Faculty Bibliography

To compare utilization of CT pulmonary angiogram (CTA) for diagnosis of pulmonary embolism (PE) in an emergency department (ED) with unstructured CT ordering to published rates of CT positivity in other EDs including those employing decision support and to identify pathways for improved utilization via collaboration with our pathology and ED colleagues. Two hundred seventeen patients over a 2.5-month time period who received a CTA for PE were reviewed with exclusion of pediatric patients and all sub-optimal, non-diagnostic, or equivocal scans; 21 were excluded leaving a sample of 196 patients. The rate of PE diagnosis and association of PE positivity with selected factors (D-dimer testing) was assessed. The percentage of cases positive for PE was 10.7 % (21/196) which is similar to the frequently published rate of 10 % in other emergency departments including settings that have studied the use of decision support. D-dimer testing was performed in 40.3 % of cases. In 29.6 % (58/196) of subjects, D-dimer was positive, 10.7 % (21/196) was negative, and 59.7 % (117/196) was not assessed. Prevalence of PE among D-dimer negative (0 %, 0/21) was lower versus positive D-dimer (12.1 %, 7/58) and unknown D-dimer patients (12.0 %, 14/117). D-dimer had 100 % (21/21) negative predictive value for the diagnosis of PE. While this suggests that D-dimer is useful to rule-out PE, due to the small number of patients with PE, the 95 % confidence intervals are wide and the post-test likelihood of PE could be as high as 14 %. The rate of CT positivity for PE in an ED with unstructured CT ordering is similar to that in other published series including as series in which decision support was used. While D-dimer had high negative predictive value, large studies are needed to confirm this high sensitivity and potentially increase its use in ruling out PE without CT and to reduce CT ordering particularly in patients with sufficiently low clinical pre-test probability of PE.

OBJECTIVE: This study aimed to demonstrate feasibility of free-breathing radial acquisition with respiratory motion-resolved compressed sensing reconstruction [extra-dimensional golden-angle radial sparse parallel imaging (XD-GRASP)] for multiphase dynamic gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced liver imaging, and to compare image quality to compressed sensing reconstruction with respiratory motion-averaging (GRASP) and prior conventional breath-held Cartesian-sampled data sets [BH volume interpolated breath-hold examination (VIBE)] in same patients. SUBJECTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant prospective study, 16 subjects underwent free-breathing continuous radial acquisition during Gd-EOB-DTPA injection and had prior BH-VIBE available. Acquired data were reconstructed using motion-averaging GRASP approach in which consecutive 84 spokes were grouped in each contrast-enhanced phase for a temporal resolution of approximately 14 seconds. Additionally, respiratory motion-resolved reconstruction was performed from the same k-space data by sorting each contrast-enhanced phase into multiple respiratory motion states using compressed sensing algorithm named XD-GRASP, which exploits sparsity along both the contrast-enhancement and respiratory-state dimensions.Contrast-enhanced dynamic multiphase XD-GRASP, GRASP, and BH-VIBE images were anonymized, pooled together in a random order, and presented to 2 board-certified radiologists for independent evaluation of image quality, with higher score indicating more optimal examination. RESULTS: The XD-GRASP reconstructions had significantly (all P < 0.05) higher overall image quality scores compared to GRASP for early arterial (reader 1: 4.3 +/- 0.6 vs 3.31 +/- 0.6; reader 2: 3.81 +/- 0.8 vs 3.38 +/- 0.9) and late arterial (reader 1: 4.5 +/- 0.6 vs 3.63 +/- 0.6; reader 2: 3.56 +/- 0.5 vs 2.88 +/- 0.7) phases of enhancement for both readers. The XD-GRASP also had higher overall image quality score in portal venous phase, which was significant for reader 1 (4.44 +/- 0.5 vs 3.75 +/- 0.8; P = 0.002). In addition, the XD-GRASP had higher overall image quality score compared to BH-VIBE for early (reader 1: 4.3 +/- 0.6 vs 3.88 +/- 0.6; reader 2: 3.81 +/- 0.8 vs 3.50 +/- 1.0) and late (reader 1: 4.5 +/- 0.6 vs 3.44 +/- 0.6; reader 2: 3.56 +/- 0.5 vs 2.94 +/- 0.9) arterial phases. CONCLUSION: Free-breathing motion-resolved XD-GRASP reconstructions provide diagnostic high-quality multiphase images in patients undergoing Gd-EOB-DTPA-enhanced liver examination.

AIM: To evaluate the performance of normalised apparent diffusion coefficient (ADC) values for prostate cancer assessment when performed by independent observers blinded to histopathology findings. MATERIALS AND METHODS: Fifty-eight patients undergoing 3 T phased-array coil magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI; maximal b-value 1000 s/mm2) before prostatectomy were included. Two radiologists independently evaluated the images, unaware of the histopathology findings. Regions of interest (ROIs) were drawn within areas showing visually low ADC within the peripheral zone (PZ) and transition zone (TZ) bilaterally. ROIs were also placed within regions in both lobes not suspicious for tumour, allowing computation of normalised ADC (nADC) ratios between suspicious and non-suspicious regions. The diagnostic performance of ADC and nADC were compared. RESULTS: For PZ tumour detection, ADC achieved significantly higher area under the receiver operating characteristic curve (AUC; p=0.026) and specificity (p=0.021) than nADC for reader 1, and significantly higher AUC (p=0.025) than nADC for reader 2. For TZ tumour detection, nADC achieved significantly higher specificity (p=0.003) and accuracy (p=0.004) than ADC for reader 2. For PZ Gleason score >3+3 tumour detection, ADC achieved significantly higher AUC (p=0.003) and specificity (p=0.005) than nADC for reader 1, and significantly higher AUC (p=0.023) than nADC for reader 2. For TZ Gleason score >3+3 tumour detection, ADC achieved significantly higher specificity (p=0.019) than nADC for reader 1. CONCLUSION: In contrast to prior studies performing unblinded evaluations, ADC was observed to outperform nADC overall for two independent observers blinded to the histopathology findings. Therefore, although strategies to improve the utility of ADC measurements in prostate cancer assessment merit continued investigation, caution is warranted when applying normalisation to improve diagnostic performance in clinical practice.

BACKGROUND: An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS: Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 mug/m2 subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simon's optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS: From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simon's two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27.6%, 95% CI 12.7-47.2) of the first 29 patients, and 11 (26.8%, 95% CI 14.2-42.9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION: The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING: New York University School of Medicine's Department of Radiation Oncology and Cancer Institute.

OBJECTIVES: As approximately 40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. METHODS: The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T2 -weighted quantitative magnetic resonance imaging (MRI) and 16x16x4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm(3) ( approximately 35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. RESULTS: The mean (+/- standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 +/- 0.9, 7.2 +/- 0.4 and 0.9 +/- 0.1 mM, respectively; these concentrations increased 28% (p approximately 0.06), 15% and 10% (both p < 0.05), respectively, post-infection. The mean concentration of neuronal marker NAA remained unchanged (7.0 +/- 0.6 mM pre-infection vs. 7.3 +/- 0.8 mM post-infection; p approximately 0.37). The mean cortex volume was also unchanged (8.1 +/- 1.1 cm(3) pre-infection vs. 8.3 +/- 0.5 cm(3) post-infection; p approximately 0.76). CONCLUSIONS: These results support the hypothesis that early cortical glial activation occurs after SIV infection prior to the onset of neurodegeneration. This suggests HIV therapeutic interventions should potentially target early glial activation in the cerebral cortex.

BACKGROUND: Non-Gaussian diffusion imaging by using diffusional kurtosis imaging (DKI) allows assessment of isotropic tissue as of gray matter (GM), an important limitation of diffusion tensor imaging (DTI). OBJECTIVE: In this study, we describe DKI and DTI metrics of GM in multiple sclerosis (MS) patients and their association with cognitive deficits. METHODS: Thirty-four patients with relapsing-remitting MS and 17 controls underwent MRI on a 3T scanner including a sequence for DKI with 30 diffusion directions and 3b values for each direction. Mean kurtosis (MK), mean diffusivity and fractional anisotropy (FA) of cortical and subcortical GM were measured using histogram analysis. Spearman rank correlations were used to characterize associations among imaging measures and clinical/neuropsychological scores. RESULTS: In cortical GM, a significant decrease of MK (0.68 vs. 0.73; p < 0.001) and increase of FA (0.16 vs. 0.13; p < 0.001) was found in patients compared to controls. Decreased cortical MK was correlated with poor performance on the Delis-Kaplan Executive Function System test (r = 0.66, p = 0.01). CONCLUSION: Mean kurtosis is sensitive to abnormality in GM of MS patients and can provide information that is complementary to that of conventional DTI-derived metrics. The association between MK and cognitive deficits suggests that DKI might serve as a clinically relevant biomarker for cortical injury.

PURPOSE: To perform image quality comparison between accelerated multiband diffusion acquisition (mb2-DWI) and conventional diffusion acquisition (c-DWI) in patients undergoing clinically indicated liver MRI. METHODS: In this prospective study 22 consecutive patients undergoing clinically indicated liver MRI on a 3-T scanner equipped to perform multiband diffusion-weighed imaging (mb-DWI) were included. DWI was performed with single-shot spin-echo echo-planar technique with fat-suppression in free breathing with matching parameters when possible using c-DWI, mb-DWI, and multiband DWI with a twofold acceleration (mb2-DWI). These diffusion sequences were compared with respect to various parameters of image quality, lesion detectability, and liver ADC measurements. RESULTS: Accelerated mb2-DWI was 40.9% faster than c-DWI (88 vs. 149 s). Various image quality parameter scores were similar or higher on mb2-DWI when compared to c-DWI. The overall image quality score (averaged over the three readers) was significantly higher for mb-2 compared to c-DWI for b = 0 s/mm2 (3.48 +/- 0.52 vs. 3.21 +/- 0.54; p = 0.001) and for b = 800 s/mm2 (3.24 +/- 0.76 vs. 3.06 +/- 0.86; p = 0.010). Total of 25 hepatic lesions were visible on mb2-DWI and c-DWI, with identical lesion detectability. There was no significant difference in liver ADC between mb2-DWI and c-DWI (p = 0.12). Bland-Altman plot demonstrates lower mean liver ADC with mb2-DWI compared to c-DWI (by 0.043 x 10-3 mm2/s or 3.7% of the average ADC). CONCLUSION: Multiband technique can be used to increase acquisition speed nearly twofold for free-breathing DWI of the liver with similar or improved overall image quality and similar lesion detectability compared to conventional DWI.

OBJECTIVE: To see if there is an association between engagement on physical examination (PE) and the location of the Hill-Sachs lesion (HSL) as assessed by the modified biceps angle. MATERIALS AND METHODS: Sixty-two patients with a history of anterior shoulder dislocation, who underwent preoperative MRI and arthroscopy at our institution and were tested for engagement on PE, were collected. Two musculoskeletal radiologists reviewed the MR studies, noting the presence of an HSL and documenting the location of the HSL with the modified biceps angle. Statistical analysis included the Mann-Whitney (MW) test and ROC (receiver-operating characteristic) curve. RESULTS: Of 62 patients, there were 58 males and 4 females with a mean age of 30 (range 18-59 years). Twenty patients demonstrated engagement on PE, while 42 did not. All patients had evidence of an HSL on MRI and arthroscopy. The mean biceps angle for the engaging group was 151.5 +/- 13.9 degrees , and 142.4 +/- 17.3 degrees for the non-engaging group. The biceps angle was statistically significantly higher among patients who had engagement compared to those who did not (p = 0.027). Overall, diagnostic accuracy was highest for a biceps angle >149 degrees , which resulted in a sensitivity of 70 % and specificity of 67 %. CONCLUSION: The modified biceps angle, as measured on MRI, was significantly higher in patients who demonstrated engagement on physical examination than in those who did not. This supports the theory that the location of the Hill-Sachs lesion may play a role in engagement and may be its most important characteristic when determining its significance.

T cells directed to endogenous tumor antigens are powerful mediators of tumor regression. Recent immunotherapy advances have identified effective interventions to unleash tumor-specific T cell activity in patients who naturally develop them. Eliciting T cell responses to a patient's individual tumor remains a major challenge. Radiation therapy can induce immune responses to model antigens expressed by tumors, but it remains unclear if it can effectively prime T cells specific for endogenous antigens expressed by poorly immunogenic tumors. We hypothesized that TGFbeta activity is a major obstacle hindering the ability of radiation to generate an in situ tumor vaccine. Here we show that antibody-mediated TGFbeta neutralization during radiation therapy effectively generates CD8+ T cell responses to multiple endogenous tumor antigens in poorly immunogenic mouse carcinomas. Generated T cells were effective at causing regression of irradiated tumors and non-irradiated lung metastases or synchronous tumors (abscopal effect). Gene signatures associated with IFNgamma and immune-mediated rejection were detected in tumors treated with radiation therapy and TGFbeta blockade in combination but not as single agents. Upregulation of programmed death (PD) ligand-1 and -2 in neoplastic and myeloid cells and PD-1 on intratumoral T cells limited tumor rejection resulting in rapid recurrence. Addition of anti-PD-1 antibodies extended survival achieved with radiation and TGFbeta blockade. Thus, TGFbeta is a fundamental regulator of radiation therapy ability to generate an in situ tumor vaccine. The combination of local radiation therapy with TGFbeta neutralization offers a novel individualized strategy for vaccinating patients against their tumors.

OBJECTIVES: Unlike adult major depressive disorder (MDD) which requires anhedonia or depressed mood for diagnosis, adolescent MDD can be sufficiently diagnosed with irritability in the absence of the former symptoms. In addition, the current Diagnostic and Statistical Manual of Mental Disorders (DSM) schema does not account for the interindividual variability of symptom severity among depressed adolescents. This practice has contributed to the high heterogeneity and diagnostic complexity of adolescent MDD. Here, we sought to examine relationships between two core symptoms of adolescent M