Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.

A Case of Glioblastoma, Isocitrate Dehydrogenase Wild Type, With Widely Disseminated Osseous Metastasis.

Glioblastoma, isocitrate dehydrogenase (IDH) wild type, is an aggressive primary brain malignancy with a poor prognosis, despite treatment including surgery, chemotherapy, and radiation therapy. Few patients with glioblastoma develop metastasis outside the neuroaxis, likely due to disease progression in the brain prior to extraneural dissemination. The driving mutations of tumors in patients with extraneural metastases are not well described. In this case, we present a severe case of extraneural metastatic glioblastoma, as well as the genetic mutations of the tumor.

Assessing fetal human neural stem cells tumorigenicity potential in athymic rats with penetrating traumatic brain injury (pTBI).

Traumatic brain injuries (TBI) often produce disability in survivors due to unresolved inflammation and progressive neurodegeneration. The central nervous system in mammals is incapable of self-repair. Two decades of preclinical studies and clinical trials have provided insights into TBI pathophysiology that could be utilized to develop clinically relevant therapy. Our laboratory recently reported efficacy of clinical trial grade fetal human neural stem cells (hNSCs) in immunosuppressed rats with penetrating traumatic brain injury (pTBI). Next, in compliance with the United States Food and Drug Administration (USFDA) guidance, this study explores safety by assessing the tumorigenicity potential of intracranial hNSC transplants in athymic rats with pTBI. First, the maximum tolerated dose (MTD) was determined. Then, forty athymic pTBI rats were randomized to either: Group A. pTBI + vehicle or Group B. pTBI + hNSCs at MTD one week after injury with 6-months survival, sufficient time to uncover transplant associated tumorigenicity. A board-certified Pathologist examined hematoxylin-eosin (H&E), Ki67 immunostained brain and spinal cord, serial sections along with several abnormal peripheral masses for evidence of lesion, transplant, and oncogenesis. There was no evidence of transplant derived tumors or oncogenic tissue necrosis. Consistent with athymic literature, the lesion remained unchanged even after robust hNSC engraftment. This safety study supports the conclusion that hNSCs are safe for transplantation in pTBI. The differences in lesion expansion between immunosuppressed and athymic rats in the presence of hNSCs suggests an unexpected role for thymus derived cells in resolution of trauma induced inflammation.

Acute Ascending Necrotizing Myelitis After COVID-19 Infection: A Clinicopathologic Report.

Objectives: Neurologic manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, COVID-19) infection are common and varied. The objective of this report was to describe clinicopathologic findings of rare acute ascending necrotizing myelitis (ANM) and briefly summarize similar COVID-19-associated longitudinally extended transverse myelitis cases. Methods: We described the clinical presentation, disease course, diagnostic workup, therapeutic measures, and pathologic findings of ANM associated with COVID-19 infection. Results: A 31-year-old previously healthy woman developed a longitudinally extensive lower thoracic myelopathy 3 weeks after COVID-19 infection. The thoracic spinal cord lesion extended to cervical level in 1 week and to the lower medullary level in 2 more weeks. Thoracic laminectomy at T5-T6 level and cord biopsy revealed necrobiotic changes without viral particles or microglial nodules. The clinical deficit stabilized after immunomodulatory and eculizumab therapies. Discussion: COVID-19 infection can cause ANM. It adds to the spectrum of reported cases of COVID-19 -associated encephalitis and myelitis.

Effect of AR42 in Primary Vestibular Schwannoma Cells and a Xenograft Model of Vestibular Schwannoma.

HYPOTHESIS: AR42, a histone deacetylase (HDAC) inhibitor, reduces viability of primary vestibular schwannoma (VS) cells and delays tumor progression and hearing loss (HL) in a xenograft model of VS. BACKGROUND: The impact of HDAC expression on AR42 response in primary VS cells is unknown, as well as the effects of AR42 on VS-associated HL and imbalance. METHODS: Primary human VS cells (n = 7) were treated with AR42 (0-3.0 µM), and viability assays were conducted. Immunohistochemistry and western blotting for phosphorylated-HDAC2 (pHDAC2) were performed on tumor chunks. Pharmacokinetic studies were conducted in Fischer rats using mass spectrometry. Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats and treated with vehicle (n=7) or AR42 (25 mg/kg/day for 4weeks; n=12). Tumor bioluminescence imaging, auditory brainstem response (ABR), and rotarod tests were conducted to 6weeks. Final tumor weight and toxicities were measured. RESULTS: AR42 caused dose-dependent reductions in viability of VS cells. Tumors with higher pHDAC2:HDAC2 ratios had greater reductions in viability with AR42. On pharmacokinetic studies, AR42 reached peak levels in nerve ~24 hours after oral administration. Although AR42-treated rats demonstrated mean ABR threshold shifts ~10 to 20 dB lower than controls, this did not persist nor reach significance. When compared to controls, AR42 did not affect tumor bioluminescence, tumor weight, and rotarod measurements. CONCLUSIONS: Response of primary VS cells to AR42 may be influenced by pHDAC2 expression in tumor. Although AR42 may delay HL in our xenograft model, it did not halt tumor growth or vestibular dysfunction. Further investigations are warranted to evaluate the AR42 effectiveness in NF2-associated VS.

Recurrent adult pilocytic astrocytoma presenting with intraventricular and leptomeningeal spread.

BACKGROUND: Infratentorial pilocytic astrocytomas are uncommon tumors in adulthood but are thought to be prognostically similar to their pediatric counterparts with excellent overall survival following gross total resection. However, given the relative rarity of these tumors, no management guidelines exist for recurrent adult pilocytic astrocytomas (APAs). This lack of consensus is especially problematic for inoperable recurrences or those with aggressive features concerning for malignant transformation. CASE DESCRIPTION: In 2017, a 26-year-old female presented with headaches, nausea, vomiting, and blurry vision. A brain magnetic resonance imaging (MRI) demonstrated a large, well-circumscribed mass within the fourth ventricle causing obstructive hydrocephalus. She underwent near-total resection through a midline suboccipital transtonsillar approach. Pathology demonstrated a World Health Organization Grade 1 pilocytic astrocytoma. Despite initial improvement in her symptoms, she developed worsening headaches and lethargy 10 months after surgery and repeat MRI demonstrated recurrent tumor within the entire ventricular system and the subarachnoid spaces of the left cerebellopontine angle suggesting leptomeningeal spread. Due to the unresectable nature of the recurrence, the patient declined any further intervention and succumbed to her disease 6 months later. CONCLUSION: We present the first case of a recurrent APA presenting with intraventricular and leptomeningeal spread. Although thought to be a benign neoplasm, close interval follow-up with serial imaging is of essential, especially in those patients with known residual tumor, to prevent aggressive recurrences such as this.

Stimulated Raman Histology for Rapid Intraoperative Diagnosis of Gliomas.

BACKGROUND: Intraoperative pathologic diagnosis traditionally involves frozen section histopathology, which may be labor and time intensive. Indeed, a technique that streamlines the acquisition and evaluation of intraoperative histologic data may expedite surgical decision-making and shorten operative time. Stimulated Raman histology (SRH) is an emerging technology that allows for more rapid acquisition and interpretation of intraoperative histopathologic data. METHODS: A blinded, prospective cohort study was performed for 82 patients undergoing resection for a central nervous system tumor. Of these, 21 patients were diagnosed with glioma either intraoperatively or postoperatively on permanent section histology and included in this study. Time to diagnosis (TTD) and diagnostic accuracy relative to permanent section (the gold standard) were compared between SRH-based diagnosis and conventional frozen section histology. Diagnostic concordance with permanent section was also compared between frozen histopathology and SRH diagnosis. RESULTS: Diagnostic accuracy was not significantly different between methods (P = 1.00). Diagnostic concordance was not significantly different between methods when comparing 95% confidence intervals for kappa values (κ = 0.215; κ = 0.297; κ = 0.369). Lastly, mean TTD was significantly shorter with SRH-based diagnosis compared with frozen section (43 vs. 9.7 minutes, P < 0.0001). SRH was able to identify key features associated with varying glioma types. CONCLUSIONS: SRH allows for rapid intraoperative diagnosis without sacrificing diagnostic accuracy. SRH may serve as a promising adjuvant to conventional histopathology to expedite intraoperative pathology consultation and surgical decision-making.

Rapid Intraoperative Diagnosis of Meningiomas using Stimulated Raman Histology.

BACKGROUND: Frozen section is a time- and labor-intensive method for intraoperative pathologic diagnosis. As a result, there exists a need to expedite and streamline the acquisition and interpretation of diagnostic histologic data to inform surgical decision making. Stimulated Raman histology (SRH) is an emerging technology that may serve to expedite the acquisition and interpretation of histologic data in the operating room. METHODS: A blinded, prospective cohort study of 82 patients undergoing resection for tumors of the central nervous system was performed. Twenty-six patients with diagnoses of meningioma on SRH, frozen, or permanent section were included in this subanalysis. Diagnostic time and accuracy of stimulated SRH histology images were compared with the gold standard (frozen section). Agreement of SRH and frozen section diagnosis with permanent section (true) diagnosis was also compared. RESULTS: Mean time-to-diagnosis was significantly shorter for SRH-mediated diagnosis compared with frozen section (9.2 vs. 35.8, P < 0.0001). Diagnostic accuracy was not significantly different between methods (P = 0.15). Diagnostic agreement was not significantly different between SRH versus frozen, SRH versus permanent, or frozen versus permanent section methods (P = 0.5, P = 0.5, P = 1.00). CONCLUSIONS: SRH is a promising adjuvant technology that may expedite intraoperative neuropathologic consult without sacrificing diagnostic accuracy.

Defining the Extracellular Matrix of Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood with a propensity to metastasize. Current treatment for patients with RMS includes conventional systemic chemotherapy, radiation therapy, and surgical resection; nevertheless, little to no improvement in long term survival has been achieved in decades-underlining the need for target discovery and new therapeutic approaches to targeting tumor cells or the tumor microenvironment. To evaluate cross-species sarcoma extracellular matrix production, we have used murine models which feature knowledge of the myogenic cell-of-origin. With focus on the RMS/undifferentiated pleomorphic sarcoma (UPS) continuum, we have constructed tissue microarrays of 48 murine and four human sarcomas to analyze expression of seven different collagens, fibrillins, and collagen-modifying proteins, with cross-correlation to RNA deep sequencing. We have uncovered that RMS produces increased expression of type XVIII collagen alpha 1 (COL18A1), which is clinically associated with decreased long-term survival. We have also identified significantly increased RNA expression of COL4A1, FBN2, PLOD1, and PLOD2 in human RMS relative to normal skeletal muscle. These results complement recent studies investigating whether soft tissue sarcomas utilize collagens, fibrillins, and collagen-modifying enzymes to alter the structural integrity of surrounding host extracellular matrix/collagen quaternary structure resulting in improved ability to improve the ability to invade regionally and metastasize, for which therapeutic targeting is possible.

Granulomatous amoebic encephalitis caused by Acanthamoeba in a patient with AIDS: a challenging diagnosis.

INTRODUCTION: Acanthamoeba spp. is a ubiquitous free-living amoeba that causes human infections affecting predominantly the cornea and central nervous system. The diagnosis and treatment of Acanthamoeba encephalitis is very challenging. CASE SUMMARY: A 53-year-old male with HIV/AIDS was admitted for altered mental status and fever. On initial examination, he had left hemianopia with left-sided weakness and numbness. MRI revealed an inflammatory and enhancing parenchymal mass associated with leptomeningeal enhancement in the occipitoparietal lobe containing multiple punctate hemorrhages. He was treated with empiric antibiotics for presumptive toxoplasmosis, brain abscess, fungal infection and tuberculosis with an unremarkable lymphoma work up. Initial brain biopsy studies were unremarkable except for non-specific granulomas and adjacent necrotic tissue. The patient passed away 2.5 months after initial presentation with no diagnosis. Post-mortem testing by the Centers for Disease Control and Prevention (CDC) confirmed the diagnosis of granulomatous amoebic encephalitis (GAE) by visualization with immunohistochemistry staining and PCR. Recovery is rare from GAE likely due to delay in diagnosis. CONCLUSIONS: This case illustrates the importance of including GAE into the differential diagnosis of brain mass. We advocate early molecular testing of tissue specimen by the CDC to achieve an appropriate diagnosis, and a multidisciplinary approach for the management of this condition.

Ivosidenib, an IDH1 inhibitor, in a patient with recurrent, IDH1-mutant glioblastoma: a case report from a Phase I study.

Glioblastoma is the most common and aggressive primary brain tumor. Despite standard multimodality therapy, median overall survival remains poor with a 5-year survival rate of approximately 5% in most studies (range 4.7-13.0%). Strong interest in targeting IDH mutations has led to a variety of studies in both hematologic malignancies and solid tumors and to the approval of IDH inhibitors such as ivosidenib, an IDH1 inhibitor, in hematologic malignancies. Here, we present the first case study of a patient with a recurrent IDH1-mutant glioblastoma who experienced improved seizure control and radiographic stable disease for more than 4 years while treated with ivosidenib. Such findings support the further development of IDH inhibitors as single agents and/or in combination for the treatment of IDH-mutant glioma.

Stimulated Raman histology for rapid and accurate intraoperative diagnosis of CNS tumors: prospective blinded study.

OBJECTIVE: In some centers where brain tumor surgery is performed, the opportunity for expert intraoperative neuropathology consultation is lacking. Consequently, surgeons may not have access to the highest quality diagnostic histological data to inform surgical decision-making. Stimulated Raman histology (SRH) is a novel technology that allows for rapid acquisition of diagnostic histological images at the bedside. METHODS: The authors performed a prospective blinded cohort study of 82 consecutive patients undergoing resection of CNS tumors to compare diagnostic time and accuracy of SRH simulation to the gold standard, i.e., frozen and permanent section diagnosis. Diagnostic accuracy was determined by concordance of SRH-simulated intraoperative pathology consultation with a blinded board-certified neuropathologist, with official frozen section and permanent section results. RESULTS: Overall, the mean time to diagnosis was 30.5 ± 13.2 minutes faster (p < 0.0001) for SRH simulation than for frozen section, with similar diagnostic correlation: 91.5% (κ = 0.834, p < 0.0001) between SRH simulation and permanent section, and 91.5% between frozen and permanent section (κ = 0.894, p < 0.0001). CONCLUSIONS: SRH-simulated intraoperative pathology consultation was significantly faster and equally accurate as frozen section.

Brain microvascular pathology in Susac syndrome: an electron microscopic study of five cases.

Susac syndrome is a rare, immune-mediated disease characterized by encephalopathy, branch retinal artery occlusion, and hearing loss. Herein, we describe the electron microscopic findings of three brain biopsies and two brain autopsies performed on five patients whose working clinical diagnosis was Susac syndrome. In all five cases, the key findings were basement membrane thickening and collagen deposition in the perivascular space involving small vessels and leading to thickening of vessel walls, narrowing, and vascular occlusion. These findings indicate that Susac syndrome is a microvascular disease. Mononuclear cells were present in the perivascular space, underlining the inflammatory nature of the pathology. Though nonspecific, the changes can be distinguished from genetic and acquired small vessel diseases. The encephalopathy of Susac syndrome overlaps clinically with degenerative and infectious conditions, and brain biopsy may be used for its diagnosis. Its vascular etiology may not be obvious on light microscopy, and electron microscopy is important for its confirmation.

A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy.

Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy.

Enhancing nodular lesions in Chiari II malformations in the setting of persistent hindbrain herniation: case report and literature review.

BACKGROUND: Chiari II malformation includes concomitant cerebellar tonsillar herniation, hydrocephalus, and myelomeningocele. Rarely, pediatric patients with persistent hindbrain herniation develop a new enhancing nodule at the cervicomedullary junction as adults. These new lesions may be suspicious for neoplastic growth, but it remains unclear if neurosurgical intervention is necessary. CASE REPORT: A 27-year-old female patient with history of Chiari II malformation and persistent hindbrain herniation presented with a 3-month history of headache and upper extremity weakness and numbness. Neuroimaging revealed a new enhancing nodule near the cervicomedullary junction suspicious for neoplasm. Following posterior fossa decompression and excision of the enhancing lesion, pathological analysis demonstrated only benign glioneural heterotopia. RESULTS: New enhancing nodules at the cervicomedullary junction in Chiari II malformation are exceedingly rare and are likely benign, reactive changes rather than a neoplastic process. Biopsy or surgical excision of these lesions is likely unnecessary for asymptomatic patients.

Exogenous expression of the glycosyltransferase LARGE1 restores α-dystroglycan matriglycan and laminin binding in rhabdomyosarcoma.

BACKGROUND: α-Dystroglycan is the highly glycosylated component of the dystrophin-glycoprotein complex (DGC) that binds with high-affinity to extracellular matrix (ECM) proteins containing laminin-G-like (LG) domains via a unique heteropolysaccharide [-GlcA-beta1,3-Xyl-alpha1,3-]n called matriglycan. Changes in expression of components of the DGC or in the O-glycosylation of α-dystroglycan result in muscular dystrophy but are also observed in certain cancers. In mice, the loss of either of two DGC proteins, dystrophin or α-sarcoglycan, is associated with a high incidence of rhabdomyosarcoma (RMS). In addition, glycosylation of α-dystroglycan is aberrant in a small cohort of human patients with RMS. Since both the glycosylation of α-dystroglycan and its function as an ECM receptor require over 18 post-translational processing enzymes, we hypothesized that understanding its role in the pathogenesis of RMS requires a complete analysis of the expression of dystroglycan-modifying enzymes and the characterization of α-dystroglycan glycosylation in the context of RMS. METHODS: A series of cell lines and biopsy samples from human and mouse RMS were analyzed for the glycosylation status of α-dystroglycan and for expression of the genes encoding the responsible enzymes, in particular those required for the addition of matriglycan. Furthermore, the glycosyltransferase LARGE1 was ectopically expressed in RMS cells to determine its effects on matriglycan modifications and the ability of α-dystroglycan to function as a laminin receptor. RESULTS: Immunohistochemistry and immunoblotting of a collection of primary RMS tumors show that although α-dystroglycan is consistently expressed and glycosylated in these tumors, α-dystroglycan lacks matriglycan and the ability to bind laminin. Similarly, in a series of cell lines derived from human and mouse RMS, α-dystroglycan lacks matriglycan modification and the ability to bind laminin. RNAseq data from RMS cell lines was analyzed for expression of the genes known to be involved in α-dystroglycan glycosylation, which revealed that, for most cell lines, the lack of matriglycan can be attributed to the downregulation of the dystroglycan-modifying enzyme LARGE1. Ectopic expression of LARGE1 in these cell cultures restored matriglycan to levels comparable to those in muscle and restored high-affinity laminin binding to α-dystroglycan. CONCLUSIONS: Collectively, our findings demonstrate that a lack of matriglycan on α-dystroglycan is a common feature in RMS due to the downregulation of LARGE1, and that ectopic expression of LARGE1 can restore matriglycan modifications and the ability of α-dystroglycan to function as an ECM receptor.

PAX8 Expression Variability in Cerebellar Hemangioblastoma: Case Series and Review of the Literature.

Hemangioblastomas are benign tumors of undetermined origin, and account for up to 2.5% of all intracranial tumors. They may occur either sporadically or as a manifestation of von Hippel-Lindau (VHL) syndrome. Central nervous system (CNS) hemangioblastomas are pathologically diagnosed by gross and microscopic morphology, with further support of the diagnosis conferred by a characteristic immunohistochemistry profile including PAX8 negativity. Although renal hemangioblastomas have previously been reported to be PAX8 positive, CNS hemangioblastoma positive PAX8 expression has never been reported. We reviewed 11 cases of cerebellar hemangioblastoma from our institution over a 7-year period (2010 to 2017). Tissue was stained for PAX8 to determine immunohistochemical labeling. Of 11 reviewed cases of cerebellar hemangioblastoma, 7 exhibited PAX8 immunohistochemical expression. A review of the literature found no previously reported cases of positive PAX8 labeling in cerebellar hemangiomas. PAX8 negativity is not as specific for cerebellar hemangioblastoma as previously thought, and caution must be used when relying solely on a panel of PAX2, PAX8, and inhibin A for pathologic diagnosis.

Utility of Magnetic Resonance Perfusion Imaging in Quantifying Active Tumor Fraction and Radiation Necrosis in Recurrent Intracranial Tumors.

BACKGROUND: Ancillary criteria to identify tumor recurrence such as the McDonald criteria or Response Assessment in Neuro-Oncology criteria can provide false diagnoses. Magnetic resonance perfusion (MRP) imaging has been proposed to differentiate post-treatment changes from recurrence. We investigated the utility of MRP to quantify the histological fraction of active tumor (AT), treatment-related changes, and radiation necrosis in recurrent post-treatment intracranial tumors. METHODS: We conducted an exploratory single-blind study of patients with intracranial glioblastoma or metastases with previous radiation therapy and MRP before surgery. Biopsy specimens (n = 19) were analyzed for the percentage of AT, radiation necrosis, and treatment effect. Nonparametric Spearman's rho analysis and multivariable analysis of covariance were performed to assess the correlation between quantitative MRP and AT histological fraction. RESULTS: The mean patient age was 58 ± 11.5 years. The mean relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) were 1.33 ± 0.71 and 1.34 ± 0.73, respectively. On analysis of covariance, significant associations were identified between increased rCBF (P = 0.0004) and increased rCBV (P = 0.007) and percentage of AT. A significant interaction was identified between rCBF and rCBV and tumor histological features (glioblastoma vs. metastases; P = 0.003 and P = 0.03, respectively). An rCBF >1 predicted a mean AT fraction of ≥53% for all intracranial tumors and 74% for glioblastoma. CONCLUSION: MRP can help quantitatively predict tumor recurrence and/or progression for glioblastomas. The AT histological fraction correlated with quantitative radiologic measurements, including rCBV and rCBF. For metastases, MRP might not be as useful in predicting the AT fraction. Clinicians must be judicious with their use of MRP in predicting tumor recurrence and radiation necrosis.