Relationship between apparent diffusion coefficient and survival as a function of distance from gross tumor volume on radiation planning MRI in newly diagnosed glioblastoma.

PURPOSE: To investigate the changes in apparent diffusion coefficient (ADC) within incrementally-increased margins beyond the gross tumor volume (GTV) on post-operative radiation planning MRI and their prognostic utility in glioblastoma. METHODS: Radiation planning MRIs of adult patients with newly diagnosed glioblastoma from 2017 to 2020 were assessed. The ADC values were normalized to contralateral normal white matter (nADC). Using 1 mm isotropic incremental margin increases from the GTV, the nADC values were calculated at each increment. Age, ECOG performance status, extent of resection and MGMT promoter methylation status were obtained from medical records. Using univariate and multivariable Cox regression analysis, association of nADC to progression-free and overall survival (PFS, OS) was assessed at each increment. RESULTS: Seventy consecutive patients with mean age of 53.6 ± 10.3 years, were evaluated. The MGMT promoter was methylated in 31 (44.3%), unmethylated in 36 (51.6%) and unknown in 3 (4.3%) patients. 11 (16%) underwent biopsy, 41 (44%) subtotal resection and 18 (26%) gross total resection. For each 1 mm increase in distance from GTV, the nADC decreased by 0.16% (p < 0.0001). At 1-5 mm increment, the nADC was associated with OS (p < 0.01). From 6 to 11 mm increment the nADC was associated with OS with the p-value gradually increasing from 0.018 to 0.046. nADC was not associated with PFS. CONCLUSION: The nADC values at 1-11 mm increments from the GTV margin were associated with OS. Future prospective multicenter studies are needed to validate the findings and to pave the way for the utilization of ADC for margin reduction in radiation planning.

Proposing a quantitative MRI-based linear measurement framework for response assessment following stereotactic body radiation therapy in patients with spinal metastasis.

PURPOSE: To provide evidence towards a quantitative response assessment framework incorporating MRI-based linear measurements for spinal metastasis that predicts outcome following stereotactic body radiation therapy (SBRT). METHODS: Adult patients with de novo spinal metastases treated with SBRT between 2008 and 2018 were retrospectively assessed. The metastatic lesions involving the pedicles, articular processes, lamina, transverse process, spinous process and vertebral body at leach level were measured separately using linear measurements on pre- and all post-SBRT MRIs. The outcome was segment-specific progression (SSP) using SPINO guidelines which was dated to the first clinical documentation of progression, or the date of the associated MRI if imaging was the reason for progression. Random forest analysis for variable selection and recursive partitioning analysis for SSP probability prediction were used. RESULTS: Five Hundred Ninety-three spinal levels (323 patients) from 4081 MRIs were evaluated. The appearance of new T1 hypointensity and increase in Bilsky grade had an odds ratio (OR) of 33.5 and 15.5 for SSP, respectively. Compared to baseline, an increase of > 3 mm in any lesion dimension, combined with a 1.67-fold increase in area, had an OR of 4.6 for SSP. The sensitivity, specificity, positive predictive value, negative predictive value, balanced accuracy and area under the curve of the training model were 96.7%, 89.6%, 28.6%, 99.8%, 93.2% and 0.905 and of the test model were 91.3%, 89.3%, 27.1% 99.6%, 90.3% and 0.933, respectively. CONCLUSION: With further refinement and validation in prospective multicentre studies, MRI-based linear measurements can help predict response assessment in SBRT-treated spinal metastases.

Quantitative CEST and MT at 1.5T for monitoring treatment response in glioblastoma: early and late tumor progression during chemoradiation.

PURPOSE: Quantitative MRI (qMRI) was performed using a 1.5T protocol that includes a novel chemical exchange saturation transfer/magnetization transfer (CEST/MT) approach. The purpose of this prospective study was to determine if qMRI metrics at baseline, at the 10th and 20th fraction during a 30 fraction/6 week standard chemoradiation (CRT) schedule, and at 1 month following treatment could be an early indicator of response for glioblastoma (GBM). METHODS: The study included 51 newly diagnosed GBM patients. Four regions-of-interest (ROI) were analyzed: (i) the radiation defined clinical target volume (CTV), (ii) radiation defined gross tumor volume (GTV), (iii) enhancing-tumor regions, and (iv) FLAIR-hyperintense regions. Quantitative CEST, MT, T1 and T2 parameters were compared between those patients progressing within 6.9 months (early), and those progressing after CRT (late), using mixed modelling. Exploratory predictive modelling was performed to identify significant predictors of early progression using a multivariable LASSO model. RESULTS: Results were dependent on the specific tumor ROI analyzed and the imaging time point. The baseline CEST asymmetry within the CTV was significantly higher in the early progression cohort. Other significant predictors included the T2 of the MT pools (for semi-solid at fraction 20 and water at 1 month after CRT), the exchange rate (at fraction 20) and the MGMT methylation status. CONCLUSIONS: We observe the potential for multiparametric qMRI, including a novel pulsed CEST/MT approach, to show potential in distinguishing early from late progression GBM cohorts. Ultimately, the goal is to personalize therapeutic decisions and treatment adaptation based on non-invasive imaging-based biomarkers.

Clinical and histopathological outcome of cervical and chest MRI involving non-MRI-conditional cardiac pacemakers: a study using sheep models.

AIM: To examine the clinical and histopathological consequences of MRI in sheep implanted with non-MRI-conditional cardiac pacemakers. MATERIALS AND METHODS: Under general anesthesia, active fixation leads of two dual-chamber, non-MRI-conditional cardiac pacemakers (St. Jude Medical and Medtronic) were implanted either at the right ventricular apex or at the right atrium of two male sheep and connected to the V and A channels of the pacemakers, respectively. The generators were placed in cervical subcutaneous pockets. On day 5, both sheep underwent 1.5 T cervical and chest MRI with continuous electrocardiogram monitoring. Obtained sequences were T1-weighted (T1W), T2-weighted (T2W), T2-gradient echo and diffusion weighted (DW). The employed modes were OVO, VOO and VVI for one sheep and OAO, AOO and AAI for the other (unipolar and bipolar configuration of pacing and sensing for both). Battery impedance, pacing lead impedance, intrinsic amplitude and capture thresholds were checked at baseline and after each sequence, as well as 48 h after imaging. Histopathological examination of the cardiac tissue around the lead tip was performed 4 weeks post-imaging. RESULTS: No significant changes in device position or configuration were observed during or after MRI. Clinical outcome was uneventful in both sheep. Minor inflammatory and necrotic changes were reported after histopathological examination of the cardiac tissue around the lead tip. CONCLUSION: 1.5 T MRI of two implanted non-MRI-conditional pacemakers was found safe in terms of device configuration and stability, clinical outcome and cardiac tissue histopathological findings.

Hypoxia Detection in Infiltrative Astrocytoma: Ferumoxytol-based Quantitative BOLD MRI with Intraoperative and Histologic Validation.

Purpose To validate ferumoxytol-based quantitative blood oxygenation level-dependent (BOLD) MRI for mapping oxygenation of human infiltrative astrocytomas by using intraoperative measurement of tissue oxygen tension and histologic staining. Materials and Methods Fifteen patients with infiltrative astrocytomas were recruited into this prospective multicenter study between July 2014 and December 2016. Prior to treatment, participants underwent preoperative quantitative BOLD MRI with ferumoxytol to generate tissue oxygen saturation (StO2) maps. Two intratumoral sites were identified, one with low StO2 and one with high StO2. Neuronavigation was used to locate sites intraoperatively for insertion of oxygen-sensing probes to measure local tissue oxygen tension (PtO2). Biopsies from both sites were taken and stained for markers of hypoxia (hypoxia-inducible factor 1α, carbonic anhydrase IX) and neoangiogenesis (vascular endothelial growth factor, endoglin [CD105]). Spearman correlation and nonparametric sign-rank tests were used to analyze data. Results Ten patients with median age of 58.5 years (interquartile range, 25 years; four men and six women) completed the study. Because there is no linear relationship between StO2 and PtO2, the ratios of low to high StO2 versus low to high PtO2 in each patient were compared and a significant correlation was found (r = 0.73; P = .01). Pathologic analyses revealed differences between carbonic anhydrase IX (P = .03) for sites of low StO2 versus high StO2. CD105 displayed a similar trend but was not significant (P = .09). Conclusion Ferumoxytol-based quantitative blood oxygenation level-dependent MRI can potentially be used as a noninvasive surrogate for oxygenation mapping in infiltrative astrocytomas. This technique can potentially be integrated in treatment planning for aggressive targeting of hypoxic areas in tumors.

Spinal metastases: multimodality imaging in diagnosis and stereotactic body radiation therapy planning.

Due to increased effectiveness of cancer treatments and increasing survival rates, metastatic disease has become more frequent compared to the past, with the spine being the most common site of bony metastases. Diagnostic imaging is an integral part of screening, diagnosis and follow-up of spinal metastases. In this article, we review the principles of multimodality imaging for tumor detection with respect to their value for diagnosis and stereotactic body radiation therapy planning for spinal metastases. We will also review the current international consensus agreement for stereotactic body radiation therapy planning, and the role of imaging in achieving the best possible treatment plan.

Radiologic Differences between Human Papillomavirus-Related and Human Papillomavirus-Unrelated Oropharyngeal Carcinoma on Diffusion-Weighted Imaging.

BACKGROUND AND PURPOSE: Human papilloma virus-related oropharyngeal carcinoma (HPV+ OPC) is a unique entity compared to HPV-unrelated (HPV-) OPC. Previous studies were inconclusive regarding the differences between HPV+ and HPV- OPCs on diffusion-weighted imaging (DWI). This study sought to determine if there is an association between HPV status and apparent diffusion coefficient (ADC) values as an imaging biomarker in OPCs. MATERIALS AND METHODS: OPC patients with pretreatment MRI including DWI were retrospectively reviewed and analyzed as a blinded, controlled cohort. HPV status was biopsy-ascertained with p16 staining. ADC values were determined by placing the largest possible circular region of interest in solid portions of primary tumors and/or metastatic lymph nodes. Necrotic and cystic portions were excluded. RESULTS: Twenty-eight HPV+ and 12 HPV- patients were included. Adjusted for age and sex, ADC values were significantly lower in HPV+ OPC primary tumors (p = 0.013) and lymph node metastases (p = 0.013). The area under the curve (AUC) was 0.85 and 0.90, respectively. A model with a linear combination of the 2 variables yielded an AUC of 0.92. CONCLUSION: ADC values were significantly lower in both the primary tumors and lymph node metastases in HPV+ OPCs compared to HPV- OPCs. These results confirm the results of prior studies.

Magnetic Resonance Imaging Frequency After Stereotactic Body Radiation Therapy for Spine Metastases.

PURPOSE: Stereotactic body radiation therapy (SBRT) is increasingly being used to treat spine metastases. Current post-SBRT imaging surveillance strategies in this patient population may benefit from a more data-driven and personalized approach. The objective of this study was to develop risk-stratified post-SBRT magnetic resonance imaging (MRI) surveillance strategies using quantitative methods. METHODS AND MATERIALS: Adult patients with bony spine metastases treated with SBRT between 2008 and 2021 and who had at least 2 follow-up spine MRIs were reviewed retrospectively. A recursive partitioning analysis model was developed to separate patients into different risk categories for post-SBRT progression anywhere within the spine. Imaging intervals were derived for each risk category using parametric survival regression based on multiple expected spine progression rates per scan. RESULTS: A total of 446 patients and 1039 vertebral segments were included. Cumulative incidence of spine progression was 19.2% at 1 year, 26.7% at 2 years, and 35.3% at 4 years. The internally validated risk stratification model was able to divide patients into 3 risk categories based on epidural disease, paraspinal disease, and Spinal Instability Neoplastic Score category. The 4-year risk of spine progression was 23.4%, 39.0%, and 51.8%, respectively, for the low-, intermediate-, and high-risk groups. Using an expected per-scan spine progression rate of 3.75%, the low-risk group would require follow-up scans every 6.0 months (95% CI, 4.9-7.6) and the intermediate-risk group would require surveillance every 3.1 months (95% CI, 2.6-3.7). At an expected spine progression rate of 5%, the high-risk group would require surveillance every 1.3 months (95% CI, 1.1-1.6) during the first 13.2 months after SBRT and every 5.9 months thereafter (95% CI, 2.8-12.3). CONCLUSIONS: Data-driven follow-up MRI surveillance intervals at a range of expected spine progression rates have been determined for patients at different risks of spine progression based on an internally validated, single-institution risk stratification model.

Chemical Exchange Saturation Transfer MRI: What Neuro-Oncology Clinicians Need To Know.

Chemical exchange saturation transfer (CEST) is a relatively novel magnetic resonance imaging (MRI) technique with an image contrast designed for in vivo measurement of certain endogenous molecules with protons that are exchangeable with water protons, such as amide proton transfer commonly used for neuro-oncology applications. Recent technological advances have made it feasible to implement CEST on clinical grade scanners within practical acquisition times, creating new opportunities to integrate CEST in clinical workflow. In addition, the majority of CEST applications used in neuro-oncology are performed without the use gadolinium-based contrast agents which are another appealing feature of this technique. This review is written for clinicians involved in neuro-oncologic care (nonphysicists) as the target audience explaining what they need to know as CEST makes its way into practice. The purpose of this article is to (1) review the basic physics and technical principles of CEST MRI, and (2) review the practical applications of CEST in neuro-oncology.

Pattern of Recurrence of Glioblastoma Versus Grade 4 IDH-Mutant Astrocytoma Following Chemoradiation: A Retrospective Matched-Cohort Analysis.

Background and Purpose: To quantitatively compare the recurrence patterns of glioblastoma (isocitrate dehydrogenase-wild type) versus grade 4 isocitrate dehydrogenase-mutant astrocytoma (wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase, respectively) following primary chemoradiation. Materials and Methods: A retrospective matched cohort of 22 wild type isocitrate dehydrogenase and 22 mutant isocitrate dehydrogenase patients were matched by sex, extent of resection, and corpus callosum involvement. The recurrent gross tumor volume was compared to the original gross tumor volume and clinical target volume contours from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the recurrent gross tumor volume outside the gross tumor volume and clinical target volume, and positional differences of the recurrent gross tumor volume centroid from the gross tumor volume and clinical target volume. Results: The gross tumor volume was smaller for wild type isocitrate dehydrogenase patients compared to the mutant isocitrate dehydrogenase cohort (mean ± SD: 46.5 ± 26.0 cm3 vs 72.2 ± 45.4 cm3, P = .026). The recurrent gross tumor volume was 10.7 ± 26.9 cm3 and 46.9 ± 55.0 cm3 smaller than the gross tumor volume for the same groups (P = .018). The recurrent gross tumor volume extended outside the gross tumor volume in 22 (100%) and 15 (68%) (P= .009) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively; however, the volume of recurrent gross tumor volume outside the gross tumor volume was not significantly different (12.4 ± 16.1 cm3 vs 8.4 ± 14.2 cm3, P = .443). The recurrent gross tumor volume centroid was within 5.7 mm of the closest gross tumor volume edge for 21 (95%) and 22 (100%) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively. Conclusion: The recurrent gross tumor volume extended beyond the gross tumor volume less often in mutant isocitrate dehydrogenase patients possibly implying a differential response to chemoradiotherapy and suggesting isocitrate dehydrogenase status might be used to personalize radiotherapy. The results require validation in prospective randomized trials.

ADC, D, f dataset calculated through the simplified IVIM model, with MGMT promoter methylation, age, and ECOG, in 38 patients with wildtype IDH glioblastoma.

Patients undergoing standard chemoradiation post-resection had MRIs at radiation planning and fractions 10 and 20 of chemoradiation. MRIs were 1.5T and 3D T2-FLAIR, pre- and post-contrast 3D T1-weighted (T1) and echo planar DWI with three b-values (0, 500, and 1000s/mm2) were acquired. T2-FLAIR was coregistered to T1C images. Non-overlapping T1 contrast-enhancing (T1C) and nonenhancing T2-FLAIR hyperintense regions were segmented, with necrotic/cystic regions, the surgical cavity, and large vessels excluded. The simplified IVIM model was used to calculate voxelwise diffusion coefficient (D) and perfusion fraction (f) maps; ADC was calculated using the natural logarithm of b = 1000 over b = 0 images. T1C and T2-FLAIR segmentations were brought into this space, and medians calculated. MGMT promoter methylation status (MGMTPMS), age at diagnosis, and Eastern Cooperative Oncology Group (ECOG) performance status were extracted from electronic medical records. The data were presented, analyzed, and described in the article, "Intravoxel incoherent motion (IVIM) modeling of diffusion MRI during chemoradiation predicts therapeutic response in IDH wildtype Glioblastoma", published in Radiotherapy and Oncology [1].

The Initial Step Towards Establishing a Quantitative, Magnetic Resonance Imaging-Based Framework for Response Assessment of Spinal Metastases After Stereotactic Body Radiation Therapy.

BACKGROUND: There are no established threshold values regarding the degree of growth on imaging when assessing response of spinal metastases treated with stereotactic body radiation therapy (SBRT). OBJECTIVE: To determine a magnetic resonance imaging-based minimum detectable difference (MDD) in gross tumor volume (GTV) and its association with 1-yr radiation site-specific (RSS) progression-free survival (PFS). METHODS: GTVs at baseline and first 2 post-SBRT scans (Post1 and Post2, respectively) for 142 spinal segments were contoured, and percentage volume change between scans calculated. One-year RSS PFS was acquired from medical records. The MDD was determined. The MDD was compared against optimal thresholds of GTV changes associated with 1-yr RSS PFS using Youden's J index, and receiver operating characteristic curves between timepoints compared to determine which timeframe had the best association. RESULTS: A total of 17 of the 142 segments demonstrated progression. The MDD was 10.9%. Baseline-Post2 demonstrated the best performance (area under the curve [AUC] 0.90). Only Baseline-Post2 had an optimal threshold > MDD at 14.7%. Due to large distribution of GTVs, volumes were split into tertiles. Small tumors (GTV < 2 cc) had optimal thresholds of 42.0%, 71.3%, and 37.2% at Baseline-Post1 (AUC 0.81), Baseline-Post2 (AUC 0.89), and Post1-Post2 (AUC 0.77), respectively. Medium tumors (2 ≤ GTV ≤ 8.3 cc) all demonstrated optimal thresholds < MDD, with AUCs ranging from 0.65 to 0.84. Large tumors (GTV > 8.3 cc) had 2 timepoints where optimal thresholds > MDD: Baseline-Post2 (13.3%; AUC 0.97) and Post1-Post2 (11.8%; AUC 0.66). Baseline-Post2 had the best association with RSS PFS for all tertiles. CONCLUSION: Given a MDD of 10.9%, for small GTVs, larger (>37%) changes were required before local failure could be determined, compared to 11% to 13% for medium/large tumors.

Intravoxel incoherent motion (IVIM) modeling of diffusion MRI during chemoradiation predicts therapeutic response in IDH wildtype glioblastoma.

BACKGROUND: Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome. METHODS: 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADCT1C, ADCT2-FLAIR) and perfusion fraction (fT1C, fT2-FLAIR) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated. RESULTS: Higher ADCT2-FLAIR at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01-1.15, p = 0.025], lower fT2-FLAIR at fraction 10 (OR = 2.11, 95% CI 1.04-4.27, p = 0.018), and lack of increase in ADCT2-FLAIR at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02-1.22, p = 0.02) were associated with early progression. Combining ADCT2-FLAIR at baseline, fT2-FLAIR at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher fT2-FLAIR at fraction 10 (HR = 0.72, 95% CI 0.56-0.95, p = 0.018) was associated with longer PFS. CONCLUSION: ADCT2-FLAIR at baseline, its lack of increase from baseline to fraction 20, or fT2-FLAIR at fraction 10 significantly predicted early progression. fT2-FLAIR at fraction 10 was associated with PFS.

Quantitative diffusion magnetic resonance imaging for prediction of human papillomavirus status in head and neck squamous-cell carcinoma: A systematic review and meta-analysis.

PURPOSE: Head and neck squamous-cell carcinoma (HNSCC) related to human papillomavirus (HPV) infection represents a distinct biological and prognostic subtype compared to the HPV-negative form. Prior studies suggest a correlation between the apparent diffusion coefficient (ADC) values on diffusion-weighted imaging (DWI) of primary tumor lesion and HPV status in HNSCC. In this meta-analysis, we compared the average ADC of primary lesion between HPV-positive and HPV-negative HNSCC. METHODS: A comprehensive literature search of PubMed and Embase was performed. Studies comparing the average ADC on echo-planar DWI of primary tumor lesions between HPV-positive and HPV-negative HNSCC were included. The standardized mean difference was calculated using fixed- and random-effects models. Tau-squared estimates of total heterogeneity and Higgins inconsistency index (I2 test) were determined. RESULTS: A total of five studies, pooling data of 264 patients, were included for meta-analysis. Among these five studies, three had included oral cavity, hypopharyngeal, and/or laryngeal HNSCC in addition to oropharyngeal subsite. Primary lesions were comprised of 185 HPV-negative and 79 HPV-positive HNSCC. The meta-analysis showed lower average ADC values in HPV-positive HNSCC compared to the HPV-negative form, with a standardized mean difference of 0.961 (95% confidence interval 0.644-1.279; p < 0.0001). Since there was no significant heterogeneity in analysis (p = 0.3852), both random- and fixed-effects models resulted in the same estimates of overall effect. CONCLUSIONS: HPV-positive HNSCC primary lesions have a lower average ADC compared to the HPV-negative form, highlighting the potential application of quantitative diffusion magnetic resonance imaging as a noninvasive imaging biomarker for prediction of HPV status.

Incidence and Time of Onset of Osseous Pseudoprogression in Patients With Metastatic Spine Disease From Renal Cell or Prostate Carcinoma After Treatment With Stereotactic Body Radiation Therapy.

BACKGROUND: Tumor osseous pseudoprogression (PP), defined as an imaging-based transient increase in tumor size following treatment, was recently described in patients with spinal metastases following stereotactic body radiation therapy. Distinguishing PP from true tumor progression is critical. OBJECTIVE: To describe the incidence, time of onset, and time range of PP following stereotactic body radiation therapy in patients treated for spinal metastases from either prostate cancer (PC) or renal cell carcinoma (RCC), and associated predictive factors. METHODS: A retrospective study was conducted on our institution's cancer database from 2009 to 2015. Selection was based on single level, no prior radiation or surgery, ≥2 follow-up spine magnetic resonance imaging (MRI), and metastases arising from either PC or RCC. Gross tumor volume was contoured on pre- and up to 5 posttreatment MRIs. Patients were sorted into groups depending on gross tumor volume response: PP, non-PP, or progressive disease. Clinical and dosimetric variables were compared using either Fisher's exact test or Kruskal-Wallis analyses. RESULTS: Forty-three spinal segments from 31 patients were analyzed. RCC and PC patients showed similar incidence of PP (∼37%). Whether the primary was lytic or sclerotic was a significant predictive factor with more PP in the lytic group (P = .0208). There was a trend of earlier PP onset in RCC (within 6-18 mo) as compared to PC; however, PC segments showed more time-confined presentation of PP (9-12 mo). CONCLUSION: There was a higher incidence of PP in lytic compared to sclerotic primary tumor type. PP in spinal metastatic sites may have variable presentations depending on the primary cancer.

Incidence of Dural Venous Sinus Thrombosis in Patients with Glioblastoma and Its Implications.

OBJECTIVE: Glioblastoma (GBM) is associated with increased risk of developing dural venous sinus thrombosis (DVST), which often goes undiagnosed as symptoms are readily attributed to tumor. The purpose of this study was to investigate the incidence of DVST, potential predictive features on imaging, complications, its effect on survival, and time of greatest risk for developing DVST. METHODS: A retrospective search of patients with GBM who had surgery followed by chemotherapy and/or radiation therapy between 2009 and 2015 at our institution was performed. Magnetic resonance imaging studies of the brain were reviewed on volumetric postgadolinium T1-weighted sequences for DVST. Tumors were characterized using the Visually Accessible REMBRANDT (Repository for Molecular Brain Neoplasia Data) Images classification, and identified thromboses were tracked for propagation, regression, or resolution. Statistical analyses were directed at identifying clinical predictors and survival differences between the DVST and no-DVST groups. RESULTS: In total, 163 cases totaling 1637 scans, were reviewed; 12 patients (7.4%) developed DVST, of whom 11 presented with thrombus before any treatment. Tumor invasion of dural sinuses and greater T1/fluid-attenuated inversion recovery ratios were significantly associated with thrombus development (P = 0.02 and P = 0.02, respectively). In patients who developed DVST, thrombosis was more likely to develop ipsilateral to tumor side (P = 0.01) and was associated with a greater likelihood of developing extracranial venous thromboembolism (P = 0.012). There were no venous infarcts and no significant difference in survival between groups (P = 0.83). CONCLUSIONS: Patients with GBM have increased risk of developing DVST, independent of surgical treatment or chemoradiation. DVST presence does not affect survival. Tumor invasion of dural sinuses and greater T1/fluid-attenuated inversion recovery ratio on preoperative imaging were the most significant predictors of DVST development.

Melanin-concentrating hormone (MCH) neurons in the developing chick brain.

The present study was undertaken because no previous developmental studies exist on MCH neurons in any avian species. After validating a commercially-available antibody for use in chickens, immunohistochemical examinations first detected MCH neurons around embryonic day (E) 8 in the posterior hypothalamus. This population increased thereafter, reaching a numerical maximum by E20. MCH-positive cell bodies were found only in the posterior hypothalamus at all ages examined, restricted to a region showing very little overlap with the locations of hypocretin/orexin (H/O) neurons. Chickens had fewer MCH than H/O neurons, and MCH neurons also first appeared later in development than H/O neurons (the opposite of what has been found in rodents). MCH neurons appeared to originate from territories within the hypothalamic periventricular organ that partially overlap with the source of diencephalic serotonergic neurons. Chicken MCH fibers developed exuberantly during the second half of embryonic development, and they became abundant in the same brain areas as in rodents, including the hypothalamus (by E12), locus coeruleus (by E12), dorsal raphe nucleus (by E20) and septum (by E20). These observations suggest that MCH cells may play different roles during development in chickens and rodents; but once they have developed, MCH neurons exhibit similar phenotypes in birds and rodents.

Activation of state-regulating neurochemical systems in newborn and embryonic chicks.

Coordinated activity in different sets of widely-projecting neurochemical systems characterize waking (W) and sleep (S). How and when this coordination is achieved during development is not known. We used embryos and newborns of a precocial bird species (chickens) to assess developmental activation in different neurochemical systems using cFos expression, which has been extensively employed to examine cellular activation during S and W in adult mammals. Similarly to adult mammals, newborn awake chicks showed significantly higher cFos expression in W-active hypocretin/orexin (H/O), serotonergic Dorsal Raphe, noradrenergic Locus Coeruleus and cholinergic Laterodorsal and Pedunculopontine Tegmental (Ch-LDT/PT) neurons when compared to sleeping chicks. cFos expression was significantly correlated both between these systems, and with the amount of W. S-active melanin-concentrating hormone (MCH) neurons showed very low cFos expression with no difference between sleeping and awake chicks, possibly due to the very short duration of S episodes. In embryonic chicks, cFos expression was low or absent across all five systems at embryonic day (E) 12. Unexpectedly, a strong activation was seen at E16 in H/O neurons. The highest activation of Ch-LDT/PT (also S-active) and MCH neurons was seen at E20. These data suggest that maturation of arousal systems is achieved soon after hatching, while S-control networks are active in late chick embryos.