Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma.

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

Disease-Based Prognostication: Neuro-Oncology.

Primary malignant and non-malignant brain and other central nervous system (CNS) tumors, while relatively rare, are a disproportionate source of morbidity and mortality. Here we provide a brief overview of approaches to modeling important clinical outcomes, such as overall survival, that are critical for clinical care. Because there are a large number of histologically distinct types of primary malignant and non-malignant brain and other CNS tumors, this chapter will provide an overview of prognostication considerations on the most common primary non-malignant brain tumor, meningioma, and the most common primary malignant brain tumor, glioblastoma. In addition, information on nomograms and how they can be used as individualized prognostication tools by clinicians to counsel patients and their families regarding treatment, follow-up, and prognosis is described. The current state of nomograms for meningiomas and glioblastomas are also provided.

tRNA Function and Dysregulation in Cancer.

Transfer RNA (tRNA) is a central component of protein synthesis and plays important roles in epigenetic regulation of gene expression in tumors. tRNAs are also involved in many cell processes including cell proliferation, cell signaling pathways and stress response, implicating a role in tumorigenesis and cancer progression. The complex role of tRNA in cell regulation implies that an understanding of tRNA function and dysregulation can be used to develop treatments for many cancers including breast cancer, colon cancer, and glioblastoma. Moreover, tRNA modifications including methylation are necessary for tRNA folding, stability, and function. In response to certain stress conditions, tRNAs can be cleaved in half to form tiRNAs, or even shorter tRNA fragments (tRF). tRNA structure and modifications, tiRNA induction of stress granule formation, and tRF regulation of gene expression through the repression of translation can all impact a cell's fate. This review focuses on how these functions of tRNAs, tiRNA, and tRFs can lead to tumor development and progression. Further studies focusing on the specific pathways of tRNA regulation could help identify tRNA biomarkers and therapeutic targets, which might prevent and treat cancers.

Managing cancer and living meaningfully (CALM) in adults with malignant glioma: a proof-of-concept phase IIa trial.

BACKGROUND: Managing Cancer and Living Meaningfully (CALM) is an evidence-based, brief, semi-structured psychotherapy designed to help patients with advanced cancer cope with the practical and profound challenges of their illness. However, no study to date has investigated its feasibility, acceptability, and preliminary effectiveness in adults with malignant glioma, despite the well-documented incidence of psychological distress in this vulnerable and underserved population. METHODS: Fourteen patients with glioma and elevated symptoms of depression and/or death anxiety enrolled in the trial: 83% glioblastoma, 75% female, Mage = 56 years (SD = 15.1; range = 27-81). Feasibility was assessed based on established metrics. Acceptability was measured by post-session surveys and post-intervention interviews. Preliminary intervention effects were explored using paired t-tests, comparing psychological distress at baseline and post-intervention. RESULTS: Of the 14 enrolled patients, 12 were evaluable. Nine completed the study (75% retention rate). Three patients withdrew due to substantial disease progression which affected their ability to participate. Participants reported high perceived benefit, and all recommended the program to others. Baseline to post-intervention assessments indicated reductions in death anxiety, generalized anxiety, and depression, and increases in spirituality. Quality of life and fear of cancer recurrence remained stable throughout the study period. CONCLUSIONS: CALM appears feasible for use with adults with malignant glioma. Enrollment and retention rates were high and comparable to psychotherapy trials for patients with advanced cancer. High perceived benefit and reductions in symptoms of death anxiety, generalized anxiety, and depression were reported by participants. These findings are extremely encouraging and support further study of CALM in neuro-oncology. TRIAL REGISTRATION NUMBER: NCT04646213 registered on 11/27/2020.

Working memory training for adult glioma patients: a proof-of-concept study.

BACKGROUND: CogMed Working Memory Training (CWMT) is a computer-based program shown to improve working memory (WM) among those with cognitive impairments. No study to date has investigated its feasibility, acceptability, and satisfaction in adult patients with glioma, despite the well-documented incidence of WM impairment in this population. METHODS: Twenty patients with glioma and objective and/or perceived WM deficits enrolled in the study: 52% high-grade, 60% female, Mage = 47 (range = 21-72 years). Adverse events were monitored to determine safety. Feasibility and acceptability were assessed based on established metrics. Satisfaction was explored by exit-interviews. Neurocognitive tests and psychological symptoms were analyzed at baseline and post-CWMT to estimate effect sizes. RESULTS: Of 20 enrolled patients, 16 completed the intervention (80% retention rate). Reasons for withdrawal included time burden (n = 2); tumor-related fatigue (n = 1) or loss to follow-up (n = 1). No adverse events were determined to be study-related. Adherence was 69% with reasons for nonadherence similar to those for study withdrawal. The perceived degree of benefit was only moderate. Baseline to post-CWMT assessments showed medium to large effects on neurocognitive tasks. Psychological symptoms remained stable throughout the study period. CONCLUSIONS: CWMT was found to be safe and acceptable in adult patients with glioma. Enrollment, retention rates, and treatment adherence were all adequate and comparable to studies recruiting similar populations. Only moderate perceived benefit was reported despite demonstrated improvements in objectively-assessed WM. This may indicate that the time commitment and intervention intensity (5 weeks of 50-min training sessions on 5 days/week) outweighed the perceived benefits of the program. (Trial Registration Number: NCT03323450 registered on 10/27/2017).

Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma.

BACKGROUND: Dimethyl fumarate (DMF), an oral agent approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), has promising preclinical activity against glioblastoma (GBM). This phase I study sought to determine the recommended phase 2 dose (RP2D) of DMF and evaluate its safety and toxicity when combined with standard concurrent radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ in patients with newly diagnosed GBM. METHODS: Using a standard 3 + 3 dose-escalation design with 3 dose levels, patients received daily DMF with 60 Gy RT and concurrent TMZ 75 mg/m2 daily, followed by maintenance DMF (continuously) and TMZ 150-200 mg/m2 on days 1-5 of each 28-day cycle for up to 6 cycles. The maximum tolerated dose (MTD) was determined by evaluation of dose-limiting toxicity (DLT) during the first 6 weeks of therapy. RESULTS: Twelve patients were treated at the 3 dose levels, and no DLTs were observed. There were no unexpected toxicities. The most common grade 3/4 treatment related adverse events (AEs) were lymphopenia (58%), decreased CD4 count (17%), and thrombocytopenia (17%). Four patients completed all planned treatment; seven patients had progression on treatment. One patient chose to withdraw from the study during maintenance. The median progression-free survival (PFS) for all patients was 8.7 months with no difference in PFS between those with stable disease or a partial response; median overall survival was 13.8 months. CONCLUSIONS: DMF may be safely combined with RT and TMZ in patients with newly diagnosed GBM. The RP2D for DMF is 240 mg three times daily.

Treatment of Primary Central Nervous System Posttransplant Lymphoproliferative Disorder in an Adult Kidney Transplant Recipient: A Case Report.

Posttransplant lymphoproliferative disorder is a serious complication of solid-organ transplant. Extranodal involvement is common; however, isolated involvement of the central nervous system is extremely rare and represents a particularly difficult therapeutic challenge with no current consensus on optimal treatment. Here, we describe a 70-year-old woman who developed Epstein-Barr virus-related primary central nervous system lymphoma 19 months after kidney transplant. Immunosuppression was reduced, and the patient was started on high-dose methotrexate, which was complicated by acute kidney injury and discontinued. She then received a rituximab and temozolomide chemotherapeutic regimen and achieved complete clinical response. Seventeen months after diagnosis, she is alive and has not developed any other posttransplant lymphoproliferative disorder. We review the current literature and discuss treatment options for patients with primary central nervous system posttransplant lymphoproliferative disorder following kidney transplant.

Autologous Stem-Cell Transplantation for Primary Central Nervous System Lymphoma: Systematic Review and Meta-analysis.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is an aggressive form of non-Hodgkin lymphoma. Methotrexate is first-line chemotherapy. Autologous stem-cell transplantation (ASCT) is increasingly used as an alternative consolidative treatment to whole-brain radiotherapy. METHODS: A systematic search of several databases was conducted up through January 10, 2018. Two investigators independently assessed study eligibility and extracted the data. Studies that reported survival outcomes after ASCT were included. RESULTS: We screened 1517 references and included 43 studies. ASCT was used as consolidative treatment or as salvage treatment/at relapse. Thiotepa, busulfan, and cyclophosphamide and carmustine/thiotepa were commonly used conditioning regimens. In the consolidation setting, 94% of patients experienced or maintained complete or partial response after ASCT. The rates of overall survival (OS) and progression-free survival (PFS) were 94%, 86%, 82%, and 70% and 79%, 70%, 64%, and 54% after 1, 2, 3, and 5 years, respectively. The overall risk of relapse at 5 years was 24%. In the salvage/relapse settings, 85% of patients experienced or maintained complete response or partial response after ASCT. The rates of OS and PFS were 75%, 63%, 56%, and 54% and 85%, 62%, 59%, and 54% after 1, 2, 3, and 5 years, respectively. The risk of relapse at 5 years was 29%. Subgroup analysis showed that the use of carmustine and thiotepa as a conditioning regimen carried the lowest risk of transplant-related mortality. The thiotepa, busulfan, and cyclophosphamide regimen, on the other hand, showed numerically superior OS and PFS rates. CONCLUSION: This review provides estimates for response and survival to aid in decision making when considering ASCT for patients with PCNSL.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review and Neuropsychological Case Study.

OBJECTIVE: Anti-N-Methyl-d-Aspartate Receptor (NMDAR) Encephalitis is an autoimmune-mediated encephalitis, which may be associated with a tumor, which occurs when antibodies bind central NMDA receptors. Although typically diagnosed in women, approximately 20% of cases have been males. Due to the challenges with identification, imaging, and diverse symptom presentation, this syndrome is often misdiagnosed. Accurate diagnosis may provide an opportunity for introduction of disease-modifying therapies, which may alter disease trajectory. Moreover, neuropsychology has yet to fully clarify the pattern of impairments expected with this disorder. METHODS: This manuscript reviews a single case study of a 42-year-old male diagnosed with NMDAR encephalitis. Neuropsychological evaluation was completed subsequent to diagnosis, treatment, and rehabilitation. Ongoing patient complaints, approximately six months post diagnosis, included reduced sustained attention, poor word retrieval, and daily forgetfulness. Adaptive skills were improved following rehabilitation. RESULTS: Direct testing revealed mildly impaired sustained attention, processing speed, oral word fluency, and executive functioning. All other cognitive domains were within estimated premorbid range, low average to average. CONCLUSIONS: Neuropsychological deficits were consistent with mild frontal brain dysfunction and continued recovery. This case illustrates the need for medical and psychological practitioners to understand NMDAR encephalitis, its symptom presentation, and related neuropsychological impact; particularly with the potential for misdiagnosis.

The use of plasma exchange in Hashimoto's encephalopathy: A case report and review of the literature.

Hashimoto's Encephalopathy (HE) is a very rare condition characterized by psychosis, seizures, cognitive fluctuations, and myoclonus. In a few published cases, plasma exchange has been used due to the theoretical removal of antithyroid peroxidase antibodies (anti-TPO), one of the postulated causes of the condition. We report a case of HE treated by plasma exchange where no clinical or neurophysiologic improvement was observed despite documented reduction of the anti-TPO antibody to levels below the limits of laboratory detection. We discuss these findings in the context of the known literature for this disease process.

Precise ex vivo histological validation of heightened cellularity and diffusion-restricted necrosis in regions of dark apparent diffusion coefficient in 7 cases of high-grade glioma.

BACKGROUND: Recent conflicting reports have found both brain tumor hypercellularity and necrosis in regions of restricted diffusion on MRI-derived apparent diffusion coefficient (ADC) images. This study precisely compares ADC and cell density voxel by voxel using postmortem human whole brain samples. METHODS: Patients with meningioma were evaluated to determine a normative ADC distribution within benign fluid attenuated inversion recovery (FLAIR) T2/hyperintensity surrounding tumor. This distribution was used to calculate a minimum ADC threshold to define regions of ADC-FLAIR mismatch (AFMM), where restricted diffusion presented in conjunction with T2/FLAIR hyperintensity. Contrast-enhancing voxels were excluded from this analysis. AFMM maps were generated using imaging acquired prior to death in 7 patients with high-grade glioma who eventually donated their brains upon death. Histological samples were taken from numerous regions of abnormal FLAIR and AFMM. Each sample was computationally processed to determine cell density. Custom software was then used to downsample coregistered microscopic histology to the more coarse MRI resolution. A voxel-by-voxel evaluation comparing ADC and cellularity was then performed. RESULTS: An ADC threshold of 0.929 × 10(-3) mm(2)/s was calculated from meningioma-induced edema and was used to define AFMM. Regions of AFMM showed significantly greater cell density in 6 of 7 high-grade glioma cases compared with regions of hyperintense FLAIR alone (P < .0001). Two patients had small regions of diffusion-restricted necrosis that had significantly lower ADC than nearby hypercellularity. CONCLUSIONS: Regions of AFMM contain hypercellularity except for regions with extremely restricted diffusion, where necrosis is present.

Comprehensive characterization of glioblastoma tumor tissues for biomarker identification using mass spectrometry-based label-free quantitative proteomics.

Cancer is a complex disease; glioblastoma (GBM) is no exception. Short survival, poor prognosis, and very limited treatment options make it imperative to unravel the disease pathophysiology. The critically important identification of proteins that mediate various cellular events during disease is made possible with advancements in mass spectrometry (MS)-based proteomics. The objective of our study is to identify and characterize proteins that are differentially expressed in GBM to better understand their interactions and functions that lead to the disease condition. Further identification of upstream regulators will provide new potential therapeutic targets. We analyzed GBM tumors by SDS-PAGE fractionation with internal DNA markers followed by liquid chromatography-tandem mass spectrometry (MS). Brain tissue specimens obtained for clinical purposes during epilepsy surgeries were used as controls, and the quantification of MS data was performed by label-free spectral counting. The differentially expressed proteins were further characterized by Ingenuity Pathway Analysis (IPA) to identify protein interactions, functions, and upstream regulators. Our study identified several important proteins that are involved in GBM progression. The IPA revealed glioma activation with z score 2.236 during unbiased core analysis. Upstream regulators STAT3 and SP1 were activated and CTNNα was inhibited. We verified overexpression of several proteins by immunoblot to complement the MS data. This work represents an important step towards the identification of GBM biomarkers, which could open avenues to identify therapeutic targets for better treatment of GBM patients. The workflow developed represents a powerful and efficient method to identify biomarkers in GBM.

PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells.

We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease.

Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma.

BACKGROUND: The anti-VEGF antibody, bevacizumab, is standard treatment for patients with recurrent glioblastoma. In this setting, traditional anatomic MRI methods such as post-contrast T1-weighted and T2-weighted imaging are proving unreliable for monitoring response. Here we evaluate the prognostic significance of pre- and posttreatment relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast MRI to predict response to bevacizumab. METHODS: Thirty-six participants with recurrent high-grade gliomas who underwent rCBV imaging 60 days before and 20-60 days after starting bevacizumab treatment were enrolled. Tumor regions of interest (ROIs) were determined from deltaT1 maps computed from the difference between standardized post and precontrast T1-weighted images. Both pre- and posttreatment rCBV maps were corrected for leakage and standardized (stdRCBV) to a consistent intensity scale. The Kaplan-Meier method was used to determine if either the pre- or post-bevacizumab stdRCBV within the tumor ROI was predictive of overall survival (OS) or progression free survival (PFS). RESULTS: The OS was significantly longer if either the pre- (380d vs 175d; P=.0024) or posttreatment stdRCBV (340d vs 186d; P = .0065) was <4400. The posttreatment stdRCBV was also predictive of PFS (167d vs 78d; P = .0006). When the stdRCBV values were both above versus both below threshold, the OS was significantly worse (100.5d vs 395d; P < .0001). With a 32.5% decrease in stdRCBV, the risk of death was reduced by about 68% but increased by 140% with a 29% increase in stdRCBV. CONCLUSIONS: Standardized rCBV is predictive of OS and PFS in patients with recurrent high-grade brain tumor treated with bevacizumab.

Effects of perfusion on diffusion changes in human brain tumors.

PURPOSE: To characterize the influence of perfusion on the measurement of diffusion changes over time when ADC is computed using standard two-point methods. MATERIALS AND METHODS: Functional diffusion maps (FDMs), which depict changes in diffusion over time, were compared with rCBV changes in patients with brain tumors. The FDMs were created by coregistering and subtracting ADC maps from two time points and categorizing voxels where ADC significantly increased (iADC), decreased (dADC), or did not change (ncADC). Traditional FDMs (tFDMs) were computed using b = 0,1000 s/mm(2). Flow-compensated FDMs (fcFDMs) were calculated using b = 500,1000 s/mm(2). Perfusion's influence on FDMs was determined by evaluating changes in rCBV in areas where the ADC change significantly differed between the two FDMs. RESULTS: The mean ΔrCBV in voxels that changed from iADC (dADC) on the tFDM to ncADC on the fcFDM was significantly greater (less) than zero. In addition, mean ΔrCBV in iADC (dADC) voxels on the tFDM was significantly higher (lower) than in iADC (dADC) voxels on the fcFDM. CONCLUSION: The ability to accurately identify changes in diffusion on traditional FDMs is confounded in areas where perfusion and diffusion changes are colocalized. Flow-compensated FDMs, which use only non-zero b-values, should therefore be the standard approach.

Vascular change measured with independent component analysis of dynamic susceptibility contrast MRI predicts bevacizumab response in high-grade glioma.

BACKGROUND: Standard pre- and postcontrast (T1 + C) anatomical MR imaging is proving to be insufficient for accurately monitoring bevacizumab treatment response in recurrent glioblastoma (GBM). We present a novel imaging biomarker that detects abnormal tumor vasculature exhibiting both arterial and venous perfusion characteristics. We hypothesized that a decrease in the extent of this abnormal vasculature after bevacizumab treatment would predict treatment efficacy and overall survival. METHODS: Dynamic susceptibility contrast perfusion MRI was gathered in 43 patients with high-grade glioma. Independent component analysis separated vasculature into arterial and venous components. Voxels with perfusion characteristics of both arteries and veins (ie, arterio-venous overlap [AVOL]) were measured in patients with de novo untreated GBM and patients with recurrent high-grade glioma before and after bevacizumab treatment. Treated patients were separated on the basis of an increase or decrease in AVOL volume (+/-ΔAVOL), and overall survival following bevacizumab onset was then compared between +/-ΔAVOL groups. RESULTS: AVOL in untreated GBM was significantly higher than in normal vasculature (P < .001). Kaplan-Meier survival curves revealed a greater median survival (348 days) in patients with GBM with a negative ΔAVOL after bevacizumab treatment than in patients with a positive change (197 days; hazard ratio, 2.51; P < .05). Analysis of patients with combined grade III and IV glioma showed similar results, with median survivals of 399 days and 153 days, respectively (hazard ratio, 2.71; P < .01). Changes in T1+C volume and ΔrCBV after treatment were not significantly different across +/-ΔAVOL groups, and ΔAVOL was not significantly correlated with ΔT1+C or ΔrCBV. CONCLUSIONS: The independent component analysis dynamic susceptibility contrast-derived biomarker AVOL adds additional information for determining bevacizumab treatment efficacy.

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.

PURPOSE: NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS: Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS: Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS: This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

Spatially quantifying microscopic tumor invasion and proliferation using a voxel-wise solution to a glioma growth model and serial diffusion MRI.

The purpose of this study was to develop a voxel-wise analytical solution to a glioma growth model using serial diffusion MRI. These cell invasion, motility, and proliferation level estimates (CIMPLE maps) provide quantitative estimates of microscopic tumor growth dynamics. After an analytical solution was found, noise simulations were performed to predict the effects that perturbations in apparent diffusion coefficient values and the time between apparent diffusion coefficient map acquisitions would have on the accuracy of CIMPLE maps. CIMPLE maps were then created for 53 patients with gliomas with WHO grades of II-IV. MR spectroscopy estimates of the choline-to-N-acetylaspartate ratio were compared to cell proliferation estimates in CIMPLE maps using Pearson's correlation analysis. Median differences in cell proliferation and diffusion rates between WHO grades were compared. A strong correlation (R(2) = 0.9714) and good spatial correspondence were observed between MR spectroscopy measurements of the choline-to-N-acetylaspartate ratio and CIMPLE map cell proliferation rate estimates. Estimates of cell proliferation and diffusion rates appear to be significantly different between low- (WHO II) and high-grade (WHO III-IV) gliomas. Cell diffusion rate (motility) estimates are highly dependent on the time interval between apparent diffusion coefficient map acquisitions, whereas cell proliferation rate estimates are additionally influenced by the level of noise present in apparent diffusion coefficient maps.