Disease Assessments in Patients with Glioblastoma.

PURPOSE OF REVIEW: The neuro-oncology team faces a unique challenge when assessing treatment response in patients diagnosed with glioblastoma. Magnetic resonance imaging (MRI) remains the standard imaging modality for measuring therapeutic response in both clinical practice and clinical trials. However, even for the neuroradiologist, MRI interpretations are not straightforward because of tumor heterogeneity, as evidenced by varying degrees of enhancement, infiltrating tumor patterns, cellular densities, and vasogenic edema. The situation is even more perplexing following therapy since treatment-related changes can mimic viable tumor. Additionally, antiangiogenic therapies can dramatically decrease contrast enhancement giving the false impression of decreasing tumor burden. Over the past few decades, several approaches have emerged to augment and improve visual interpretation of glioblastoma response to therapeutics. Herein, we summarize the state of the art for evaluating the response of glioblastoma to standard therapies and investigational agents as well as challenges and future directions for assessing treatment response in neuro-oncology. RECENT FINDINGS: Monitoring glioblastoma responses to standard therapy and novel agents has been fraught with many challenges and limitations over the past decade. Excitingly, new promising methods are emerging to help address these challenges. Recently, the Response Assessment in Neuro-Oncology (RANO) working group proposed an updated response criteria (RANO 2.0) for the evaluation of all grades of glial tumors regardless of IDH status or therapies being evaluated. In addition, advanced neuroimaging techniques, such as histogram analysis, parametric response maps, morphometric segmentation, radio pharmacodynamics approaches, and the integrating of amino acid radiotracers in the tumor evaluation algorithm may help resolve equivocal lesion interpretations without operative intervention. Moreover, the introduction of other techniques, such as liquid biopsy and artificial intelligence could complement conventional visual assessment of glioblastoma response to therapies. Neuro-oncology has evolved over the past decade and has achieved significant milestones, including the establishment of new standards of care, emerging therapeutic options, and novel clinical, translational, and basic research. More recently, the integration of histopathology with molecular features for tumor classification has marked an important paradigm shift in brain tumor diagnosis. In a similar manner, treatment response monitoring in neuro-oncology has made considerable progress. While most techniques are still in their inception, there is an emerging body of evidence for clinical application. Further research will be critically important for the development of impactful breakthroughs in this area of the field.

Epidemiology and survival outcomes of synchronous and metachronous brain metastases: a retrospective population-based study.

OBJECTIVE: Brain metastases (BMs) are the most common CNS tumors, yet their prevalence is difficult to determine. Most studies only report synchronous metastases, which make up a fraction of all BMs. The authors report the incidence and prognosis of patients with synchronous and metachronous BMs over a decade. METHODS: Study data were obtained from the TriNetX Research Network. Patients were included if they had a primary cancer diagnosis and a BM diagnosis, with primary cancer occurring between January 1, 2013, and January 1, 2023. Metachronous BM was defined as BM diagnosed more than 2 months after the primary cancer. Cohorts were balanced by propensity score matching for age, extracranial metastasis, and antineoplastic or radiation therapy. Kaplan-Meier plots were used to evaluate survival differences between synchronous and metachronous BMs and associations with clinical conditions. A log-rank test was used to evaluate BM-free survival for metachronous BM and overall survival (OS) for all BMs. Hazard ratios and 95% CIs were calculated. RESULTS: Of the 11,497,663 patients with 15 primary cancers identified, 300,863 (2.6%) developed BMs. BMs most commonly arose from lung and breast cancers and melanoma. Of all BMs, 113,827 (37.8%) presented synchronously and 187,036 (62.2%) presented metachronously. Lung and bronchial cancer had the highest metastasis rate (11.0%) and the highest synchronous presentation (51.0%). For metachronous presentations, the time from primary diagnosis to metastasis ranged from 1.3 to 2.5 years, averaging 1.8 years. Metachronous BM diagnosis was associated with longer survival over synchronous BM from primary diagnosis (11.54 vs 37.41 months, p < 0.0001), but shorter survival than extracranial metastases without BM (38.75 vs 69.18 months, p < 0.0001). Antineoplastic therapy prior to BM was associated with improved BM-free survival (4.46 vs 17.80 months, p < 0.0001) and OS (25.15 vs 42.26 months, p < 0.0001). Radiotherapy showed a similar effect that was statistically significant but modest for BM-free survival (5.25 vs 11.44 months, p < 0.0001) and OS (30.13 vs 32.82 months, p < 0.0001). CONCLUSIONS: The majority of BMs present metachronously and arise within 2 years of primary cancer diagnosis. The substantial rate of BMs presenting within 6 months of primary cancer, especially liver, lung, and pancreatic cancer, may guide future recommendations on intracranial staging. Antineoplastic therapy prior to the development of BM may prolong the time before metastasis and improve survival. Further characterization of this population can better inform screening, prevention, and treatment efforts.

Dynamic contrast-enhanced CEST MRI using a low molecular weight dextran.

Natural and synthetic sugars have great potential for developing highly biocompatible and translatable chemical exchange saturation transfer (CEST) MRI contrast agents. In this study, we aimed to develop the smallest clinically available form of dextran, Dex1 (molecular weight, MW ~ 1 kDa), as a new CEST agent. We first characterized the CEST properties of Dex1 in vitro at 11.7 T and showed that the Dex1 had a detectable CEST signal at ~1.2 ppm, attributed to hydroxyl protons. In vivo CEST MRI studies were then carried out on C57BL6 mice bearing orthotopic GL261 brain tumors (n = 5) using a Bruker BioSpec 11.7 T MRI scanner. Both steady-state full Z-spectral images and single offset (1.2 ppm) dynamic dextran-enhanced (DDE) images were acquired before and after the intravenous injection of Dex1 (2 g/kg). The steady-state Z-spectral analysis showed a significantly higher CEST contrast enhancement in the tumor than in contralateral brain (∆MTRasym1.2 ppm  = 0.010 ± 0.006 versus 0.002 ± 0.008, P = 0.0069) at 20 min after the injection of Dex1. Pharmacokinetic analyses of DDE were performed using the area under the curve (AUC) in the first 10 min after Dex1 injection, revealing a significantly higher uptake of Dex1 in the tumor than in brain tissue for tumor-bearing mice (AUC[0-10 min] = 21.9 ± 4.2 versus 5.3 ± 6.4%·min, P = 0.0294). In contrast, no Dex1 uptake was foundling in the brains of non-tumor-bearing mice (AUC[0-10 min] = -1.59 ± 2.43%·min). Importantly, the CEST MRI findings were consistent with the measurements obtained using DCE MRI and fluorescence microscopy, demonstrating the potential of Dex1 as a highly translatable CEST MRI contrast agent for assessing tumor hemodynamics.

Tryptophan PET predicts spatial and temporal patterns of post-treatment glioblastoma progression detected by contrast-enhanced MRI.

Amino acid PET is increasingly utilized for the detection of recurrent gliomas. Increased amino acid uptake is often observed outside the contrast-enhancing brain tumor mass. In this study, we evaluated if non-enhancing PET+ regions could predict spatial and temporal patterns of subsequent MRI progression in previously treated glioblastomas. Twelve patients with a contrast-enhancing area suspicious for glioblastoma recurrence on MRI underwent PET scanning with the amino acid radiotracer alpha-[(11)C]-methyl-L-tryptophan (AMT). Brain regions showing increased AMT uptake in and outside the contrast-enhancing volume were objectively delineated to include high uptake consistent with glioma (as defined by previous studies). Volume and tracer uptake of such non-enhancing PET+ regions were compared to spatial patterns and timing of subsequent progression of the contrast-enhancing lesion, as defined by serial surveillance MRI. Non-enhancing PET+ volumes varied widely across patients and extended up to 24 mm from the edge of MRI contrast enhancement. In ten patients with clear progression of the contrast-enhancing lesion, the non-enhancing PET+ volumes predicted the location of new enhancement, which extended beyond the PET+ brain tissue in six. In two patients, with no PET+ area beyond the initial contrast enhancement, MRI remained stable. There was a negative correlation between AMT uptake in non-enhancing brain and time to subsequent progression (r = -0.77, p = 0.003). Amino acid PET imaging could complement MRI not only for detecting glioma recurrence but also predicting the location and timing of subsequent tumor progression. This could support decisions for surgical intervention or other targeted therapies for recurrent gliomas.

Comparison of amino acid positron emission tomographic radiotracers for molecular imaging of primary and metastatic brain tumors.

Positron emission tomography (PET) is an imaging technology that can detect and characterize tumors based on their molecular and biochemical properties, such as altered glucose, nucleoside, or amino acid metabolism. PET plays a significant role in the diagnosis, prognostication, and treatment of various cancers, including brain tumors. In this article, we compare uptake mechanisms and the clinical performance of the amino acid PET radiotracers (l-[methyl-11C]methionine [MET], 18F-fluoroethyl-tyrosine [FET], 18F-fluoro-l-dihydroxy-phenylalanine [FDOPA], and 11C-alpha-methyl-l-tryptophan [AMT]) most commonly used for brain tumor imaging. First, we discuss and compare the mechanisms of tumoral transport and accumulation, the basis of differential performance of these radioligands in clinical studies. Then we summarize studies that provided direct comparisons among these amino acid tracers and to clinically used 2-deoxy-2[18F]fluoro-d-glucose [FDG] PET imaging. We also discuss how tracer kinetic analysis can enhance the clinical information obtained from amino acid PET images. We discuss both similarities and differences in potential clinical value for each radioligand. This comparative review can guide which radiotracer to favor in future clinical trials aimed at defining the role of these molecular imaging modalities in the clinical management of brain tumor patients.

Velocity-Selective Arterial Spin Labeling Perfusion in Monitoring High Grade Gliomas Following Therapy: Clinical Feasibility at 1.5T and Comparison with Dynamic Susceptibility Contrast Perfusion.

MR perfusion imaging is important in the clinical evaluation of primary brain tumors, particularly in differentiating between true progression and treatment-induced change. The utility of velocity-selective ASL (VSASL) compared to the more commonly utilized DSC perfusion technique was assessed in routine clinical surveillance MR exams of 28 patients with high-grade gliomas at 1.5T. Using RANO criteria, patients were assigned to two groups, one with detectable residual/recurrent tumor ("RT", n = 9), and the other with no detectable residual/recurrent tumor ("NRT", n = 19). An ROI was drawn to encompass the largest dimension of the lesion with measures normalized against normal gray matter to yield rCBF and tSNR from VSASL, as well as rCBF and leakage-corrected relative CBV (lc-rCBV) from DSC. VSASL (rCBF and tSNR) and DSC (rCBF and lc-rCBV) metrics were significantly higher in the RT group than the NRT group allowing adequate discrimination (p < 0.05, Mann-Whitney test). Lin's concordance analyses showed moderate to excellent concordance between the two methods, with a stronger, moderate correlation between VSASL rCBF and DSC lc-rCBV (r = 0.57, p = 0.002; Pearson's correlation). These results suggest that VSASL is clinically feasible at 1.5T and has the potential to offer a noninvasive alternative to DSC perfusion in monitoring high-grade gliomas following therapy.

Relapsing Anti-GAD65-Associated Encephalitis Responsive to Thymoma Resection, Radiation, and Immunomodulatory Therapy.

Herein we describe a case of relapsing anti-GAD65-associated encephalitis which was responsive to the combination of thymoma resection, external beam radiotherapy, and immunomodulatory therapy. The case illustrates the value of remaining vigilant for the possibility of paraneoplastic syndromes in the context of anti-GAD65 antibodies and thymoma. It also illustrates that tumor-directed therapies may offer additional benefit beyond immunomodulatory therapy alone.

Radiation immunodynamics in patients with glioblastoma receiving chemoradiation.

Introduction: This is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease. Methods: 16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics. Results: We identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8+ T lymphocytes that produced IFNγ, the potent anti-tumor cytokine. Discussion: These data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.

Differentiation of glioblastomas from metastatic brain tumors by tryptophan uptake and kinetic analysis: a positron emission tomographic study with magnetic resonance imaging comparison.

Differentiating high-grade gliomas from solitary brain metastases is often difficult by conventional magnetic resonance imaging (MRI); molecular imaging may facilitate such discrimination. We tested the accuracy of α[11C]methyl-l-tryptophan (AMT)-positron emission tomography (PET) to differentiate newly diagnosed glioblastomas from brain metastases. AMT-PET was performed in 36 adults with suspected brain malignancy. Tumoral AMT accumulation was measured by standardized uptake values (SUVs). Tracer kinetic analysis was also performed to separate tumoral net tryptophan transport (by AMT volume of distribution [VD]) from unidirectional uptake rates using dynamic PET and blood input function. Differentiating the accuracy of these PET variables was evaluated and compared to conventional MRI. For glioblastoma/metastasis differentiation, tumoral AMT SUV showed the highest accuracy (74%) and the tumor/cortex VD ratio had the highest positive predictive value (82%). The combined accuracy of MRI (size of contrast-enhancing lesion) and AMT-PET reached up to 93%. For ring-enhancing lesions, tumor/cortex SUV ratios were higher in glioblastomas than in metastatic tumors and could differentiate these two tumor types with > 90% accuracy. These results demonstrate that evaluation of tryptophan accumulation by PET can enhance pretreatment differentiation of glioblastomas and metastatic brain tumors. This approach may be particularly useful in patients with a newly diagnosed solitary ring-enhancing mass.

Tryptophan PET in pretreatment delineation of newly-diagnosed gliomas: MRI and histopathologic correlates.

Pretreatment delineation of infiltrating glioma volume remains suboptimal with current neuroimaging techniques. Gadolinium-enhanced T1-weighted (T1-Gad) MR images often underestimate the true extent of the tumor, while T2-weighted images preferentially highlight peritumoral edema. Accumulation of α-[(11)C]methyl-L-tryptophan (AMT) on positron emission tomography (PET) has been shown in gliomas. To determine whether increased uptake on AMT-PET would detect tumor-infiltrated brain tissue outside the contrast-enhancing region and differentiate it from peritumoral vasogenic edema, volumes and spatial concordance of T1-Gad and T2 MRI abnormalities as well as AMT-PET abnormalities were analyzed in 28 patients with newly-diagnosed WHO grade II-IV gliomas. AMT-accumulating grade I meningiomas were used to define an AMT uptake cutoff threshold that detects the tumor but excludes peri-meningioma vasogenic edema. Tumor infiltration in AMT-accumulating areas was studied in stereotactically-resected specimens from patients with glioblastoma. In the 28 gliomas, mean AMT-PET-defined tumor volumes were greater than the contrast-enhancing volume, but smaller than T2 abnormalities. Volume of AMT-accumulating tissue outside MRI abnormalities increased with higher tumor proliferative index and was the largest in glioblastomas. Tumor infiltration was confirmed by histopathology from AMT-positive regions outside contrast-enhancing glioblastoma mass, while no or minimal tumor cells were found in AMT-negative specimens. These results demonstrate that increased AMT accumulation on PET detects glioma-infiltrated brain tissue extending beyond the contrast-enhanced tumor mass. While tryptophan uptake is low in peritumoral vasogenic edema, AMT-PET can detect tumor-infiltrated brain outside T2-lesions. Thus, AMT-PET may assist pretreatment delineation of tumor infiltration, particularly in high-grade gliomas.

Downfield Proton MRSI at 3 Tesla: A Pilot Study in Human Brain Tumors.

PURPOSE: To investigate the use of 3D downfield proton magnetic resonance spectroscopic imaging (DF-MRSI) for evaluation of tumor recurrence in patients with glioblastoma (GBM). METHODS: Seven patients (4F, age range 44-65 and mean ± standard deviation 59.3 ± 7.5 years) with previously treated GBM were scanned using a recently developed 3D DF-MRSI sequence at 3T. Short TE 3D DF-MRSI and water reference 3D-MRSI scans were collected with a nominal spatial resolution of 0.7 cm3. DF volume data in eight slices covered 12 cm of brain in the cranio-caudal axis. Data were analyzed using the 'LCModel' program and a basis set containing nine peaks ranging in frequency between 6.83 to 8.49 ppm. The DF8.18 (assigned to amides) and DF7.90 peaks were selected for the creation of metabolic images and statistical analysis. Longitudinal MR images and clinical history were used to classify brain lesions as either recurrent tumor or treatment effect, which may include necrosis. DF-MRSI data were compared between lesion groups (recurrent tumor, treatment effect) and normal-appearing brain. RESULTS: Of the seven brain tumor patients, two were classified as having recurrent tumor and the rest were classified as treatment effect. Amide metabolite levels from recurrent tumor regions were significantly (p < 0.05) higher compared to both normal-appearing brain and treatment effect regions. Amide levels in lesion voxels classified as treatment effect were significantly lower than normal brain. CONCLUSIONS: 3D DF-MRSI in human brain tumors at 3T is feasible and was well tolerated by all patients enrolled in this preliminary study. Amide levels measured by 3D DF-MRSI were significantly different between treatment effect and tumor regrowth.

Epidemiological trends, prognostic factors, and survival outcomes of synchronous brain metastases from 2015 to 2019: a population-based study.

Background: Brain metastases (BM) constitute a significant cause of oncological mortality. Statistics on the incidence of BM are limited because of the lack of systematic nationwide reporting. We report the incidence of synchronous brain metastases (sBM), defined as BM identified at the time of primary cancer diagnosis from 2015 to 2019 using National Cancer Institute's (NCI's) Surveillance, Epidemiology, and End Results Program database. Methods: We identified 1,872,057 patients with malignancies diagnosed between 2015 and 2019 from the SEER 17 Registries database, including 35,986 (1.9%) patients with sBM. Age-adjusted incidence rates were examined using the NCI Joinpoint software. Kaplan-Meier curves and a multivariate Cox regression model were used to investigate survival. Results: The incidence rate of sBM from 2015 to 2019 was 7.1 persons per 100,000. Lung and bronchus cancers had the highest incidence of sBM (5.18 to 5.64 per 100,000), followed by melanoma (0.30 to 0.34 per 100,000) and breast cancers (0.24 to 0.30 per 100,000). In children, renal tumors had the highest sBM incidence. sBM were associated with poorer survival than extracranial metastases only (hazard ratio [HR]: 1.40 [95% CI: 1.39-1.42], P < .001). We observed better survival in white patients relative to nonwhite patients with sBM (HR: 0.91 [95% CI: 0.90-0.94], P < .001). Conclusions: The incidence rate of sBM has remained similar to rates reported over the last 9 years, with the majority associated with primary lung and bronchus cancers. sBM represent a national healthcare burden with tremendous mortality in pediatric and adult populations. This population may benefit from improved screening and treatment strategies.

In-vivo magnetic resonance spectroscopy of lactate as a non-invasive biomarker of dichloroacetate activity in cancer and non-cancer central nervous system disorders.

The adverse effects of lactic acidosis in the cancer microenvironment have been increasingly recognized. Dichloroacetate (DCA) is an orally bioavailable, blood brain barrier penetrable drug that has been extensively studied in the treatment of mitochondrial neurologic conditions to reduce lactate production. Due to its effect reversing aerobic glycolysis (i.e., Warburg-effect) and thus lactic acidosis, DCA became a drug of interest in cancer as well. Magnetic resonance spectroscopy (MRS) is a well-established, non-invasive technique that allows detection of prominent metabolic changes, such as shifts in lactate or glutamate levels. Thus, MRS is a potential radiographic biomarker to allow spatial and temporal mapping of DCA treatment. In this systematic literature review, we gathered the available evidence on the use of various MRS techniques to track metabolic changes after DCA administration in neurologic and oncologic disorders. We included in vitro, animal, and human studies. Evidence confirms that DCA has substantial effects on lactate and glutamate levels in neurologic and oncologic disease, which are detectable by both experimental and routine clinical MRS approaches. Data from mitochondrial diseases show slower lactate changes in the central nervous system (CNS) that correlate better with clinical function compared to blood. This difference is most striking in focal impairments of lactate metabolism suggesting that MRS might provide data not captured by solely monitoring blood. In summary, our findings corroborate the feasibility of MRS as a pharmacokinetic/pharmacodynamic biomarker of DCA delivery in the CNS, that is ready to be integrated into currently ongoing and future human clinical trials using DCA.

Label-Free Assessment of Mannitol Accumulation Following Osmotic Blood-Brain Barrier Opening Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging.

PURPOSE: Mannitol is a hyperosmolar agent for reducing intracranial pressure and inducing osmotic blood-brain barrier opening (OBBBO). There is a great clinical need for a non-invasive method to optimize the safety of mannitol dosing. The aim of this study was to develop a label-free Chemical Exchange Saturation Transfer (CEST)-based MRI approach for detecting intracranial accumulation of mannitol following OBBBO. METHODS: In vitro MRI was conducted to measure the CEST properties of D-mannitol of different concentrations and pH. In vivo MRI and MRS measurements were conducted on Sprague-Dawley rats using a Biospec 11.7T horizontal MRI scanner. Rats were catheterized at the internal carotid artery (ICA) and randomly grouped to receive either 1 mL or 3 mL D-mannitol. CEST MR images were acquired before and at 20 min after the infusion. RESULTS: In vitro MRI showed that mannitol has a strong, broad CEST contrast at around 0.8 ppm with a mM CEST MRI detectability. In vivo studies showed that CEST MRI could effectively detect mannitol in the brain. The low dose mannitol treatment led to OBBBO but no significant mannitol accumulation, whereas the high dose regimen resulted in both OBBBO and mannitol accumulation. The CEST MRI findings were consistent with 1H-MRS and Gd-enhanced MRI assessments. CONCLUSION: We demonstrated that CEST MRI can be used for non-invasive, label-free detection of mannitol accumulation in the brain following BBBO treatment. This method may be useful as a rapid imaging tool to optimize the dosing of mannitol-based OBBBO and improve its safety and efficacy.

Treatment of Déjerine-Roussy syndrome pain with scrambler therapy.

Aim: Déjerine-Roussy syndrome or central thalamic pain can be devastating, and treatment with drugs and even deep brain stimulation can be unsatisfactory. Scrambler therapy is a form of neuromodulation that uses external skin electrodes to send a 'non-pain' signal to the brain, with some success in difficult-to-treat syndromes such as neuromyelitis optica spectrum disorder. We used scrambler therapy to treat a patient with 6 years of disabling Déjerine-Roussy syndrome pain. Methods: A 56-year-old man received multiple daily then monthly treatments with electrode pairs placed just above the area of distal pain. Each treatment was for 40 min. Results: His allodynia and hyperalgesia resolved within 10 min, and his pain score fell to almost zero after 30 min. Months later, he resumed normal activity and is off all his pain medications. No side effects were noted. Conclusion: Scrambler therapy appeared to reverse 6 years of disabling pain safely and economically, and continues to be effective. Further multi-institutional trials are warranted for this rare syndrome.

Diagnostic Evaluation in Primary CNS Lymphoma.

The diagnosis of primary central nervous system lymphoma (PCNSL) may be fraught with difficulty. After initial imaging reveals enhancing intracranial mass lesions steroids are often initiated. This leads to a decreased diagnostic yield of tumor biopsies which may be associated with delay in treatment initiation. We review a case of PCNSL treated with a very brief steroid course. Initial nondiagnostic biopsy histopathology is juxtaposed against subsequent diagnostic pathology. Imaging before and after steroids is presented, as is imaging after tumor regrowth in a noncontiguous location. Elements in the clinical history and radiographic presentation which should raise suspicion for PCNSL are reviewed. Increased understanding of the potential pitfalls surrounding PCNSL diagnosis may limit their future occurrence.

Occult teratoma in a case of N-methyl-D-aspartate receptor encephalitis.

N-methyl-D-aspartate receptor encephalitis (NMDARe) is one of 13 autoimmune-mediated encephalitides that have been discovered over the last decade. This case report describes the course of a 26-year-old female who presented with new-onset seizures and insomnia, complicated by encephalitis. The initial workup ruled out common causes of encephalitis, while a transvaginal ultrasound (TVUS), and computed tomography (CT) scans of the chest, abdomen, and pelvis did not identify a mass. Based on the suspicion that she may have autoimmune encephalitis, the patient was treated with intravenous immunoglobulins and plasma exchange, but continued to deteriorate. Whole-body positron emission tomography (PET) scan identified a small hypermetabolic pelvic mass. Shortly thereafter serum and cerebral spinal fluid NMDAR antibody titers were reported as positive, prompting repetition of the TVUS, which confirmed the presence of an ovarian teratoma. The patient had a laparoscopic oophorectomy with subsequent resolution of her symptoms, further confirming the diagnosis. Despite the sensitivities of TVUS and CT of up to 94% and 98%, respectively, the teratoma was unusually small, necessitating the addition of a PET scan to identify the lesion. These neoplasms are thought to have low uptake on PET; however, it is possible that focal inflammation may have enhanced the detection. It is unlikely that the teratoma grew during hospitalization as the average growth rate is 1.8 mm per year. Regardless, the lesson that can be learned is that imaging modalities beyond CT and TVUS, such as PET, can be helpful, as identification of a resectable tumor may alter management and ultimately improve outcomes.

State-of-the-art considerations in small cell lung cancer brain metastases.

BACKGROUND: Small cell lung cancer (SCLC) frequently leads to development of brain metastases. These unfortunately continue to be associated with short survival. Substantial advances have been made in our understanding of the underlying biology of disease. This understanding on the background of previously evaluated and currently utilized therapeutic treatments can help guide the next steps in investigations into this disease with the potential to influence future treatments. DESIGN: A comprehensive review of the literature covering epidemiology, pathophysiology, imaging characteristics, prognosis, and therapeutic management of SCLC brain metastases was performed. RESULTS: SCLC brain metastases continue to have a poor prognosis. Both unique aspects of SCLC brain metastases as well as features seen more universally across other solid tumor brain metastases are discussed. Systemic therapeutic studies and radiotherapeutic approaches are reviewed. CONCLUSIONS: A clearer understanding of SCLC brain metastases will help lay the framework for studies which will hopefully translate into meaningful therapeutic options for these patients.

Prognostic Molecular and Imaging Biomarkers in Primary Glioblastoma.

PURPOSE: Several molecular glioma markers (including isocitrate dehydrogenase 1 [IDH1] mutation, amplification of the epidermal growth factor receptor [EGFR], and methylation of the O6-methylguanine-DNA methyltransferase [MGMT] promoter) have been associated with glioblastoma survival. In this study, we examined the association between tumoral amino acid uptake, molecular markers, and overall survival in patients with IDH1 wild-type (primary) glioblastoma. PATIENTS AND METHODS: Twenty-one patients with newly diagnosed IDH1 wild-type glioblastomas underwent presurgical MRI and PET scanning with alpha[C-11]-L-methyl-tryptophan (AMT). MRI characteristics (T2- and T1-contrast volume), tumoral tryptophan uptake, PET-based metabolic tumor volume, and kinetic variables were correlated with prognostic molecular markers (EGFR and MGMT) and overall survival. RESULTS: EGFR amplification was associated with lower T1-contrast volume (P = 0.04) as well as lower T1-contrast/T2 volume (P = 0.04) and T1-contrast/PET volume ratios (P = 0.02). Tumors with MGMT promoter methylation showed lower metabolic volume (P = 0.045) and lower tumor/cortex AMT unidirectional uptake ratios than those with unmethylated MGMT promoter (P = 0.009). While neither EGFR amplification nor MGMT promoter methylation was significantly associated with survival, high AMT tumor/cortex uptake ratios on PET were strongly prognostic for longer survival (hazards ratio, 30; P = 0.002). Estimated mean overall survival was 26 months in patients with high versus 8 months in those with low tumoral AMT uptake ratios. CONCLUSIONS: The results demonstrate specific MRI and amino acid PET imaging characteristics associated with EGFR amplification and MGMT promoter methylation in patients with primary glioblastoma. High tryptophan uptake on PET may identify a subgroup with prolonged survival.