MRI and PET of Brain Tumor Neuroinflammation in the Era of Immunotherapy, From the AJR Special Series on Inflammation.

With the emergence of immune-modulating therapies, brain tumors present important diagnostic imaging challenges. These challenges include planning personalized treatment and adjudicating accurate monitoring approaches and therapeutically specific response criteria. The challenges have been due, in part reliance on nonspecific imaging metrics, such as gadolinium contrast-enhanced MRI or FDG PET, and rapidly evolving biologic understanding of neuroinflammation. The importance of the tumor immune interaction and ability to therapeutically augment inflammation to improve clinical outcomes make it necessary for radiologists to develop a working knowledge of the immune system and its role in clinical neuroimaging. The purpose of this article is to review relevant biologic concepts of the tumor microenvironment of primary and metastatic brain tumors, the interactions between the tumors and the immune system, and MRI and PET methods for imaging inflammatory elements associated with these malignancies. In recognition of the growing fields of immunotherapeutics and precision oncology, clinically translatable imaging metrics for the diagnosis and monitoring of brain tumor neuroinflammation are highlighted. Practical guidance is provided for implementing iron nanoparticle imaging, including imaging indications, protocols, interpretation, and pitfalls. A comprehensive understanding of the inflammatory mechanisms within brain tumors and their imaging features will facilitate the development of innovative noninvasive prognostic and predictive imaging strategies for precision oncology.

Impact of maintenance rituximab on duration of response in primary central nervous system lymphoma.

PURPOSE: The role of maintenance immunotherapy with anti-CD20 monoclonal antibody rituximab in primary central nervous system lymphoma (PCNSL) is unclear. We retrospectively reviewed the medical records of all immunocompetent adults with newly diagnosed PCNSL treated at our institution between1996 and 2017. METHODS: We identified 66 patients who attained complete response (CR) after completion of first-line regimen; 20 received maintenance therapy (maintenance therapy group) and 46 were observed with serial MRI scans without maintenance therapy (no-maintenance therapy group). RESULTS: Compared to the surveillance group, there was a significant increase in duration of survival (HR 0.27, 95% CI 0.08-0.98, P = 0.046) in the maintenance therapy group while the reduction in the risk of progression was not significant (HR: 0.61, 95% CI 0.26-1.43, P = 0.259). CONCLUSION: We are evaluating the effectiveness of maintenance immunotherapy in PCNSL in a prospective multicenter randomized clinical trial.

Ferumoxytol-Enhanced MRI Is Not Inferior to Gadolinium-Enhanced MRI in Detecting Intracranial Metastatic Disease and Metastasis Size.

OBJECTIVE. The goal of this intraindividual comparison study was to investigate whether ferumoxytol-enhanced MRI is as effective as standard-of-care gadolinium-enhanced MRI in detecting intracranial metastatic disease. MATERIALS AND METHODS. We retrospectively reviewed all patients who underwent imaging as part of two ongoing ferumoxytol-enhanced and gadolinium-enhanced MRI protocol studies to compare the number and size of enhancing metastatic lesions. Two neuroradiologists independently measured enhancing metastases on ferumoxytol-enhanced MR images and on control gadolinium-enhanced MR images. The number and size of metastases were compared on an intraindividual basis. Primary diagnoses were recorded. A linear mixed-effects model was used to compare differences in cubic root of volume between gadolinium-enhanced and ferumoxytol-enhanced MRI. A signed rank test was used to evaluate differences between reviewers. RESULTS. MR images from 19 patients with brain metastases were analyzed (seven with lung cancer, three with breast cancer, three with melanoma, two with ovarian cancer, one with colon cancer, one with renal cell carcinoma, one with carcinoid tumor, and one with uterine cancer). Reviewer 1 identified 77 masses on ferumoxytol-enhanced MRI and 72 masses on gadolinium-enhanced MRI. Reviewer 2 identified 83 masses on ferumoxytol-enhanced MRI and 78 masses on gadolinium-enhanced MRI. For reviewer 1, ferumoxytol-enhanced MRI showed a mean tumor size measuring 1.1 mm larger in each plane compared with gadolinium-enhanced MRI (p = 0.1887). For reviewer 2, ferumoxytol-enhanced MRI showed a mean tumor size measuring 1.0 mm larger in each plane (p = 0.2892). No significant differences in number of metastases or tumor sizes were observed between contrast agents or reviewers. CONCLUSION. Intracranial metastatic disease detection with ferumoxytol-enhanced MRI was not inferior to detection with gadolinium-enhanced MRI. Ferumoxytol-enhanced MRI could improve workup and monitoring of patients with brain metastases if gadolinium-enhanced MRI is contraindicated.

Quantitative comparison of delayed ferumoxytol T1 enhancement with immediate gadoteridol enhancement in high grade gliomas.

PURPOSE: Delayed ferumoxytol enhancement on T1 -weighted images appears visually similar to gadoteridol enhancement. The purpose of this study was to quantitatively compare ferumoxytol T1 enhancement to gadoteridol enhancement with an objective, semi-automated method. METHODS: 206 sets of post-gadoteridol and 24 h post-ferumoxytol T1 -weighted scans from 58 high grade glioma patients were analyzed (9 pre-chemoradiation, 111 < 90 days post-chemoradiation, 21 > 90 days post-chemoradiation, 65 post-bevacizumab scans). Enhancement volumes and signal intensities normalized to normal appearing tissue proximal to enhancement were calculated with a semi-automated method. Enhancement cube root volumes (D) and signal intensities (SI) were compared between the 2 contrast agents, and relative difference of D and SI were compared in different treatment groups with multivariate analysis. Within patient differences in D and SI before and after treatment with bevacizumab or steroid were assessed in 26 patients in each treatment group. RESULTS: When compared to gadoteridol, ferumoxytol D was 13.83% smaller and SI was 7.24% lower (P < 0.0001). The relative differences in D and SI between the 2 contrast agents were not significantly different between treatment groups (P > 0.05). Relative difference in D and SI did not change significantly in response to bevacizumab (P = 0.5234 and P = 0.2442, respectively) or to steroid (P = 0.3774, P = 0.0741) in the within patient comparison. CONCLUSION: The correlation between the 2 contrast agents' enhancement size and signal intensity and their similar behavior in response to therapy suggest that ferumoxytol can be used for revealing enhancement in high grade glioma patients. Magn Reson Med 80:224-230, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Current and potential imaging applications of ferumoxytol for magnetic resonance imaging.

Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phase and delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material.

Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas.

Radiation (RT), temozolomide (TMZ), and dexamethasone in newly diagnosed high grade gliomas (HGG) produces severe treatment-related lymphopenia (TRL) that is associated with early cancer-related deaths. This TRL may result from inadvertent radiation to circulating lymphocytes. This study reinfused lymphocytes, harvested before chemo-radiation, and assessed safety, feasibility, and trends in lymphocyte counts. Patients with newly diagnosed HGG and total lymphocyte counts (TLC) ≥ 1000 cells/mm(3) underwent apheresis. Cryopreserved autologous lymphocytes were reinfused once radiation was completed. Safety, feasibility, and trends in TLC, T cell subsets and cytokines were studied. Serial TLC were also compared with an unreinfused matched control group. Ten patients were harvested (median values: age 56 years, dexamethasone 3 mg/day, TLC/CD4 1980/772 cells/mm(3)). After 6 weeks of RT/TMZ, TLC fell 69 % (p < 0.0001) with similar reductions in CD4, CD8 and NK cells but not Tregs. Eight patients received lymphocyte reinfusions (median = 7.0 × 10(7) lymphocytes/kg) without adverse events. A post-reinfusion TLC rise of ≥300 cells/mm(3) was noted in 3/8 patients at 4 weeks and 7/8 at 14 weeks which was similar to 23 matched controls. The reduced CD4/CD8 ratio was not restored by lymphocyte reinfusion. Severe lymphopenia was not accompanied by elevated serum interleukin-7 (IL-7) levels. This study confirms that severe TRL is common in HGG and is not associated with high plasma IL-7 levels. Although lymphocyte harvesting/reinfusion is feasible and safe, serial lymphocyte counts are similar to unreinfused matched controls. Studies administering higher lymphocyte doses and/or IL-7 should be considered to restore severe treatment-related lymphopenia in HGG.

Comparison of dynamic susceptibility contrast (DSC) using gadolinium and iron-based contrast agents in high-grade glioma at high-field MRI.

PURPOSE: To compare DSC-MRI using Gadolinium (GBCA) and Ferumoxytol (FBCA) in high-grade glioma at 3T and 7T MRI field strengths. We hypothesized that using FBCA at 7T would enhance the performance of DSC, as measured by contrast-to-noise ratio (CNR). METHODS: Ten patients (13 lesions) were assigned to 3T (6 patients, 6 lesions) or 7T (4 patients, 7 lesions). All lesions received 0.1 mmol/kg of GBCA on day 1. Ten lesions (4 at 3T and 6 at 7T) received a lower dose (0.6 mg/kg) of FBCA, followed by a higher dose (1.0-1.2 mg/kg), while 3 lesions (2 at 3T and 1 at 7T) received only a higher dose on Day 2. CBV maps with leakage correction for GBCA but not for FBCA were generated. The CNR and normalized CBV (nCBV) were analyzed on enhancing and non-enhancing high T2W lesions. RESULTS: Regardless of FBCA dose, GBCA showed higher CNR than FBCA at 7T, which was significant for high-dose FBCA (p < .05). Comparable CNR between GBCA and high-dose FBCA was observed at 3T. There was a trend toward higher CNR for FBCA at 3T than 7T. GBCA also showed nCBV twice that of FBCA at both MRI field strengths with significance at 7T. CONCLUSION: GBCA demonstrated higher image conspicuity, as measured by CNR, than FBCA on 7T. The stronger T2* weighting realized with higher magnetic field strength, combined with FBCA, likely results in more signal loss rather than enhanced performance on DSC. However, at clinical 3T, both GBCA and FBCA, particularly a dosage of 1.0-1.2 mg/kg (optimal for perfusion imaging), yielded comparable CNR.

Mismatch repair-deficient glioma with spatially distinct IDH-mutant and IDH-wild type components arising in the setting of Lynch syndrome.

Pathogenic mutations in MLH1, MSH2, PMS2, and MSH6 compromise DNA mismatch repair mechanisms and in the heterozygous state result in Lynch syndrome, which is typified by a predisposition to endometrial, ovarian, colorectal, gastric, breast, hematologic, and soft tissue cancers. Rarely, germline pathogenic aberrations in these genes are associated with the development of primary central nervous system tumors. We present a report of an adult female with no prior cancer history who presented with a multicentric, infiltrative supratentorial glioma involving both the left anterior temporal horn and left precentral gyrus. Surgical treatment and neuropathological/molecular evaluation of these lesions revealed discordant isocitrate dehydrogenase (IDH) status and histologic grade at these spatially distinct disease sites. A frameshift alteration within the MLH1 gene (p.R217fs*12, c.648delT) was identified in both lesions and subsequently identified in germline testing of a blood sample, consistent with Lynch syndrome. Despite distinct histopathologic features and divergent IDH status of the patient's tumors, the molecular findings suggest that both sites of intracranial neoplasia may have developed as a consequence of underlying monoallelic germline mismatch repair deficiency. This case illustrates the importance of characterizing the genetic profile of multicentric gliomas and highlights the oncogenic potential of germline mismatch repair gene pathogenic alterations within central nervous system gliomas.

Deciphering spatially distinct immune microenvironments in glioblastoma using ferumoxytol and gadolinium-enhanced and FLAIR hyperintense MRI phenotypes.

Background: MRI with gadolinium (Gd)-contrast agents is used to assess glioblastoma treatment response but does not specifically reveal heterogeneous biology or immune microenvironmental composition. Ferumoxytol (Fe) contrast is an iron nanoparticle that localizes glioblastoma macrophages and microglia. Therefore, we hypothesized that the use of Fe contrast improves upon standard Gd-based T1-weighted and T2/FLAIR analysis by specifically delineating immune processes. Methods: In this, HIPAA-compliant institutional review board-approved prospective study, stereotactic biopsy samples were acquired from patients with treatment-naïve and recurrent glioblastoma based on MR imaging phenotypes; Gd and Fe T1 enhancement (Gd+, Fe+) or not (Gd-, Fe-), as well as T2-Flair hyperintensity (FLAIR+, FLAIR-). Analysis of genetic expression was performed with RNA microarrays. Imaging and genomic expression patterns were compared using false discovery rate statistics. Results: MR imaging phenotypes defined a variety of immune pathways and Hallmark gene sets. Gene set enrichment analysis demonstrated that Gd+, Fe+, and FLAIR+ features were individually correlated with the same 7 immune process gene sets. Fe+ tissue showed the greatest degree of immune Hallmark gene sets compared to Gd+ or Flair+ tissues and had statistically elevated M2 polarized macrophages, among others. Importantly, the FLAIR+ Gd+ and Fe- imaging phenotypes did not demonstrate expression of immune Hallmark gene sets. Conclusions: Our study demonstrates the potential of Fe and Gd-enhanced MRI phenotypes to reveal spatially distinct immune processes within glioblastoma. Fe improves upon the standard of care Gd enhancement by specifically localizing glioblastoma-associated inflammatory processes, providing valuable insights into tumor biology.

The IDH1 inhibitor ivosidenib improved seizures in a patient with drug-resistant epilepsy from IDH1 mutant oligodendroglioma.

Compared to high grade gliomas, low grade gliomas such as oligodendrogliomas are often more epileptogenic. Epilepsy develops in 70-90% of patients with oligodendrogliomas and 40% of these are resistant to anti-seizure medications and surgery [3]. IDH1/2 mutation is one defining feature of oligodendrogliomas and confers improved prognosis when found in astrocytomas [7]. One possible etiology of the high rate of epileptogenicity in oligodendrogliomas is D-2-Hydroxyglutarate (D2HG), an oncometabolite seen in IDH mutation [8]. D2HG can mimic the effect of glutamate at the NMDA receptor and increase the seizure risk [11]. In this case report, we present a patient with drug resistant focal epilepsy from IDH1 mutant oligodendroglioma with markedly improved seizure frequency after starting Ivosidenib, an IDH1 inhibitor, in the absence of any changes to traditional anti-seizure medications. Our case suggests the possibility that IDH1 inhibitors may help reduce seizure burden in patients with difficult to control epilepsy from IDH1 mutant oligodendrogliomas. This is significant because we show that a targeted cancer therapy is able to improve seizure frequency through a unique pathway, and suggests that research into similar targeted, precision medicine therapies in brain lesions associated with epilepsy may be beneficial.

Advances in Intraarterial Chemotherapy Delivery Strategies and Blood-Brain Barrier Disruption.

Chemotherapeutics play a significant role in the management of most brain tumors. First pass effect, systemic toxicity, and more importantly, the blood-brain barrier pose significant challenges to the success of chemotherapy. Over the last 80 years, different techniques of intraarterial chemotherapy delivery have been performed in many studies but failed to become standard of care. The purpose of this article is to review the history of intraarterial drug delivery and osmotic blood-brain barrier disruption, identify the challenges for clinical translation, and identify future directions for these approaches.

Diagnostic performance of DSC perfusion MRI to distinguish tumor progression and treatment-related changes: a systematic review and meta-analysis.

Background: In patients with high-grade glioma (HGG), true disease progression and treatment-related changes often appear similar on magnetic resonance imaging (MRI), making it challenging to evaluate therapeutic response. Dynamic susceptibility contrast (DSC) MRI has been extensively studied to differentiate between disease progression and treatment-related changes. This systematic review evaluated and synthesized the evidence for using DSC MRI to distinguish true progression from treatment-related changes. Methods: We searched Ovid MEDLINE and the Ovid MEDLINE in-process file (January 2005-October 2019) and the reference lists. Studies on test performance of DSC MRI using relative cerebral blood volume in HGG patients were included. One investigator abstracted data, and a second investigator confirmed them; two investigators independently assessed study quality. Meta-analyses were conducted to quantitatively synthesize area under the receiver operating curve (AUROC), sensitivity, and specificity. Results: We screened 1177 citations and included 28 studies with 638 patients with true tumor progression, and 430 patients with treatment-related changes. Nineteen studies reported AUROC and the combined AUROC is 0.85 (95% CI, 0.81-0.90). All studies contributed data for sensitivity and specificity, and the pooled sensitivity and specificity are 0.84 (95% CI, 0.80-0.88), and 0.78 (95% CI, 0.72-0.83). Extensive subgroup analyses based on study, treatment, and imaging characteristics generally showed similar results. Conclusions: There is moderate strength of evidence that relative cerebral blood volume obtained from DSC imaging demonstrated "excellent" ability to discriminate true tumor progression from treatment-related changes, with robust sensitivity and specificity.

[18F]-fluoromisonidazole (FMISO) PET/MRI hypoxic fraction distinguishes neuroinflammatory pseudoprogression from recurrent glioblastoma in patients treated with pembrolizumab.

Response assessment after immunotherapy remains a major challenge in glioblastoma due to an expected increased incidence of pseudoprogression. Gadolinium-enhanced magnetic resonance imaging (MRI) is the standard for monitoring therapeutic response, however, is markedly limited in characterizing pseudoprogression. Given that hypoxia is an important defining feature of glioblastoma regrowth, we hypothesized that [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) could provide an additional physiological measure for the diagnosis of immunotherapeutic failure. Six patients with newly diagnosed glioblastoma who had previously received maximal safe resection followed by Stupp protocol CRT concurrent with pembrolizumab immunotherapy were recruited for FMISO PET and Gd-MRI at the time of presumed progression. The hypoxic fraction was defined as the ratio of hypoxic volume to T1-weighted gadolinium-enhancing volume. Four patients diagnosed with pseudoprogression demonstrated a mean hypoxic fraction of 9.8 ±â€…10%. Two with recurrent tumor demonstrated a mean hypoxic fraction of 131 ±â€…66%. Our results, supported by histopathology, suggest that the noninvasive assessment of hypoxic fraction by FMISO PET/MRI is clinically feasible and may serve as a biologically specific metric of therapeutic failure.

Radiation enhances the delivery of antisense oligonucleotides and improves chemo-radiation efficacy in brain tumor xenografts.

Overexpression of O6-methylguanine DNA methyltransferase (MGMT) contributes to resistance to chemo-radiation therapy (CRT) in brain tumors. We previously demonstrated that non-ablative radiation improved delivery of anti-MGMT morpholino oligonucleotides (AMONs) to reduce MGMT levels in subcutaneous tumor xenografts. We evaluate this approach to enhance CRT efficacy in rat brain tumor xenograft models. The impact of radiation on targeted delivery was evaluated using fluorescent oligonucleotides (f-ON). In vitro, f-ON was localized to clathrin-coated vesicles, endosomes, and lysosomes using confocal microscopy in T98G glioma cells. In vivo, fluorescence was detected in pre-radiated, but not non-radiated Long Evans (non-tumor bearing) rat brains. Cranial radiation (2 Gy) followed by AMONs (intravenous, 10.5 mg/kg) reduced MGMT expression by 50% in both orthotopic cerebellar D283 medulloblastoma and intracerebral H460 non-small cell lung carcinoma (NSCLC) xenograft models. To evaluate the efficacy, AMONs concurrent with CRT (2 Gy radiation plus oral 20 mg/kg temozolomide ×4 days) reduced tumor volumes in the medulloblastoma model (p = 0.012), and a similar trend was found in the NSCLC brain metastasis model. We provide proof of concept for the use of non-ablative radiation to guide and enhance the delivery of morpholino oligonucleotides into brain tumor xenograft models to reduce MGMT levels and improve CRT efficacy.

Safety of intra-arterial chemotherapy with or without osmotic blood-brain barrier disruption for the treatment of patients with brain tumors.

Background: Intra-arterial administration of chemotherapy with or without osmotic blood-brain barrier disruption enhances delivery of therapeutic agents to brain tumors. The aim of this study is to evaluate the safety of these procedures. Methods: Retrospectively collected data from a prospective database of consecutive patients with primary and metastatic brain tumors who received intra-arterial chemotherapy without osmotic blood-brain barrier disruption (IA) or intra-arterial chemotherapy with osmotic blood-brain barrier disruption (IA/OBBBD) at Oregon Health and Science University (OHSU) between December 1997 and November 2018 is reported. Chemotherapy-related complications are detailed per Common Terminology Criteria for Adverse Events (CTCAE) guidelines. Procedure-related complications are grouped as major and minor. Results: 4939 procedures (1102 IA; 3837 IA/OBBBD) were performed on 436 patients with various pathologies (primary central nervous system lymphoma [26.4%], glioblastoma [18.1%], and oligodendroglioma [14.7%]). Major procedure-related complications (IA: 12, 1%; IA/OBBBD: 27, 0.7%; P = .292) occurred in 39 procedures including 3 arterial dissections requiring intervention, 21 symptomatic strokes, 3 myocardial infarctions, 6 cervical cord injuries, and 6 deaths within 3 days. Minor procedure-related complications occurred in 330 procedures (IA: 41, 3.7%; IA/OBBBD: 289, 7.5%; P = .001). Chemotherapy-related complications with a CTCAE attribution and grade higher than 3 was seen in 359 (82.3%) patients. Conclusions: We provide safety and tolerability data from the largest cohort of consecutive patients who received IA or IA/OBBBD. Our data demonstrate that IA or IA/OBBBD safely enhance drug delivery to brain tumors and brain around the tumor.

Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice.

Despite recent therapeutic progress and improved survival for many patients with primary central nervous system lymphoma (PCNSL), up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens. The majority of such events occur within 2 years of diagnosis although, unlike their systemic counterpart, the risk of PCNSL relapse remains, even for patients in radiologic complete response at 10 years following diagnosis. Currently, there are no approved therapies, and no widely accepted 'standard-of-care' approaches for the treatment of refractory or recurrent primary central nervous system lymphoma (rrPCNSL). Re-treatment with HD-MTX based regimens, use of non-cross resistant chemotherapy regimens, high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), and brain irradiation all remain important therapeutic approaches for rrPCNSL. However, the survival outcomes for patients with rrPCNSL remain extremely poor and the vast majority of patients will die of their disease. Increasingly, novel treatment approaches are being investigated in early phase clinical studies. Importantly, such therapies need to be evaluated in the context of both refractory and relapsed disease; in older patients and those with co-morbid conditions; and those with neurocognitive dysfunction. A deeper understanding of the molecular genetic mechanisms underpinning rrPCNSL and its unique tumor microenvironment is urgently needed to inform biologically rational and effective therapies. rrPCNSL remains a clear unmet clinical need and a high priority area for clinical research that will require national and international collaborative studies with embedded translational science in order to improve outcomes for patients.

Primary central nervous system lymphoma: a narrative review of ongoing clinical trials and goals for future studies.

Primary central nervous system lymphoma (PCNSL) is a rare disease of the brain, spine, cerebrospinal fluid (CSF) and/or vitreoretinal space. PCNSL is chemo and radiosensitive but relapse is common even years after initial treatment. Outside of consensus regarding the use of high-dose methotrexate (HD-MTX) for first line treatment, there is little uniformity in the management of newly diagnosed or relapsed PCNSL. The lack of consensus is driven by a paucity of randomized trials in this disease. Prospective studies are troubled by low enrollment, the lack of a standard induction regimen, and a varied approach to consolidation strategies. Moreover, the PCNSL patient population is heterogeneous and includes a high proportion of elderly or frail patients and consists of patients manifesting disease in varied compartments of the central nervous system (CNS). As a result, current treatment strategies vary widely and are often dictated by physician and institutional preference or regional practice. This review provides an overview of recently completed and ongoing therapeutic studies for patients with newly diagnosed and recurrent or refractory PCNSL. It discusses the existing evidence behind common approaches to induction and consolidation or maintenance regimens as well as the recent data regarding management of recurrent disease. Finally, it highlights the complexity of trial design in this disease and provides a framework for the design of future studies, which are needed to identify patient populations likely to benefit from specific induction, consolidation, or maintenance therapies.

Primary central nervous system lymphoma: advances in MRI and PET imaging.

Contrast enhanced magnetic resonance imaging (CE-MRI) remains the imaging modality of choice for initial workup, staging, and response assessment after therapy in patients with primary central nervous system lymphoma (PCNSL). While CE-MRI is a sensitive test to detect blood brain barrier (BBB) dysfunction, it does not biologically represent the true tumor burden. Current response assessment criteria relies heavily on two dimensional anatomical measurements on post contrast T1-weighted (T1W) images, as well as pre-contrast T2-weighted (T2W) imaging. Additional MRI features, such as diffusion-weighted imaging (DWI) and perfusion weighted imaging, can be routinely obtained at most centers with MRI capabilities. Emerging evidence supports the incorporation of these data to better define tumor physiology and provide additional valuable clinical tools capable of identifying high risk subgroups as well as early predictors of response to therapies. Further, novel advanced molecular and pathophysiologic characterization of PCNSL provides insights into promising targeted therapeutic approaches. However, significant institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability, reproducibility and eventual translation in day to day management of patients with PCNSL. Here we review established neuroimaging concepts and provide an overview of published literature about novel imaging techniques that may improve diagnosis and response assessments. Finally, we highlight the need for standardization of image acquisition, post-processing, and incorporation of novel imaging biomarkers in early phase PCNSL clinical trials.