Faculty Bibliography

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: 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.

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.

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: Diffusional kurtosis imaging is an advanced diffusion MRI method that yields, in addition to conventional diffusion information, non-Gaussian diffusion effects, which may allow a more comprehensive characterization of tissue microstructure. The purpose of this study is to use diffusional kurtosis to assess white matter integrity in patients with hydrocephalus and to determine whether changes in kurtosis correlate with the severity of hydrocephalus and leukoaraiosis, a commonly seen comorbidity in hydrocephalus. METHODS: 26 patients with imaging evidence of hydrocephalus and 26 age- and sex- matched subjects with normal ventricular size were retrospectively analyzed. Standard diffusion tensor imaging and diffusional kurtosis metrics were compared between the two groups. Correlation between kurtosis and severity of hydrocephalus and presence and severity of leukoaraiosis was determined. RESULTS: Hydrocephalus patients relative to controls demonstrated statistically significant decrease in all kurtosis metrics in most brain regions studied. The severity of hydrocephalus was associated with greater decrease in kurtosis in the corpus callosum. There was more leukoaraiosis in the hydrocephalus group, and severity of leukoaraiosis was associated with decrease in kurtosis. After controlling for the degree of leukoaraiosis, kurtosis was still decreased in hydrocephalus relative to the controls. CONCLUSION: Diffusional kurtosis imaging detects microstructural changes in the white matter of patients with hydrocephalus. Our results suggest that hydrocephalus plays a role in altering white matter integrity.

BACKGROUND: Rapid and accurate diagnosis of appendicitis, particularly with respect to the presence or absence of perforation, is essential in guiding appropriate management. Although many studies have explored sonographic findings associated with acute appendicitis, few investigations discuss specific signs that can reliably differentiate perforated appendicitis from acute appendicitis prior to abscess formation. OBJECTIVE: The purpose of our study was to identify sonographic findings that improve the specificity of US in the diagnosis of perforated appendicitis. Our assessment of hepatic periportal echogenicity, detailed analysis of intraperitoneal fluid, and formulation of select constellations of sonographic findings expands upon the literature addressing this important diagnostic challenge. MATERIALS AND METHODS: We retrospectively reviewed 116 abdominal US examinations for evaluation of abdominal pain in children ages 2 to 18 years from January 2008 to September 2011 at a university hospital pediatric radiology department. The study group consisted of surgical and pathology proven acute appendicitis (n = 51) and perforated appendicitis (n = 22) US exams. US exams without a sonographic diagnosis of appendicitis (n = 43) confirmed by follow-up verbal communication were included in the study population as the control group. After de-identification, the US exams were independently reviewed on a PACS workstation by four pediatric radiologists blinded to diagnosis and all clinical information. We recorded the presence of normal or abnormal appendix, appendicolith, appendiceal wall vascularity, thick-walled bowel, dilated bowel, right lower quadrant (RLQ) echogenic fat, increased hepatic periportal echogenicity, bladder debris and abscess or loculated fluid. We also recorded the characteristics of intraperitoneal fluid, indicating the relative quantity (number of abdominal regions) and quality of the fluid (simple fluid or complex fluid). We used logistic regression for correlated data to evaluate the association of diagnosis with the presence versus absence of each US finding. We conducted multivariable analysis to identify constellations of sonographic findings that were predictive of perforated appendicitis. RESULTS: The individual US findings of abscess/loculated fluid, appendicolith, dilated bowel and increased hepatic periportal echogenicity were significantly associated with perforated appendicitis when compared with acute appendicitis (P < 0.01). The sonographic observation of increased hepatic periportal echogenicity demonstrated a statistically significant association with perforated appendicitis compared with acute appendicitis (P < 0.01). The presence of complex fluid yielded a specificity of 87.7% for perforated appendicitis compared with the acute appendicitis group. The US findings of >/=2 regions or >/=3 regions with fluid had specificity of 87.3% and 99.0%, respectively, for perforated appendicitis compared with the acute appendicitis group. Select combinations of sonographic findings yielded high specificity in the diagnosis of perforated appendicitis compared with acute appendicitis. These constellations yielded higher specificity than that of each individual finding in isolation. The constellation of dilated bowel, RLQ echogenic fat, and complex fluid had the highest specificity (99.5%) for perforated appendicitis (P < 0.01). CONCLUSION: Our study demonstrates that identification of select constellations of findings using abdominal sonography, in addition to focused US examination of the right lower quadrant, can improve sonographic diagnosis of perforated appendicitis in the pediatric population.

PURPOSE: To determine how subchondral bone microarchitecture is altered in patients with mild knee osteoarthritis. MATERIALS AND METHODS: This study had Institutional Review Board approval. We recruited 24 subjects with mild radiographic knee osteoarthritis and 16 healthy controls. The distal femur was scanned at 7T using a high-resolution 3D FLASH sequence. We applied digital topological analysis to assess bone volume fraction, markers of trabecular number (skeleton density), trabecular network osteoclastic resorption (erosion index), plate-like structure (surface), rod-like structure (curve), and plate-to-rod ratio (surface-curve ratio). We used two-tailed t-tests to compare differences between osteoarthritis subjects and controls. RESULTS: 7T magnetic resonance imaging (MRI) detected deterioration in subchondral bone microarchitecture in both medial and lateral femoral condyles in osteoarthritis subjects as compared with controls. This was manifested by lower bone volume fraction (-1.03% to -5.43%, P < 0.04), higher erosion index (+8.49 to +22.76%, P < 0.04), lower surface number (-2.31% to -9.63%, P < 0.007), higher curve number (+6.85% to +16.93%, P < 0.03), and lower plate-to-rod ratio (-7.92% to -21.71%, P < 0.05). CONCLUSION: The results provide further support for the concept that poor subchondral bone quality is associated with osteoarthritis and may serve as a potential therapeutic target for osteoarthritis interventions.J. Magn. Reson. Imaging 2014. (c) 2014 Wiley Periodicals, Inc.

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

PURPOSE: The aim of this study was to determine if voxel-based histogram analysis of intravoxel incoherent motion imaging (IVIM) parameters can differentiate various subtypes of renal tumors, including benign and malignant lesions. SUBJECTS AND METHODS: A total of 44 patients with renal tumors who underwent surgery and had histopathology available were included in this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved, single-institution prospective study. In addition to routine renal magnetic resonance imaging examination performed on a 1.5-T system, all patients were imaged with axial diffusion-weighted imaging using 8 b values (range, 0-800 s/mm). A biexponential model was fitted to the diffusion signal data using a segmented algorithm to extract the IVIM parameters perfusion fraction (fp), tissue diffusivity (Dt), and pseudodiffusivity (Dp) for each voxel. Mean and histogram measures of heterogeneity (standard deviation, skewness, and kurtosis) of IVIM parameters were correlated with pathology results of tumor subtype using unequal variance t tests to compare subtypes in terms of each measure. Correction for multiple comparisons was accomplished using the Tukey honestly significant difference procedure. RESULTS: A total of 44 renal tumors including 23 clear cell (ccRCC), 4 papillary (pRCC), 5 chromophobe, and 5 cystic renal cell carcinomas, as well as benign lesions, 4 oncocytomas (Onc) and 3 angiomyolipomas (AMLs), were included in our analysis. Mean IVIM parameters fp and Dt differentiated 8 of 15 pairs of renal tumors. Histogram analysis of IVIM parameters differentiated 9 of 15 subtype pairs. One subtype pair (ccRCC vs pRCC) was differentiated by mean analysis but not by histogram analysis. However, 2 other subtype pairs (AML vs Onc and ccRCC vs Onc) were differentiated by histogram distribution parameters exclusively. The standard deviation of Dt [sigma(Dt)] differentiated ccRCC (0.362 +/- 0.136 x 10 mm/s) from AML (0.199 +/- 0.043 x 10 mm/s) (P = 0.002). Kurtosis of fp separated Onc (2.767 +/- 1.299) from AML (-0.325 +/- 0.279; P = 0.001), ccRCC (0.612 +/- 1.139; P = 0.042), and pRCC (0.308 +/- 0.730; P = 0.025). CONCLUSIONS: Intravoxel incoherent motion imaging parameters with inclusion of histogram measures of heterogeneity can help differentiate malignant from benign lesions as well as various subtypes of renal cancers.