Tumor microenvironment in a minipig model of spinal cord glioma.

BACKGROUND: Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs. METHODS: Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo. RESULTS: We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1ß, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model. CONCLUSIONS: Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.

The genomic profiling and MAMLD1 expression in human and canines with Cushing's disease.

BACKGROUND: Cushing's disease (CD) is defined as hypercortisolemia caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (corticotroph PA) that afflicts humans and dogs. In order to map common aberrant genomic features of CD between humans and dogs, we performed genomic sequencing and immunostaining on corticotroph PA. METHODS: For inclusion, humans and dog were diagnosed with CD. Whole exome sequencing (WES) was conducted on 6 human corticotroph PA. Transcriptome RNA-Seq was performed on 6 human and 7 dog corticotroph PA. Immunohistochemistry (IHC) was complete on 31 human corticotroph PA. Corticotroph PA were compared with normal tissue and between species analysis were also performed. RESULTS: Eight genes (MAMLD1, MNX1, RASEF, TBX19, BIRC5, TK1, GLDC, FAM131B) were significantly (P < 0.05) overexpressed across human and canine corticotroph PA. IHC revealed MAMLD1 to be positively (3+) expressed in the nucleus of ACTH-secreting tumor cells of human corticotroph PA (22/31, 70.9%), but absent in healthy human pituitary glands. CONCLUSIONS: In this small exploratory cohort, we provide the first preliminary insights into profiling the genomic characterizations of human and dog corticotroph PA with respect to MAMLD1 overexpression, a finding of potential direct impact to CD microadenoma diagnosis. Our study also offers a rationale for potential use of the canine model in development of precision therapeutics.

Lentiviral-Induced Spinal Cord Gliomas in Rat Model.

Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats (n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future.

Safety and effectiveness of stereotactic laser ablation for epileptogenic cerebral cavernous malformations.

OBJECTIVE: Magnetic resonance (MR) thermography-guided laser interstitial thermal therapy, or stereotactic laser ablation (SLA), is a minimally invasive alternative to open surgery for focal epilepsy caused by cerebral cavernous malformations (CCMs). We examined the safety and effectiveness of SLA of epileptogenic CCMs. METHODS: We retrospectively analyzed 19 consecutive patients who presented with focal seizures associated with a CCM. Each patient underwent SLA of the CCM and adjacent cortex followed by standard clinical and imaging follow-up. RESULTS: All but one patient had chronic medically refractory epilepsy (median duration 8 years, range 0.5-52 years). Lesions were located in the temporal (13), frontal (five), and parietal (one) lobes. CCMs induced magnetic susceptibility artifacts during thermometry, but perilesional cortex was easily visualized. Fourteen of 17 patients (82%) with >12 months of follow-up achieved Engel class I outcomes, of which 10 (59%) were Engel class IA. Two patients who were not seizure-free from SLA alone became so following intracranial electrode-guided open resection. Delayed postsurgical imaging validated CCM involution (median 83% volume reduction) and ablation of surrounding cortex. Histopathologic examination of one previously ablated CCM following open surgery confirmed obliteration. SLA caused no detectable hemorrhages. Two symptomatic neurologic deficits (visual and motor) were predictable, and neither was permanently disabling. SIGNIFICANCE: In a consecutive retrospective series, MR thermography-guided SLA was an effective alternative to open surgery for epileptogenic CCM. The approach was free of hemorrhagic complications, and clinically significant neurologic deficits were predictable. SLA presents no barrier to subsequent open surgery when needed.

Patterns of Treatment Failure in Primary Central Nervous System Lymphoma.

OBJECTIVES: Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. METHODS: This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. RESULTS: Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P =0.02), KPS (HR: 0.10, P =0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P <0.01), and use of intrathecal chemotherapy (HR: 0.03, P <0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P =0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT ( P =0.37), Rituximab ( P =0.12), or attempted gross total resection ( P =0.72). CONCLUSIONS: Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.

Caution with interpreting laboratory results after lipid rescue therapy.

Intravenous lipid rescue therapy (LRT) may be implemented to attenuate drug toxicity. Little is known about LRT interference with laboratory tests in overdose settings. A 54-year-old man with a history of depression consumed unknown amounts of diphenhydramine, amitriptyline, and acetaminophen (APAP). Initial workup showed aspartate aminotransferase (AST) of 138 U/L, APAP of 177 µg/mL, and a QRS interval of 136 milliseconds. N-acetylcysteine, sodium bicarbonate, and 20% intravenous LRT were initiated. Laboratory test results drawn less than 6 hours later showed an APAP level of 44 µg/mL and an undetectable AST (Siemens Vista 1500 analyzer, lower limit of detection: alanine aminotransferase, 6 U/L; AST, 3 U/L). N-acetylcysteine and LRT infusions were stopped. Eight hours later, serum AST was measured at 488 U/L and increased over the next 2 days to a peak of 1600 U/L before recovery. Given a gradually rising course of AST following APAP ingestion, a single undetectable measurement is highly unlikely and probably erroneous. For this Siemens analyzer, serum lipid concentrations greater than 400 mg/dL cause interference with the AST measurement. Because lipid levels greater than 400 mg/dL with other similar analyzers are known to falsely decrease the AST, it is possible that extreme lipemia caused this laboratory result; a triglyceride level of 3648 mg/dL has been reported after LRT infusion. This conclusion is limited by the lack of repeat measurement of liver enzymes or measurement of serum lipid levels. Lipid rescue therapy may cause lipemia that interferes with the assay for liver enzymes. Suspected abnormal laboratory values should be repeated, or other techniques can be used to remove lipemic interference.

Using Brain Tumor MRI Structured Reporting to Quantify the Impact of Imaging on Brain Tumor Boards.

Multidisciplinary tumor boards (TB) are an essential part of brain tumor care, but quantifying the impact of imaging on patient management is challenging due to treatment complexity and a lack of quantitative outcome measures. This work uses a structured reporting system for classifying brain tumor MRIs, the brain tumor reporting and data system (BT-RADS), in a TB setting to prospectively assess the impact of imaging review on patient management. Published criteria were used to prospectively assign three separate BT-RADS scores (an initial radiology report, secondary TB presenter review, and TB consensus) to brain MRIs reviewed at an adult brain TB. Clinical recommendations at TB were noted and management changes within 90 days after TB were determined by chart review. In total, 212 MRIs in 130 patients (median age = 57 years) were reviewed. Agreement was 82.2% between report and presenter, 79.0% between report and consensus, and 90.1% between presenter and consensus. Rates of management change increased with increasing BT-RADS scores (0-3.1%, 1a-0%, 1b-66.7%, 2-8.3%, 3a-38.5%, 3b-55.9, 3c-92.0%, and 4-95.6%). Of 184 (86.8%) cases with clinical follow-up within 90 days after the tumor board, 155 (84.2%) of the recommendations were implemented. Structured scoring of MRIs provides a quantitative way to assess rates of agreement interpretation alongside how often management changes are recommended and implemented in a TB setting.

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS.

The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS's impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.

Functioning Crooke Cell Adenomas: Case Series and Literature Review.

BACKGROUND: Crooke cell adenomas (CCAs) are rare, potentially aggressive pituitary adenomas. Data regarding prevalence and clinical course are sparse. METHODS: We performed a retrospective review of 59 consecutive functioning corticotroph adenomas operated on between October 2017 and November 2020 and a literature review of CCA publications since 1991. RESULTS: The prevalence of CCAs among functioning corticotroph adenomas at our institution was 8.5% (5/59). In the 4 other surgical case series, prevalence of CCAs was 0%-6.8%. Our patients (4 women and 1 man, mean age 46 ± 11 years) presented with hypercortisolism (3/5), with vision loss (1/5), and incidentally (1/5). All patients had elevated adrenocorticotropic hormone (151 ± 54 pg/mL) and urinary free cortisol (830 ± 796.5 µg/day). Radiologically, 3 tumors were macroadenomas and 2 had cavernous sinus invasion. All patients achieved biochemical remission at 3 months postoperatively. One patient with a giant pituitary adenoma underwent fractionated radiation for residual tumor. During follow-up (range, 3.1-31.0 months), no patients had evidence of radiological or biochemical recurrence. The literature review identified 22 functioning corticotroph adenomas with outcome data. Additional treatments included reoperation (50%), radiation (59%), bilateral adrenalectomy (23%), and temozolomide (36%). CONCLUSIONS: We found a higher CCA prevalence among functioning adrenocorticotropic hormone adenomas after implementation of the 2017 World Health Organization classification. In our series and the literature, most CCAs were macroadenomas with high adrenocorticotropic hormone levels. Postoperative outcomes were excellent in our series, while some cases from the literature were refractory to standard treatments. Larger clinical and molecular studies are needed to identify patients at risk.

Sweet Syndrome Imitating Cutaneous Cryptococcal Disease.

Cryptococcoid Sweet syndrome is a rare histologic variant of the neutrophilic dermatosis presenting clinically with skin lesions typical of classical Sweet syndrome but with yeast-like structures suggestive of Cryptococcus on histopathology. Histochemical stains for fungus and cultures are negative whereas staining for myeloperoxidase is positive. We present 2 cases of cryptococcoid Sweet syndrome with atypical skin manifestations, including hemorrhagic bullae and plaques, and provide a brief review of the literature. Clinicians should be aware that this variant of Sweet syndrome can present with uncommon clinical findings and has histopathologic findings suggestive of Cryptococcus species.

Distinct phenotypic states and spatial distribution of CD8+ T cell clonotypes in human brain metastases.

Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8+ T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8+ T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8+ T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8+ T cells, including bystander CD8+ T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8+ T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8+ T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.

Acanthamoeba castellanii encephalitis in a patient with AIDS: a case report and literature review.

Amoebic encephalitis is a rare cause of CNS infection for which mortality exceeds 90%. We present the case of a 27-year-old man with AIDS who presented to a hospital in Atlanta (Georgia, USA) with tonic-clonic seizures and headache. His clinical condition deteriorated over several days. Brain biopsy revealed lymphohistiocytic inflammation and necrosis with trophozoites and encysted forms of amoebae. Immunohistochemical and PCR testing confirmed Acanthamoeba castellanii encephalitis, typically described as granulomatous amoebic encephalitis (GAE). No proven therapy for GAE is available, although both surgical and multiagent antimicrobial treatment strategies are often used. Most recently, these include the antileishmanial agent miltefosine. Here we review all cases of GAE due to Acanthamoeba spp in people with HIV/AIDS identified in the literature and reported to the Centers for Disease Control and Prevention. We describe this case as a reminder to the clinician to consider protozoal infections, especially free-living amoeba, in the immunocompromised host with a CNS infection refractory to traditional antimicrobial therapy.

Development and validation of a prognostic gene expression signature for lower-grade glioma following surgery and adjuvant radiotherapy.

BACKGROUND AND PURPOSE: Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases. MATERIALS AND METHODS: Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II-III glioma) treated by surgery and adjuvant RT were randomized 1:1 to a discovery cohort or an internal validation cohort. Using the discovery cohort only, associations between tumor RNA-seq expression and progression-free survival (PFS) as well as overall survival (OS) were evaluated with adjustment for clinicopathologic covariates. A Genomic Risk Score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was further assessed in the internal validation cohort of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA). RESULTS: From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition: MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1. High GRS, defined as having a GRS in the top third, was significantly associated with poorer outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the discovery cohort (PFS HR 1.61, 95% CI 1.10-2.36, P = 0.014; OS HR 2.74, 95% CI 1.68-4.47, P < 0.001). These findings were replicated in the internal validation cohort (PFS HR 1.58, 95% CI 1.05-2.37, P = 0.027; OS HR 1.84, 95% CI 1.13-3.00, P = 0.015) and the CGGA external validation cohort (OS HR 1.72, 95% CI 1.27-2.34, P < 0.001). Association between GRS and outcomes was observed only among patients who underwent RT, in both TCGA and CGGA. CONCLUSION: This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with PFS and OS only among patients whose treatment included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes may be considered in the multidisciplinary management of LGG.

Comparative assessment of thermal injury induced by bipolar electrocautery systems in a porcine model.

BACKGROUND: Bipolar electrocautery systems used during neurosurgical procedures have been shown to induce thermal injury to surrounding tissue. The goal of this study was to compare the thermal injury induced by two different systems commonly used in neurosurgical procedures (Silverglide by Stryker Corporation and SpetzlerMalis by Codman Neuro), with that of a newly introduced device (TRIOwand by NICO Corporation). METHODS: A farm swine underwent craniectomy and durotomy with subsequent exposure of cortical brain tissue. Electrocoagulation for the duration of 3 s was conducted with three different bipolar systems under comparable power settings. The maximal depth of thermal injury and mean area of injury in Hematoxylin and Eosin stained slides were quantified using Image J. The tissues were evaluated for vacuolization and ischemic damage. One-way ANOVA followed by post hoc Tukey test was utilized for statistical analysis. Alpha level was set at 0.05. RESULTS: TRIOwand lesions showed less depth of injury when compared to both Spetzler-Malis (P < 0.001) and Silverglide lesions (P = 0.048). Silverglide lesions showed significantly less depth of injury when compared to SpetzlerMalis lesions (P < 0.001). The injury area induced by the TRIOwand was significantly less than that of Spetzler-Malis (P < 0.001) and Silverglide systems (P < 0.001). Ischemic changes and vacuolization were seen in all three groups. CONCLUSION: Thermal damage is induced to varying extents by all bipolar systems. In this porcine model and under the conditions tested, bipolar cauterization with the TRIOwand resulted in less depth and decreased mean area of injury. Further studies are needed to characterize the injury caused by different bipolar systems with other settings and under surgical conditions in humans.

YAP/TAZ Transcriptional Coactivators Create Therapeutic Vulnerability to Verteporfin in EGFR-mutant Glioblastoma.

PURPOSE: Glioblastomas (GBMs), neoplasms derived from glia and neuroglial progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases, such as amplification and mutation of EGFR. EXPERIMENTAL DESIGN: Using a Drosophila glioma model and human patient-derived GBM stem cells and xenograft models, we genetically and pharmacologically tested whether the YAP and TAZ transcription coactivators, effectors of the Hippo pathway that promote gene expression via TEA domain (TEAD) cofactors, are key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling. RESULTS: YAP and TAZ are highly expressed in EGFR-amplified/mutant human GBMs, and their knockdown in EGFR-amplified/mutant GBM cells inhibited proliferation and elicited apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulates transcription of SOX2, C-MYC, and EGFR itself to create a feedforward loop to drive survival and proliferation of human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD-mediated transcription, preferentially induced apoptosis of cultured patient-derived EGFR-amplified/mutant GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe verteporfin uptake into tumor cells in GBM tumors in human patients. CONCLUSIONS: Together, our data suggest that verteporfin is a promising therapeutic agent for EGFR-amplified and -mutant GBM.

MRI Imaging Characteristics of Glioblastoma with Concurrent Gain of Chromosomes 19 and 20.

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Some of the genetic variations identified thus far, such as IDH mutation and MGMT promotor methylation, have implications for survival and response to therapy. A recent analysis of long-term GBM survivors showed that concurrent gain of chromosomes 19 and 20 (19/20 co-gain) is a positive prognostic factor that is independent of IDH mutation status. In this study, we retrospectively identified 18 patients with 19/20 co-gain and compared their imaging features to a control cohort without 19/20 co-gain. Imaging features such as tumor location, size, pial invasion, and ependymal extension were examined manually. When compared without further genetic subclassification, both groups showed similar imaging features except for rates of pial invasion. When each group was subclassified by MGMT promotor methylation status however, the two groups showed different imaging features in a number of additional ways including tumor location, size, and ependymal extension. Our results indicate that different permutations of various genetic mutations that coexist in GBM may interact in unpredictable ways to affect imaging appearance, and that imaging prognostication may be better approached in the context of the global genomic profile rather than individual genetic alterations.

Co-Occurrence Conundrum: Brain Metastases from Lung Adenocarcinoma, Radiation Necrosis, and Gliosarcoma.

Non-small cell lung cancer (NSCLC) commonly presents with metastasis to the brain. When brain metastases are treated with stereotactic radiosurgery (SRS), longitudinal imaging to monitor treatment response may identify radiation necrosis, metastasis progression, and/or another primary brain malignancy. A 60-year-old female with metastatic NSCLC involving the brain underwent treatment with systemic therapy and SRS. While some brain metastases resolved, two remaining sites evolved to resemble radiation necrosis on magnetic resonance imaging and spectroscopy. One of those sites was later confirmed to be radiation necrosis after receding with steroids and bevacizumab. The other lesion continued to enlarge and was then surgically resected, pathologically proven to be a gliosarcoma. When scan findings diverge among multiple treated disease sites, imaging should be cautiously interpreted in conjunction with clinical information as well as early surgical consultation for biopsy consideration, especially when there is suspicion of unusual or superimposed pathologies.

High-Grade Sarcoma Arising within a Previously Irradiated Vestibular Schwannoma: A Case Report and Literature Review.

BACKGROUND: Vestibular schwannomas are benign tumors of the cerebellopontine angle that are often treated with radiation therapy. Radiation therapy maintains good tumor control rates but involves a small risk of radiation-induced malignancies. We present a case of high-grade sarcoma arising within a previously irradiated vestibular schwannoma and a literature review of this rare but important clinical entity. METHODS: A 66-year-old woman presented with rapid clinical and radiographic deterioration 17 years after receiving stereotactic radiosurgery for vestibular schwannoma. After resection, pathology revealed a high-grade sarcoma arising within a conventional schwannoma. After further decline and tumor growth, the patient died of her disease 7 months postoperatively. Literature review was performed using PubMed and EMBASE databases and key words "vestibular schwannoma," "acoustic," "triton," "malignant," "sarcoma," "malignant peripheral nerve sheath tumor," "radiation," and "radiosurgery." All previous cases and the clinical circumstances related to these radiation-induced malignancies were assessed and quantified. RESULTS: The systematic review yielded 20 prior cases of radiation-induced malignant transformation of a vestibular schwannoma in patients without neurofibromatosis. Most tumors (60%) transformed into malignant nerve sheath tumors. At the time of presentation, 70% of patients had new cranial neuropathies, and all had evidence of tumor growth with brainstem compression. Prognosis was poor with mean time to death of 7.6 months. CONCLUSIONS: Radiation-induced malignant transformation of vestibular schwannomas is a rare but important clinical entity. Given its scarcity, the risk of malignancy should not sway initial management, but rapid clinical deterioration and radiographic growth during follow-up should prompt consideration of malignant transformation.

Characterization of dysregulated glutamine metabolism in human glioma tissue with 1H NMR.

Gliomas are one of the most common types of brain tumors. Given low survival and high treatment resistance rates, particularly for high grade gliomas, there is a need for specific biomarkers that can be used to stratify patients for therapy and monitor treatment response. Recent work has demonstrated that metabolic reprogramming, often mediated by inflammation, can lead to an upregulation of glutamine as an energy source for cancer cells. As a result, glutamine pathways are an emerging pharmacologic target. The goal of this pilot study was to characterize changes in glutamine metabolism and inflammation in human glioma samples and explore the use of glutamine as a potential biomarker. 1H high-resolution magic angle spinning nuclear magnetic resonance spectra were acquired from ex vivo glioma tissue (n = 16, grades II-IV) to quantify metabolite concentrations. Tumor inflammatory markers were quantified using electrochemiluminescence assays. Glutamate, glutathione, lactate, and alanine, as well as interleukin (IL)-1ß and IL-8, increased significantly in samples from grade IV gliomas compared to grades II and III (p ≤ .05). Following dimension reduction of the inflammatory markers using probabilistic principal component analysis, we observed that glutamine, alanine, glutathione, and lactate were positively associated with the first inflammatory marker principal component. Our findings support the hypothesis that glutamine may be a key marker for glioma progression and indicate that inflammation is associated with changes in glutamine metabolism. These results motivate further in vivo investigation of glutamine as a biomarker for tumor progression and treatment response.