Identification of the Language Network from Resting-State fMRI in Patients with Brain Tumors: How Accurate Are Experts?

BACKGROUND AND PURPOSE: Resting-state fMRI helps identify neural networks in presurgical patients who may be limited in their ability to undergo task-fMRI. The purpose of this study was to determine the accuracy of identifying the language network from resting-state-fMRI independent component analysis (ICA) maps. MATERIALS AND METHODS: Through retrospective analysis, patients who underwent both resting-state-fMRI and task-fMRI were compared by identifying the language network from the resting-state-fMRI data by 3 reviewers. Blinded to task-fMRI maps, these investigators independently reviewed resting-state-fMRI ICA maps to potentially identify the language network. Reviewers ranked up to 3 top choices for the candidate resting-state-fMRI language map. We evaluated associations between the probability of correct identification of the language network and some potential factors. RESULTS: Patients included 29 men and 14 women with a mean age of 41 years. Reviewer 1 (with 17 years' experience) demonstrated the highest overall accuracy with 72%; reviewers 2 and 3 (with 2 and 7 years' experience, respectively) had a similar percentage of correct responses (50% and 55%). The highest accuracy used ICA50 and the top 3 choices (81%, 65%, and 60% for reviewers 1, 2, and 3, respectively). The lowest accuracy used ICA50, limiting each reviewer to the top choice (58%, 35%, and 42%). CONCLUSIONS: We demonstrate variability in the accuracy of blinded identification of resting-state-fMRI language networks across reviewers with different years of experience.

High-Resolution MRI for Evaluation of Ventriculostomy Tubes: Assessment of Positioning and Proximal Patency.

BACKGROUND AND PURPOSE: Imaging evaluation of ventriculostomy tubes, despite the frequency of malfunction, has remained inadequate due to the absence of a systematic way of assessing the catheter itself. In this retrospective review, we assessed the utility of high-resolution 3D MR imaging techniques, including CISS and volumetric interpolated breath-hold examination sequences, in the evaluation of ventriculostomy catheters. MATERIALS AND METHODS: We performed a retrospective review of 23 clinical MR imaging cases of shunted hydrocephalus spanning a 3-year period, all depicting ventriculostomy catheters. The MR imaging examinations included isotropic CISS and volumetric interpolated breath-hold examination sequences performed with and without contrast. These were independently evaluated by 2 neuroradiologists with respect to the catheter course, side hole position, relationship of the side holes to the ventricles, patency, and the presence or absence of intraluminal debris. RESULTS: The catheter tip was best seen on isotropic CISS sequences reformatted in an oblique plane, and side holes were visualized as CSF signal defects along the catheter wall in 10/23 (43%) cases. The relationship of the catheter side holes to the ventricles was seen in 47% of cases and was best visualized on the coronal CISS sequences. Catheter patency was confirmed in 12/23 (52%) cases, while the other 48% were notable for T2 hypointense filling defects compatible with luminal obstruction. Enhancement of some of these filling defects on imaging is suggestive of choroid plexus ingrowth rather than debris. CONCLUSIONS: High-resolution 3D MR imaging using isotropic CISS sequences allows systematic evaluation of catheter positioning, patency, and potential etiologic differentiation of filling defects when shunt dysfunction is suspected.

Preoperative Mapping of the Supplementary Motor Area in Patients with Brain Tumor Using Resting-State fMRI with Seed-Based Analysis.

BACKGROUND AND PURPOSE: The supplementary motor area can be a critical region in the preoperative planning of patients undergoing brain tumor resection because it plays a role in both language and motor function. While primary motor regions have been successfully identified using resting-state fMRI, there is variability in the literature regarding the identification of the supplementary motor area for preoperative planning. The purpose of our study was to compare resting-state fMRI to task-based fMRI for localization of the supplementary motor area in a large cohort of patients with brain tumors presenting for preoperative brain mapping. MATERIALS AND METHODS: Sixty-six patients with brain tumors were evaluated with resting-state fMRI using seed-based analysis of hand and orofacial motor regions. Rates of supplementary motor area localization were compared with those in healthy controls and with localization results by task-based fMRI. RESULTS: Localization of the supplementary motor area using hand motor seed regions was more effective than seeding using orofacial motor regions for both patients with brain tumor (95.5% versus 34.8%, P < .001) and controls (95.2% versus 45.2%, P < .001). Bilateral hand motor seeding was superior to unilateral hand motor seeding in patients with brain tumor for either side (95.5% versus 75.8%/75.8% for right/left, P < .001). No difference was found in the ability to identify the supplementary motor area between patients with brain tumors and controls. CONCLUSIONS: In addition to task-based fMRI, seed-based analysis of resting-state fMRI represents an equally effective method for supplementary motor area localization in patients with brain tumors, with the best results obtained with bilateral hand motor region seeding.

Presurgical Brain Mapping of the Ventral Somatomotor Network in Patients with Brain Tumors Using Resting-State fMRI.

BACKGROUND AND PURPOSE: Resting-state fMRI readily identifies the dorsal but less consistently the ventral somatomotor network. Our aim was to assess the relative utility of resting-state fMRI in the identification of the ventral somatomotor network via comparison with task-based fMRI in patients with brain tumor. MATERIALS AND METHODS: We identified 26 surgically naïve patients referred for presurgical fMRI brain mapping who had undergone both satisfactory ventral motor activation tasks and resting-state fMRI. Following standard preprocessing for task-based fMRI and resting-state fMRI, general linear model analysis of the ventral motor tasks and independent component analysis of resting-state fMRI were performed with the number of components set to 20, 30, 40, and 50. Visual overlap of task-based fMRI and resting-state fMRI at different component levels was assessed and categorized as full match, partial match, or no match. Rest-versus-task-fMRI concordance was calculated with Dice coefficients across varying fMRI thresholds before and after noise removal. Multithresholded Dice coefficient volume under the surface was calculated. RESULTS: The ventral somatomotor network was identified in 81% of patients. At the subject level, better matches between resting-state fMRI and task-based fMRI were seen with an increasing order of components (53% of cases for 20 components versus 73% for 50 components). Noise-removed group-mean volume under the surface improved as component numbers increased from 20 to 50, though ANOVA demonstrated no statistically significant difference among the 4 groups. CONCLUSIONS: In most patients, the ventral somatomotor network can be identified with an increase in the probability of a better match at a higher component number. There is variable concordance of the ventral somatomotor network at the single-subject level between resting-state and task-based fMRI.

The NAD(+) salvage pathway modulates cancer cell viability via p73.

The involvement of the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD(+) salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD(+) salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.

Oncolytic reovirus induces intracellular redistribution of Ras to promote apoptosis and progeny virus release.

Reovirus is a naturally oncolytic virus that preferentially replicates in Ras-transformed cells and is currently undergoing clinical trials as a cancer therapeutic. Ras transformation promotes reovirus oncolysis by enhancing virion disassembly during entry, viral progeny production, and virus release through apoptosis; however, the mechanism behind the latter is not well understood. Here, we show that reovirus alters the intracellular location of oncogenic Ras to induce apoptosis of H-RasV12-transformed fibroblasts. Reovirus infection decreases Ras palmitoylation levels and causes accumulation of Ras in the Golgi through Golgi fragmentation. With the Golgi being the site of Ras palmitoylation, treatment of target cells with the palmitoylation inhibitor, 2-bromopalmitate (2BP), prompts a greater accumulation of H-RasV12 in the Golgi, and a dose-dependent increase in progeny virus release and subsequent spread. Conversely, tethering H-RasV12 to the plasma membrane (thereby preventing its movement to the Golgi) allows for efficient virus production, but results in basal levels of reovirus-induced cell death. Analysis of Ras downstream signaling reveals that cells expressing cycling H-RasV12 have elevated levels of phosphorylated JNK (c-Jun N-terminal kinase), and that Ras retained at the Golgi body by 2BP increases activation of the MEKK1/MKK4/JNK signaling pathway to promote cell death. Collectively, our data suggest that reovirus induces Golgi fragmentation of target cells, and the subsequent accumulation of oncogenic Ras in the Golgi body initiates apoptotic signaling events required for virus release and spread.

Gemcitabine enhances the efficacy of reovirus-based oncotherapy through anti-tumour immunological mechanisms.

BACKGROUND: Reovirus preferentially infects and kills cancer cells and is currently undergoing clinical trials internationally. While oncolysis is the primary mode of tumour elimination, increasing evidence illustrates that reovirus additionally stimulates anti-tumour immunity with a capacity to target existing and possibly relapsing cancer cells. These virus-induced anti-tumour immune activities largely determine the efficacy of oncotherapy. On the other hand, anti-viral immune responses can negatively affect oncotherapy. Hence, the strategic management of anti-tumour and anti-viral immune responses through complementary therapeutics is crucial to achieve the maximum anti-cancer benefits of oncotherapy. METHODS: Intra-peritoneal injection of mouse ovarian surface epithelial cells (ID8 cells) into wild-type C57BL/6 mice was treated with a therapeutic regimen of reovirus and/or gemcitabine and then analysed for prolonged survival, disease pathology, and various immunological parameters. Furthermore, in vitro analyses were conducted to assess apoptosis, viral spread, and viral production during reovirus and/or gemcitabine treatment. RESULTS: We demonstrate that reovirus and gemcitabine combination treatment postpones peritoneal carcinomatosis development and prolongs the survival of cancer-bearing hosts. Importantly, these anti-cancer benefits are generated through various immunological mechanisms, including: (1) inhibition of myeloid-derived suppressor cells recruitment to the tumour microenvironment, (2) downmodulation of pro-MDSC factors, and (3) accelerated development of anti-tumour T-cell responses. CONCLUSION: The complementation of reovirus with gemcitabine further potentiates virus-initiated anti-cancer immunity and enhances the efficacy of oncotherapy. In the context of ongoing clinical trials, our findings represent clinically relevant information capable of enhancing cancer outcomes.

Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy.

Gemcitabine is a chemotherapeutic that is widely used for the treatment of a variety of haematological malignancies and has become the standard chemotherapy for the treatment of advanced pancreatic cancer. Combinational gemcitabine regimes (e.g.with doxorubicin) are being tested in clinical trials to treat a variety of cancers, including colon cancer. The limited success of these trials has prompted us to pursue a better understanding of gemcitabine's mechanism of cell killing, which could dramatically improve the therapeutic potential of this agent. For comparison, we included gamma irradiation that triggers robust cell cycle arrest and Cr(VI), which is a highly toxic chemical that induces a robust p53-dependent apoptotic response. Gemcitabine induced a potent p53-dependent apoptosis that correlated with the accumulation of pro-apoptotic proteins such as PUMA and Bax. This is accompanied by a drastic reduction in p2l and 14-3-3σ protein levels, thereby significantly sensitizing the cells to apoptosis. In vitro and in vivo studies demonstrated that gemcitabine required PUMA transcription to instigate an apoptotic programme. This was in contrast to Cr(VI)-induced apoptosis that required Bax and was independent of transcription. An examination of clinical colon and pancreatic cancer tissues shows higher p53, p21, 14-3-3σ and Bax expression compared with matched normal tissues, yet there is a near absence of PUMA protein. This may explain why gemcitabine shows only limited efficacy in the treatment of these cancers. Our results raise the possibility that targeting the Bax-dependent cell death pathway, rather than the PUMA pathway, could result in significantly improved patient outcome and prognosis for these cancers.

Comparison of carotid plaque ulcer detection using contrast-enhanced and time-of-flight MRA techniques.

BACKGROUND AND PURPOSE: Ulceration in carotid plaque is a risk indicator for ischemic stroke. Our aim was to compare plaque ulcer detection by standard TOF and CE-MRA techniques and to identify factors that influence its detection. MATERIALS AND METHODS: Carotid MR imaging scans were acquired on 2066 participants in the ARIC study. We studied the 600 thickest plaques. TOF-MRA, CE-MRA, and black-blood MR images were analyzed together to define ulcer presence (plaque surface niche ≥2 mm in depth). Sixty ulcerated arteries were detected. These arteries were randomly assigned, along with 40 nonulcerated plaques from the remaining 540, for evaluation of ulcer presence by 2 neuroradiologists. Associations between ulcer detection and ulcer characteristics, including orientation, location, and size, were determined and explored by CFD modeling. RESULTS: One CE-MRA and 3 TOF-MRAs were noninterpretable and excluded. Of 71 ulcers in 56 arteries, readers detected an average of 39 (55%) on both TOF-MRA and CE-MRA, 26.5 (37.5%) only on CE-MRA, and 1 (1.5%) only on TOF-MRA, missing 4.5 (6%) ulcers by both methods. Ulcer detection by TOF-MRA was associated with its orientation (distally pointing versus perpendicular: OR = 5.57 [95% CI, 1.08-28.65]; proximally pointing versus perpendicular: OR = 0.21 [95% CI, 0.14-0.29]); location relative to point of maximum stenosis (distal versus isolevel: OR = 5.17 [95% CI, 2.10-12.70]); and neck-to-depth ratio (OR = 1.96 [95% CI, 1.11-3.45]) after controlling for stenosis and ulcer volume. CONCLUSIONS: CE-MRA detects more ulcers than TOF-MRA in carotid plaques. Missed ulcers on TOF-MRA are influenced by ulcer orientation, location relative to point of maximum stenosis, and neck-to-depth ratio.

Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma.

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

Treatment response assessment of head and neck cancers on CT using computerized volume analysis.

BACKGROUND AND PURPOSE: Head and neck cancer can cause substantial morbidity and mortality. Our aim was to evaluate the potential usefulness of a computerized system for segmenting lesions in head and neck CT scans and for estimation of volume change of head and neck malignant tumors in response to treatment. MATERIALS AND METHODS: CT scans from a pretreatment examination and a post 1-cycle chemotherapy examination of 34 patients with 34 head and neck primary-site cancers were collected. The computerized system was developed in our laboratory. It performs 3D segmentation on the basis of a level-set model and uses as input an approximate bounding box for the lesion of interest. The 34 tumors included tongue, tonsil, vallecula, supraglottic, epiglottic, and hard palate carcinomas. As a reference standard, 1 radiologist outlined full 3D contours for each of the 34 primary tumors for both the pre- and posttreatment scans and a second radiologist verified the contours. RESULTS: The correlation between the automatic and manual estimates for both the pre- to post-treatment volume change and the percentage volume change for the 34 primary-site tumors was 0.95, with an average error of -2.4 ± 8.5% by automatic segmentation. There was no substantial difference and specific trend in the automatic segmentation accuracy for the different types of primary head and neck tumors, indicating that the computerized segmentation performs relatively robustly for this application. CONCLUSIONS: The tumor size change in response to treatment can be accurately estimated by the computerized segmentation system relative to radiologists' manual estimations for different types of head and neck tumors.

Adult lumbar scoliosis: underreported on lumbar MR scans.

BACKGROUND AND PURPOSE: Adult lumbar scoliosis is an increasingly recognized entity that may contribute to back pain. We investigated the epidemiology of lumbar scoliosis and the rate at which it is unreported on lumbar MR images. MATERIALS AND METHODS: The coronal and sagittal sequences of lumbar spine MR imaging scans of 1299 adult patients, seeking care for low back pain, were reviewed to assess for and measure the degree of scoliosis and spondylolisthesis. Findings were compared with previously transcribed reports by subspecialty trained neuroradiologists. Inter- and intraobserver reliability was calculated. RESULTS: The prevalence of adult lumbar scoliosis on MR imaging was 19.9%, with higher rates in ages >60 years (38.9%, P < .001) and in females (22.6%, P = .002). Of scoliotic cases, 66.9% went unreported, particularly when the scoliotic angle was <20 degrees (73.9%, P < .001); 10.5% of moderate to severe cases were not reported. Spondylolisthesis was present in 15.3% (199/1299) of cases, demonstrating increased rates in scoliotic patients (32.4%, P < .001), and it was reported in 99.5% of cases. CONCLUSIONS: Adult lumbar scoliosis is a prevalent condition with particularly higher rates among older individuals and females but is underreported on spine MR images. This can possibly result in delayed 1) identification of a potential cause of low back pain, 2) referral to specialized professionals for targeted evaluation and management, and 3) provision of health care. The coronal "scout images" should be reviewed as part of the complete lumbar spine evaluation if dedicated coronal sequences are not already part of the spine protocol.

Are C1-2 punctures for routine cervical myelography below the standard of care?

BACKGROUND AND PURPOSE: Recently, the performance of C1-2 punctures for cervical myelography was challenged in a medicolegal proceeding as being below the standard of care. We sought to examine current neuroradiologic practices and opinions on the technique. MATERIALS AND METHODS: An 11-question survey was sent to 120 program directors of neuroradiology via e-mail links regarding cervical myelography using a C1-2 puncture. Reminders were sent during a 2-month period before data were finalized. RESULTS: Eighty-five of 120 (71%) surveys were returned. In the previous year, 14.3% (12/85) of institutions had not performed a C1-2 puncture. Thirty-eight percent (32/85) had performed >or=6 in the same period. Seventy-nine percent (54/68 responding) favored a lumbar approach to cervical myelography, with 6% (4/68) having a predilection for a C1-2 puncture. Ninety-five percent (76/80 responding) thought that performing a C1-2 puncture for cervical myelography reflected the standard of care. Every institution except 1 had staff with expertise to perform C1-2 punctures, and 73% of the institutions teach their fellows the procedure. Ninety-three percent (78/84) of programs would perform a C1-2 puncture for thoracolumbar pathology if MR imaging was contraindicated and there was a contraindication such as a local wound infection precluding a lumbar puncture. Indications for a C1-2 approach included severe lumbar spinal stenosis, infection in the lumbar region, upper limit of the block to be delineated, technical issues preventing lumbar puncture, and the best assessment of the cervical region for myelographic films. CONCLUSIONS: C1-2 puncture for cervical myelography, though currently not the most frequently performed method at most institutions, continues to be practiced and is considered within the standard of care by most neuroradiology programs across the country.

Interventional neuroradiology of the head and neck.

Interventional neuroradiology procedures are a valuable asset in the diagnosis, treatment, and surgical management of various disorders affecting the extracranial head and neck. A detailed understanding of cross-sectional and vascular anatomy and an awareness of potential collateral pathways between extracranial and intracranial vessels are essential for ensuring safe and successful procedures. With the use of high-quality imaging and a meticulous technique, the incidence of major complications is extremely low.

Color Doppler sonographic diagnosis of dissecting aneurysm of the superior mesenteric artery.

We report a case of dissecting aneurysm of the superior mesenteric artery (SMA) diagnosed on gray-scale and color Doppler sonography and confirmed on angiography. Spontaneous dissection of the SMA is rare, and there are few reported cases of the color Doppler sonographic findings. Gray-scale sonography revealed an aneurysmal dilatation of the SMA 3-4 cm from the SMA's origin, with an echogenic linear membrane (an intimal flap) within the aneurysm. Color Doppler sonography showed color flow within the aneurysm and showed that the intimal flap separated the aneurysm into 2 lumina. Spectral analysis revealed anterograde flow in the anterior (ie, true) lumen and retrograde flow in the posterior (ie, false) lumen.

Intercostal lung herniation--depiction on spiral CT.

Computed tomography (CT) is the imaging modality of choice for the demonstration of intercostal lung herniation. The use of forced expiration and Valsalva's manouevre during CT scanning has been recommended in selected cases. We report a case of intercostal lung herniation, demonstrated only on coughing on spiral CT.