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Current clinical and imaging tools remain suboptimal for predicting treatment response and prognosis in CNS lymphomas. We investigated the prognostic value of baseline [18F]FDG PET in patients with CNS lymphoma receiving ibrutinib-based treatments. Fifty-three patients enrolled in a prospective clinical trial and underwent brain PET before receiving single-agent ibrutinib or ibrutinib in combination with methotrexate with or without rituximab. [18F]FDG uptake in these lesions was quantified by drawing PET volumes of interest around up to five [18F]FDG-avid lesions per patient (with uptake greater than surrounding brain). We measured standardized uptake values (SUVmax), metabolic tumor volumes, total lesion glycolysis (TLG), and the sum thereof in these lesions. We analyzed the relationship between PET parameters and mutation status, overall response rates, and progression-free survival (PFS). Thirty-eight patients underwent single-agent therapy and 15 received combination therapy. On PET, 15/53 patients had no measurable disease. In the other 38 patients, a total of 71 lesions were identified on PET. High-intensity [18F]FDG uptake and a larger volume of [18F]FDG-avid disease were inversely related to treatment outcome (p ≤ 0.005). In univariable analysis, PFS was linearly correlated with all PET parameters, with stronger association when sum-values were used. A multivariable model showed that risk of progression increased by 9% for every 5-unit increase in sumSUVmax (hazard ratio = 1.09 [95% CI: 1.04 to 1.14]). Higher lesional metabolic parameters are inversely related to outcome in patients undergoing ibrutinib-based therapies, and sumSUVmax emerged as a strong independent prognostic factor. NCT02315326; https://clinicaltrials.gov/ct2/show/NCT02315326?term=NCT02315326&draw=2&rank=1

Background Patients with human papillomavirus–related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. Methods In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. Results Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation–related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). Conclusions Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

BACKGROUND AND PURPOSE: Cognitive challenges are prevalent in survivors of glioma, but their neurobiology is incompletely understood. The purpose of this study was to investigate the effect of glioma presence and tumor characteristics on resting-state functional connectivity and amplitude of low-frequency fluctuations of the salience network, a key neural network associated with cognition. MATERIALS AND METHODS: Sixty-nine patients with glioma (mean age, 48.74 [SD, 14.32] years) who underwent resting-state fMRI were compared with 31 healthy controls (mean age, 49.68 [SD, 15.54] years). We identified 4 salience network ROIs: left/right dorsal anterior cingulate cortex and left/right anterior insula. Average salience network resting-state functional connectivity and amplitude of low-frequency fluctuations within the 4 salience network ROIs were computed. RESULTS: Patients with gliomas showed decreased overall salience network resting-state functional connectivity (P = .001) and increased amplitude of low-frequency fluctuations in all salience network ROIs (P

BACKGROUND AND PURPOSE: To determine the ability of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict long-term response of brain metastases prior to and within 72 hours of stereotactic radiosurgery (SRS). METHODS: In this prospective pilot study, multiple b-value DWI and T1-weighted DCE-MRI were performed in patients with brain metastases before and within 72 hours following SRS. Diffusion-weighted (DW) images were analyzed using the monoexponential and intravoxel incoherent motion (IVIM) models. DCE-MRI data were analyzed using the extended Tofts pharmacokinetic model. The parameters obtained with these methods were correlated with brain metastasis outcomes according to modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. RESULTS: We included 25 lesions from 16 patients; 16 patients underwent pre-SRS MRI and 12/16 patients underwent both pre- and early (within 72 hours) post-SRS MRI. The perfusion fraction (f) derived from IVIM early post-SRS was higher in lesions demonstrating progressive disease than in lesions demonstrating stable disease, partial response, or complete response (q = 0.041). Pre-SRS extracellular extravascular volume fraction, v(e), and volume transfer coefficient, k(trans), derived from DCE-MRI were higher in non-responders versus responders (q = 0.041). CONCLUSIONS: Quantitative DWI and DCE-MRI are feasible imaging methods in the pre- and early (within 72 hours) post-SRS evaluation of brain metastases. DWI- and DCE-MRI-derived parameters demonstrated physiologic changes (tumor cellularity and vascularity) and offer potentially useful biomarkers that can predict treatment response. This allows for initiation of alternate therapies within an effective time window that may help prevent disease progression.

Objectives The aim of this study was to [1] characterize distribution of Erdheim-Chester Disease (ECD) by 18F-FDG PET/CT and [2] determine the utility of metabolic (18F-FDG PET/CT) imaging versus anatomic imaging (CT or MRI) in evaluating ECD patients for clinical trial eligibility. Methods 18F-FDG PET/CT and corresponding CT or MRI studies for ECD patients enrolled in a prospective registry study were reviewed. Sites of disease were classified as [1] detectable by 18F-FDG PET only, CT/MRI only, or both and as [2] measurable by modified PERCIST (mPERCIST) only, RECIST only, or both. Descriptive analysis was performed and paired t test for between-group comparisons. Results Fifty patients were included (mean age 51.5 years; range 18–70 years). Three hundred thirty-three disease sites were detected among all imaging modalities, 188 (56%) by both 18F-FDG PET and CT/MRI, 67 (20%) by 18F-FDG PET only, 75 (23%) by MRI brain only, and 3 (1%) by CT only. Of 178 disease sites measurable by mPERCIST or RECIST, 40 (22%) were measurable by both criteria, 136 (76%) by mPERCIST only, and 2 (1%) by RECIST only. On the patient level, 17 (34%) had mPERCIST and RECIST measurable disease, 30 (60%) had mPERCIST measurable disease only, and 0 had RECIST measurable disease only (p Conclusion Compared with anatomic imaging, 18F-FDG PET/CT augments evaluation of disease extent in ECD and increases identification of disease sites measurable by formal response criteria and therefore eligibility for clinical trials. Complementary organ-specific anatomic imaging offers the capacity to characterize sites of disease in greater anatomic detail. Trial registration ClinicalTrials.gov Identifier: NCT03329274

Invasive lobular carcinoma (ILC) demonstrates lower conspicuity on 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET than the more common invasive ductal carcinoma (IDC). Other molecular imaging methods may be needed for evaluation of this malignancy. As ILC is nearly always (95%) estrogen receptor (ER) positive, ER-targeting PET tracers such as 16α-[18F]-fluoroestradiol ([18F]FES) may have value. We reviewed prospective trials at Memorial Sloan Kettering Cancer Center (MSK) utilizing [18F]FES PET/CT to evaluate metastatic ILC patients with synchronous [18F]FDG and [18F]FES PET/CT imaging, which allowed a head-to-head comparison of these two PET tracers. Methods: Six prospective clinical trials utilizing [18F]FES PET/CT in patients with metastatic breast cancer were performed at MSK from 2008-2019. These trials included 92 patients, of which 14 (15%) were of ILC histology. Seven of 14 patients with ILC had an [18F]FDG PET/CT performed within 5 weeks of the research [18F]FES PET/CT and no intervening change in management. For these 7 patients, the [18F]FES and [18F]FDG PET/CT studies were analyzed to determine the total number of tracer avid lesions, organ systems of involvement, and SUVmax of each organ system for both tracers. Results: In the seven comparable pairs of scans, there were a total of 254 [18F]FES-avid lesions (SUVmax 2.6 to 17.9) and 111 [18F]FDG-avid lesions (SUVmax 3.3 to 9.9) suspicious for malignancy. For 5 of 7 (71%) of ILC patients, [18F]FES PET/CT detected more metastatic lesions than [18F]FDG PET/CT. In the same 5 of 7 patients, the SUVmax of [18F]FES-avid lesions was greater than the SUVmax of [18F]FDG-avid lesions. One patient had [18F]FES avid metastases with no corresponding [18F]FDG avid metastases. There were no patients with [18F]FDG avid distant metastases without [18F]FES avid distant metastases, although in one patient liver metastases were evident on [18F]FDG but not [18F]FES PET. Conclusion: [18F]FES PET/CT compared favorably with [18F]FDG PET/CT for detection of metastases in patients with metastatic ILC. Larger prospective trials of [18F]FES PET/CT in ILC should be considered to evaluate ER-targeted imaging for clinical value in patients with this histology of breast cancer.

We developed and tested the feasibility of computational fluid modeling (CFM) based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for quantitative estimation of interstitial fluid pressure (IFP) and velocity (IFV) in patients with head and neck (HN) cancer with locoregional lymph node metastases. Twenty-two patients with HN cancer, with 38 lymph nodes, underwent pretreatment standard MRI, including DCE-MRI, on a 3-Tesla scanner. CFM simulation was performed with the finite element method in COMSOL Multiphysics software. The model consisted of a partial differential equation (PDE) module to generate 3D parametric IFP and IFV maps, using the Darcy equation and Ktrans values (min−1, estimated from the extended Tofts model) to reflect fluid influx into tissue from the capillary microvasculature. The Spearman correlation (ρ) was calculated between total tumor volumes and CFM estimates of mean tumor IFP and IFV. CFM-estimated tumor IFP and IFV mean ± standard deviation for the neck nodal metastases were 1.73 ± 0.39 (kPa) and 1.82 ± 0.9 × (10−7 m/s), respectively. High IFP estimates corresponds to very low IFV throughout the tumor core, but IFV rises rapidly near the tumor boundary where the drop in IFP is precipitous. A significant correlation was found between pretreatment total tumor volume and CFM estimates of mean tumor IFP (ρ = 0.50, P = 0.004). Future studies can validate these initial findings in larger patients with HN cancer cohorts using CFM of the tumor in concert with DCE characterization, which holds promise in radiation oncology and drug-therapy clinical trials.

We aimed to compare the geometric distortion (GD) correction performance and apparent diffusion coefficient (ADC) measurements of single-shot diffusion-weighted echo-planar imaging (SS-DWEPI), multiplexed sensitivity encoding (MUSE)-DWEPI, and MUSE-DWEPI with reverse-polarity gradient (RPG) in phantoms and patients. We performed phantom studies at 3T magnetic resonance imaging (MRI) using the American College of Radiology phantom and Quantitative Imaging Biomarker Alliance DW-MRI ice-water phantom to assess GD and effect of distortion in the measurement of ADC, respectively. Institutional review board approved the prospective clinical component of this study. DW-MRI data were obtained from 11 patients with head and neck cancer using these three DW-MRI methods. Wilcoxon signed-rank (WSR) and Kruskal–Wallis (KW) tests were used to compare ADC values, and qualitative rating by radiologist between three DW-MRI methods. In the ACR phantom, GD of 0.17% was observed for the b = 0 s/mm2 image of the MUSE-DWEPI with RPG method compared with that of 1.53% and 2.1% of MUSE-DWEPI and SS-DWEPI, respectively, The corresponding methods root-mean-square errors were 0.58, 3.37, and 5.07 mm. WSR and KW tests showed no significant difference in the ADC measurement between these three DW-MRI methods for both healthy masseter muscles and neoplasms (P &gt, 05). We observed improvement in spatial accuracy for MUSE-DWEPI with RPG in the head and neck region with a higher correlation (R2 = 0.791) compared with that for SS-DWEPI (R2 = 0.707) and MUSE-DWEPI (R2 = 0.745). MUSE-DWEPI with RPG significantly reduces the distortion compared with MUSE-DWEPI or conventional SS-DWEPI techniques, and the ADC values were similar.

Purpose To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. Materials and Methods Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with Results Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2–69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. Conclusion The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

Background Erdheim–Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the MAPK (mitogen-activating protein kinase) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. Methods We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. Results Median age was 52 years (range, 7–77), and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 patients (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%). Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and 2 fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppressants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 patients (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%), and complete metabolic response in 1/16 (6%) by 18F-fluorodeoxyglucose (FDG)-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. Conclusions These data highlight underrecognized symptomatology, heterogeneous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

Histiocytic neoplasms are rare hematologic disorders characterized by pathologic infiltration of activated histiocytes in affected tissues. The treatment of histiocytic neoplasms, including Langerhans cell histiocytosis (LCH) and non-LCH, has advanced in recent years owing to targeted kinase inhibitors (BRAF and MEK) as patients with somatic mutations in the mitogen activated protein kinase (MAPK) pathway derive robust and durable responses with these therapies.1 However, there are patients with non-LCH who do not benefit from targeted therapies, particularly those with histiocytic infiltration of the nervous system, which is associated with mortality in 1 non-LCH disorder. BRAF and MEK inhibitors have limited penetration into the nervous system and worsening neurologic disease despite targeted therapy has been observed.2 These treatments can be limited or contraindicated by disease-related organ dysfunction or comorbidities. The subset of patients without MAPK alterations may not benefit from targeted therapies.

The present study aimed to investigate the correlation at pre-treatment (TX) between quantitative metrics derived from multimodality imaging (MMI), including 18F-FDG-PET/CT, 18F-FMISO-PET/CT, DW- and DCE-MRI, using a community detection algorithm (CDA) in head and neck squamous cell carcinoma (HNSCC) patients. Twenty-three HNSCC patients with 27 metastatic lymph nodes underwent a total of 69 MMI exams at pre-TX. Correlations among quantitative metrics derived from FDG-PET/CT (SUL), FMSIO-PET/CT (K1, k3, TBR, and DV), DW-MRI (ADC, IVIM [D, D*, and f]), and FXR DCE-MRI [Ktrans, ve, and τi]) were investigated using the CDA based on a “spin-glass model” coupled with the Spearman’s rank, ρ, analysis. Mean MRI T2 weighted tumor volumes and SULmean values were moderately positively correlated (ρ = 0.48, p = 0.01). ADC and D exhibited a moderate negative correlation with SULmean (ρ ≤ −0.42, p &lt, 0.03 for both). K1 and Ktrans were positively correlated (ρ = 0.48, p = 0.01). In contrast, Ktrans and k3max were negatively correlated (ρ = −0.41, p = 0.03). CDA revealed four communities for 16 metrics interconnected with 33 edges in the network. DV, Ktrans, and K1 had 8, 7, and 6 edges in the network, respectively. After validation in a larger population, the CDA approach may aid in identifying useful biomarkers for developing individual patient care in HNSCC.

Current state-of-the-art models for estimating the pharmacokinetic parameters do not account for intervoxel movement of the contrast agent (CA). We introduce an optimal mass transport (OMT) formulation that naturally handles intervoxel CA movement and distinguishes between advective and diffusive flows. Ten patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in the study between June 2014 and October 2015 and under-went DCE MRI imaging prior to beginning treatment. The CA tissue concentration information was taken as the input in the data-driven OMT model. The OMT approach was tested on HNSCC DCE data that provides quantitative information for forward flux (ΦF) and backward flux (ΦB). OMT-derived ΦF was compared with the volume transfer constant for CA, Ktrans, derived from the Extended Tofts Model (ETM). The OMT-derived flows showed a consistent jump in the CA diffusive behavior across the images in accordance with the known CA dynamics. The mean forward flux was 0.0082 ± 0.0091 (min-1) whereas the mean advective component was 0.0052±0.0086 (min-1) in the HNSCC patients. The diffusive percentages in forward and backward flux ranged from 8.67–18.76% and 12.76–30.36%, respectively. The OMT model accounts for intervoxel CA movement and results show that the forward flux (ΦF) is comparable with the ETM-derived Ktrans. This is a novel data-driven study based on optimal mass transport principles applied to patient DCE imaging to analyze CA flow in HNSCC.

ObjectiveTo perform a retrospective analysis examining the incidence and prognosis of glioma patients with leptomeningeal disease (LMD) at Memorial Sloan Kettering Cancer Center over a 15-year period and correlate these findings with clinicopathologic characteristics.MethodsWe conducted a retrospective review of glioma patients with LMD at Memorial Sloan Kettering Cancer Center diagnosed from 2001 to 2016. Patients were identified through a keyword search of their electronic medical record and by ICD-9 codes.ResultsOne hundred three patients were identified with disseminated LMD and 85 patients with subependymal spread of disease, 4.7% of all patients with glioma. These cohorts were analyzed separately for time to development of disseminated LMD/subependymal LMD, median overall survival, and survival from LMD diagnosis. Patients were pooled for subsequent analyses (n = 188) because of comparable clinical behavior. LMD was present at glioma diagnosis in 10% of patients. In the remaining 90% of patients diagnosed at recurrence, time to LMD diagnosis, survival after LMD diagnosis, and overall survival varied by original histology. Patients with oligodendroglioma had a median survival of 10.8 (range 1.8–67.7) months, astrocytoma 6.5 (0.1–28.5) months, and glioblastoma 3.8 (0.1–32.6) months after LMD diagnosis. In addition, we found that treatment of LMD was associated with superior performance status and increased survival.ConclusionPatients with LMD diagnosed at relapse may not have decreased overall survival as compared to historical controls with parenchymal relapse and may benefit from treatment.

The aim of the present study was to identify whether the quantitative metrics from pre-treatment (TX) non-Gaussian intravoxel incoherent motion (NGIVIM) diffusion weighted (DW-) and fast exchange regime (FXR) dynamic contrast enhanced (DCE)-MRI can predict patients with locoregional failure (LRF) in nasopharyngeal carcinoma (NPC). Twenty-nine NPC patients underwent pre-TX DW- and DCE-MRI on a 3T MR scanner. DW imaging data from primary tumors were fitted to monoexponential (ADC) and NGIVIM (D, D*, f, and K) models. The metrics Ktrans, ve, and τi were estimated using the FXR model. Cumulative incidence (CI) analysis and Fine-Gray (FG) modeling were performed considering death as a competing risk. Mean ve values were significantly different between patients with and without LRF (p = 0.03). Mean f values showed a trend towards the difference between the groups (p = 0.08). Histograms exhibited inter primary tumor heterogeneity. The CI curves showed significant differences for the dichotomized cutoff value of ADC ≤ 0.68 × 10−3 (mm2/s), D ≤ 0.74 × 10−3 (mm2/s), and f ≤ 0.18 (p &lt, 0.05). τi ≤ 0.89 (s) cutoff value showed borderline significance (p = 0.098). FG’s modeling showed a significant difference for the K cutoff value of ≤0.86 (p = 0.034). Results suggest that the role of pre-TX NGIVIM DW- and FXR DCE-MRI-derived metrics for predicting LRF in NPC than alone.

Background: Early imaging-based treatment response assessment of brain metastases following stereotactic radiosurgery (SRS) remains challenging. The aim of this study is to determine whether early (within 12 weeks) intratumoral changes in interstitial fluid pressure (IFP) and velocity (IFV) estimated from computational fluid modeling (CFM) using dynamic contrast-enhanced (DCE) MRI can predict long-term outcomes of lung cancer brain metastases (LCBMs) treated with SRS. Methods: Pre- and post-treatment T1-weighted DCE-MRI data were obtained in 41 patients treated with SRS for intact LCBMs. The imaging response was assessed using RANO-BM criteria. For each lesion, extravasation of contrast agent measured from Extended Tofts pharmacokinetic Model (volume transfer constant, Ktrans) was incorporated into a computational fluid model to estimate tumor IFP and IFV. Estimates of mean IFP and IFV and heterogeneity (skewness and kurtosis) were calculated for each lesion from pre- and post-SRS imaging. The Wilcoxon rank-sum test was utilized to assess for significant differences in IFP, IFV, and IFP/IFV change (Δ) between response groups. Results: Fifty-three lesions from 41 patients were included. Median follow-up time after SRS was 11 months. The objective response (OR) rate (partial or complete response) was 79%, with 21% demonstrating stable disease (SD) or progressive disease (PD). There were significant response group differences for multiple posttreatment and Δ CFM parameters: post-SRS IFP skewness (mean −0.405 vs. −0.691, p = 0.022), IFP kurtosis (mean 2.88 vs. 3.51, p = 0.024), and IFV mean (5.75e-09 vs. 4.19e-09 m/s, p = 0.027); and Δ IFP kurtosis (mean −2.26 vs. −0.0156, p = 0.017) and IFV mean (1.91e-09 vs. 2.38e-10 m/s, p = 0.013). Posttreatment and Δ thresholds predicted non-OR with high sensitivity (sens): post-SRS IFP skewness (−0.432, sens 84%), kurtosis (2.89, sens 84%), and IFV mean (4.93e-09 m/s, sens 79%); and Δ IFP kurtosis (−0.469, sens 74%) and IFV mean (9.90e-10 m/s, sens 74%). Conclusions: Objective response was associated with lower post-treatment tumor heterogeneity, as represented by reductions in IFP skewness and kurtosis. These results suggest that early post-treatment assessment of IFP and IFV can be used to predict long-term response of lung cancer brain metastases to SRS, allowing a timelier treatment modification.

Introduction In ret proto-oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%–32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%–58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)–rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3–2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0–4.9 months). Conclusions Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor–associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells. Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018–29. ©2017 AACR. See related commentary by Lakshmanan and Byrd, p. 940. This article is highlighted in the In This Issue feature, p. 920

BACKGROUND: Imaging criteria to evaluate the response of brain metastases to stereotactic radiosurgery (SRS) in the early posttreatment period remains a crucial unmet need. The aim of this study is to correlate early (within 12 wk) posttreatment perfusion MRI changes with long-term outcomes after treatment of lung cancer brain metastases with SRS. METHODS: Pre- and posttreatment perfusion MRI scans were obtained in patients treated with SRS for intact non–small cell lung cancer brain metastases. Time-dependent leakage (K(trans)), blood plasma volume (Vp), and extracellular extravascular volume (Ve) were calculated for each lesion. Patients were followed longitudinally with serial MRI until death, progression, or intervention (whole brain radiation or surgery). RESULTS: We included 53 lesions treated with SRS from 41 total patients. Median follow-up after treatment was 11 months. Actuarial local control at one year was 85%. Univariate analysis demonstrated a significant difference (P = 0.032) in posttreatment K(trans) SD between patients with progressive disease (mean = 0.0317) and without progressive disease (mean = 0.0219). A posttreatment K(trans) SD cutoff value of 0.017 was highly sensitive (89%) for predicting progressive disease and no progressive disease. Early posttreatment volume change was not associated with outcome (P = 0.941). CONCLUSION: Posttreatment K(trans) SD may be used as an early posttreatment imaging biomarker to help predict long-term response of lung cancer brain metastases to SRS. This can help identify patients who will ultimately fail SRS and allow for timelier adjustment in treatment approach. These data should be prospectively validated in larger patient cohorts and other histologies.

Brain metastases originating from different primary sites overlap in appearance and are difficult to differentiate with conventional MRI. Dynamic contrast‐enhanced (DCE)‐MRI can assess tumor microvasculature and has demonstrated utility in characterizing primary brain tumors. Our aim was to evaluate the performance of plasma volume (Vp) and volume transfer coefficient (K trans) derived from DCE‐MRI in distinguishing between melanoma and nonsmall cell lung cancer (NSCLC) brain metastases. Forty‐seven NSCLC and 23 melanoma brain metastases were retrospectively assessed with DCE‐MRI. Regions of interest were manually drawn around the metastases to calculate Vpmean and Kmeantrans. The Mann–Whitney U test and receiver operating characteristic analysis (ROC) were performed to compare perfusion parameters between the two groups. The Vpmean of melanoma brain metastases (4.35, standard deviation [SD] = 1.31) was significantly higher (P = 0.03) than Vpmean of NSCLC brain metastases (2.27, SD = 0.96). The Kmeantrans values were higher in melanoma brain metastases, but the difference between the two groups was not significant (P = 0.12). Based on ROC analysis, a cut‐off value of 3.02 for Vpmean (area under curve = 0.659 with SD = 0.074) distinguished between melanoma brain metastases and NSCLC brain metastases (P

Background and purpose: In this study we investigated the ability of textures from T1-weighted MRI scans post-contrast (T1wpost) to identify the critical muscle(s) for radiation-induced trismus. Materials and methods: The study included ten cases (Trismus: ≥Grade 1), and ten age-sex-tumor-location-and-stage-matched controls treated with intensity-modulated radiotherapy to 70 Gy@2.12 Gy in 2005–2009. Trismus status and T1wPost were conducted within one year post-radiotherapy. For the masseter, lateral and medial pterygoids, and temporalis (M/LP/MP/T), 24 textures were extracted (Grey Level Co-Occurrence (GLCM), Histogram, and Shape). Univariate logistic regression with Bootstrapping (1000 populations) was applied to compare the muscle mean dose (Dmean) and textures between cases and controls (ipsilateral muscles); candidate predictors were suggested by an average p ≤ 0.20 across all Bootstrap populations. Results: Dmean to M/LP/MP (p = 0.03/0.14/0.09), one MP/T (p = 0.12/0.17), and three M (p = 0.14–0.19) textures were candidate predictors. Three of these textures were GLCM- and two Histogram textures with the former being generally higher and the latter lower for cases compared to controls. The Dmean to M and MP, and Haralick Correlation (GLCM) of MP presented with the best discriminative ability (area under the receiver-operating characteristic curve: 0.85, 0.77, and 0.78), and the correlation between Dmean and this texture was weak (Spearman’s rank correlation coefficient: 0.26–0.27). Conclusions: Our exploratory study points towards an interplay between the dose to the masseter, and the medial pterygoid together with the local relationship between the mean MRI intensity relative to its variance of the medial pterygoid for radiation-induced trismus. This opens up for exploration of this interplay within the radiation-induced trismus etiology in the larger multi-institutional setting. Keywords: Head and neck cancer, Radiotherapy, Trismus, Quantitative image, Texture, Radiomics

AIM To noninvasively investigate tumor cellularity measured using diffusion-weighted magnetic resonance imaging (DW-MRI) and glucose metabolism measured by 18F-labeled fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) during radiation therapy (RT) for human papillomavirus negative (HPV-) head and neck squamous cell carcinoma (HNSCC). METHODS In this prospective study, 6 HPV- HNSCC patients underwent a total of 34 multimodality imaging examinations DW-MRI at 1.5 T Philips MRI scanner [(n = 24) pre-, during- (2-3 wk), and post-treatment (Tx), and 18F-FDG PET/CT pre- and post-Tx (n = 10)]. All patients received RT. Monoexponential modeling of the DW-MRI data yielded the imaging metric apparent diffusion coefficient (ADC) and the mean of standardized uptake value (SUV) was measured from 18F-FDG PET uptake. All patients had a clinical follow-up as the standard of care and survival status was documented at 1 year. RESULTS There was a strong negative correlation between the mean of pretreatment ADC (ρ = -0.67, P = 0.01) and the pretreatment 18F-FDG PET SUV. The percentage (%) change in delta (∆) ADC for primary tumors and neck nodal metastases between pre- and Wk2-3 Tx were as follows: 75.4% and 61.6%, respectively, for the patient with no evidence of disease, 27.5% and 32.7%, respectively, for those patients who were alive with disease, and 26.9% and 7.31%, respectively, for those who were dead with disease. CONCLUSION These results are preliminary in nature and are indicative, and not definitive, trends rendered by the imaging metrics due to the small sample size of HPV- HNSCC patients in a Meixoeiro Hospital of Vigo Experience.

We present an exceedingly rare case of a Ewing sarcoma metastasis manifesting as a sellar mass mimicking a pituitary adenoma. The differential diagnosis of the young adult with a sellar mass is presented and correlated with a review of available literature, demonstrating this case's unique potential for clinical teaching. More specifically, this case illustrates that in a patient with a clinical history of Ewing sarcoma, a metastasis may involve the sella and suprasellar cistern without apparent osseous involvement.

BACKGROUND AND PURPOSE: Glioblastoma and primary CNS lymphoma dictate different neurosurgical strategies; it is critical to distinguish them preoperatively. However, current imaging modalities do not effectively differentiate them. We aimed to examine the use of DWI and T1-weighted dynamic contrast-enhanced–MR imaging as potential discriminative tools. MATERIALS AND METHODS: We retrospectively reviewed 18 patients with primary CNS lymphoma and 36 matched patients with glioblastoma with pretreatment DWI and dynamic contrast-enhanced–MR imaging. VOIs were drawn around the tumor on contrast-enhanced T1WI and FLAIR images; these images were transferred onto coregistered ADC maps to obtain the ADC and onto dynamic contrast-enhanced perfusion maps to obtain the plasma volume and permeability transfer constant. Histogram analysis was performed to determine the mean and relative ADCmean and relative 90th percentile values for plasma volume and the permeability transfer constant. Nonparametric tests were used to assess differences, and receiver operating characteristic analysis was performed for optimal threshold calculations. RESULTS: The enhancing component of primary CNS lymphoma was found to have significantly lower ADCmean (1.1 × 10−3 versus 1.4 × 10−3; P CONCLUSIONS: ADC was superior to dynamic contrast-enhanced–MR imaging perfusion, alone or in combination, in differentiating primary CNS lymphoma from glioblastoma.

PurposeTo construct robust and validated radiomic predictive models, the development of a reliable method that can identify reproducible radiomic features robust to varying image acquisition methods and other scanner parameters should be preceded with rigorous validation. Due to the property of high correlation present between radiomic features, we hypothesize that reproducible radiomic features across different datasets that are obtained from different image acquisition settings preserve some level of connectivity between features in the form of a network.MethodsWe propose a regularized partial correlation network to identify robust and reproducible radiomic features. This approach was tested on two radiomic feature sets generated with two different reconstruction methods from a cohort of 47 lung cancer patients. The commonality of the resulting two networks was assessed. A largest common network component from the two networks was tested on phantom data consisting of 5 cancer samples. We further propose a novel K-means algorithm coupled with the optimal mass transport (OMT) theory to cluster samples. This approach following the regularized partial correlation analysis was tested on computed tomography (CT) scans from 77 head and neck cancer patients that were downloaded from The Cancer Imaging Archive (TCIA) and validated on CT scans from 83 head and neck cancer patients treated at our institution.ResultsCommon radiomic features were found in relatively large network components between the resulting two partial correlation networks from a cohort of 47 lung cancer patients. The similarity of network components in terms of the common number of radiomic features was statistically significant. For phantom data, the Wasserstein distance on a largest common network component from the lung cancer data was much smaller than the Wasserstein distance on the same network using random radiomic features, implying the reliability of those radiomic features present in the network. Further analysis using the proposed Wasserstein K-means algorithm on TCIA head and neck cancer data showed that the resulting clusters separate tumor subsites and this was validated on our institution data.ConclusionsWe showed that a network-based analysis enables identifying reproducible radiomic features. This was validated using phantom data and external data via the Wasserstein distance metric and the proposed Wasserstein K-means method.

We assessed a priori aggressive features using quantitative diffusion-weighted imaging metrics to preclude an active surveillance management approach in patients with papillary thyroid cancer (PTC) with tumor size 1–2 cm. This prospective study enrolled 24 patients with PTC who underwent pretreatment multi-b-value diffusion-weighted imaging on a GE 3 T magnetic resonance imaging scanner. The apparent diffusion coefficient (ADC) metric was calculated from monoexponential model, and the perfusion fraction (f), diffusion coefficient (D), pseudo-diffusion coefficient (D*), and diffusion kurtosis coefficient (K) metrics were estimated using the non-Gaussian intravoxel incoherent motion model. Neck ultrasonography examination data were used to calculate tumor size. The receiver operating characteristic curve assessed the discriminative specificity, sensitivity, and accuracy between PTCs with and without features of tumor aggressiveness. Multivariate logistic regression analysis was performed on metrics using a leave-1-out cross-validation method. Tumor aggressiveness was defined by surgical histopathology. Tumors with aggressive features had significantly lower ADC and D values than tumors without tumor-aggressive features (P &lt, 05). The absolute relative change was 46% in K metric value between the 2 tumor types. In total, 14 patients were in the critical size range (1–2 cm) measured by ultrasonography, and the ADC and D were significantly different and able to differentiate between the 2 tumor types (P &lt, 05). ADC and D can distinguish tumors with aggressive histological features to preclude an active surveillance management approach in patients with PTC with tumors measuring 1–2 cm.

BACKGROUND The purpose of this study was to investigate the utility and clinical impact of second-opinion interpretations of outside neuroimaging studies by oncologic neuroradiologists at a National Cancer Institute–designated cancer center. METHODS We performed a retrospective analysis of initial outside and second-opinion radiology reports from 300 computed tomography and magnetic resonance imaging studies and identified cases with discrepancies between the two reports. An adult neuro-oncologist, pediatric neuro-oncologist, and head and neck surgeon reviewed each pair of discrepant reports based on their area of expertise, patient age, and the type of study performed. The clinicians were blinded to the origin of each report and recorded whether the differences in the reports would have led to a change in patient management and/or disease staging. Histopathologic analysis, clinical assessment, and/or minimum 3-month imaging follow-up served as the reference standards to establish which of the 2 reports was correct. RESULTS Among the 283 cases that met our study criteria, there were 55 neuroimaging studies with disagreements (19%) between the initial outside report and second-opinion interpretation. Patient management and/or disease stage would have been altered in 42 of 283 cases (15%) based on report differences as determined by the 2 neuro-oncologists and the surgeon participating in the study. Sufficient follow-up was available in 35 of 42 cases (83%). The second-opinion interpretation was correct 100% of the time (35/35). CONCLUSION Second-opinion interpretations of neuroimaging studies by subspecialized oncologic neuroradiologists provide added value by reducing error and optimizing the care of cancer patients. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2708–2714. © 2016 American Cancer Society.

BACKGROUND AND PURPOSE Low-grade and anaplastic oligodendrogliomas are often difficult to differentiate on the basis of conventional MR imaging characteristics. Dynamic contrast-enhanced (DCE) MRI can assess tumor microvasculature and has demonstrated utility for predicting glioma grade and prognosis in primary brain tumors. The aim of our study was to evaluate the performance of plasma volume (Vp) and volume transfer coefficient (Ktrans) derived from DCE MRI in differentiating between grade II and grade III oligodendrogliomas. MATERIALS AND METHODS Twenty-four consecutive patients with pathologically confirmed oligodendroglioma (World Health Organization grade II, n = 14 and grade III, n = 10) were retrospectively assessed. Pretreatment DCE MRI was performed and regions of interest were manually drawn around the entire tumor volume to calculate Vp and Ktrans. The Mann-Whitney U test and receiver operating characteristic (ROC) analysis were performed to compare pharmacokinetic parameters between the 2 groups. RESULTS The Vpmean values for grade III oligodendrogliomas were significantly higher (P = .03) than those for grade II oligodendrogliomas. The Ktransmean values were higher in grade III lesions, but the difference between the 2 groups was not statistically significant (P > .05). Based on ROC analysis, the Vpmean (area under curve = .757, SD = .1) cut-off value that provided the best combination of high sensitivity and specificity to distinguish between grade II and III oligodendrogliomas was 2.35 (P < .03). CONCLUSION The results of our study suggest the DCE MRI parameter Vpmean can noninvasively differentiate between grade II and grade III oligodendrogliomas.

PURPOSE: To identify whether radiomic features from pre-treatment computed tomography (CT) scans can predict molecular differences between head and neck squamous cell carcinoma (HNSCC) using The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). METHODS: 77 patients from the TCIA with HNSCC had imaging suitable for analysis. Radiomic features were extracted and unsupervised consensus clustering was performed to identify subtypes. Genomic data was extracted from the matched patients in the TCGA database. We explored relationships between radiomic features and molecular profiles of tumors, including the tumor immune microenvironment. A machine learning method was used to build a model predictive of CD8+ T-cells. An independent cohort of 83 HNSCC patients was used to validate the radiomic clusters. RESULTS: We initially extracted 104 two-dimensional radiomic features, and after feature stability tests and removal of volume dependent features, reduced this to 67 features for subsequent analysis. Consensus clustering based on these features resulted in two distinct clusters. The radiomic clusters differed by primary tumor subsite (p=0.0096), HPV status (p=0.0127), methylation-based clustering results (p=0.0025), and tumor immune microenvironment. A random forest model using radiomic features predicted CD8+ T-cells independent of HPV status with R(2)=0.30 (p

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

PURPOSE: Prediction of clinical outcomes in patients with primary central nervous system lymphoma (PCNSL) is important for optimization of treatment planning. Quantitative imaging biomarkers for PCNSL have not yet been established. This study evaluated the prognostic value of pretreatment dynamic contrast-enhanced MRI and diffusion-weighted imaging for progression-free survival (PFS) in patients with PCNSL. METHODS: Pretreatment dynamic contrast-enhanced MRI and diffusion-weighted imaging were retrospectively analyzed in 18 immunocompetent patients with PCNSL. Volumes of interest encompassing the tumors were assessed for measurements of blood plasma volume (Vp), volume transfer constant (K(trans)), and apparent diffusion coefficient. Patients were divided into short and long PFS groups based on median PFS. Imaging and clinical variables were correlated with PFS. RESULTS: Median PFS was 19.6 months. Lower Vp(mean) and K(trans)(mean) values increased risk for rapid progression (< 19.6 months). Receiver operating characteristic curve analysis demonstrated an optimal Vp(mean) cutoff value of 2.29 (area under the curve [AUC] = 0.74, sensitivity and specificity = 0.78, p = 0.023) for separating patients with short and long PFS. The optimal K(trans)(mean) cutoff was 0.08 (AUC = 0.74, sensitivity = 0.67, specificity = 0.78, p = 0.025). Kaplan–Meier survival analysis with log-rank test demonstrated significantly (p = 0.015) increased risk of rapid progression for patients with Vp(mean) < 2.29. Vp(mean) was significantly (p = 0.03) associated with PFS on univariate Cox analysis. Apparent diffusion coefficient values and clinical factors did not influence PFS. CONCLUSIONS: Pretreatment Vp and K(trans) derived from dynamic contrast-enhanced MRI may be novel prognostic quantitative imaging biomarkers of progression-free survival in patients with PCNSL. These data should be prospectively validated in larger patient cohorts.

The purpose of this study was to identify the optimal tracer kinetic model from dynamic contrast-enhanced T(1)‐weighted magnetic resonance imaging (DCE-MRI) data and evaluate whether parameters estimated from the optimal model predict tumor aggressiveness determined from histopathology in patients with papillary thyroid carcinoma (PTC) prior to surgery. In this prospective study, 18 PTC patients underwent pretreatment DCE-MRI on a 3T MR scanner prior to thyroidectomy. This study was approved by the institutional review board and informed consent was obtained from all patients. The two-compartment exchange model (2CXM), compartmental tissue uptake model (CTUM), extended Tofts model (ETM), and standard Tofts model (TM) were compared on a voxel-wise basis to determine the optimal model using the corrected Akaike information criterion (AICc) for PTC. The optimal model is the one with the lowest AICc. Statistical analysis included paired and unpaired t-tests and a one-way Analysis of variance. Bonferroni correction was applied for multiple comparisons. Receiver operating characteristic (ROC) curves were generated from the optimal model parameters to differentiate PTC with and without aggressive features, and AUC’s were compared. ETM performed the best with the lowest AICc and highest weights (0.44) among the four models. ETM was preferred in 44% of all 3419 voxels. The ETM estimates of K(trans) in PTCs with aggressive feature extrathyroidal extension (ETE) were significantly higher than those without ETE (0.78±0.29 vs. 0.34±0.18 min(−1), P=0.005). From ROC analysis, cut-off values of K(trans), v(e), and v(p) which discriminated between PTCs with and without ETE were determined at 0.45 min(−1), 0.28, and 0.014, respectively. The sensitivities and specificities were 86% and 82% (K(trans)), 71% and 82% (v(e)), and 86% and 55% (v(p)). Their respective AUC’s were 0.90, 0.71, and 0.71. We conclude the ETM K(trans) has shown potential to classify tumors with and without aggressive ETE in patients with PTC.

The diagnosis of leptomeningeal metastasis (LM) has increased in frequency, as new therapies have lengthened the survival of patients with cancer. Early diagnosis and intervention help improve quality of life and prevent further neurological deterioration in LM. The detection of LM is often established by magnetic resonance imaging examinations, cerebrospinal fluid analysis, or both. We present a series of cases where LM was identified on fluid-attenuated inversion recovery or T2-weighted image but was nonenhancing on the traditionally more sensitive postcontrast T1-weighted sequences. Nonenhancing LM is unusual and not yet fully understood but should be considered in the appropriate clinical context and may become more common with increased utilization of antiangiogenic therapies.

Initial management recommendations of papillary thyroid carcinoma (PTC) are very dependent on preoperative studies designed to evaluate the presence of PTC with aggressive features. The purpose of this study was to evaluate whether diffusion-weighted magnetic resonance imaging (DW-MRI) before surgery can be used as a tool to stratify tumor aggressiveness in patients with PTC.In this prospective study, 28 patients with PTC underwent DW-MRI studies on a three Tesla MR scanner prior to thyroidectomy. Due to image quality, 21 patients were finally suitable for further analysis. Apparent diffusion coefficients (ADCs) of normal thyroid tissues and PTCs for 21 patients were calculated. Tumor aggressiveness was defined by surgical histopathology. The Mann-Whitney U test was used to compare the difference in ADCs among groups of normal thyroid tissues and PTCs with and without features of tumor aggressiveness. Receiver operating characteristic (ROC) analysis was performed to assess the discriminative specificity, sensitivity, and accuracy of and determine the cutoff value for the ADC in stratifying PTCs with tumor aggressiveness.There was no significant difference in ADC values between normal thyroid tissues and PTCs. However, ADC values of PTCs with extrathyroidal extension (ETE; 1.53±0.25×10(-3) mm2/s) were significantly lower than corresponding values from PTCs without ETE (2.37±0.67×10(-3) mm2/s; p0.005). ADC values identified 3 papillary carcinoma patients with extrathyroidal extension that would have otherwise been candidates for observation based on ultrasound evaluations. The cutoff value of ADC to discriminate PTCs with and without ETE was determined at 1.85×10(-3) mm2/s with a sensitivity of 85%, specificity of 85%, and ROC curve area of 0.85.ADC value derived from DW-MRI before surgery has the potential to stratify ETE in patients with PTCs.

227 Background: BM are rarely seen with PCa, but the incidence may be increasing with contemporary therapies. We sought to evaluate the clinical phenotypes associated with BM and their outcomes. Methods: The MSKCC institutional clinical database from 01/2001 through 06/2018 was reviewed to identify pts with PCa and (1) secondary malignant neoplasm of the brain / spinal cord per ICD-9 (198.3), (2) radiation treatment plan targeting the brain, (3) craniotomy, or (3) notes containing the terms “brain metastasis”. Medical charts were reviewed to confirm diagnosis (dx) and extract data. The logrank statistic and the Cox proportional hazards model were used to determine correlations with overall survival (OS). Results: Of 575 pts who met search criteria, 43 had BM and prostate adenocarcinoma. At PCa dx, median age was 60 years (range: 44 –77 years) and 51% had metastasis (mets). Median time from PCa dx to BM was 4.2 years. At the time of BM dx, 36 had metastatic castration-resistant PCa (mCRPC), 55% had liver mets and 66% had lung mets. 45% had ≥3 lines of therapy for mCRPC prior to BM dx (abiraterone/enzalutamide: 47%, chemotherapy: 91%). The median OS from BM dx was 5.8 months (Table). 4/10 pts with sequencing data had germline mutations ( ATM, BRCA1, BRIP1, MUTYH). To date, 4 BM were sequenced, and 3 showed PTEN loss. Conclusions: BM associated with a poor prognosis and occurred after prolonged treatment. Presence of liver/lung mets, 3 or more BM, and surgical resection (SR) prognosticate for OS in univariate analysis; SR in multivariate analysis. Further analysis is needed to determine if germline mutations and/or PTEN loss associate with BM. [Table: see text]

BACKGROUND AND PURPOSE Brain metastases from prostate cancer are uncommon and their imaging appearance has not been well defined. The main objectives of this study were to evaluate the incidence, MRI characteristics, and prognosis of parenchymal brain metastases originating in prostate cancer. METHODS We retrospectively identified 21 patients with prostate cancer and evidence of brain metastases from 2000 to 2010. We reviewed the initial brain MRI scans and characterized the lesions according to location and appearance on MRI, while also determining patient demography, staging, and survival. RESULTS The incidence of brain metastasis from prostate cancer was .16%. At the time of brain metastasis detection, 95% of the patients had concurrent osseous metastases, 86% lymph node metastases, and 76% liver and/or lung metastases. Brain metastases were multifocal in 71% of patients, hemorrhagic in 33%, diffusion restricted in 19%, and partially cystic/necrotic in 19%. The median overall survival after brain metastasis detection was 2.8 months. CONCLUSIONS Brain metastasis from prostate cancer remains a rare phenomenon that most frequently occurs in the setting of widely disseminated bone and soft tissue disease. Patients with nonadenocarcinoma pathology are more likely to develop brain metastases. The MRI appearance is highly variable and prognosis is poor.

Background Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis characterized by systemic inflammation and granulomatous infiltration of multiple organs including the central nervous system (CNS), bones, and retroperitoneum. CNS infiltration occurs in one third of patients, but cognitive changes are common in patients without CNS disease. Here we investigate whether there is a neuroanatomic basis to observed cognitive deficits, even in absence of CNS disease. Methods We present a volumetric analysis of eleven ECD patients without CNS tumors or prior neurotoxic treatments. Results Compared to age-matched controls, ECD patients have diffuse, bihemispheric reduction in cortical thickness and subcortical gray matter. Conclusions These findings provide the first corroborating evidence for neurologic disease in ECD patients without direct CNS infiltration.

Toxoplasma encephalitis is a well recognized complication of acquired immune deficiency syndrome, solid organ transplantation, and allogeneic hematopoietic stem cell transplantation (HSCT). However, patients with hematologic malignancies not treated with allogeneic HSCT may also develop this condition, which requires high clinical suspicion and consideration for prophylactic therapy.

BACKGROUND The aim of this study was to assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) PET-CT and dynamic contrast-enhanced (DCE) MRI in differentiating tumor progression and radiation injury in patients with indeterminate enhancing lesions after radiation therapy (RT) for brain malignancies. METHODS Patients with indeterminate enhancing brain lesions on conventional MRI after RT underwent brain DCE-MRI and PET-CT in a prospective trial. Informed consent was obtained. Lesion outcomes were determined by histopathology and/or clinical and imaging follow-up. Metrics obtained included plasma volume (Vp) and volume transfer coefficient (K(trans)) from DCE-MRI, and maximum standardized uptake value (SUVmax) from PET-CT; lesion-to-normal brain ratios of all metrics were calculated. The Wilcoxon rank sum test and receiver operating characteristic analysis were performed. RESULTS The study included 53 patients (29 treated for 29 gliomas and 24 treated for 26 brain metastases). Progression was determined in 38/55 (69%) indeterminate lesions and radiation injury in 17 (31%). Vpratio (VP lesion/VP normal brain, P < .001), K(trans) ratio (P = .002), and SUVratio (P = .002) correlated significantly with diagnosis of progression versus radiation injury. Progressing lesions exhibited higher values of all 3 metrics compared with radiation injury. Vpratio had the highest accuracy in determining progression (area under the curve = 0.87), with 92% sensitivity and 77% specificity using the optimal, retrospectively determined threshold of 2.1. When Vpratio was combined with K(trans) ratio (optimal threshold 3.6), accuracy increased to 94%. CONCLUSIONS Vpratio was the most effective metric for distinguishing progression from radiation injury. Adding K(trans) ratio to Vpratio further improved accuracy. DCE-MRI is an effective imaging technique for evaluating nonspecific enhancing intracranial lesions after RT.

BACKGROUND: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in various B-cell malignancies. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. METHODS: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL, systemic disease needed to be absent. All patients needed to have at least one prior CNS directed therapy. RESULTS: Forty-four patients were enrolled; 3 received ibrutinib at 560mg and 41 at 840mg. Median age was 68 years (range 21-90); 20 were women. Median ECOG was 1 (0: 11, 1: 22, 2: 11); 29 had PCNSL and 15 SCNSL; 61% had recurrent disease. Twenty-four had isolated parenchymal disease, 4 isolated cerebrospinal fluid (CSF) involvement and 16 both. No grade 5 event has been observed. Eleven patients experienced 12 grade 4 adverse events: neutropenia (in 5 patients), lymphopenia (2), ALT elevation (1), combined ALT/AST elevation (1), sepsis (1), and pneumonitis (1). Seventeen patients experienced 35 grade 3 adverse events (most common: lymphopenia in 4, ALT elevation (3), hyperglycemia (3), urinary tract infection (3), decreased WBC (2), lung infection (2), and thrombocytopenia (2)). Treatment was stopped due to adverse events in 3 patients (grade 4 pulmonitis, grade 4 liver toxicity, grade 3 infectious encephalitis). Twenty-four patients did not experience ≥3 grade adverse events. The most common toxicities at any grade were thrombocytopenia (73%), hyperglycemia (55%), anemia (43%), hypercholesterolemia (43%) and hypertriglyceridemia (43%) of which most were grade 1/2. Only 1 Aspergillus infection has been observed in a patient with chronic steroid use. After a median follow-up of 22 months (range 1.5-39), 40/44 patients were evaluated for response (4 did not complete at least 15 days of drug treatment due to deteriorating clinical status or withdrawal from study). Overall response was 78% (31/40; 81% (22/27) in PCNSL; 69% (9/13) in SCNSL) with 17 CR, 14 PR, 4 SD and 5 PD as best response. The median PFS is 4 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 16.5 months). The median overall survival is 19.5 months. CONCLUSION: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 78% of CNS lymphoma patients. Disclosures No relevant conflicts of interest to declare.

We report a case of fibrodysplasia ossificans progressive in a 34-year-old male who presented with bilateral lower-extremity numbness. This rare disease results in abnormal ossification of various muscles, tendons, and ligaments. In this case, there was ossification of the posterior longitudinal ligament and resultant thoracic spinal-cord compression. Recognizing the MR features of this disease and this serious complication is very important in the management of these complex patients.

Background Wernicke-Korsakoff Syndrome (WKS) is a neuropsychiatric syndrome caused by thiamine deficiency. Cancer predisposes to thiamine deficiency through various mechanisms. Although many case reports exist on nonalcoholic WKS in cancer, larger qualitative studies are lacking. Method Retrospective study of patients admitted to a cancer hospital and diagnosed with WKS during routine care on a psychiatric consultation service. Only patients with at least 1 additional supporting feature (magnetic resonance imaging findings, low serum thiamine concentrations, or response to treatment) were included. Data pertaining to demographics, risk factors, phenomenology, and outcomes were abstracted from medical records by chart review. Results In all, 18 patients were included. All patients developed WKS during cancer treatment. Hematologic malignancy, gastrointestinal tract tumors, low oral intake, and weight loss were common risk factors. All patients presented with cognitive dysfunction, most commonly impaired alertness, attention, and short-term memory. All were diagnosed by operational criteria proposed by Caine et al., 1997 (where 2 of the following are required: nutritional deficiency, ocular signs, cerebellar signs, and either altered mental status or mild memory impairment). Few exhibited Wernicke's classic triad. Diagnostic and treatment delay were common. Only 3 patients recovered fully. Conclusion Nonalcoholic WKS can occur during cancer treatment and manifests clinically as delirium. Diagnosis should be made using operational criteria, not Wernicke's triad. Most patients were not underweight and had normal serum concentration of vitamin B 12 and folate. A variety of mechanisms might predispose to thiamine deficiency and WKS in cancer. Given the high frequency of residual morbidity, studies should focus on decreasing diagnostic and treatment delay.

The spectrum of West Nile virus (WNV) infection continues to be elucidated. Many cases of WNV are asymptomatic; however, in immunocompromised patients, symptoms are more likely to be severe. We describe fatal WNV central nervous system disease in lymphoma patients who received rituximab, blunting the inflammatory response and complicating diagnosis.

7515 Background: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in Mantle cell lymphoma, CLL, Marginal Zone, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. Methods: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Twenty-five patients were enrolled (3 at 560 mg; 22 at 840 mg). Median age was 68 (range 21-85); 15 were women. Median ECOG was 1 (0: 2, 1: 15, 2: 8). 64% had PCNSL and 36% SCNSL; 68% had recurrent disease. Seventeen had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 5 both. Seven grade 4 adverse events were observed in 7 patients neutropenia (in 3 patients), lymphopenia (2), sepsis (1), and ALT elevation (1). Fourteen patients developed 20 grade 3 toxicities, including lymphopenia in 5 patients, hyperglycemia in 3, ALT elevation in 2, thrombocytopenia in 2, lung infection in 2, AST elevation in 1, neutropenia in 1, urinary tract infection in 1, colitis in 1, febrile neutropenia in 1 and fungal encephalitis in 1. The most common toxicities at any grade were hyperglycemia, thrombocytopenia and anemia of which most were grade 1/2. No grade 5 events have been observed. After a median follow-up of 414 days (range 289-674), 22/25 patients were evaluated for response (3 did not complete at least 15 days of drug treatment). Over all response was 68% (17/22; 77% (17/22) in patient that completed at least 15 days of drug treatment) with 10 CR, 7 PR, 2 SD and 3 PD as best response. The median PFS is 4.6 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 15.3 months). The median overall survival has not been reached. Conclusions: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 68% of CNS lymphoma patients. Clinical trial information: NCT02315326.