Erlotinib is effective for epidermal growth factor receptor (EGFR) mutant lung cancer, but CNS penetration at standard daily dosing is limited. We previously reported that intermittent “pulsatile” administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patients. We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR tyrosine kinase inhibitors. Mutations in available lung and CNS tissue were correlated with efficacy. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (6/9, including 2 with isolated leptomeningeal metastases), stable disease in 11% (1/9), and progressive disease in 22% (2/9). Median time to CNS progression was 2.7 months (range, 0.8–14.5 months) and median overall survival was 12 months (range, 2.5 months–not reached). Treatment was well tolerated. No acquired resistance mutations in EGFR were identified in the CNS metastases of 4 patients, including 1 harboring T790M outside the CNS. Pulsatile erlotinib can control CNS metastases from EGFR mutant lung cancer after failure of standard daily dosing. CNS disease may not harbor acquired resistance mutations that develop systemically. A prospective trial is planned.

Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response. Significance: Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg. Cancer Res; 78(14); 3755–60. ©2018 AACR.

The majority of WHO grades II and III gliomas harbor a missense mutation in the metabolic gene isocitrate dehydrogenase (IDH) and accumulate the metabolite R-2-hydroxyglutarate (R-2HG). Prior studies showed that this metabolite can be detected in vivo using proton magnetic-resonance spectroscopy (MRS), but the sensitivity of this methodology and its clinical implications are unknown. We developed an MR imaging protocol to integrate 2HG-MRS into routine clinical glioma imaging and examined its performance in 89 consecutive glioma patients. Detection of 2-hydroxyglutarate (2HG) in IDH-mutant gliomas was closely linked to tumor volume, with sensitivity ranging from 8% for small tumors (8 mL). In patients undergoing 2HG-MRS prior to surgery, tumor levels of 2HG corresponded with tumor cellularity but not with tumor grade or mitotic index. Cytoreductive therapy resulted in a gradual decrease in 2HG levels with kinetics that closely mirrored changes in tumor volume. Our study demonstrates that 2HG-MRS can be linked with routine MR imaging to provide quantitative measurements of 2HG in glioma and may be useful as an imaging biomarker to monitor the abundance of IDH-mutant tumor cells noninvasively during glioma therapy and disease monitoring.

Objective: To examine the potential utility of conventional MRI signs in differentiating pseudoprogression (PsP) from early progression (EP). Methods: This retrospective study reviewed initial postradiotherapy MRI scans of 321 patients with glioblastoma undergoing chemotherapy and radiotherapy. A total of 93 patients were found to have new or increased enhancing mass lesions, raising the possibility of PsP. Final diagnosis of PsP or EP was established upon review of surgical specimens from a second resection or by clinical and radiologic follow-up. A total of 11 MRI signs potentially helpful in the differentiation between PsP and EP were examined on the initial post-RT MRI and were correlated with the final diagnosis through χ² or Fisher exact test. Results: Sixty-three (67.7%) of the 93 patients had EP, of which 22 (34.9%) were diagnosed by pathology. Thirty patients (32.3%) had PsP; 6 (16.7% of the 30) were diagnosed by pathology. Subependymal enhancement was predictive for EP (p = 0.001) with 38.1% sensitivity, 93.3% specificity, and 41.8% negative predictive value. The other 10 signs had no predictive value (p = 0.06–1.0). Conclusions: Conventional MRI signs have limited utility in diagnosing PsP in patients with recently treated glioblastomas and worsening enhancing lesions. We did not find a sign with a high negative predictive value for PsP that would have been the most useful for the clinical physician. When present, subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP.

Object. The purpose of this study was to evaluate the efficacy of noninvasive preoperative functional imaging data used in an interactive fashion in the operating room. The authors describe a method of registering preoperative functional magnetic resonance (fMR) imaging localization of sensorimotor cortex with a frameless stereotactic surgical navigation device. Methods. The day before surgery, patients underwent blood oxygen level—dependent fMR imaging while performing a finger-tapping motor paradigm. Immediately afterward an anatomical stereotactic MR image was acquired. Raw fMR imaging data were analyzed offline at a separate workstation, and the resulting functional maps were registered to a high-resolution anatomical scan. The fused functional—anatomical images were then downloaded onto a surgical navigation computer via an ethernet connection. At surgery, the brain was exposed in the standard fashion, and the sensorimotor cortex was identified by direct cortical stimulation, the use of somatosensory evoked potentials, or both. This localization was then compared with that predicted by the registered fMR study. Thirteen procedures were performed in 12 patients. The mean registration error was 2.2 mm. The predicted location of motor and/or sensory cortex matched that found on intraoperative mapping in all 12 patients tested. Maximal tumor resection was accomplished in each case and no new permanent neurological deficits resulted. Conclusions. Compared with conventional brain mapping techniques, fMR image—guided surgery may allow for smaller brain exposures, localization of the language cortex with the patient under general anesthesia, and the mapping of multiple functional sites. The scanning equipment used in this method may be more readily available than for other functional imaging techniques such as positron emission tomography or magnetoencephalography.