RESULTS: Kaplan-Meier curves showed improved survival in NEAA, expansive tumors, and RPA 1 class patients. Within RPA class I patients, expansive growth pattern remained a significant advantage in survival time. Examining extent of resection also showed that patients with gross total resections (GTR) had a better prognosis. A multivariate (Cox proportional hazards) analysis showed that patient age and expansive tumor phenotype affected outcome, whereas RPA class, enhancement, and GTR did not. CONCLUSION: Circumscribed growth in histologically proven anaplastic astrocytoma, which has not been emphasized in past studies, has a considerable survival advantage.

Revisiting anaplastic astrocytomas II: further characterization of an expansive growth pattern with visually enhanced diffusion tensor imaging.

PURPOSE: To seek to distinguish and visualize the different magnetic resonance imaging (MRI) growth patterns among malignant gliomas utilizing visually enhanced diffusion tensor imaging (DTI). MATERIALS AND METHODS: Nineteen consecutive patients undergoing image-guided resection of a newly diagnosed malignant glioma underwent add-on acquisition of DTI data based on an Institutional Review Board (IRB)-approved imaging protocol during preoperative MRI scans for routine intraoperative image guidance. Tumor growth patterns were assigned to expansive or mixed/infiltrative classes as described in the companion article (24). Infiltrating tumors were WHO Grade IV astrocytomas and all expansive tumors were either WHO Grade III astrocytomas or WHO Grade II astrocytomas. DTI-based white matter tractography was conducted and the DTI data were fused with anatomical images using an in-house software package we developed to enhance the visualization of the tumor/fiber interface. In one case additional analysis was performed with 2D multivoxel (1)H-MRSI utilizing a 2D chemical shift imaging (CSI) technique to corroborate the nature of this interface. RESULTS: Out of the 19 tumor patients studied, 11 had infiltrative tumors and the other 8 had expansive tumors. While less clear with 2D axial diffusion color maps, visually enhanced 3D reconstructions of the tumor/fiber interface successfully corroborated distinctive growth patterns. This was particularly evident when viewed in 3D video loops of each tumor/fiber interface. CONCLUSION: We have successfully developed software that visually enhances the anatomic details of the tumor/fiber interface in patients with anaplastic astrocytomas. These data support the existence of a subgroup of patients within the WHO Grade III classification with expansive tumors and a significantly better prognosis.